Clinical trial NCT03439280
Conditions: Relapsed/Refractory Multiple Myeloma
Keywords: Drug therapy, TAK-079, pomalidomide and dexamethasone, CD38 monoclonal antibody
Sponsor: Millennium Pharmaceuticals, Inc.
Start date: 2018-04-20; Completion date: 2022-01-28
Enrollment: 50 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to assess the safety and tolerability, maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of TAK-079 monotherapy and when combined with a backbone regimen of pomalidomide and dexamethasone (PomDex) in Phase 1, and to provide a preliminary evaluation of the clinical activity of TAK-079 monotherapy in Phase 2a in participants with r/r MM.

Detailed description:
The drug being tested in this study is called TAK-079. TAK-079 is being tested to treat people who have relapsed and/or refractory multiple myeloma (RRMM). This study will assess the safety, tolerability, efficacy, pharmacokinetics, and immunogenicity of TAK-079 monotherapy and will provide a preliminary assessment of its activity against MM. The study is designed to consist of 2 phases: Phase 1 and Phase 2a.

The study could enroll approximately 100 participants. The study population of Phase 1 will consist of approximately 55 participants. Participants in Phase 1 will be assigned to TAK-079 and dose-escalation will range from 45 mg to 1800 mg.

The study population of Phase 2a will consist of approximately 48 participants. Dose for Phase 2a will be based upon review of the available safety, efficacy, pharmacokinetic, and pharmacodynamic data from the preceding cohorts of Phase 1.

This multi-center trial will be conducted in the United States. The overall time to participate in this study is 42 months (3.5 years). In Phase 1, participants who stop treatment for any other reason other than PD will continue to have progression-free survival (PFS) follow-up at the site every 4 weeks from the last dose of study drug up to 12 months or until PD, death, loss to follow-up, consent withdrawal or study termination. Participants will be followed 30 days after last dose of study drug or until the start of subsequent alternative anti-cancer therapy, whichever occurs first, for a follow up assessment.

Arms: arm 1: Mezagitamab 45 mg, subcutaneously (SC), once weekly for 8 weeks, then once every 2 weeks for 16 weeks, and then once every 4 weeks thereafter in a 28-day treatment cycle until progressive disease (PD), unacceptable toxicities or withdrawal due to other reasons. arm 2: Mezagitamab 135 mg, SC, once weekly for 8 weeks, then once every 2 weeks for 16 weeks, and then once every 4 weeks thereafter in a 28-day treatment cycle until PD, unacceptable toxicities or withdrawal due to other reasons. arm 3: Mezagitamab 300 mg, SC, once weekly for 8 weeks, then once every 2 weeks for 16 weeks, and then once every 4 weeks thereafter in a 28-day treatment cycle until PD, unacceptable toxicities or withdrawal due to other reasons. arm 4: Mezagitamab 600 mg, SC, once weekly for 8 weeks, then once every 2 weeks for 16 weeks, and then once every 4 weeks thereafter in a 28-day treatment cycle until PD, unacceptable toxicities or withdrawal due to other reasons. arm 5: Mezagitamab 1200 mg, SC, once weekly for 8 weeks, then once every 2 weeks for 16 weeks, and then once every 4 weeks thereafter in a 28-day treatment cycle until PD, unacceptable toxicities or withdrawal due to other reasons. arm 6: Mezagitamab 300 mg, SC, once weekly for 8 weeks, then once every 2 weeks for 16 weeks, and then once every 4 weeks thereafter along with pomalidomide, at product-labelled dose, orally, once daily on Days 1 to 21 and dexamethasone, at product-labelled dose, orally, once on Days 1, 8, 15, and 22 in a 28-day treatment cycle until PD. arm 7: Mezagitamab, SC, once weekly for 8 weeks, then once every 2 weeks for 16 weeks, and then once every 4 weeks thereafter in a 28-day treatment cycle until PD, unacceptable toxicities or withdrawal due to other reasons. TAK-079 dose for this phase was to be determined based on review of the available safety, efficacy, pharmacokinetic, and pharmacodynamic data obtained from the Phase 1 portion of the study. However, Phase 2a of the study was not opened for enrollment due to changes in the Sponsor's overall clinical development plan.
Interventions: intervention 1: Mezagitamab intervention 2: Pomalidomide intervention 3: Dexamethasone
Intervention descriptions: intervention 1: Mezagitamab subcutaneously. intervention 2: Pomalidomide orally. intervention 3: Dexamethasone orally.

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL 
NCT Number: 
Study Title: 
Protocol Versions and Date:
Version 3.0: 02 April 2019
Version 2.0: 18 May 2018
Version 1.0: 08 December 2017 
Original Protocol: 12 October 2017
NCT03439280 
A Phase 1/2a Open-label, Dose-Escalation Study to Investigate 
the Safety and Tolerability, Efficacy, Pharmacokinetics, and 
Immunogenicity of TAK-079 Administered Subcutaneously as a 
Single Agent in Patients With Relapsed/Refractory Multiple 
Myeloma
TAK-079-1501
Study Number: 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


PROTOCOL
A Phase 1/2a Open-label, Dose-Escalation Study to Investigate the Safety and Tolerability, 
Efficacy, Pharmacokinetics, and Immunogenicity of TAK-079 Administered 
Subcutaneously as a Single Agent in Patients With Relapsed/Refractory Multiple Myeloma 
Sponsor:
Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda 
Pharmaceutical Company Limited
40 Landsdowne Street
Cambridge, MA  02139 USA
Telephone: +1 (617) 679-7000
Please note: Millennium Pharmaceuticals, Inc, a wholly owned 
subsidiary of Takeda Pharmaceutical Company Limited, may be 
referred to in this protocol as “Millennium,” “Sponsor,” or “Takeda”.
Study Number:
TAK-079-1501 
IND Number:
136,414
EudraCT Number:
Not applicable
Compound:
TAK-079
Date:
12 October 2017
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1.0
ADMINISTRATIVE
1.1
Contacts 
A separate contact information list will be provided to each site.
Serious adverse event and pregnancy reporting information is presented in Section 10.0, as is 
information on reporting product complaints.
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.0 and relevant guidelines 
provided to the site.
Contact Type/Role
United States Contact
Serious adverse event and pregnancy reporting
See Section 10.0
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INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, and any 
other product information provided by the sponsor. I agree to conduct this study in accordance 
with the requirements of this protocol and also to protect the rights, safety, privacy, and well-being 
of study subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events defined in Section 10.0 of this 
protocol.

Terms outlined in the Clinical Study Site Agreement.

Responsibilities of the Investigator
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix D of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Province)
Location of Facility (Country)
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TABLE OF CONTENTS
1.0
ADMINISTRATIVE.......................................................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
2.0
STUDY SUMMARY ....................................................................................................10
3.0
STUDY REFERENCE INFORMATION ......................................................................15
3.1
List of Abbreviations ...............................................................................................16
4.0
INTRODUCTION.........................................................................................................19
4.1
Background .............................................................................................................19
4.2
Findings From Nonclinical and Clinical Studies.......................................................19
4.2.1
20
4.3
Known and Potential Benefits and Risks to Patients with TAK-079 .........................22
4.3.1
Risks..................................................................................................................22
4.3.2
Overall Benefit and Risk Assessment for This Study..........................................25
4.4
Rationale for the Proposed Study.............................................................................25
4.4.1
Rationale for the Starting Dose of TAK-079 ......................................................26
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................27
5.1
Objectives................................................................................................................27
5.1.1
Phase 1 Primary Objective .................................................................................27
5.1.2
Phase 1 Secondary Objectives............................................................................27
5.1.3
Phase 2a Primary Objective................................................................................27
5.1.4
Phase 2a Secondary Objectives ..........................................................................27
5.1.5
Phase 1 and Phase 2a Exploratory Objectives.....................................................27
5.2
Endpoints.................................................................................................................28
5.2.1
Phase 1 Primary Endpoints.................................................................................28
5.2.2
Phase 2a Primary Endpoint ................................................................................28
5.2.3
Phase 1 Secondary Endpoints.............................................................................28
5.2.4
Phase 2a Secondary Endpoints...........................................................................29
5.2.5
Exploratory Endpoints .......................................................................................29
6.0
STUDY DESIGN..........................................................................................................30
6.1
Overview of Study Design.......................................................................................30
6.2
Number of Patients ..................................................................................................31
6.3
Duration of Study ....................................................................................................32
6.3.1
Duration of an Individual Patient’s Study Participation ......................................32
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6.3.2
End of Study/Study Completion Definition and Planned Reporting....................32
6.3.3
Timeframes for Primary and Secondary Endpoints to Support Disclosures.........32
6.3.4
Total Study Duration..........................................................................................34
7.0
STUDY POPULATION................................................................................................35
7.1
Inclusion Criteria .....................................................................................................35
7.2
Exclusion Criteria ....................................................................................................37
8.0
STUDY DRUG .............................................................................................................40
8.1
Study Drug Administration......................................................................................40
8.1.1
Premedication ....................................................................................................40
8.1.2
TAK-079 Formulation and Administration.........................................................40
8.2
Definitions of DLT ..................................................................................................41
8.3
Dose-Escalation Design and Criteria........................................................................42
8.3.1
Dose Level(s):....................................................................................................42
8.3.2
Escalation Schema .............................................................................................43
8.4
Dose Modification Guidelines..................................................................................44
8.4.1
Criteria for Beginning or Delaying a Subsequent Treatment Cycle.....................44
8.4.2
Criteria for Dose Reduction................................................................................45
8.4.3
Criteria for Discontinuing TAK-079 in Individual Patients (When Considering 
Dose Modification) ............................................................................................46
8.5
Excluded Concomitant Medications and Procedures ................................................47
8.6
Permitted Concomitant Medications and Procedures................................................47
8.7
Precautions and Restrictions ....................................................................................48
8.8
Management of Specific Adverse Reactions ............................................................49
8.8.1
Handling of IRs..................................................................................................49
8.8.2
Handling of Low Platelet Counts........................................................................49
8.8.3
Risk of Infection ................................................................................................49
8.8.4
Transfusion Risks...............................................................................................50
8.9
Blinding and Unblinding..........................................................................................50
8.10
Description of Investigational Agents ......................................................................50
8.11
Preparation, Reconstitution, and Dispensation..........................................................50
8.12
Packaging and Labeling...........................................................................................51
8.13
Storage, Handling, and Accountability.....................................................................51
8.13.1 Storage and Handling.........................................................................................51
8.13.2 Accountability and Destruction of Sponsor Supplied Drugs ...............................52
8.14
Investigational Drug Assignment and Dispensing Procedures ..................................53
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9.0
STUDY CONDUCT......................................................................................................54
9.1
Study Personnel and Organizations..........................................................................54
9.2
Arrangements for Recruitment of Patients................................................................54
9.3
Treatment Group Assignments.................................................................................54
9.4
Study Procedures.....................................................................................................54
9.4.1
Informed Consent...............................................................................................54
9.4.2
Patient Demographics ........................................................................................54
9.4.3
Medical History .................................................................................................54
9.4.4
Physical Examination.........................................................................................55
9.4.5
Patient Height and Weight .................................................................................55
9.4.6
Vital Signs .........................................................................................................55
9.4.7
Eligibility Criteria ..............................................................................................55
9.4.8
Pregnancy Test...................................................................................................55
9.4.9
Concomitant Medications and Procedures..........................................................56
9.4.10 AEs....................................................................................................................56
9.4.11 Enrollment .........................................................................................................56
9.4.12 ECG...................................................................................................................56
9.4.13 Clinical Laboratory Evaluations .........................................................................57
9.4.14 Disease Response Assessments ..........................................................................58
9.4.15
, PK, 
, and Immunogenicity Samples.....................61
9.5
Completion of Study Treatment (for Individual Patients) .........................................64
9.6
Completion of Study (for Individual Patients)..........................................................64
9.7
Discontinuation of Treatment With Study Drug and Patient Replacement................64
9.8
Withdrawal of Patients From Study .........................................................................65
9.9
Study Compliance....................................................................................................65
9.10
Posttreatment Follow-up Assessments (PFS and OS)...............................................66
10.0
ADVERSE EVENTS ....................................................................................................67
10.1
Definitions...............................................................................................................67
10.1.1 Pretreatment Event Definition............................................................................67
10.1.2 AE Definition ....................................................................................................67
10.1.3 SAE Definition ..................................................................................................67
10.2
Procedures for Recording and Reporting AEs and SAEs..........................................68
10.3
Monitoring of AEs and Period of Observation .........................................................69
10.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events.........69
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10.5
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose) ................................................................................................................70
10.6
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities...........70
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................71
12.0
DATA HANDLING AND RECORDKEEPING............................................................72
12.1
eCRFs......................................................................................................................72
12.2
Record Retention .....................................................................................................72
13.0
STATISTICAL METHODS..........................................................................................74
13.1
Statistical and Analytical Plans ................................................................................74
13.1.1 Analysis Sets......................................................................................................74
13.1.2 Analysis of Demographics and Other Baseline Characteristics ...........................74
13.1.3 Efficacy Analysis...............................................................................................75
13.1.4 PK Analysis .......................................................................................................75
13.1.5
75
13.1.6 Immunogenicity Analyses..................................................................................75
13.1.7 Safety Analysis ..................................................................................................76
13.2
Interim Analysis and Criteria for Early Termination ................................................76
13.3
Determination of Sample Size..................................................................................76
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................81
14.1
Study Site Monitoring Visits....................................................................................81
14.2
Protocol Deviations..................................................................................................81
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................81
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................82
15.1
IRB and/or IEC Approval ........................................................................................82
15.2
Patient Information, Informed Consent, and Patient Authorization...........................83
15.3
Patient Confidentiality .............................................................................................84
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................84
15.4.1 Publication.........................................................................................................84
15.4.2 Clinical Trial Registration..................................................................................85
15.4.3 Clinical Trial Results Disclosure ........................................................................85
15.5
Insurance and Compensation for Injury....................................................................85
16.0
REFERENCES..............................................................................................................86
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2.0
STUDY SUMMARY
Name of Sponsor(s):
Millennium Pharmaceuticals, Inc, a wholly owned 
subsidiary of Takeda Pharmaceutical Company Limited
Compound:
TAK-079
Title of Protocol: A Phase 1/2a, Open-label, 
Dose-Escalation Study to Investigate the Safety and 
Tolerability, Efficacy, Pharmacokinetics, and 
Immunogenicity of TAK-079 Administered Subcutaneously 
as a Single Agent in Patients With Relapsed/Refractory 
Multiple Myeloma 
Study Number: TAK-079-1501
Phase: 1/2a
Study Design:
This is a multicenter, open-label, dose-escalation, single-arm, phase 1/2a study designed to determine the safety and 
tolerability of TAK-079 monotherapy in patients with relapsed or refractory (r/r) multiple myeloma (MM), and to 
provide a preliminary assessment of its activity against r/r MM. 
Once enrolled into the study, patients will receive TAK-079 via subcutaneous (SC) administration in each 28-day 
cycle of treatment, administered as once weekly for 8 weeks (8 doses), once every 2 weeks for 16 weeks (8 doses), and 
once every 4 weeks thereafter until disease progression (PD). Patients will receive ongoing treatment with TAK-079 
until PD, unacceptable toxicities, or withdrawal due to other reasons. 
The phase 1 portion of the study will evaluate administration of TAK-079 for dose-limiting toxicity (DLT) to 
determine the maximum tolerated dose (MTD) or the recommended phase 2 dose (RP2D) for further assessment in 
phase 2a. A recommended dose below the MTD may be identified based on the review of safety, pharmacokinetic 
(PK), 
, and clinical data from the phase 1 portion of the study. 
The safety and tolerability of TAK-079 will be assessed by recording and analyzing treatment-emergent adverse 
events (TEAEs), dose modifications, treatment discontinuations, vital signs, physical examinations, serum chemistry 
and hematology, urinalysis, electrocardiograms, and concomitant medications. In phase 1, approximately 5 doses of 
TAK 079 will be evaluated in ascending cohorts of 3 to 6 patients per cohort. Cohorts may be expanded by enrolling 
additional patients to further inform selection of the RP2D. 
It is expected that approximately 39 patients will be enrolled in the study. The estimated duration of the study is 
approximately 48 months (ie, 4 years).
Primary Objectives:
Phase 1
To determine the safety, tolerability, and the MTD/RP2D of TAK-079 monotherapy in patients with r/r MM.
Phase 2a
To provide a preliminary evaluation of the clinical activity of TAK-079 monotherapy in patients with r/r MM.
Secondary Objectives:
Phase 1

To investigate a potential MTD/RP2D of TAK-079.

To evaluate the immunogenicity of TAK-079.

To characterize the PK of TAK-079.

To provide a preliminary evaluation of the clinical activity of TAK-079.
Phase 2a

To further evaluate safety at the MTD/ RP2D.

To further evaluate the immunogenicity of TAK-079.

To further characterize the PK of TAK-079.
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Main Criteria for Inclusion:
Male and female patients, aged ≥18 years, with ECOG performance status of ≤2, requiring additional therapy as 
determined by the investigator. Patients must have received the final dose of the following treatments/procedures 
within the specified minimum intervals before the first dose of TAK-079: 120 days for antibody therapy (including 
anti-CD38), 90 days for autologous transplantation, and 30 days for chemotherapy, corticosteroid therapy (up to 
systemic equivalent of 10 mg daily prednisone allowed), radiation therapy, and major surgery. Patients must have 
adequate organ function as determined by the following laboratory values: absolute neutrophil count ≥1.0×109/L; 
platelets ≥75,000/mm3 (≥75×109/L); hemoglobin ≥7.5 g/dL; creatinine clearance ≥30 mL/min (Cockcroft-Gault); 
total bilirubin ≤1.5 times the upper limit of the normal range (ULN); and alanine aminotransferase/aspartate 
aminotransferase ≤2.5×ULN. Patients must have documented r/r MM per the International Myeloma Working Group
(IMWG) criteria, with measurable disease defined as one of the following: serum M-protein ≥500 mg/dL (≥0.5 g/L) 
and urine M-protein ≥200 mg/24 hours. Patients without measurable M-protein in serum protein electrophoresis or 
urine protein electrophoresis must have a serum free light chain (FLC) assay result with involved FLC level 
≥10 mg/dL (≥100 mg/L), provided serum FLC ratio is abnormal. Patients must have evidence of r/r MM as defined by 
the IMWG criteria, previously received at least 2 lines of myeloma therapy (including both an immunomodulatory 
agent and a proteasome inhibitor), and either be refractory or intolerant to at least one of these regimens. Prior 
treatment with an anti-CD38 monoclonal antibody (mAb) is allowed; however, CD38 expression must be significantly 
expressed on target cells for this mechanism of action to be effective. In the phase 2a portion of the study, patients 
must have been refractory to an anti-CD38 mAb therapy at any time during treatment. 
Main Criteria for Exclusion:
Sensory or motor neuropathy of Grade ≥3, based on the National Cancer Institute Common Criteria for Adverse 
Events  (NCI CTCAE) or not recovered from adverse reactions to prior myeloma treatments/procedures to NCI 
CTCAE Grade ≤1 or baseline; allogeneic stem cell transplant; congestive heart failure (New York Heart Association) 
Grade ≥II, cardiac myopathy, active ischemia, clinically significant arrhythmia, history of acute myocardial infarction 
within 5 months before enrollment, clinically significant uncontrolled hypertension, or any other uncontrolled cardiac 
condition or concurrent illness that would preclude study conduct and assessment; QT interval corrected by the 
Fridericia method >480 msec (Grade ≥2); history of severe allergic or anaphylactic reactions to recombinant proteins 
or excipients used in TAK-079 formulation (including patients who were previously discontinued from an anti-CD38 
treatment due to an infusion-related reaction); history of myelodysplastic syndrome or another malignancy other than 
MM; clinical signs of central nervous system involvement of MM; or active chronic hepatitis B or C infection, active 
HIV infection, or active cytomegalovirus infection. Also excluded are patients with POEMS (polyneuropathy, 
organomegaly, endocrinopathy, monoclonal gammopathy and skin changes) syndrome, monoclonal gammopathy of 
unknown significance; smoldering myeloma; solitary plasmacytoma; amyloidosis; Waldenström macroglobulinemia 
or immunoglobulin M myeloma.
Endpoints (in order of importance):
Primary: 
Phase 1

The number of patients with TEAEs overall and per dose level.
–
Patients with DLTs at each dose level.
–
Patients with Grade ≥3 TEAEs.
–
Patients with SAEs.
–
Patients who discontinue because of TEAEs.
–
Patients with dose modifications (delays, interruptions, dose reductions).
o
Clinically significant laboratory values as determined by the investigator.
o
Clinically significant vital sign measurements as determined by the investigator.
Phase 2a

Overall response rate (ORR), defined as the proportion of patients who achieved a partial response ([PR]; 50% 
tumor reduction) or better during study as defined by IMWG Uniform Response Criteria.

Secondary: 
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For each dose level, the posterior probability of having DLT rates that fall into the following intervals will be 
estimated:

[0, 0.16): underdosing.

[0.16, 0.33): target toxicity.

[0.33, 1.00]: excessive toxicity.
The selection of the next recommended dose will be determined from BLRM, along with consideration of other safety, 
clinical, PK, 
 data. Dose-escalation cohorts may be expanded to include additional patients to 
obtain a more comprehensive assessment of disease response before the phase 2a portion of this study is opened to 
enrollment. Approximately 5 dose levels are planned. For phase 1, the number of patients is planned to be 
approximately 21. 
In phase 2a, approximately 18 additional patients will be treated to provide a preliminary estimate of the ORR in 
patients with r/r MM. All patients with MM must show clear evidence of PD with anti-CD38 therapy. 
Phase 2a of the study will also provide a more robust estimate of the safety profile at the MTD/RP2D.
No prospective calculations of statistical power have been made; however, the following table shows the width 
of the 80% CI, based on the observed ORR in a cohort size of 18 patients, for a range of observed response 
rates. An observed ORR greater than 20% would be of interest in this r/r population.
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3.0
STUDY REFERENCE INFORMATION
Study-Related Responsibilities 
The sponsor will perform all study-related activities with the exception of those identified in the 
Study-Related Responsibilities (Appendix C). The identified vendors in the template for specific 
study-related activities will perform these activities in full or in partnership with the sponsor.
Principal Investigator
Takeda will select a Signatory Coordinating Investigator from the investigators who participate in 
the study. Selection criteria for this investigator will include significant knowledge of the study 
protocol, the study medication, their expertise in the therapeutic area and the conduct of clinical 
research as well as study participation. The Signatory Coordinating Investigator will be required to 
review and sign the clinical study report and by doing so agrees that it accurately describes the 
results of the study.
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3.1
List of Abbreviations
Abbreviation
Term
ADA
antidrug antibody
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUClast
area under the concentration-time curve from time 0 to the time of the last quantifiable 
concentration
BLRM
Bayesian Logistic Regression Modeling
BMA
bone marrow aspirate
CFR
Code of Federal Regulations
CLL
chronic lymphocytic leukemia
Cmax
maximum observed concentration
CMV
cytomegalovirus
CNS
central nervous system
COPD
chronic obstructive pulmonary disease
CR
complete response
CRO
contract research organization
CRS
cytokine release syndrome
CT
computed tomography
DLT
dose-limiting toxicity
DOR 
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form (refers to any media used to collect study data [ie, paper or electronic])
EOI
end of infusion
EOT
end of treatment
FDA
United States Food and Drug Administration
FIH
first-in-human
FLC
free light chain
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
HBV
hepatitis B virus
HCV
hepatitis C virus
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IEC
independent ethics committee
Ig
immunoglobulin
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Abbreviation
Term
IMiD
immunomodulatory drug
IMWG
International Myeloma Working Group
IR
injection reaction
IRB
institutional review board
IV
intravenous(ly)
LPLD
last patient, last dose
mAb
monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
MM
multiple myeloma
MR
minimal response
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NAB
neutralizing antibody
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NK
natural killer
NOAEL
no observed adverse effect level
NSAID
nonsteroidal anti-inflammatory drugs
ORR
overall response rate
OS
overall survival
PB
plasmablast
PD
progressive disease; disease progression
PET-CT
positron emission tomography–computed tomography
PFS
progression-free survival
PI
proteasome inhibitor
PK
pharmacokinetic(s)
POEMS 
syndrome
polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes
PR
partial response
QTc
QT interval corrected for heart rate
RBC
red blood cell(s)
r/r
relapsed or refractory
RP2D
recommended phase 2 dose
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
sCR
stringent complete response
SCRS
severe cytokine release syndrome
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Abbreviation
Term
SOE
Schedule of Events
SPEP
serum protein electrophoresis
SUSAR
suspected unexpected serious adverse reactions
TEAE
treatment-emergent adverse event
tmax
time of first occurrence of maximum observed concentration
TTR
time to response
ULN
upper limit of the normal range
UPEP
urine protein electrophoresis
VGPR
very good partial response
WOCBP
women of child-bearing potential
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4.3
Known and Potential Benefits and Risks to Patients with TAK-079
TAK-079 was administered only in healthy human subjects in the first-in-human (FIH) study
(TAK-079_101). Only mild or moderate AEs were observed in the FIH study in healthy subjects.
Therefore, clinical benefits and risks have not been assessed in the disease setting. 
A summary of findings is discussed in Section 4.3.1. See details for precautions and restrictions in 
Section 8.7. Additional information regarding potential risks from treatment is provided in the 
TAK-079 IB.
4.3.1
Risks
Based on the mechanism of action of TAK-079, potential risks may include infusion or injection
reactions, hematological effects, and serious infections.
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4.3.1.3
Severe Cytokine Release Syndrome 
Severe cytokine release syndrome (SCRS) is characterized by severe dyspnea, often accompanied 
by bronchospasm and hypoxia, in addition to fever, chills, rigors, urticaria, and angioedema. This 
syndrome may be associated with some features of tumor lysis syndrome such as hyperuricemia, 
hyperkalemia, hypocalcemia, hyperphosphatemia, acute renal failure, and elevated lactate 
dehydrogenase, and may be associated with acute respiratory failure and death. The acute 
respiratory failure may be accompanied by events such as pulmonary interstitial infiltration or 
edema, visible on a chest x-ray. The syndrome frequently manifests within 1 or 2 hours of 
initiating the first infusion. Patients with a history of pulmonary insufficiency or those with 
pulmonary tumor infiltration may be at greater risk of poor outcome and should be treated with 
increased caution. 
Patients who develop SCRS should have dosing interrupted immediately and should receive 
aggressive symptomatic treatment.
4.3.1.4
Hematologic Effects
Reductions in platelets, lymphocytes, and RBCs occurred in nonclinical studies in some animals 
administered doses of TAK-079 higher than the NOAEL. Subjects in clinical studies of TAK-079 
should be monitored closely, including testing of hematology parameters. 
The important potential risk of these hematologic changes will be monitored throughout this 
clinical study, as described in Section 9.4.13 and Appendix A.
4.3.1.5
Serious Infections
In a GLP-compliant 13-week toxicology study, bacterial and/or viral infection secondary to 
immune suppression was observed in cynomolgus monkeys at IV doses of 3, 30, and 80 mg/kg 
administered once every 2 weeks. The NOAEL dose of 0.3 mg/kg, administered IV once every 
week, was not associated with infections.
Subjects will be monitored for any signs and symptoms of the important potential risk of serious 
infections throughout this clinical study (see Section 8.8.3).
4.3.1.6
Drug Interactions
Nonclinical drug interaction studies have not been conducted with TAK-079. However, as a fully 
human IgG1 monoclonal antibody (mAb), the risk of drug-drug interactions is low.
4.3.1.7
ADA Interactions
ADA responses were detected in most monkeys in the single-dose PK studies and the 4-week
(non-GLP) and 13-week (GLP) toxicology studies. Strong positive ADA responses were generally 
associated with lower serum concentrations of TAK-079, and this was especially notable in the 
13-week repeat-dose toxicity studies and at lower doses.
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In the single-dose healthy subject study (TAK-079_101), 5 of 54 TAK-079–treated subjects were 
positive for ADA (3 subjects with transient ADA and 2 subjects with persistent ADA). Of these, 
1 subject was treated in the 0.06 mg IV cohort and the remaining 4 subjects were treated with 
either 0.03 mg/kg (2 subjects), 0.1 mg/kg (1 subject), or 0.6 mg/kg (1 subject) SC TAK-079.
Immunogenicity was not associated with clinically significant AEs, even in the 2 subjects with 
persistent immunogenicity.
4.3.1.8
Pregnancy and Lactation
TAK-079 has not been administered to women who are pregnant or lactating. Dedicated fertility 
and embryo-fetal development toxicology studies have not been conducted with TAK-079. 
However, there were no TAK-079-related changes in organ weights or microscopic findings noted 
in the male and female reproductive tract of monkeys following administration for up to 13 weeks. 
Women of child bearing potential (WOCBP) may be enrolled in clinical trials with appropriate 
precautions to prevent pregnancy (additional details in Section 8.7).
At this stage of development TAK-079 should not be administered to women who are pregnant or 
breastfeeding.
4.3.1.9
Overdose
TAK-079 has been administered only to healthy subjects in the FIH study. To date, there is no 
experience with overdose. If an overdose does occur, close monitoring and supportive treatment as 
required are recommended.
4.3.2
Overall Benefit and Risk Assessment for This Study
The overall clinical benefits and risks of TAK-079 have not been determined. 
Based on the mechanism of action of TAK-079, nonclinical data to date, as well as some exposure 
in healthy human subjects, risks of TAK-079 include but are not limited to IRs, CRS, 
hypersensitivity reactions, changes in hematologic parameters, and serious infections. Patients 
will be monitored closely for these risks in this clinical study.
4.4
Rationale for the Proposed Study
Although multiple therapies are available for patients with MM, this disease remains incurable; 
thus, significant unmet medical need exists for this patient population. Frequent relapses highlight 
a need for new therapies for patients in whom prior treatments have failed. 
TAK-079 binds a partially distinct epitope of CD38 and possesses a different binding profile than 
the approved cytolytic anti-CD38 therapeutic antibody daratumumab. Unlike daratumumab, 
TAK-079 does not bind to RBCs and platelets. Therefore, TAK-079 may possess higher 
tumoricidal activity than daratumumab because cytolytic effector activity is focused on CD38+ 
leukocytes/tumors and is not misdirected to RBCs and platelets. Consequently, TAK-079 may 
demonstrate higher potency (ie, activity at lower doses and exposures) and activity in 
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daratumumab-refractory tumors (ie, tumors expressing lower levels of CD38) and thus be more 
efficient at eliminating tumors.
In the FIH study (TAK-079_101), TAK-079 demonstrated pharmacodynamic effects (ie, cytolysis 
of NK cells and PBs) following single-dose administration, with no unexpected and unwanted 
clinical or hematologic effects observed.
In summary, it is feasible to investigate administration of TAK-079 in patients with relapsed or 
refractory (r/r) MM.
4.4.1
Rationale for the Starting Dose of TAK-079
In the FIH study (TAK-079_101), TAK-079 was well tolerated after SC administration of 
single-doses ranging from 0.03 to 0.6 mg/kg.
To avoid unnecessary exposure of patients to sub-therapeutic doses while preserving safety, the
starting dose for this study in patients with r/r MM will be 45 mg, the fixed-dose equivalent of 
0.6 mg/kg (assuming a body weight of 75 kg), which was the highest SC dose administered in 
Study TAK-079_101. The 0.6 mg/kg dose was well tolerated in healthy human subjects in 
Study TAK-079_101 and demonstrated depletion of peripheral blood PBs, a surrogate for tumor 
cells.
TAK-079 is a mAb targeting CD38, which is a cell surface molecule that is constitutively 
expressed on plasma cells, PBs, and NK cells, and is induced on activated T cells and B cells [7]. 
Therefore, the anticipated elimination routes for TAK-079 are via proteolytic catabolism and 
intracellular degradation after binding to its target. Both of these clearance mechanisms are not 
thought to be significantly influenced by body weight. Additionally, the distribution volume of 
mAbs is generally limited to the volume of the blood and extracellular fluids, such that body 
composition is a less important determinant of distribution volume as compared with small 
molecule drugs [8]. For these reasons, body weight is not expected to have a clinically significant 
effect on the disposition of TAK-079, thereby supporting the investigation of fixed-dose 
administration.
The 45 mg starting dose of TAK-079 will be tested in 3 patients with r/r MM to assess the safety 
and tolerability of TAK-079 after multiple dose administration. TAK-079 will be administered 
using the same dosing schedule as the anti-CD38 antibody, daratumumab, which is approved for 
the treatment of patients with MM [5]. Specifically, TAK-079 will be administered once weekly 
for 8 weeks (8 doses), once every 2 weeks for 16 weeks (8 doses), then once every 4 weeks until 
the patient experiences disease progression (PD), unacceptable toxicities, or withdrawal due to 
other reasons. The subsequent planned dose levels are 135, 400, 1200, and 1800 mg.
Escalation to a subsequent cohort may take place after the treatment in the first cycle of the 
previous (sequential) cohort has completed.
Additional details for dose escalation are provided in Section 8.3.
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5.2
Endpoints
5.2.1
Phase 1 Primary Endpoints
The primary endpoints for phase 1 are: 

The number of patients with TEAEs overall and per dose level. 
–
Patients with dose-limiting toxicities (DLTs) at each dose level. 
–
Patients with Grade 3 TEAEs.
–
Patients with SAEs.
–
Patients who discontinue because of TEAEs.
–
Patients with dose modifications (delays, interruptions, dose reductions).
–
Clinically significant laboratory values, as determined by the investigator.
–
Clinically significant vital sign measurements, as determined by the investigator.
5.2.2
Phase 2a Primary Endpoint
The primary endpoint for phase 2a is:

ORR, defined as the proportion of patients who achieved a partial response (PR) or better 
during the study as defined by International Myeloma Working Group (IMWG) Uniform 
Response Criteria [9,10]. 
5.2.3
Phase 1 Secondary Endpoints
The secondary endpoints for phase 1 are: 

Summary statistics for the following PK parameters:
–
Maximum observed concentration (Cmax).
–
Time of first occurrence of Cmax (tmax).
–
Area under the concentration-time curve from time 0 to the time of the last quantifiable 
concentration (AUClast).

Preliminary evaluation of antitumor activity of TAK-079 will be assessed for patients with 
MM:
–
ORR, defined as the proportion of patients who achieved a PR (50% tumor reduction) or 
better during the study as defined by the IMWG Uniform Response Criteria ([9,10]; 
Appendix E).
–
Proportion of patients who achieved a minimal response (MR), defined as 25% tumor 
reduction ([[9,10]; Appendix E).

Anti-TAK-079 antibody incidence and characteristics.
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6.0
STUDY DESIGN
6.1
Overview of Study Design
This is a multicenter, dose-escalation, open-label, single-arm, phase 1/2a study designed to 
determine the safety, tolerability, efficacy, PK, and immunogenicity of TAK-079 monotherapy in 
patients with r/r MM, and to provide a preliminary assessment of its activity against MM.
The phase 1 portion of the study will evaluate administration of TAK-079 for DLT(s) to determine 
the MTD/RP2D for further assessment in phase 2a. A recommended dose below the MTD may be 
identified based on safety, clinical, PK, 
 data. The safety and tolerability of 
TAK-079 will be assessed by recording and analyzing TEAEs, dose modifications, treatment 
discontinuations, vital signs, physical examinations, serum chemistry and hematology analyses, 
urinalyses, ECGs, and review of concomitant medications.
The preliminary efficacy of TAK-079 will be evaluated by measuring the ORR, defined as the 
proportion of patients who achieved a PR or better during study, as defined by IMWG
(Appendix E; [9,10]). In addition, the efficacy of TAK-079 will be assessed by measuring PFS, 
DOR, and OS; TTR will also be measured.
Once enrolled into the study, patients will receive TAK-079 via SC administration in each 28-day 
cycle of treatment, administered as once weekly for 8 weeks (8 doses), once every 2 weeks for 
16 weeks (8 doses), and once every 4 weeks thereafter until PD. Patients will receive ongoing 
treatment with TAK-079 until they experience PD, unacceptable toxicities, or withdrawal due to 
other reasons.
Phase 1 will consist of the following phases/periods: Screening, Treatment, and Follow-up:

Screening period (visit 1): Days -21 to Day -1.

Treatment period (visit 2/ongoing): Once-weekly treatment for 8 doses (Cycles 1 and 2), 
starting on Day 1, followed by treatment once every 2 weeks for 8 doses (Cycles 3-6), followed 
by treatment once every 4 weeks thereafter (Cycle 7 and beyond), continuing until patients 
experience PD, unacceptable toxicities, or withdrawal due to other reasons. 

Follow-up Period (follow-up visit): Patients who discontinue for PD will be followed for 30 
days after the last dose of study drug or until the start of subsequent alternative anticancer 
therapy to monitor safety/AEs. Patients who discontinue treatment for reasons other than PD 
will continue to be followed for PFS every 4 weeks until PD, death, loss to follow-up, consent 
withdrawal, study termination, or 12 months after the last patient has received their last dose 
(last patient, last dose [LPLD]). All patients will be followed for OS every 12 weeks until 
death, loss to follow-up, consent withdrawal, study termination, or 12 months after LPLD.
In phase 1, approximately 5 doses will be evaluated in ascending cohorts of 3-6 patients per 
cohort. Cohorts may be expanded by enrolling additional patients to further inform selection of the 
RP2D. Dose selection for phase 2a will take place after review of the available safety, efficacy, 
PK, 
 data obtained from the phase 1 portion of the study.
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It is expected that approximately 39 patients will be enrolled in total for phase 1 and 2a combined. 
The estimated duration of the study is approximately 48 months (4 years; Section 6.3).
Study procedures and assessments, with their time points, are shown in Appendix A. The study 
schematic diagram is shown in Figure 6.a.
Figure 6.a
Overall Study Schematic Diagram 
6.2
Number of Patients
For phase 1, approximately 21 patients are planned to be enrolled, including the expansion of 
additional patients in selected cohorts to further inform selection of the RP2D. For phase 2a, 
approximately 18 patients are planned. Details on the definition of evaluable patients and sample 
size are given in Section 13.1.
The study is planned to be conducted in the United States in approximately 4 investigational 
centers for phase 1 and in a total of 6 investigational centers for phase 2a.
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6.3
Duration of Study
6.3.1
Duration of an Individual Patient’s Study Participation
Patients will receive TAK-079 until they experience PD as defined by IMWG for patients with 
MM ([9,10]; Appendix E), unacceptable toxicity, withdrawal of consent, death, termination of the 
study by the sponsor, until any other discontinuation criterion is met, or until 12 months after 
LPLD (additional participation details are provided in Sections 6.1, 8.4.3, 9.6, and 9.7). 
Patients will be evaluated 30±7 days after the last dose of TAK-079 (follow-up visit) or before 
initiating subsequent systemic anticancer therapy, for detection of any delayed TEAEs.
6.3.2
End of Study/Study Completion Definition and Planned Reporting
The final data cutoff for the clinical study report will be conducted 12 months after all patients 
have been discontinued from treatment or transferred to a long-term safety study, a single-patient 
investigational new drug application, or a similar program (Table 6.a).
6.3.3
Timeframes for Primary and Secondary Endpoints to Support Disclosures
Refer to Table 6.a for disclosures information for all primary and secondary endpoints.
Table 6.a
Primary and Secondary Endpoints for Disclosures
Endpoint
Definition
Maximum Time 
Frame From Final 
Clinical Study Report
Phase 1
Primary: 
Number of patients with TEAEs
overall and per dose level: number 
of patients with TEAEs overall and 
per dose level; patients with DLTs 
at each dose level; patients with 
Grade 3 TEAEs; patients with 
SAEs; patients who discontinue 
because of TEAEs; patients with 
dose modifications (delays 
interruptions, dose reductions), 
clinically significant laboratory and 
vital sign values, as determined by 
the investigator
Includes assessments for patients with 
DLTs, Grade 3 TEAEs, SAEs, 
discontinuations because of TEAEs, 
dose modifications, and clinically 
significant laboratory values and vital 
signs.
1 year
Secondary: Summary statistics for PK 
parameters: Cmax, tmax, and AUClast.
Summary statistics for maximum 
observed concentration, time to first 
occurrence of Cmax, and area under the 
concentration-time curve from time 0 
to the time of the last quantifiable 
concentration (AUClast). See Section
13.1.4.
1 year
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Endpoint
Definition
Maximum Time 
Frame From Final 
Clinical Study Report
Secondary: Preliminary evaluation of antitumor 
activity of TAK-079: ORR
Proportion of patients who achieved a 
PR (50% tumor reduction) or better 
during the study as defined by the 
IMWG Uniform Response Criteria.
See Section 13.1.3.
1 year
Secondary: Preliminary evaluation of antitumor 
activity of TAK-079: MR
Proportion of patients who achieved a 
minimal response, defined as 25% 
tumor reduction. See Section 13.1.3.
1 year
Secondary: Anti-TAK-079 antibody incidence 
and characteristics
Assessment of ADA antibodies 
following treatment. See Section 
13.1.6.
1 year
Phase 2a
Primary: ORR
Proportion of patients who achieved a 
PR (50% tumor reduction) or better 
during the study as defined by the 
IMWG Uniform Response Criteria. 
See Section 13.1.3.
1 year
Secondary: DLT-like frequencies and other 
TEAEs occurring over the course of 
extended treatment with TAK-079,
including information about dose 
modification, treatment 
discontinuation, clinically 
significant laboratory values, and 
vital signs.
Includes assessments for patients with 
DLTs and other TEAEs, dose 
modifications, treatment 
discontinuations, clinically significant 
laboratory values, and vital signs.
1 year
Secondary: Summary statistics for PK 
parameters of Cmax, tmax, and 
AUClast.
Summary statistics for maximum 
observed concentration, time to first 
occurrence of Cmax, and area under the 
concentration-time curve from time 0 
to the time of the last quantifiable 
concentration (AUClast).See Section 
13.1.4.
1 year
Secondary: Anti-TAK-079 antibody incidence 
and characteristics
Assessment of ADA antibodies 
following treatment. See Section 
13.1.6.
1 year
Secondary: MR
Proportion of patients who achieved 
MR, defined as 25% tumor reduction.
See Section 13.1.3.
1 year
Secondary: DOR
Time from the date of the first 
documentation of response to the date 
of the first documented PD. See 
Section 13.1.3.
1 year
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Endpoint
Definition
Maximum Time 
Frame From Final 
Clinical Study Report
Secondary: PFS 
Time from the date of the first dose 
until the earliest date of PD, or the date 
of death due to any cause. See Section 
13.1.3.
1 year
Secondary: OS
Defined as the time from the date of 
first dose to the date of death due to 
any cause. See Section 13.1.3.
1 year
Secondary: TTR
Time from the date of the first dose to 
the date of the first documentation of 
response (PR or better). See Section 
13.1.3.
1 year
DLT=dose-limiting toxicity; DOR=duration of response; IMWG=International Myeloma Working Group; 
MR=minimal response; ORR=overall response rate; OS=overall survival; PFS=progression-free survival; 
PK=pharmacokinetics; SAE=serious adverse event; TEAE=treatment-emergent adverse event; TTR=time to 
response.
6.3.4
Total Study Duration
It is anticipated that this study will last for approximately 48 months (4 years).
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7.0
STUDY POPULATION
7.1
Inclusion Criteria
Each patient must meet all the following inclusion criteria to be enrolled in the study:
1. Male or female patients aged 18 years or older.
2. Eastern Cooperative Oncology Group (ECOG) performance status of ≤2 [11].
3. Patient has received the final dose of any of the following treatments/procedures within the 
specified minimum intervals before the first dose of TAK-079 (Table 7.a):
Table 7.a
Required Washout Periods for Previous Treatments or Procedures Prior to 
Administration of TAK-079 
Previous Treatment or Procedure
Washout Period
Myeloma-specific therapy
30 days
Antibody therapy (including anti-CD38)
120 days
Corticosteroid therapy (a)
30 days
Autologous transplantation 
90 days
Radiation therapy
30 days
Major surgery
30 days
(a) Systemic corticosteroid use ≤10 mg/day (prednisone or equivalent) is allowed.
4. Patient has adequate organ function as determined by the following laboratory values
(Table 7.b):
Table 7.b
Laboratory Criteria for Determining Adequate Organ Function for 
Study TAK-079-1501 Eligibility
Laboratory Parameter
Acceptable Laboratory Criteria 
Absolute neutrophil count (a)
≥1000/mm3 (≥1.0×109/L); ≥750/mm3 (≥0.75109/L) maybe 
acceptable for patients with >50% of plasma cells in bone marrow 
after discussion with sponsor
Platelets (a)
≥75,000/mm3 (≥75×109/L); a value of ≥50,000/mm3
(≥50×109/L) may be acceptable for patients with >50% bone 
marrow burden following discussion with the sponsor
Hemoglobin 
≥7.5 g/dL  (it is not permissible to transfuse a subject to reach this 
level)
Creatinine clearance
≥30 mL/min (Cockcroft-Gault)
Total serum bilirubin
≤1.5×ULN; an exception for patients with Gilbert’s syndrome 
may be granted after discussion with the sponsor
Liver transaminases (ALT/AST)
≤2.5×ULN
ALT=alanine aminotransferase; AST=aspartate aminotransferase; ULN=upper limit of the normal range.
(a) Without ongoing growth factor or transfusion support for at least 1 week before Day 1.
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5. Female patients who:

Are WOCBP must not be pregnant or lactating. 

Are postmenopausal for at least 1 year before the screening visit, OR

Are surgically sterile, OR

If they are of childbearing potential, agree to practice 1 highly effective method of 
contraception and 1 additional effective (barrier) method at the same time, from the time of 
signing the informed consent through at least 30 days or 5 half-lives after the last dose of study 
drug, whichever time period is longest, OR

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of 
the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, and postovulation 
methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.)
6. Male patients, even if surgically sterilized (ie, status postvasectomy), who:

Agree to practice effective barrier contraception during the entire study treatment period and 
through 120 days (or if the drug has a very long half-life, for 90 days plus 5 half-lives) after the 
last dose of study drug, OR

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of 
the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, and postovulation 
methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.)
7. Voluntary written consent must be given before performance of any study-related procedure 
not part of standard medical care, with the understanding that consent may be withdrawn by 
the patient at any time without prejudice to future medical care.
8. The patient must be willing and able to comply with study restrictions and to remain at the 
investigational center for the required duration during the study period, and must be willing to 
return to the investigational center for the follow-up procedures and assessments specified in 
this protocol.
9. Requires additional therapy, as determined by the investigator.
10. Documentation of r/r MM as defined by the IMWG criteria (Appendix E; [9,10]).
11. For patients with MM, measurable disease defined as one of the following:

Serum M-protein ≥500 mg/dL (≥5 g/L).

Urine M-protein ≥200 mg/24 hours.

In patients without measurable M-protein in serum protein electrophoresis (SPEP) or urine 
protein electrophoresis (UPEP), a serum free light chain (FLC) assay result with involved FLC 
level ≥10 mg/dL (≥100 mg/L), provided serum FLC ratio is abnormal.
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12. Previously received at least 2 lines of standard therapy (including both an IMiD and a PI), and 
is either refractory to or intolerant of at least one of these regimens. Prior treatment with an 
anti-CD38 mAb is allowed; however, CD38 expression must be significantly expressed on 
target cells for this mechanism of action to be effective.
13. In the phase 2a portion of the study, patients with MM must also have been refractory to at 
least 1 anti-CD38 mAb therapy at any time during treatment.
NOTE: 

Refractory is defined as at least a 25% increase in M-protein or PD during treatment or within 
60 days after cessation of treatment.

A line of therapy is defined as 1 or more cycles of a planned treatment program. This may 
consist of 1 or more planned cycles of single-agent therapy or combination therapy, as well as 
a sequence of treatments administered in a planned manner. A new line of therapy starts when 
a planned course of therapy is modified to include other treatment agents (alone or in 
combination) as a result of PD, relapse, or toxicity. A new line of therapy also starts when a 
planned period of observation off therapy is interrupted by a need for additional treatment for 
the disease [9].
7.2
Exclusion Criteria
Patients meeting any of the following exclusion criteria are not to be enrolled in the study:
1. Sensory or motor neuropathy of National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE) Grade ≥3 [12].
2. Patients who have received allogeneic stem cell transplant.
3. Patients who have received anti-CD38 antibody therapy and do not fulfill a 120-day washout 
period before receiving TAK-079.
4. Not recovered from adverse reactions to prior myeloma treatment or procedures 
(chemotherapy, immunotherapy, radiation therapy) to NCI CTCAE Grade ≤1 or baseline.
5. Congestive heart failure (New York Heart Association) Grade ≥II; cardiac myopathy, active 
ischemia, or any other uncontrolled cardiac condition such as angina pectoris, clinically 
significant arrhythmia requiring therapy including anticoagulants, or clinically significant 
uncontrolled hypertension.
6. History of acute myocardial infarction within 5 months before enrollment or ECG 
abnormalities during the screening period that are deemed medically relevant by the 
investigator.
7. QT interval corrected by the Fridericia method >480 msec (Grade ≥2).
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8. Concurrent illness that would preclude study conduct and assessment including, but not 
limited to, uncontrolled medical conditions, uncontrolled systemic or body organ active 
infection (considered opportunistic, life threatening, or clinically significant), uncontrolled 
risk of bleeding, uncontrolled diabetes mellitus, pulmonary disease (including obstructive 
pulmonary disease such as severe chronic obstructive pulmonary disease [COPD] with forced 
expiratory volume <50%, or persistent asthma, pulmonary fibrosis, and history of 
symptomatic bronchospasm), inflammatory bowel disease, ongoing symptomatic 
pneumonitis, alcoholic liver disease, or primary biliary cirrhosis. 
9. History of stroke or intracranial hemorrhage within 12 months of randomization; patients 
requiring anticoagulation therapy for any indication should be discussed with the medical 
monitor before screening.
10. Active autoimmune disease including autoimmune hemolytic anemia, idiopathic 
thrombocytopenic purpura, or any chronic condition requiring a higher corticosteroid systemic 
equivalent than prednisone 10 mg daily. Higher doses of corticosteroids prescribed for any 
indication must be stopped 30 days prior to randomization; exceptions may be made for 
corticosteroids prescribed specifically for management of MM symptoms after discussion with 
the medical monitor.
11. History of myelodysplastic syndrome or another malignancy other than MM, except for the 
following: any malignancy that has been in complete remission for 3 years, adequately treated 
local basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial 
bladder cancer, or asymptomatic prostate cancer without known metastatic disease and with no 
requirement for therapy or requiring only hormonal therapy and with normal prostate-specific 
antigen for 1 year before the start of study therapy.
12. Clinical signs of CNS involvement of MM.
13. Female patients who are pregnant with a positive serum pregnancy test or lactating during the 
screening period, or a positive urine pregnancy test on Day 1 before the first dose of study 
drug, if applicable. 
14. Any serious medical or psychiatric illness that could, in the investigator’s opinion, potentially 
interfere with the completion of treatment according to this protocol.
15. Active chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, active HIV, or 
cytomegalovirus (CMV) infection.
16. History of severe allergic or anaphylactic reactions to recombinant proteins or excipients used 
in the TAK-079 formulation. This includes patients who were previously discontinued from an 
anti-CD38 treatment due to an infusion-related reaction.
17. The patient is currently participating in another antimyeloma or antileukemia clinical study, or 
has participated in another investigational clinical trial within the past 4 weeks prior to 
randomization.
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18. Patients who are not able and/or willing to comply with the study requirements, rules, and 
procedures.
19. POEMS (Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin 
changes) syndrome, monoclonal gammopathy of unknown significance, smoldering myeloma, 
solitary plasmacytoma, amyloidosis, Waldenström macroglobulinemia, or IgM myeloma.
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8.0
STUDY DRUG
8.1
Study Drug Administration
All protocol-specific criteria for administration of study drug must be met and documented before 
drug administration. Study drug will be administered only to eligible patients under the 
supervision of the investigator or identified subinvestigator(s).
8.1.1
Premedication
Before each injection, patients will receive the following premedications 1 to 3 hours prior to the 
start of TAK-079 administration on each dosing day:

Dexamethasone: 20 mg IV dose for the initial injection. Oral dexamethasone (20 mg) or an 
equivalent long-acting corticosteroid may be used before subsequent injections.

Antipyretics: oral acetaminophen (650 to 1000 mg).

Antihistamine: oral or IV diphenhydramine (25 to 50 mg, or equivalent).

Montelukast 10 mg (or equivalent leukotriene inhibitor) is optional for Cycle 1, Day 1.
NOTE: Patients with a higher risk of respiratory complications (eg, patients with COPD who have 
a forced expiratory volume in 1 second of <80%; and patients with asthma) will be treated with 
post-injection medication consisting of the following:

An antihistamine (diphenhydramine or equivalent) on the first and second days after all 
injections,

A short-acting βadrenergic receptor agonist, such as salbutamol (albuterol) aerosol, and

Control medications for lung disease (eg, inhaled corticosteroids with or without long-acting 
β2 adrenergic receptor agonists for patients with asthma; long-acting bronchodilators such as 
tiotropium or salmeterol with or without inhaled corticosteroids for patients with COPD).
Premedication will be mandatory in phase 1. The decision to premedicate in phase 2a will be 
determined based on data from phase 1.
The clinical site is responsible for sourcing any premedications outlined in the protocol.
8.1.2
TAK-079 Formulation and Administration
The strength of the TAK-079 drug product for SC use in the current study (TAK-079-1501) is 
100 mg TAK-079 in 1 mL (100 mg/mL). The drug product is supplied in clear borosilicate glass 
vials (see additional details in Section 8.10).
After patients have received premedication treatment, TAK-079 doses will be administered with 
syringes as SC injections up to a maximum volume of 2 mL per injection (ie, 200 mg/2 mL), 
injected every 30 minutes until the full scheduled dose has been administered.
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Patients may receive low-dose methylprednisolone (< 20 mg) for the prevention of delayed 
injection related reaction, as clinically indicated. 
Refer to the Pharmacy Manual for detailed instructions regarding preparation of each dose.
8.2
Definitions of DLT
Toxicity will be evaluated according to the NCI CTCAE, Version 4.03, effective 14 June 2010 
[12]. These criteria are provided in the Study Manual. DLT will be defined as any of the following 
events that are considered by the investigator to be at least possibly related to therapy with
TAK-079.

Nonhematologic TEAEs of NCI CTCAE Grade 3 clearly unrelated to the underlying disease 
and occurring during the first cycle will be considered DLTs (see Section 10.2 for relatedness 
guidance), with the following exceptions:
–
Asymptomatic laboratory changes (other than renal and hepatic laboratory values, and 
Grade 4 lipase/amylase) that can be successfully supplemented (reversion of Grade 4 
events to Grade ≤2, reversion of Grade 3 events to Grade ≤1 or baseline) within 72 hours.
–
Grade 3 nausea/vomiting that can be managed subsequently with anti-emetics (Grade 3 
nausea or vomiting that persists beyond 48 hours with or without appropriate medical 
intervention will be considered a DLT).
–
Grade 3 fatigue lasting less than 72 hours.
–
Grade 3 elevation of ALT or AST that resolves to Grade ≤1 or baseline within 7 days.
–
Grade 3 IR that responds to symptomatic treatment (eg, antihistamines, nonsteroidal 
anti-inflammatory drugs (NSAIDs), narcotics, IV fluids), without recurrence of Grade 3 
symptoms.

Hematologic TEAEs of NCI CTCAE Grade ≥4 clearly unrelated to the underlying disease and 
occurring during the first cycle will be considered DLTs, with the following exceptions:
–
Grade ≥3 hemolysis clearly unrelated to the underlying disease (eg, negative direct 
Coombs test) will be included in the definition of DLT.
–
Grade 3 low platelet or higher count with clinically meaningful bleeding will be included 
in the definition of DLT.
–
Grade 4 low platelet count of duration <2 weeks will not be included in the definition of 
DLT.
–
Grade 4 lymphopenia will not be included in the definition of DLT.
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Once the dose is escalated above the starting dose level, BLRM will be used for all subsequent 
dose recommendations, along with consideration of other safety, clinical, PK, 
 
 data. More conservative dose escalation, evaluation of intermediate doses, and 
expansion of an existing dose level are all permissible following discussions between the sponsor 
and the investigators, if such measures are needed for patient safety or for a better understanding of 
the dose-related toxicity, exposure, or 
.
Before initiating the dosing of the next cohort, when safety data are available for all patients in the 
current cohort, key safety data will be reviewed and evaluated by the study team consisting of 
sponsor representatives and investigators who will review the safety of all treated patients and 
make decisions regarding dose escalation. In addition, changes to the dose-escalation scheme or 
dose schedule (dosing interval) may be considered. All decisions will be documented in writing. 
Any decision to modify the dose-escalation scheme (with the exception of testing intermediate 
dose levels) or dose schedule will be communicated to institutional review boards (IRBs), and the 
protocol will be amended accordingly.
8.4
Dose Modification Guidelines
Dose modification guidelines for toxicities are described below for TAK-079 on the basis of the 
type and severity of AEs and causality determination by investigators. Further clarification can be 
obtained in consultation with the sponsor clinician (or designee).
8.4.1
Criteria for Beginning or Delaying a Subsequent Treatment Cycle
Treatment with TAK-079 will use a cycle length of 28 days. For a new cycle of treatment to begin, 
the patient must meet the following criteria:

Absolute neutrophil count must be ≥1000/mm3.

Platelet count must be ≥75,000/mm3.

For therapy to resume, toxicity considered to be related to treatment with TAK-079 must have 
resolved to Grade 1 or baseline, or to a level considered acceptable by the physician. If the 
patient fails to meet the above-cited criteria for retreatment, initiation of the next cycle of 
treatment should be delayed for 1 week. At the end of that week, the patient should be 
re-evaluated to determine whether the criteria for re-treatment have been met. If there is a 
delay of a subsequent cycle longer than 2 weeks because of a drug-related AE, the patient may 
be withdrawn from treatment unless there is clinical benefit as assessed by the investigator, 
with agreement by the sponsor’s medical monitor. TAK-079 dosing may be continued at the 
previously established safe dose level or below.

For TAK-079 injections within the same cycle, the decision of holding treatment is left to the 
investigator’s discretion based on clinical and analytical data, and also based on the toxicity 
that the patient experienced with previous injections in the same cycle. The investigator should 
differentiate between acute toxicity (like an IR) from which the patient is recovered at the time 
of the next injection, and subacute toxicity (for example, neutropenia) that might be worsened 
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upon another injection if it is not on a clear recovery path. If the dose cannot be administered 
on the scheduled day, the patient can be reviewed at the investigator’s discretion in the 
following 48 hours. If TAK-079 cannot be administered within a cycle in this 48-hour 
window, the dose will be missed and the patient scheduled for the next administration per the 
Schedule of Events (SOE; Appendix A).
8.4.2
Criteria for Dose Reduction
All toxicities that occur during the study will be actively managed following the standard of care 
unless otherwise specified in the protocol. Patients experiencing AEs attributed to TAK-079 may 
continue study treatment with the same dose, may have TAK-079 treatment held, may have their 
dose reduced, or may be permanently discontinued from the study. Patients who have study drug 
held because of treatment-related or possibly related AEs may resume study drug treatment after 
resolution of the AE at the same dose level or at a reduced dose, depending on the nature and 
severity of the AE and whether it is the first occurrence or it is recurrent.
TEAEs that are not attributed by the investigator to the study drug may be treated as per local 
standard of care, dose-modifications, interruptions and permanent discontinuations may be 
discussed upfront with the medical monitor.
Table 8.a provides general dose modification recommendations. When the dose of TAK-079 is 
withheld on the basis of these criteria, clinical and laboratory re-evaluation should be repeated at 
least weekly or more frequently, depending on the nature of the toxicity observed, until the toxicity 
resolves to Grade ≤1 or baseline. If there are transient laboratory abnormalities that, per
investigator assessment, are not clinically significant or drug related, continuation of therapy 
without dose modification is permissible upon discussion with the sponsor. See details for 
managing specific AEs in Section 8.8.
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Table 8.a
Dose Modification Recommendations for TAK-079 Toxicities
Criteria
Action
Grade 1 AEs
No dose reductions or interruptions.
Grade 2 AEs
Treat according to local practice. Whether to hold treatment or to continue it 
at the same or a reduced dose is at the discretion of the investigator.
Patients experiencing Grade 2 AEs considered related to study treatment that 
are not easily managed or corrected and are not tolerable to the patient, or 
AEs that are not acceptable in the investigator’s judgment, should have study 
treatment interrupted until the AE resolves to Grade ≤1 or baseline, then 
restarted at the same dose or, depending on the toxicity, at the previous safe 
dose level or below.
Grade 3 AEs
Hold TAK-079 until resolution to Grade ≤1 or baseline, then resume 
treatment at either the same dose or a reduced dose level at the discretion of 
the investigator.
Grade 4 (life-threatening) AEs
Consider permanently withdrawing the patient from the study, except when 
the investigator determines that the patient is receiving clinical benefit and 
has discussed this with the sponsor. Treatment may be restarted at a reduced 
dose level or below when toxicity recovers to Grade ≤1 or baseline.
AEs of all grades
If treatment has been held for >14 consecutive days without resolution of the 
toxicity (to baseline or Grade ≤1), consider permanently discontinuing study 
treatment unless there is clinical benefit for the patient as assessed by the 
investigator and with sponsor’s approval. Treatment can be resumed at a 
reduced dose level after resolution of AEs to Grade ≤1 or baseline.
AE=adverse event.
When a dose reduction occurs, the TAK-079 dose will be reduced to the next lower dose that has 
been established as a safe dose during dose escalation. If initial dose adjustment does not provide 
sufficient relief, the dose of TAK-079 can be further reduced if the treating physician considers 
that the patient is receiving benefit. In general, after a dose is reduced, it should not be re-escalated 
even if there is minimal or no toxicity with the reduced dose. However, if further evaluation 
reveals that the AE that led to the dose reduction was not study drug related, the dose may be 
re-escalated to the original dose level. Up to 2 dose level reductions of TAK-079 because of AE 
are generally recommended.
If dose-reduction is not possible because the lowest dose-level has already been reached, treatment 
may be permanently discontinued.
The dose of TAK-079 will not be reduced for an individual patient during Cycle 1 unless a DLT 
has been declared and it is still possible for the patient to receive treatment within the remaining 
dosing period scheduled. In this case, the patient can complete Cycle 1 at a reduced dose level.
8.4.3
Criteria for Discontinuing TAK-079 in Individual Patients (When Considering Dose 
Modification)
TAK-079 should be discontinued in patients experiencing an AE in Cycle 1 meeting criteria for a 
DLT for which the investigator considers that re-treatment of the patient could be dangerous. For 
Grade 4 (life-threatening) TEAEs, consider permanently withdrawing the patient from the study, 
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except when the investigator determines that the patient is receiving clinical benefit, there are 
opportunities to provide supportive care to mitigate risk for the Grade 4 event to reoccur, and this 
approach (ie, the specific situation and mitigation plan) has been discussed with the sponsor. In 
these circumstances, treatment may be restarted at the previously safe dose level or below when 
toxicity recovers to Grade ≤1 or baseline.
If the next cycle of TAK-079 is delayed for >14 days because of TAK-079–related toxicities, then 
the patient should have study treatment discontinued unless the investigator considers that the 
patient will receive benefit from continuing in the study. If treatment discontinuation occurs, the 
end of treatment (EOT)/early termination visit should be completed and the follow-up visit should 
occur within 30 (±7) days after the last administration of TAK-079. Additional details for study 
treatment discontinuation are provided in Section 9.7.
8.5
Excluded Concomitant Medications and Procedures
The following medications and procedures are prohibited during the study:

Chemotherapy and radiation therapy for the disease under study. Local radiotherapy for bone 
pain is permitted after agreement with the sponsor’s medical monitor and once PD is ruled out.

Systemic corticosteroid use >10 mg/day (prednisone or equivalent). 

Live vaccines.

Any investigational agent other than TAK-079, including agents that are commercially 
available for indications other than MM that are under investigation for the treatment of MM.
8.6
Permitted Concomitant Medications and Procedures 

All necessary supportive care consistent with optimal patient care will be available to patients 
as necessary. All blood products and concomitant medications received from the first dose of 
the study drug regimen until 30 days after the final dose will be recorded in the electronic case 
report forms (eCRFs).

The following medications and procedures are permitted while the patient is receiving the 
study drug:
–
Systemic corticosteroid use ≤10 mg/day (prednisone or equivalent).
–
Myeloid growth factors (eg, granulocyte colony stimulating factor, granulocyte 
macrophage-colony stimulating factor) and erythropoietin are permitted. Their use should 
follow the product label, published guidelines, and institutional practice. 
–
Transfusions with RBCs and platelets as clinically indicated; localized radiation for pain 
management for osteolytic lesions.
–
Concomitant treatment with bisphosphonates will be encouraged for all patients with 
evidence of lytic destruction of bone or with osteopenia, according to the American 
Society of Clinical Oncology Clinical Practice Guidelines or institutional practice in 
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accordance with the product label, unless specifically contraindicated. If bisphosphonate 
therapy was not started before the study start, it should be initiated as soon as clinically 
indicated.
–
Topical or inhaled steroids and short-acting β2 adrenergic receptor agonists (eg, for the 
treatment of asthma) are permitted.
–
Nonresorbable corticosteroids (eg, budesonide).
–
Plasmapheresis.
8.7
Precautions and Restrictions
Fluid deficit should be corrected before initiation of treatment and during treatment.
NSAIDs should be avoided with impaired renal function given the reported NSAID-induced renal 
failure in patients with decreased renal function.
Patients should not drive, operate dangerous tools or machinery, or engage in any other potentially 
hazardous activity that requires full alertness and coordination if they experience sedation while 
enrolled in this study.
Patients are to be instructed to limit the use of alcohol while enrolled in this study.
It is not known what effects TAK-079 has on human pregnancy or development of the embryo or 
fetus; therefore, female patients participating in this study should avoid becoming pregnant, and 
male patients should avoid impregnating a female partner. Nonsterilized female patients of 
reproductive age and male patients should use effective methods of contraception through defined 
periods during and after study treatment as specified below.
Female patients must meet the following:

WOCBP must not be pregnant or lactating. 

Postmenopausal for at least 1 year before the Screening Visit, OR

Surgically sterile, OR

If they are of childbearing potential, agree to practice 1 highly effective method and 
1 additional effective (barrier) method of contraception at the same time, from the time of 
signing of the informed consent form (ICF) through 5 half-lives after the last dose of study 
drug (whichever is longer), OR

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of 
the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, and postovulation 
methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.)
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Male patients, even if surgically sterilized (ie, status postvasectomy) must agree to one of the 
following:

Agree to practice effective barrier contraception during the entire study treatment period and 
through 120 days (or if the drug has a very long half-life, for 90 days plus 5 half-lives) after the 
last dose of study drug, OR

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of 
the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, and postovulation 
methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.)
In addition, a close monitoring of serum chemistry, particularly creatinine, potassium, and uric 
acid levels must be performed. Patients with tumor lysis syndrome should be treated per 
institutional practice (including correction of electrolyte abnormalities, monitoring of renal 
function and fluid balance, and administration of supportive care, including dialysis as indicated).
8.8
Management of Specific Adverse Reactions
8.8.1
Handling of IRs
Patients should be carefully observed during TAK-079 injections. Trained trial staff at the clinic 
should be prepared to intervene in case of any IRs and resources necessary for resuscitation (eg, 
agents such as epinephrine and aerosolized bronchodilators; also medical equipment such as 
oxygen tanks, tracheostomy equipment, and a defibrillator) must be available at bedside.
In case of an IR, blood draws should be performed for central evaluation of 
, 
ADAs, 
. These draws must not interfere with patient care and blood 
tests necessary for the acute care of the patient. 
For additional details, refer to Section 9.4.15.3.
8.8.2
Handling of Low Platelet Counts
Treatment decisions will be based on patient platelet counts assessed before any transfusion. Low 
platelet counts (Grade 4) should cause scheduled treatment to be postponed or to be permanently 
discontinued. If at any time the platelet count is less than 10×109/L, or if the patient shows a 
bleeding tendency considered to be due to thrombocytopenia occurring after initiation of 
TAK-079 treatment, the patient should be withdrawn from TAK-079 treatment. Platelet 
transfusion and daily monitoring of platelet counts are recommended. These patients should be 
considered as having experienced an SAE.
8.8.3
Risk of Infection
The intended mechanism of action of TAK-079 may involve reduction of the subject’s immune 
response. Patients may be at an increased risk of infection, including reactivation of herpes zoster 
and herpes simplex viruses. Prophylaxis treatment may be initiated as clinically indicated, as 
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8.12
Packaging and Labeling
Supplies of TAK-079 will be labeled according to the current International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines 
on Good Clinical Practice (GCP) and Good Manufacturing Practice and will include any locally 
required statements. 
8.13
Storage, Handling, and Accountability
8.13.1 Storage and Handling
The investigator or designee must confirm that appropriate temperature conditions have been 
maintained for all TAK-079 received and that any discrepancies are reported and resolved before 
use of TAK-079.
TAK-079 must be stored according to the manufacturer’s stipulation, as specified on the label.
During shipping, vials will be protected from light and maintained below -15°C (5°F). Each 
TAK-079 shipment will include a packing slip listing the contents of the shipment, and any 
applicable forms.
All clinical trial material must be kept in an appropriate, limited-access, secure location until used 
or returned to the sponsor or designee. All study medication must be stored under the conditions 
specified on the label, and remain in the original container until dispensed. A daily temperature log 
of the drug storage area must be maintained every day.
The investigator or designee must confirm that appropriate temperature conditions have been 
maintained for all TAK-079 received and that any discrepancies are reported and resolved before 
use of TAK-079.
The investigator is responsible for ensuring that deliveries of TAK-079 and other study materials 
from the sponsor are correctly received, recorded, and handled, and stored safely and properly in 
accordance with the Code of Federal Regulations (CFR) or national and local regulations, and used 
in accordance with this protocol.
Detailed dosage preparation instructions are provided in the Directions for Use section of the 
Pharmacy Manual. Complete receipt, inventory, accountability, reconciliation, and destruction 
records must be maintained for all used and unused study drug vials. Detailed instructions and the 
associated forms for these activities are in the Pharmacy Manual.
Upon receipt of study medication, the investigator or designee must verify the contents of the 
shipments against the packing list. The verifier should ensure that the quantity is correct, the 
medication is received within the labeled storage conditions, and is in good condition. If quantity 
and conditions are acceptable, investigator or designee should acknowledge the receipt of the 
shipment by signing bottom half of the packing list and faxing per instructions provided on the 
form. If there are any discrepancies between the packing list versus the actual product received, 
Takeda must be contacted to resolve the issue. The packing list should be filed in the investigator’s 
essential document file.
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The sponsor must be notified immediately of any temperature excursions, shipping and handling 
or storage discrepancies.
Drug supplies will be counted and reconciled at the site before being returned to Takeda or 
designee or being destroyed.
The investigator or designee must ensure that the study medication is used in accordance with
the approved protocol and is dispensed only to subjects enrolled in the study. To document
appropriate use of study medication (TAK-079), the investigator must maintain records of all 
study medication delivery to the site, site inventory, use by each subject, and return to the 
sponsor or designee.
The investigator will be notified of any expiry date or retest date extension of clinical study
material during the study conduct. On expiry date notification from the sponsor or designee, the
site must complete all instructions outlined in the notification, including segregation of expired
clinical study material for return to the sponsor or its designee.
Further guidance and information are provided in the Pharmacy Manual.
8.13.2 Accountability and Destruction of Sponsor Supplied Drugs
The investigator, institution, or head of the medical institution (where applicable) is responsible 
for TAK-079 accountability, reconciliation, and record maintenance (ie, receipt, reconciliation, 
and final disposition records).
The investigator must maintain 100% accountability for all study medication (TAK-079) received 
and dispensed during his or her entire participation in the study. Proper drug accountability 
includes, but is not limited to:

Continuously monitoring expiration dates if expiry date/retest date is provided to the 
investigator.

Frequently verifying that actual inventory matches documented inventory.

Verifying that the log is completed for the drug lot used to prepare each dose.

Verifying that all containers used are documented accurately on the log.

Verifying that required fields are completed accurately and legibly.

A site representative, otherwise uninvolved with study conduct, will review the subject dosing 
log prior to Day 1 dosing and following dosing to ensure all subjects received the correct dose 
of study medication. This review will be documented at the site.
If any dispensing errors or discrepancies are discovered, the sponsor must be notified immediately.
Empty, partially used, and unused TAK-079 will be disposed of, retained, or returned to the 
sponsor or designee.
The investigator must maintain a current inventory (Drug Accountability Log) of all 
sponsor-supplied study medication delivered to the site, inventory at the site, and subjects’ use 
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records. This log must accurately reflect the drug accountability of the study medication at all 
times. The following information will be recorded at a minimum: protocol number and title, name 
of investigator, site identifier and number, description of sponsor-supplied medication, 
expiry/retest date and amount dispensed, including the initials of the person dispensing and 
receiving the study medication. The log should include all required information as a separate entry 
for each subject to whom study medication is dispensed.
Prior to site closure or at appropriate intervals, a representative from the sponsor or its designee 
will perform clinical study material accountability and reconciliation before clinical study 
materials are returned to the sponsor or its designee or destroyed at the site, as applicable. The 
investigator will retain the original documentation regarding clinical study material accountability, 
return, and/or destruction, and copies will be sent to the sponsor or designee.
Further guidance and information are provided in the Pharmacy Manual.
8.14
Investigational Drug Assignment and Dispensing Procedures
Subjects will be assigned using an IVRS/IWRS accessible 24 hours a day to authorized users. At 
screening, the site will contact the IVRS/IWRS to register the subject into the study. During this 
contact, the investigator or designee will provide the necessary subject-identifying information. At 
drug dispensing visits, the investigator or designee will contact the IVRS/IWRS to request study 
medication assignments for a subject. Medication ID numbers (MED IDs) of the study 
medications to be dispensed will be assigned by the IVRS/IWRS. Documentation of the 
IVRS/IWRS assigned MED IDs should be included in the source documents.
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9.0
STUDY CONDUCT
This study will be conducted in compliance with the protocol, GCP, applicable regulatory 
requirements, and ICH guidelines.
9.1
Study Personnel and Organizations
The contact information for the project clinician for this study, the central laboratory, and any 
additional clinical laboratories, the coordinating investigator for each member state/country, and 
the contract research organization (CRO) team may be found in the Study Manual. A full list of 
investigators is available in the sponsor’s investigator database.
9.2
Arrangements for Recruitment of Patients
Recruitment and enrollment strategies for this study may include recruitment from the 
investigator’s local practice or referrals from other physicians. If advertisements become part of 
the recruitment strategy, they will be reviewed by the IRB/independent ethics committee (IEC). 
The screening period for this study is 21 days.
9.3
Treatment Group Assignments
All patients will receive open-label treatment with TAK-079 as indicated in respectively assigned 
treatment cohorts.
9.4
Study Procedures
Refer to the SOE (Appendix A) for timing of assessments. Additional details are provided as 
necessary in the sections that follow.
9.4.1
Informed Consent
Each patient must provide written informed consent before any study-required procedures are 
conducted, unless those procedures are performed as part of the patient’s standard care.
9.4.2
Patient Demographics
The date of birth, race, ethnicity, and sex of the patient are to be recorded during screening.
9.4.3
Medical History
During the screening period, a complete medical history will be compiled for each patient. This 
includes initial diagnosis date and MM staging at initial diagnosis using the International Staging 
System and Salmon-Durie Staging. Before dosing, the investigator should select the International 
Staging System, which should be consistently used throughout the study.
Known cytogenetic alterations should also be collected. Prior treatment regimens, with each 
treatment duration (start and stop dates), and the best response obtained with each therapy should 
be recorded. Refractoriness to previous treatments should be collected following IMWG criteria
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(Appendix E). Confirm that the patient’s current medical status does not include active chronic 
HBV, HCV, CMV, or HIV infection.
For patients who have received previous anti-CD38 therapy, the worst grade of infusion-related 
reactions should be recorded. In addition, concomitant medications will be recorded as specified in 
Section 9.4.9.
9.4.4
Physical Examination
A physical examination will be completed per standard of care at the times specified in the SOE
(Appendix A).
9.4.5
Patient Height and Weight
Height will be measured during the Screening Visit only. Weight will be measured on Day 1 of 
each treatment cycle, as indicated in Appendix A.
9.4.6
Vital Signs
Vital signs include temperature, pulse, respiratory rate, and blood pressure. Vital sign 
measurements will be made before TAK-079 injection, and include supine or seated 
measurements of diastolic and systolic blood pressure (after 3 to 5 minutes in this position). All 
measurements should be performed in the same initial position, including heart rate and body 
temperature.
Blood pressure will also be measured before each injection, and at any time the patient complains 
of symptoms consistent with IR. If the patient experiences hypotension (with or without 
symptoms), intensive blood pressure monitoring according to local practice should be instituted. 
The patient should not be released from the site until blood pressure has returned to Grade 1 or 
baseline for at least 1 hour.
Vital signs will be measured at the visits specified in the SOE (Appendix A). Any vital sign value 
that is judged by the investigator as clinically significant will be recorded on both the source 
documentation and in the eCRF as an AE, and monitored as described in Section 10.2.
9.4.7
Eligibility Criteria
Eligibility criteria and confirmatory study assessments must be confirmed during the screening 
period, after a patient has signed the ICF, and before receiving study drug.
9.4.8
Pregnancy Test
WOCBP must have 2 negative pregnancy tests (human chorionic gonadotropin >5 mI/mL) prior to 
starting study drug. A serum pregnancy test will be used during the screening period (within 10 to 
14 days before the start of study drug). A serum pregnancy test must also be performed at baseline 
(within 24 hours before the start of study drug). A WOCPB is a sexually mature female who: 1) 
has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally 
postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) 
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for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive 
months).
During the study, if a menstrual period is delayed, absence of pregnancy in WOCBP must be 
confirmed by serum pregnancy test. Pregnancy tests may also be repeated during the study upon
request by an IRB or if required by local regulations. 
A urine pregnancy test is required in WOCBP at designated treatment visits (Appendix A) and also 
at the follow-up visit. 
9.4.9
Concomitant Medications and Procedures
Any prior or concomitant medication a patient has had within 21 days before TAK-079
administration and up to 30 days after the last dose of TAK-079 (or the start of subsequent 
anticancer therapy, whichever occurs first) will be recorded on the eCRF. Trade name and 
international nonproprietary name (if available), indication, and start and end dates of the 
administered medication will be recorded. Medications used by the patient and therapeutic 
procedures completed by the patient will be recorded in the eCRF. See Section 8.5 and Section 8.6
for a list of medications and therapies that are prohibited or allowed during the study.
9.4.10 AEs
Monitoring of TEAEs, serious and nonserious, will be conducted throughout the study as specified 
in the SOE. Refer to Section 10.0 for details regarding definitions, documentation, and reporting of 
TEAEs and SAEs.
9.4.11
Enrollment
A patient is considered to be enrolled in the study at the first injection.
Procedures for completing the enrollment information are described in the Study Manual.
9.4.12
ECG
A single ECG will be collected at the screening visit for assessment of eligibility. A qualified 
person will interpret the ECG.
Time-matched triplicate 12-lead ECGs and PK samples will be collected in this study during 
Cycles 1 and 2 as specified in Appendix B. Although the number of scheduled ECG measurements 
will not be increased, the timing may be changed if emerging data indicate that an alteration in the 
ECG schedule is needed. Triplicate ECGs will be recorded electronically and transmitted to a 
central vendor for storage. 
The triplicate ECG measurements should be completed before the PK blood draw. Collection of 
triplicate ECGs should begin after the patient has rested in supine position for approximately 
5 minutes. Each ECG recording of the triplicate ECGs should occur within 3 minutes of each other 
and over a 10-minute window. It is recommended that patients refrain from eating or limit 
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Table 9.a
Clinical Chemistry and Hematology Tests
Hematology
Serum Chemistry
ANC
Hematocrit
Hemoglobin
Platelet (count) 
Reticulocyte count
RBC count
WBC count 
WBC with differential
Coagulation panel
Albumin
ALP
ALT
AST
Bilirubin (total)
BUN
Calcium
Chloride
CO2 (bicarbonate) 
Creatinine
Creatinine clearance
CRP
Glucose (nonfasting)
GGT
LDH
Phosphate
Potassium
Sodium
Total protein
Urate (uric acid)
ALP=alkaline phosphatase; ALT=alanine aminotransferase; ANC=absolute neutrophil count; AST=serine 
aminotransferase; BUN=blood urea nitrogen; CO2=carbon dioxide; CRP=C-reactive protein; GGT=Gamma glutamyl 
transferase; LDH=lactate dehydrogenase RBC=red blood cell; WBC=white blood cell.
Table 9.b
Clinical Urinalysis Tests
Urinalysis
Bilirubin
Glucose
Ketones
Leukocytes
Nitrite
Occult blood
pH
Protein
Specific gravity
Turbidity and color
Urobilinogen
For estimation of creatinine clearance, the Cockroft-Gault formula will be employed as follows:
	
 
	
 
		
= [(140 −
) ∗	() ] / [72 ∗
! 
	
(/")] 
For female patients, the result of the formula above should be multiplied by 0.85. 
9.4.13.2 Prestudy Prognostic Risk Assessment
A blood sample will be collected for serum 2 microglobulin at screening to assess patient disease 
status. Results will be analyzed locally.
9.4.14
Disease Response Assessments
Patients will be assessed for disease response according to the IMWG for MM ([9,10]; 
Appendix E).
Serum and urine response assessments will be performed no later than the first day of every 
treatment cycle, before the patient receives treatment with TAK-079.
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Imaging tests as specified in Appendix A are to be performed as defined below or when there is a 
clinical suspicion of progression. Response and relapse categories are described in Appendix E. 
Imaging tests will be taken during the screening phase before treatment, at the beginning of 
Cycles 2, 4, 7, 13, 19, 25, and every 6 cycles thereafter until PD or intolerance.
CR should be confirmed with follow-up assessments of SPEP, UPEP, immunofixation of blood 
and urine, and serum FLCs as outlined in Appendix A. One BMA assessment has to occur to 
document CR; no second bone marrow confirmation is needed.
Note that to determine a response of sCR, BMA immunohistochemistry or immunofluorescence 
for kappa:lambda ratio, as well as serum FLC assay, should be performed for all patients suspected 
to be in CR to meet this response category’s requirements.
PD may be confirmed per standard clinical practice at the site. Local laboratory results may be 
used to confirm PD.
9.4.14.1 Computed Tomography/Magnetic Resonance Imaging
For patients with documented extramedullary disease, a whole body x-ray, positron emission 
tomography–computed tomography (PET-CT) scan, computed tomography (CT) scan (includes 
low-dose CT), or magnetic resonance imaging (MRI) scan will be performed at screening (if the 
patient has adequate image test performed within 5 weeks of the planned first dose of study drug, 
that image be used as baseline and does not need to be repeated as part of screening) as needed for 
evaluation of disease. If disease is documented, then a repeat PET-CT scan, CT scan, or MRI scan 
should be performed as required to document response or PD.
Scans will be performed at screening and at the EOT/early termination visit. All treatment phase 
and follow-up scans should use the same imaging modality used at screening.
Surveys (x-ray, CT, or MRI) may also be performed at the investigator’s discretion, eg, in case of 
bone pain. The screening scan may be performed up to 21 days before first dose of TAK-079. 
Radiographs will be analyzed locally and reports maintained with the patient record for retrieval 
during monitoring visits.
9.4.14.2 Quantification of Immunoglobulins
A blood sample for quantification of Ig (IgM, IgG, and IgA) will be obtained at the screening visit, 
predose on Day 1 of every cycle, and at the follow-up visit. Analysis of Ig will be performed 
locally.
9.4.14.3 Quantification of M-Protein
A predose blood and 24-hour urine sample will be obtained at the screening visit, Day 1 of every 
cycle, and at the follow-up visit. Urine sampling at designated timepoints is required only if urine 
M-protein is measurable at Day 1.
The samples will be tested locally. M-protein in serum and urine will be quantified by SPEP and 
UPEP.
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9.4.14.4 Serum FLC Assay
Serum and urine samples will be obtained for serum and urine immunofixation tests at the 
screening visit, predose on Day 1 of every cycle, and at the follow-up visit for the serum FLC assay 
(including quantification of kappa and lambda chains and ratio). Blood samples will be analyzed 
locally.
9.4.14.5 Immunofixation of Serum and Urine
Serum and urine samples will be obtained for serum and urine immunofixation tests at the 
screening visit, predose on Day 1 of every cycle, at the follow-up visit, and to confirm CR.
Immunofixation testing will be performed in a local laboratory.
9.4.14.6 BMAs 
BMAs will be taken during the screening period and at the beginning of designated study visits at 
Cycles 2, 4, 7, and every 6 cycles thereafter (ie, 13, 19, 25, etc.) until PD or intolerance, as 
described in Appendix A for the BMA measurements. Requirements for BMA assessments to 
confirm disease responses are defined at the beginning (Section 9.4.14).
Central Laboratory Evaluations
Molecular Analyses and Cytogenetics
The sample of BMA obtained at screening will be used for molecular analyses and for evaluation 
of cytogenetics. For response assessment purposes, when a CR is suspected on laboratory values, a 
BMA is required to confirm a CR as per routine clinical practice. At the time of this procedure, 1 
sample is analyzed locally for evaluation of disease, while a separate aspirate sample must be sent 
directly to the central laboratory on the day of collection in accordance with the procedures 
outlined in the Study Manual/Laboratory Manual. 
It is also highly encouraged (optional) to perform an aspiration procedure for the same purpose in 
patients who achieve PR as best response.
An aspirate for molecular analysis will also be collected at the time of disease relapse. This sample 
will be collected at the time of PD confirmation, before starting a new therapy, and will be sent to 
the central laboratory for analysis.
Local Laboratory Evaluations
Disease Assessment
A BMA will be obtained at screening for disease assessment and at any time a BMA sample is 
obtained to assess CR or to investigate suspected PD. This evaluation will be performed locally. 
Determination of the kappa/lambda ratio by immunohistochemistry or immunofluorescence 
should be performed to assess for sCR when CR has been documented. 
A standard BMA drawn before consent is acceptable provided it is collected within 5 weeks prior 
to the first dose. 
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9.4.15.4 Immunogenicity Assessments
ADA Assessment
Serum samples for the assessment of anti-TAK-079 immunogenicity will be collected at the study 
visits specified in Appendix A. A blood sample will be collected before administration of 
TAK-079 (ie, prior to dosing on Day 1; baseline value), then subsequently before TAK-079 
dosing at each designated visit (postbaseline values), and at visits for any patient who experiences 
a TEAE considered by the investigator to be consistent with hypersensitivity/IR. 
A sample will initially be screened for ADA titer. If a sample is detected as ADA positive, it may 
be assessed for neutralizing activity.
Direct and Indirect Coomb’s Testing
Serum samples for direct and indirect Coomb’s testing will be collected at time points specified in 
Appendix A. These tests will be performed locally.
9.5
Completion of Study Treatment (for Individual Patients)
Patients will be considered as having completed study treatment if they discontinued study drug
for any reason as outlined below in Section 9.7.
9.6
Completion of Study (for Individual Patients)
Patients will receive TAK-079 until they experience PD, unacceptable toxicity, withdrawal of 
consent, death, or termination of the study by the sponsor (see additional details in Section 9.8). 
Patients will have a follow-up visit 30 days after the last dose of study drug or prior to the start of 
subsequent alternative anticancer therapy, to permit the detection of any delayed AEs. Patients 
who discontinue study treatment for reasons other than PD will continue PFS follow-up every 4 
weeks from EOT until the occurrence of PD, death, loss to follow-up, consent withdrawal, study 
termination, or 12 months after LPLD. 
Patients will be followed every 12 weeks for OS until death, loss to follow-up, consent withdrawal, 
study termination, or 12 months after LPLD.
It is anticipated that the duration of the study will be approximately 48 months (4 years).
9.7
Discontinuation of Treatment With Study Drug and Patient Replacement
Study drug must be permanently discontinued for patients meeting any of the following criteria:

Patient experiences an AE or other medical condition that indicates to the investigator that 
continued participation is not in the best interest of the patient. 

Withdrawal by patient.

Female patient has confirmed pregnancy.
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Treatment with study drug may also be discontinued for any of the following reasons:

AE/SAE.

Protocol deviation.

PD. 

Symptomatic deterioration. 

Unsatisfactory therapeutic response. 

Study terminated by sponsor.

Lost to follow-up.
Once study drug has been discontinued, all study procedures outlined for the EOT/early 
termination visit will be completed as specified in the SOE. The primary reason for study drug 
discontinuation will be recorded on the eCRF.
In phase 1, patients who do not receive 4 injections of TAK-079 within the 28-day (±2) treatment 
window or the Day 29 (ie, Cycle 2 Day 1) assessment for reasons other than a DLT will be 
replaced. In phase 2a, patients who receive 1 or more injections of study drug will not be replaced. 
Note that some patients may discontinue study drug for reasons other than PD before completing 
the full treatment course; these patients will remain in the study for posttreatment assessments as 
outlined in the SOE until PD occurs.
9.8
Withdrawal of Patients From Study
A patient may be withdrawn from the study for any of the following reasons:

Lost to follow-up.

Study terminated by sponsor.

Withdrawal by patient (mandatory immediate discontinuation of study agent).

Death. 

PD. 
The consequence of study withdrawal is that no new information will be collected from the 
withdrawn patient and added to the existing data or any database.
9.9
Study Compliance
Study drug will be administered only to eligible patients under the supervision of the investigator 
or identified subinvestigator(s). The appropriate study personnel will maintain records of study 
drug receipt and dispensing.
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9.10
Posttreatment Follow-up Assessments (PFS and OS)
Patients who stop treatment for any reason other than progressive disease will continue to have 
progression-free follow-up visits (additional details in Section 9.6). Patients who discontinue 
study treatment for reasons other than PD will continue PFS follow-up every 4 weeks from EOT 
until the occurrence of PD, death, loss to follow-up, consent withdrawal, study termination, or 
12 months after LPLD, whichever occurs first.
Patients who stop treatment due to PD will continue to have OS visits. Patients will be followed 
every 12 weeks for OS after documented PD until death, loss to follow-up, consent withdrawal, 
study termination, or 12 months after LPLD, whichever occurs first.
Survival information and death details may be collected by methods that include, but are not 
limited to, telephone, email, mail, or retrieval from online or other databases (eg, Social Security 
indexes). In addition, the start of another anticancer therapy for the disease under study will be 
collected.
See the SOE (Appendix A) for appropriate assessments during follow-up.
NOTE: All SAEs must be reported to the Takeda Global Pharmacovigilance department or 
designee. This includes deaths that the investigator considers related to study drug that occur 
during the posttreatment follow-up. Refer to Section 10.0 for details regarding definitions, 
documentation, and reporting of SAEs.
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10.0
ADVERSE EVENTS
10.1
Definitions
10.1.1 Pretreatment Event Definition
A pretreatment event is any untoward medical occurrence in a patient or subject who has signed 
informed consent to participate in a study but before administration of any study medication; it 
does not necessarily have to have a causal relationship with study participation.
10.1.2 AE Definition
AE means any untoward medical occurrence in a patient or subject administered a pharmaceutical 
product; the untoward medical occurrence does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product whether or not it is related to the medicinal product. This includes any 
newly occurring event, or a previous condition that has increased in severity or frequency since the 
administration of study drug.
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is considered 
by the investigator to be a clinically significant change from baseline.
10.1.3 SAE Definition
SAE means any untoward medical occurrence that at any dose:

Results in death.

Is life-threatening (refers to an AE in which the patient was at risk of death at the time of the 
event. It does not refer to an event which hypothetically might have caused death if it were 
more severe).

Requires inpatient hospitalization or prolongation of an existing hospitalization (see 
clarification in the paragraph in Section 10.2 on planned hospitalizations).

Results in persistent or significant disability or incapacity. (Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions).

Is a congenital anomaly/birth defect.

Is a medically important event. This refers to an AE that may not result in death, be 
immediately life threatening, or require hospitalization, but may be considered serious when, 
based on appropriate medical judgment, may jeopardize the patient, require medical or 
surgical intervention to prevent one of the outcomes listed above, or involves suspected 
transmission via a medicinal product of an infectious agent. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
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blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse; any organism, virus, or infectious particle 
(eg, prion protein transmitting transmissible spongiform encephalopathy), pathogenic or 
nonpathogenic, is considered an infectious agent.
In this study, intensity for each AE, including any lab abnormality, will be determined using the 
NCI CTCAE, Version 4.03, effective date 14 June 2010 [12]. Clarification should be made 
between an SAE and an AE that is considered severe in intensity (Grade 3 or 4), because the terms 
serious and severe are not synonymous. The general term severe is often used to describe the 
intensity (severity) of a specific event; the event itself, however, may be of relatively minor 
medical significance (such as a Grade 3 headache). This is not the same as serious, which is based 
on patient/event outcome or action criteria described above, and usually associated with events 
that pose a threat to a patient’s life or ability to function. A severe AE (Grade 3 or 4) does not 
necessarily need to be considered serious. For example, a white blood cell count of 1000/mm3 to 
<2000 mm3 is considered Grade 3 (severe) but may not be considered serious. Seriousness (not 
intensity) serves as a guide for defining regulatory reporting obligations.
10.2
Procedures for Recording and Reporting AEs and SAEs
All AEs spontaneously reported by the patient and/or in response to an open question from study 
personnel or revealed by observation, physical examination, or other diagnostic procedures will be 
recorded on the appropriate page of the eCRF (see Section 10.3 for the period of observation). Any 
clinically relevant deterioration in laboratory assessments or other clinical finding is considered an 
AE. When possible, signs and symptoms indicating a common underlying pathology should be 
noted as 1 comprehensive event.
Regardless of causality, SAEs and serious pretreatment events (as defined in Section 10.1) must be 
reported (see Section 10.3 for the period of observation) by the investigator to the Takeda Global 
Pharmacovigilance department or designee (contact information provided below). This should be 
done by faxing the SAE Form within 24 hours after becoming aware of the event. The SAE Form, 
created specifically by Takeda, will be provided to each clinical study site. A sample of the SAE 
Form may be found in the Study Manual. Follow-up information on the SAE or serious 
pretreatment event may be requested by Takeda. SAE report information must be consistent with 
the data provided on the eCRF.
SAE Reporting Contact Information
Cognizant
United States and Canada
Toll-free fax #:  1-800-963-6290
E-mail:  takedaoncocases@cognizant.com
Planned hospital admissions or surgical procedures for an illness or disease that existed before 
study drug was given are not to be considered AEs unless the condition deteriorated in an 
unexpected manner during the trial (eg, surgery was performed earlier or later than planned).
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For both serious and nonserious AEs, the investigator must determine both the severity (toxicity 
grade) of the event and the relationship of the event to study drug administration. For serious 
pretreatment events, the investigator must determine both the severity (toxicity grade) of the event 
and the causality of the event in relation to study procedures.
Severity (toxicity grade) for each AE, including any lab abnormality, will be determined using the 
NCI CTCAE, version 4.03, effective date 14 June 2010 [12]. The criteria are provided in the Study 
Manual.
Relationship of the event to study drug administration (ie, its causality) will be determined by the 
investigator responding yes (related) or no (unrelated) to this question: “Is there a reasonable 
possibility that the AE is associated with the study drug?”
10.3
Monitoring of AEs and Period of Observation
AEs, both nonserious and serious, will be monitored throughout the study as follows:
AEs will be reported from the signing of informed consent through 30 days after administration of 
the last dose of study drug and recorded in the eCRFs. 
SAEs:

Serious pretreatment events will be reported to the Takeda Global Pharmacovigilance 
department or designee from the time of the signing of the ICF up to the first dose of study 
drug, and will also be recorded in the eCRF.

Related and unrelated treatment-emergent SAEs will be reported to the Takeda Global 
Pharmacovigilance department or designee from the first dose of study drug through 30 days 
after administration of the last dose of study drug and recorded in the eCRF. After this period, 
only related SAEs must be reported to the Takeda Global Pharmacovigilance department or 
designee. SAEs should be monitored until they are resolved or are clearly determined to be 
caused by a patient’s stable or chronic condition or intercurrent illness(es).
10.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events
If a woman becomes pregnant or suspects that she is pregnant while participating in this study, she 
must inform the investigator immediately and permanently discontinue study drug. The sponsor 
must also be contacted immediately by faxing a completed Pregnancy Form to the Takeda Global 
Pharmacovigilance department or designee (see Section 10.2). The pregnancy must be followed 
for the final pregnancy outcome.
If a female partner of a male patient becomes pregnant during the male patient’s participation in 
this study, the sponsor must also be contacted immediately by faxing a completed Pregnancy Form 
to the Takeda Global Pharmacovigilance department or designee (see Section 10.2). Every effort 
should be made to follow the pregnancy for the final pregnancy outcome.
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10.5
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose)
A product complaint is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product. Individuals who 
identify a potential product complaint situation should immediately report this via the phone 
numbers or email addresses provided below.
A medication error is a preventable event that involves an identifiable patient and that leads to 
inappropriate medication use, which may result in patient harm. Whereas overdoses and 
underdoses constitute medication errors, doses missed inadvertently by a patient do not. 
Individuals who identify a potential medication error (including overdose) situation should 
immediately report this via the phone numbers or email addresses provided below.
Product
Call Center
Phone Number
E-mail
Fax
TAK-079
DLSS
1-844-662-8532 
Non-toll-free 
number: 
1-510-740-1273 
GlobalOncologyMedinfo@takeda.com 
1-800-881-6092
Product complaints in and of themselves are not AEs. If a product complaint results in an SAE, an 
SAE Form should be completed and sent to Cognizant (refer to Section 10.2)
10.6
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, investigators, and IRBs or 
IECs as applicable, in accordance with national regulations in the countries where the study is 
conducted. Relative to the first awareness of the event by/or further provision to the sponsor or 
sponsor’s designee, SUSARs will be submitted to the regulatory authorities as an expedited report
within 7 days for fatal and life-threatening events and 15 days for other serious events, unless 
otherwise required by national regulations. The sponsor will also prepare an expedited report for 
other safety issues where these might materially alter the current benefit-risk assessment of an 
investigational medicinal product or that would be sufficient to consider changes in the 
investigational medicinal product’s administration or in the overall conduct of the trial. The 
investigational site also will forward a copy of all expedited reports to his or her IRB or IEC in 
accordance with national regulations.
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11.0
STUDY-SPECIFIC COMMITTEES
No steering committee, external data safety monitoring committee, or clinical endpoint committee 
will be used in this study.
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12.0
DATA HANDLING AND RECORDKEEPING 
The full details of procedures for data handling will be documented in the data management plan. 
If selected for coding, AEs, pretreatment events, medical history, and concurrent conditions will 
be coded using the Medical Dictionary for Regulatory Activities (MedDRA). Drugs will be coded 
using the World Health Organization Drug Dictionary.
12.1
eCRFs 
Completed eCRFs are required for each patient who signs an ICF.
The sponsor or its designee will supply investigative sites with access to eCRFs and will make 
arrangements to train appropriate site staff in the use of the eCRF. These forms are used to transmit 
the information collected in the performance of this study to the sponsor, CRO partners, and 
regulatory authorities. Investigative sites must complete eCRFs in English.
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site.
Any change of, modification of, or addition to the data on the eCRFs should be made by the 
investigator or appropriate site personnel. Corrections to eCRFs are recorded in an audit trail that 
captures the old information, the new information, identification of the person making the 
correction, the date the correction was made, and the reason for change.
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the principal investigator must retain 
full responsibility for the accuracy and authenticity of all data entered on the eCRFs.
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The sponsor or its designee will be permitted to review the patient’s medical 
and hospital records pertinent to the study to ensure accuracy of the eCRFs. The completed eCRFs 
are the sole property of the sponsor and should not be made available in any form to third parties, 
except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the sponsor.
12.2
Record Retention
The investigator agrees to keep the records stipulated in Section 12.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating patients, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated ICFs, patient authorization forms regarding the use of 
personal health information (if separate from the ICFs), electronic copy of eCRFs, including the 
audit trail, and detailed records of drug disposition to enable evaluations or audits from regulatory 
authorities, the sponsor or its designees. Any source documentation printed on degradable thermal 
sensitive paper should be photocopied by the site and filed with the original in the patient’s chart to 
ensure long-term legibility. Furthermore, ICH E6 Section 4.9.5 requires the investigator to retain 
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essential documents specified in ICH E6 (Section 8) until at least 2 years after the last approval of 
a marketing application for a specified drug indication being investigated or, if an application is 
not approved, until at least 2 years after the investigation is discontinued and regulatory authorities 
are notified. In addition, ICH E6 Section 4.9.5 states that the study records should be retained until 
an amount of time specified by applicable regulatory requirements or for a time specified in the 
Clinical Study Site Agreement between the investigator and sponsor.
Refer to the Clinical Study Site Agreement for the sponsor’s requirements on record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of any 
such documents.
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summarized. The effect of immunogenicity on PK, safety, and efficacy will be examined. NABs
may also be assessed in patients.
The immunogenicity of TAK-079 will be assessed by determining anti–TAK-079 antibody 
incidence and characteristics (eg, titer, transiently, and persistently ADA; and possible 
neutralizing activity). Analysis will be based on available data from patients with a baseline 
assessment and at least 1 postbaseline immunogenicity assessment. Summaries will be provided 
separately for each study phase and by dose, as applicable. The incidence of immunogenicity will 
be calculated. The impact of anti–TAK-079 antibodies on the PK profile, drug efficacy, and 
clinical safety will be evaluated, if possible.
13.1.7 Safety Analysis
The safety and tolerability of TAK-079 will be assessed by the recording and analysis of TEAEs 
(NCI CTCAE version 4.03; [12]), vital signs, physical examination, serum chemistry and 
hematology, urinalysis, ECG, and concomitant medications.
TEAEs will be summarized using the safety analysis set and will be coded using the MedDRA. 
Data will be summarized using preferred term and primary system organ class.
13.2
Interim Analysis and Criteria for Early Termination
No interim analysis is planned.
13.3
Determination of Sample Size
It is expected that approximately 39 patients will be enrolled in total for phase 1 and 2a combined. 
Once the RP2D is determined in phase 1, approximately 18 patients will be treated in phase 2a to 
provide a preliminary estimate of the ORR in patients with r/r MM.
An adaptive approach with BLRM will be used for dose escalation. BLRM implements dose 
escalation with overdose control principle [13,14] that informs dose-escalation decisions and 
MTD/RP2D estimation, along with consideration of other safety, clinical, PK, 
 
data.
The 2-parameter logistic regression model used is as follows: 
logit(()) = log(*) +  , log- .
)
.
/01
2 ,
* > 0, , > 0
where πi is the DLT rate for dose i and doseref is a reference dose. A quantile-based, 
non-informative, bivariate normal prior will be used for ln(α) and ln(β). This prior will be assigned 
based on prestudy estimates of the DLT rate at each dose level, as described in Neuenschwander, 
et al. [13].
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The model will be updated after each group of 3 patients is enrolled in the current dose level
cohort. For each dose level, the posterior probability of having DLT rates that fall into the 
following intervals will be estimated:

[0, 0.16): underdosing.

[0.16, 0.33): target toxicity.

[0.33, 1.00]: excessive toxicity.
The next recommended dose will be selected as described in Section 8.3.2.
A group of 3 to 6 patients will be enrolled in each TAK-079 dose cohort based on BLRM, with
consideration for other safety, clinical, PK, 
data. Each patient will 
participate in only 1 dose cohort. The actual dose levels may be adjusted based on the observed 
safety profile. The simulation to evaluate the sample size is performed based on possible dose level 
range (45, 135, 400, 1200, and 1800 mg). The simulation is performed based on 6 scenarios of the 
assumed true DLT rates at the different dose levels (45, 135, 400, 1200, and 1800 mg), 
representing various distributions of toxicity across dose levels, detailed as shown in Table 13.a. 
The curve of the dose-DLT relationship becomes steeper and MTD is reached earlier from 
Scenario 1 to Scenario 6. The quantile-based, non-informative, bivariate normal prior of ln(α) and 
ln(β) is determined based on prestudy estimates of DLT rate (0.02, 0.05, 0.10, 0.20, and 0.30) at 
various dose levels (45, 135, 400, 1200, and 1800 mg). Table 13.b shows 
 
In Scenario 1, the probability of recommending the highest dose level (1800 mg) is 100% when 
there is close to a 0 true DLT rate with the current doses. In Scenario 1, the average number of 
patients required is approximately 18 with 0 DLTs expected on average. Similar results are 
observed in the Scenario 2 where the true DLT rate increases very slowly and none of the target 
true DLT occurs at any of the current dose levels. The true DLT rates in Scenario 3 increases faster 
than in Scenario 1 and 2, and has 55.7% chance of successfully recommending target dose levels. 
Since the dose level just below the lowest target dose level (1200 mg) has a DLT rate very close to 
16%, there is a 44% chance of recommending the lower dose. The chance of recommending a 
toxic dose is very low in Scenario 3 (0.3%). The average number of patients required is 
approximately 18, with approximately 2 DLTs expected on average. In Scenario 4, with an even
faster increase of DLT rate over doses, there is a 71.3% probability of recommending target dose 
levels, and the probability of recommending toxic doses is 11.7%. The average number of patients 
required is approximately 17 with 3 DLTs expected on average. In Scenario 5, when the starting 
dose is the only target dose, and the second dose level has a DLT rate relatively close to 33%, there 
is a 24.1% chance of claiming that the starting dose is the MTD, and an approximately 46.0% 
chance of claiming that all doses are toxic. Most of the patients (~60%) do not receive doses above 
the MTD dose. The average number of patients required is approximately 10 with fewer than 4
DLTs expected on average. In Scenario 6, where all doses are toxic, there is a 96.3% chance of 
successfully claiming that all doses are toxic. The average number of patients required is 
approximately 5, and fewer than 3 DLTs are expected on average.
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Table 13.c
Additional patients may be enrolled in a limited cohort expansion to confirm the safety and 
 before the phase 2a of this study is opened to enrollment. 
Approximately 5 dose levels are planned. For phase 1, the number of patients is planned to be 
approximately 21.
In phase 2a, up to a total of 18 patients will be treated to provide a preliminary estimate of the ORR 
in patients with r/r MM. All patients must show a clear evidence of PD with anti-CD38 therapy. 
Phase 2a of the study will also provide a more robust estimate of the safety profile to determine 
whether the MTD is appropriate for future studies as the RP2D.
No prospective calculations of statistical power have been made; however, Table 13.d shows the 
width of the 80% CI, based on the observed ORR in a cohort size of 18 patients, for a range of 
observed response rates. An observed ORR greater than 20% would be of interest in this 
relapse/refractory population.
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Table 13.d
80% Confidence Interval Based on the Observed ORR
N=18 patients.
ORR=overall response rate.
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14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
Study Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and institution guarantee access to source documents by the sponsor or its 
designee (CRO) and by the IRB or IEC.
All aspects of the study and its documentation will be subject to review by the sponsor or designee 
(as long as blinding is not jeopardized), including but not limited to the Investigator’s Binder, 
study medication, patient medical records, informed consent documentation, documentation of 
patient authorization to use personal health information (if separate from the ICFs), and review of 
eCRFs and associated source documents. It is important that the investigator and other study 
personnel are available during the monitoring visits and that sufficient time is devoted to the 
process.
14.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study patients. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the sponsor or 
designee (and IRB or IEC, as required) to determine the appropriate course of action. There will be 
no exemptions (a prospectively approved deviation) from the inclusion or exclusion criteria.
The site should document all protocol deviations in the patient’s source documents. In the event of 
a significant deviation, the site should notify the sponsor or its designee (and IRB or IEC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the patient, or confound interpretation of primary study 
assessment. A Protocol Deviation Form should be completed by the site and signed by the sponsor 
or designee for any significant deviation from the protocol.
14.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the FDA, the United Kingdom Medicines and Healthcare 
products Regulatory Agency, the Pharmaceuticals and Medical Devices Agency of Japan). If the 
study site is contacted for an inspection by a regulatory body, the sponsor should be notified 
immediately. The investigator and institution guarantee access for quality assurance auditors to all 
study documents as described in Section 14.1.
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15.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, patients) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct 
the study according to applicable local or regional regulatory requirements and align his or her 
conduct in accordance with the “Responsibilities of the Investigator” that are listed in Appendix C. 
The principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities.
15.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable federal/local requirements of each 
participating region. The sponsor or designee will require documentation noting all names and 
titles of members who make up the respective IRB or IEC. If any member of the IRB or IEC has 
direct participation in this study, written notification regarding his or her abstinence from voting 
must also be obtained. Those American sites unwilling to provide names and titles of all members 
due to privacy and conflict of interest concerns should instead provide a Federal Wide Assurance 
Number or comparable number assigned by the Department of Health and Human Services.
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the IB, a copy of the ICF, and if 
applicable, patient recruitment materials and/or advertisements and other documents required by 
all applicable laws and regulations, must be submitted to a central or local IRB or IEC for 
approval. The IRB’s or IEC’s written approval of the protocol and patient informed consent must 
be obtained and submitted to the sponsor or designee before commencement of the study (ie, 
before shipment of the sponsor-supplied drug or study-specific screening activity). The IRB or 
IEC approval must refer to the study by exact protocol title, number, and version date; identify 
versions of other documents (eg, ICF) reviewed; and state the approval date. The sponsor will ship 
drug the sponsor has confirmed the adequacy of site regulatory documentation and, when 
applicable, the sponsor has received permission from competent authority to begin the trial. Until 
the site receives notification, no protocol activities, including screening, may occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the ICF, recruitment 
materials intended for viewing by patients, local safety reporting requirements, reports, and 
updates regarding the ongoing review of the study at intervals specified by the respective IRB or 
IEC, and submission of the investigator’s final status report to IRB or IEC. All IRB and IEC 
approvals and relevant documentation for these items must be provided to the sponsor or its 
designee.
Subject incentives should not exert undue influence for participation. Payments to patients must be 
approved by the IRB or IEC and sponsor.
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15.2
Patient Information, Informed Consent, and Patient Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The ICF, patient authorization form (if applicable), and patient
information sheet (if applicable) describe the planned and permitted uses, transfers, and 
disclosures of the patient’s personal and personal health information for purposes of conducting 
the study. The ICF and the patient information sheet (if applicable) further explain the nature of the 
study, its objectives, and potential risks and benefits, as well as the date informed consent are 
given. The ICF will detail the requirements of the participant and the fact that he or she is free to 
withdraw at any time without giving a reason and without prejudice to his or her further medical 
care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the ICF 
and if applicable, the patient authorization form. The ICF, patient authorization form (if 
applicable), and patient information sheet (if applicable) must be approved by both the IRB or IEC 
and the sponsor prior to use.
The ICF, patient authorization form (if applicable), and patient information sheet (if applicable) 
must be written in a language fully comprehensible to the prospective patient. It is the 
responsibility of the investigator to explain the detailed elements of the ICF, patient authorization 
form (if applicable), and patient information sheet (if applicable) to the patient. Information should 
be given in both oral and written form whenever possible and in the manner deemed appropriate by 
the IRB or IEC. In the event the patient is not capable of rendering adequate written informed 
consent, then the patient’s legally acceptable representative may provide such consent for the 
patient in accordance with applicable laws and regulations.
The patient, or the patient’s legally acceptable representative, must be given ample opportunity to: 
(1) inquire about details of the study and (2) decide whether or not to participate in the study. If the 
patient, or the patient’s legally acceptable representative, determines he or she will participate in 
the study, then the ICF and patient authorization form (if applicable) must be signed and dated by 
the patient, or the patient’s legally acceptable representative, at the time of consent and prior to the 
patient entering into the study. The patient or the patient’s legally acceptable representative should 
be instructed to sign using their legal names, not nicknames, using blue or black ballpoint ink. The 
investigator must also sign and date the ICF and patient authorization (if applicable) at the time of 
consent and prior to patient entering into the study; however, the sponsor may allow a designee of 
the investigator to sign to the extent permitted by applicable law.
Once signed, the original ICF, patient authorization form (if applicable), and patient information 
sheet (if applicable) will be stored in the investigator’s site file. The investigator must document 
the date the patient signs the informed consent in the patient’s medical record. Copies of the signed 
ICF, the signed patient authorization form (if applicable), and patient information sheet (if 
applicable) shall be given to the patient.
All revised ICFs must be reviewed and signed by relevant patients or the relevant patient’s legally 
acceptable representative in the same manner as the original informed consent. The date the 
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revised consent was obtained should be recorded in the patient’s medical record, and the patient
should receive a copy of the revised ICF.
15.3
Patient Confidentiality
The sponsor and designees affirm and uphold the principle of the patient’s right to protection 
against invasion of privacy. Throughout this study, a patient’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited patient attributes, such as sex, age, or date 
of birth, and patient initials may be used to verify the patient and accuracy of the patient’s unique 
identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, the FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the patient’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a patient’s study participation, 
and autopsy reports. Access to a patient’s original medical records requires the specific 
authorization of the patient as part of the informed consent process (see Section 15.2).
Copies of any patient source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, patient name, address, and other identifier fields 
not collected on the patient’s eCRF).
15.4
Publication, Disclosure, and Clinical Trial Registration Policy
15.4.1 Publication 
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the Clinical Study Site Agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
this section and the Clinical Study Site Agreement. In the event of any discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail.
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15.4.2 Clinical Trial Registration
To ensure that information on clinical trials reaches the public in a timely manner and to comply 
with applicable laws, regulations and guidance, Takeda will, at a minimum register interventional 
clinical trials it sponsors anywhere in the world on ClinicalTrials.gov or other publicly accessible 
websites on or before start of study, as defined in Takeda Policy/Standard. Takeda contact 
information, along with investigator’s city, state (for America’s investigators), country, and 
recruiting status will be registered and available for public viewing. 
As needed, Takeda and investigator/site contact information may be made public to support 
participant access to trials via registries. In certain situations/registries, Takeda may assist 
participants or potential participants to find a clinical trial by helping them locate trial sites closest 
to their homes by providing the investigator name, address, and phone number via email/phone or 
other methods callers requesting trial information. Once patients receive investigator contact 
information, they may call the site requesting enrollment into the trial. The investigative sites are 
encouraged to handle the trial inquiries according to their established patient screening process. If 
the caller asks additional questions beyond the topic of trial enrollment, they should be referred to 
the sponsor. 
Any investigator who objects to Takeda providing this information to callers must provide Takeda 
with a written notice requesting that their information not be listed on the registry site. 
15.4.3 Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites (including the Takeda corporate site) and registries, as required by Takeda 
Policy/Standard, applicable laws and/or regulations.
Data Sharing
The sponsor is committed to responsible sharing of clinical data with the goal of advancing 
medical science and improving patient care. Qualified independent researchers will be permitted 
to use data collected from patients during the study to conduct additional scientific research, which 
may be unrelated to the study drug or the patient’s disease. The data provided to external 
researchers will not include information that identifies patients personally. 
15.5
Insurance and Compensation for Injury
Each patient in the study must be insured in accordance with the regulations applicable to the site 
where the patient is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to clinical study patients. 
Refer to the Clinical Study Site Agreement regarding the sponsor’s policy on patient compensation 
and treatment for injury. If the investigator has questions regarding this policy, he or she should 
contact the sponsor or sponsor’s designee.
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16.0
REFERENCES
1. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin 2014;64(1):9-29.
2. Chapman MA, Lawrence MS, Keats JJ, Cibulskis K, Sougnez C, Schinzel AC, et al. Initial 
genome sequencing and analysis of multiple myeloma. Nature 2011;471(7339):467-72.
3. Kumar SK, Lee JH, Lahuerta JJ, Morgan G, Richardson PG, Crowley J, et al. Risk of 
progression and survival in multiple myeloma relapsing after therapy with IMiDs and 
bortezomib: a multicenter international myeloma working group study. Leukemia 
2012;26(1):149-57.
4. Poh A. Multiple Myeloma Gets Three New Drugs. Cancer Discovery 2016;6(1):4.
5. DARZALEX (daratumumab) [prescribing informatoin]. USPI. Horsham, PA: Janssen 
Biotech, Inc., November, 2015.
6. Nijhof IS, Casneuf T, van Velzen J, van Kessel B, Axel AE, Syed K, et al. CD38 expression 
and complement inhibitors affect response and resistance to daratumumab therapy in 
myeloma. Blood 2016;128(7):959-70.
7. Malavasi F, Deaglio S, Funaro A, Ferrero E, Horenstein AL, Ortolan E, et al. Evolution and 
function of the ADP ribosyl cyclase/CD38 gene family in physiology and pathology. 
Physiological Reviews 2008;88(3):841-86.
8. Hendrikx J, Haanen J, Voest EE, Schellens JHM, Huitema ADR, Beijnen JH. Fixed Dosing of 
Monoclonal Antibodies in Oncology. Oncologist 2017.
9. Rajkumar SV, Harousseau JL, Durie B, Anderson KC, Dimopoulos M, Kyle R, et al. 
Consensus recommendations for the uniform reporting of clinical trials: report of the 
International Myeloma Workshop Consensus Panel 1. Blood 2011;117(18):4691-5.
10. Palumbo A, Rajkumar SV, San Miguel JF, Larocca A, Niesvizky R, Morgan G, et al. 
International myeloma working group consensus statement for the management, treatment, 
and supportive care of patients with myeloma not eligible for standard autologous stem-cell 
transplantation. J Clin Oncol 2014;32(6):587-600.
11. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. American Journal of Clinical 
Oncology 1982;5(6):649-55.
12. Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03. U.S. Department 
of Health and Human Services National Cancer Institute. 14 June 2010.
13. Neuenschwander B, Branson M, Gsponer T. Critical aspects of the Bayesian approach to phase 
I cancer trials. Statistics in Medicine 2008;27(13):2420-39.
14. Babb J, Rogatko A, Zacks S. Cancer phase I clinical trials: efficient dose escalation with 
overdose control. Statistics in Medicine 1998;17(10):1103-20.
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15. Rajkumar SV. Multiple myeloma: 2014 Update on diagnosis, risk-stratification, and 
management. American Journal of Hematology 2014;89(10):998-1009.
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Appendix A
Schedule of Events
Screening, Baseline, Treatment Period Cycles 1 and 2
Study Period (Phases 1 and 2a)
Screeni
ng (a)
Treatment Phase (Weekly)
Cycle 1
Cycle 2
Cycle Day
C1D1
C1D8
C1D15
C1D22
C2D1
C2D8
C2D15
C2D22
Window Allowed
±2 days
±2 days
±2 days
±2 days
±2 days
±2 days
±2 days
±2 days
Informed consent (b)
X
Eligibility criteria
X
Demographics
X
Medical history
X
Prior medication and treatment history
X
HBV, HCV, CMV, and HIV
X
Height and weight (c)
X
X
X
ECOG performance status 
X
X
X
ECG (d)
X
X
X
ECG measurements additionally on Days 2, 3, and 4 for Cycles 1 and 2 (see Section 9.4.12).
Physical examination
X
X
X
X
X
X
X
X
X
Vital signs (e)
X
X
X
X
X
X
X
X
X
Monitoring of concomitant medication and 
procedures
Recorded from up to 21 days before the first dose of TAK-079 through 30 days after last dose of study drug or the start of subsequent 
anticancer therapy, whichever occurs first.
AE reporting
Recorded from signing of the ICF through 30 days after the last dose of study drug (Section 10.3).
SAEs (includes pretreatment, and related and unrelated treatment-emergent events) will be reported from signing of the ICF through 
30 days after last dose of study drug, even if the patient starts nonprotocol therapy (Section 10.3).
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Treatment Phase (Every 2 Weeks)
Study Period
(Phases 1 and 2a)
Cycle 3
Cycle 4
Cycle 5
Cycle 6
Cycle Day
C3D1
C3D15
C4D1
C4D15
C5D1
C5D15
C6D1
C6D15
Window Allowed
±2 days
±2 days
±2 days
±2 days
±2 days
±2 days
±2 days
±2 days
Serum sample for immunogenicity 
(ADA/titer) (s)
X
X
X
X
Serum sample for direct and indirect 
Coomb’s test (s)
X
X
X
X
Footnotes added on last page of SOE tables.
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ADA=antidrug antibody; AE=adverse event; ALP=alkaline phosphatase ;ALT=alanine aminotransferase ; ANC=absolute neutrophil count ; AST=aspartate 
aminotransferase; BMA=bone marrow aspirate; BMMCs=bone marrow mononuclear cells; BUN=blood urea nitrogen; C=cycle; CMV=cytomegalovirus; 
CR=complete response; CT=computed tomography; CXD1=Day 1 of additional treatment cycles (ie, after Cycle 8); ECG=electrocardiogram; ECOG=Eastern 
Cooperative Oncology Group; EOT=end of treatment; FLC=free light chain; GGT=gamma glutamyl transferase; HBV=hepatitis B virus; HCV=hepatitis C virus; 
ICF=Informed Consent Form; Ig=immunoglobulin; IR=injection reaction; LDH=lactate dehydrogenase; LPLV=last patient last visit; MM=multiple myeloma ; 
MRI=magnetic resonance imaging; OS=overall survival; PD=disease progression; PET-CT=positron emission tomography-computed tomography; 
PFS=progression-free survival; PK=pharmacokinetics; RBC=red blood cell(s);SAE=serious adverse event(s); SOE=Schedule of Events; V=visit; WB=whole 
body; WBC=white blood cell(s).
(a) The screening period is 21 days (ie, Days -21 to Day -1).
(b) Written informed consent must be obtained before performing any protocol-specific procedure.
(c) Height will be measured only at the Screening Visit. Weight will be measured at indicated visits.
(d) A single ECG will be collected at the screening visit. PK time-matched triplicate 12-lead ECGs will be collected during Cycles 1 and 2, as specified in 
Appendix B. Single 12-lead ECGs will be administered for all other designated visits (ie, after Cycle 2). 
(e) Vital signs are measured prior to TAK-079 injection. Blood pressure will also be measured before starting each 2 mL injection, and at any time the patient 
complains of symptoms consistent with IR. Vital signs include temperature, pulse, respiratory rate, and blood pressure.
(f) Time and anatomical site should be recorded for each injection.
(g) Serum β2 microglobulin levels will be measured at screening only. Refer to Section 9.4.13.1 for a list of clinical chemistry laboratory assessments.
(h) Refer to Section 9.4.13.1 for a list of hematology laboratory assessments.
(i) Microscopic analyses will be performed only as clinically indicated: bacteria, RBCs, WBCs, casts, and crystals. Refer to Section 9.4.13.1 for a list of 
urinalysis assessments. 
(j) Pregnancy test (Refer to Section 9.4.8): 
Women of childbearing potential must have 2 negative pregnancy tests prior to starting study drug. A serum pregnancy test will be performed during screening 
(within 10-14 days before start of study drug). 
A serum pregnancy test is required within 24 hours before start of study drug. 
(k) Pregnancy test (refer to Section 9.4.8): 
On-treatment: a urine pregnancy test is required at designated study visits.
A urine pregnancy test is required at the follow-up visit in women of childbearing potential. 
If menstrual period is delayed, absence of pregnancy in women of childbearing potential must be confirmed by serum pregnancy test.
(l) Sampling required only if urine M-protein is measurable at Day 1 (visit 2).
(m) Blood sample obtained for the serum FLC assay to include quantification of kappa and lambda chains and ratio). To be analyzed locally.
(n) Will also be collected to confirm a CR.
(o) May be performed up to 21 days before first dose of TAK-079. Additional surveys (x-ray, CT, or MRI) may be performed at the investigator’s discretion, eg, in 
case of bone pain. If disease is documented, then a repeat scan should be performed as required to document a response or PD.
(p) BMAs:
Samples will be taken during the screening phase, prior to treatment, and at the beginning of Cycles 2, 4, 7, and every 6 cycles (ie, 13, 19, 25, etc.) thereafter until 
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Appendix B
Pharmacokinetic Sampling Schedule
Pharmacokinetic Assessments: Cycle 1
Cycle 1
Day 1 (a)
Day 2
Day 3
Day 4
Day 8 (a)
Day 15 (a)
Day 22 (a)
Triplicate 
ECG (b)
PK
Triplicate 
ECG (b)
PK
Triplicate 
ECG (b)
PK
Triplicate 
ECG (b)
PK
PK
PK
PK
Predose (within 1 hour before SC 
administration)
X
X
X
X
X
1 hour after SC administration (15 min)
X
2 hours after SC administration (15 min)
X
4 hours after SC administration (30 min)
X
X
8 hours after SC administration (1 hour)
X
X
24 hours after SC administration  (2 hours)
X
X
48 hours after SC administration (2 hours)
X
X
72 hours after SC administration (2 hours)
X
X
ECG=electrocardiogram; PK=pharmacokinetic(s); SC=subcutaneous.
When the timing of a PK or safety laboratory blood sample coincides with the timing of ECG measurements, the ECG will be completed before the collection of the 
blood sample. The triplicate ECG measurements should be completed immediately before the corresponding PK blood draw. If multiple SC injections are required 
to administer the intended dose, post-dose PK and ECG assessments are to begin after administration of the final injection.
(a) The timing of the morning visits should occur at approximately the same time as the morning SC administration times on previous days of the cycle.
(b) Collection of triplicate ECGs should begin after the patient has rested in supine position for approximately 5 minutes. Each ECG recording of the triplicate 
ECGs should occur within 3 minutes of each other and over a 10-minute window.
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Pharmacokinetic Assessments: Cycle 2
Cycle 2
Day 1 (a)
Day 2
Day 3
Day 4
Day 8 (a)
Day 15 (a)
Day 22 (a)
Triplicate 
ECG (b)
PK
Triplicate 
ECG (b)
PK
Triplicate 
ECG (b)
PK
Triplicate 
ECG (b)
PK
PK
PK
PK
Predose (within 1 hour before SC 
administration)
X
X
X
X
X
1 hour after SC administration (15 min)
X
2 hours after SC administration (15 min)
X
4 hours after SC administration (30 min)
X
X
8 hours after SC administration (1 hour)
X
X
24 hours after SC administration  (2 hours)
X
X
48 hours after SC administration (2 hours)
X
X
72 hours after SC administration (2 hours)
X
X
ECG=electrocardiogram; PK=pharmacokinetic(s); SC=subcutaneous.
When the timing of a PK or safety laboratory blood sample coincides with the timing of ECG measurements, the ECG will be completed before the collection of the 
blood sample. The triplicate ECG measurements should be completed immediately before the corresponding PK blood draw. If multiple SC injections are required 
to administer the intended dose, post-dose PK and ECG assessments are to begin after administration of the final injection.
(a) The timing of the morning visits should occur at approximately the same time as the morning SC administration times on previous days of the cycle.
(b) Collection of triplicate ECGs should begin after the patient has rested in supine position for approximately 5 minutes. Each ECG recording of the triplicate 
ECGs should occur within 3 minutes of each other and over a 10-minute window.
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Pharmacokinetic Assessments: Cycle 3 to Cycle 10
Cycle 3 to Cycle 6
Cycle 7 to Cycle 10
Day 1 (a)
Day 15 (a)
Day 1 (a)
Predose (within 1 hour before SC 
administration) 
X 
X
X
PK=pharmacokinetic; SC=subcutaneous.
If multiple SC injections are required in order to administer the intended dose, post-dose PK assessments are to begin after administration of the final injection.
(a) The timing of the morning visits should occur at approximately the same time as the morning SC administration times on previous days of the cycle.
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Appendix C
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. 
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on investigators by the FDA are 
summarized in the “Statement of Investigator” (Form FDA 1572), which must be completed and 
signed before the investigator may participate in this study.
The investigator agrees to assume the following responsibilities by signing a Form FDA 1572:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff that will assist in the protocol.
3. Ensure that study-related procedures, including study-specific (nonroutine/nonstandard panel) 
screening assessments are NOT performed on potential patients, prior to the receipt of written 
approval from relevant governing bodies/authorities.
4. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
5. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to 
21 CFR Part 56, ICH, and local regulatory requirements.
6. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to patients. Make at least yearly reports on the progress of the study to the 
IRB/IEC, and issue a final report within 3 months of study completion.
7. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH and local 
regulations, are met.
8. Obtain valid informed consent from each patient who participates in the study, and document 
the date of consent in the patient’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each ICF should contain a patient authorization section that 
describes the uses and disclosures of a patient’s personal information (including personal 
health information) that will take place in connection with the study. If an ICF does not include 
such a patient authorization, then the investigator must obtain a separate patient authorization 
form from each patient or the patient’s legally acceptable representative.
9. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents.
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10. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
11. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor.
12. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.
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Appendix D
Investigator Consent to Use of Personal Information
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, United States, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study medication.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s own 
country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.
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Appendix E
IMWG Criteria
IMWG Definition of MM

Clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary 
plasmacytoma* and any one or more of the following myeloma-deﬁning events:
–
Evidence of end organ damage that can be attributed to the underlying plasma cell 
proliferative disorder, specifically.
–
Hypercalcemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than the upper limit of 
the normal range or >2.75 mmol/L (>11 mg/dL).
–
Renal insuﬃciency: creatinine clearance <40 mL per min† or serum creatinine 
>177 μmol/L (>2 mg/dL).
–
Anemia: hemoglobin value of >20 g/L below the lower limit of normal, or a hemoglobin 
value <100 g/L.
–
Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CT‡.

Any one or more of the following biomarkers of malignancy:
–
Clonal bone marrow plasma cell percentage* ≥60%.
–
Involved: uninvolved serum free light chain ratio§ (FLC) ≥100.
–
>1 focal lesions on MRI studies.
* Clonality should be established by showing κλ light-chain restriction on ﬂow cytometry, immunohistochemistry, or 
immunoﬂuorescence. Bone marrow plasma cell percentage should preferably be estimated from a core biopsy 
specimen; in case of a disparity between the aspirate and core biopsy, the highest value should be used.
† Measured or estimated by validated equations.
‡ If bone marrow has less than 10% clonal plasma cells, more than 1 bone lesion is required to distinguish from 
solitary plasmacytoma with minimal marrow involvement.
§ These values are based on the serum Freelite assay (The Binding Site Group, Birmingham, United Kingdom). The 
involved FLC must be ≥100 mg/L. Each focal lesion must be 5 mm or greater in size [15].
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IMWG Uniform Criteria for Response 
Category of 
Response
Response Criteria
sCR
Criteria for CR as defined below, with the addition of a normal FLC ratio, and an absence of 
clonal plasma cells by immunohistochemistry or 2- to 4-color flow cytometry; 2 consecutive 
assessments of laboratory parameters are needed (a).
CR
Negative immunofixation of serum and urine, disappearance of any soft tissue plasmacytomas, 
and <5% plasma cells in bone marrow; bone marrow; in patients for whom only measurable 
disease is by serum FLC level, normal FLC ratio of 0.26 to 1.65 in addition to CR criteria is 
required; 2 consecutive assessments are needed (b).
Immunophenotypic 
CR
sCR as defined, plus absence of phenotypically aberrant plasma cells (clonal) in bone marrow 
with minimum of 1 million total bone marrow cells analyzed by multiparametric ﬂow 
cytometry (with >4 colors).
Molecular CR
CR as deﬁned, plus negative allele-speciﬁc oligonucleotide polymerase chain reaction 
(sensitivity 10-5).
VGPR
Serum and urine M-protein detectable by immunofixation but not on electrophoresis, or ≥90% 
reduction in serum M-protein plus urine M-protein <100 mg/24 hours; in patients for whom 
only measurable disease is by serum FLC level, >90% decrease in difference between involved 
and uninvolved FLC levels, in addition to VGPR criteria, is required; 2 consecutive 
assessments are needed (c).
PR
≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to 
<200 mg/24 hours.
If the serum and urine M-protein are not measurable, a ≥50% decrease in the difference 
between involved and uninvolved FLC levels is required in place of the M-protein criteria.
If serum and urine M-protein are not measurable, and serum FLC is also not measurable, ≥50% 
reduction in bone marrow plasma cells is required in place of M-protein, provided the baseline 
percentage was ≥30%.
In addition to the above criteria, if present at baseline, ≥50% reduction in the size of soft tissue 
plasmacytomas is also required.
Two consecutive assessments are needed (a) no known evidence of progressive or new bone 
lesions if radiographic studies were performed.
Minimal response 
(MR) (b)
≥25% but ≤49% reduction of serum M-protein and reduction in 24-hour urine M-protein by 
50% to 89%.
In addition to the above criteria, if present at baseline, 25% to 49% reduction in the size of soft 
tissue plasmacytomas is also required.
No increase in size or number of lytic bone lesions (development of compression fracture does 
not exclude response).
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Category of 
Response
Response Criteria
SD (c)
Does not meet the response criteria for CR (any variant), VGPR, PR, MR, or PD; no known 
evidence of progressive or new bone lesions if radiographic studies were performed.
Source: Rajkumar SV et al, 2011 and Palumbo A et al, 2014 [9,10].
CR=complete response; FLC=free light chain; IMWG=International Myeloma Working Group; MR=minimal 
response; ORR=overall response rate; PR=partial response; sCR=stringent complete response; SD=stable disease; 
VGPR=very good partial response.
(a) Clonality should be established by showing κλ light-chain restriction on ﬂow cytometry, immunohistochemistry, 
or immunoﬂuorescence. Bone marrow plasma cell percentage should preferably be estimated from a core biopsy 
specimen; in case of a disparity between the aspirate and core biopsy, the highest value should be used.
(b) For relapse-refractory myeloma only.
(c) These categories do not contribute to the ORR.
Before the institution of any new therapy, sCR, CR, and VGPR categories require serum and urine 
studies regardless of whether disease at baseline was measurable on serum, urine, both, or neither. 
Radiographic studies are not required to satisfy these response requirements. Bone marrow 
assessments need not be conﬁrmed.
PD is defined as an increase of ≥25% from lowest response value in any of the following:
a) Serum M-protein (absolute increase must be ≥0.5 g/dL); serum M component increases 
≥1 g/dL are sufficient to deﬁne relapse if starting M component is ≥5 g/dL), and/or
b) Urine M-protein (absolute increase must be ≥200 mg/24 hour), and/or
c) Only in patients without measurable serum and urine M-protein levels: the difference between 
involved and uninvolved FLC levels (absolute increase must be >10 mg/dL).
d) Only in patients without measurable serum and urine M-protein levels and without measurable 
disease by FLC levels, bone marrow plasma cell percentage (absolute percentage must be 
≥10%).
Or
a) Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in 
the size of existing bone lesions or soft tissue plasmacytomas.
b) Development of hypercalcemia (corrected serum calcium >11.5 mg/dL) that can be attributed 
solely to the plasma cell proliferative disorder.
A diagnosis of PD must be confirmed by 2 consecutive assessments.
Clarifications to IMWG criteria for coding PD: Bone marrow criteria for PD are to be used only in 
patients without measurable disease by M-protein and by FLC levels; “25% increase” refers to 
M-protein, FLC, and bone marrow results, and does not refer to bone lesions, soft tissue 
plasmacytomas, or hypercalcemia, and the “lowest response value” does not need to be a 
confirmed value.
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Appendix F
ECOG Scale for Performance Status
Grade
Description
0
Normal activity. Fully active, able to carry on all predisease performance without restriction.
1
Symptoms but ambulatory. Restricted in physically strenuous activity, but ambulatory and able to 
carry out work of a light or sedentary nature (eg, light housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, but unable to carry out any work 
activities. Up and about more than 50% of waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair.
5
Dead.
Source: Oken MM et al, 1982 [11].
ECOG=Eastern Cooperative Oncology Group.
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PROTOCOL
A Phase 1/2a Open-label, Dose-Escalation Study to Investigate the Safety and Tolerability, 
Efficacy, Pharmacokinetics, and Immunogenicity of TAK-079 Administered 
Subcutaneously as a Single Agent in Patients With Relapsed/Refractory Multiple Myeloma
Sponsor:
Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda 
Pharmaceutical Company Limited
40 Landsdowne Street
Cambridge, MA 02139 USA
Telephone: +1 (617) 679-7000
Please note: Millennium Pharmaceuticals, Inc, a wholly owned 
subsidiary of Takeda Pharmaceutical Company Limited, may be 
referred to in this protocol as “Millennium,” “Sponsor,” or “Takeda”.
Study Number:
TAK-079-1501 
IND Number:
136,414
EudraCT Number:
Not applicable
Compound:
TAK-079
Date:
08 December 2017
Amendment Number:
01 
Amendment History: 
Date
Amendment Number
Region
12 October 2017
Initial Protocol
Global
08 December 2017
01
Global
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Protocol Incorporating Amendment 01
08 December 2017
1.0
ADMINISTRATIVE
1.1
Contacts
A separate contact information list will be provided to each site.
Serious adverse event and pregnancy reporting information is presented in Section 10.0, as is 
information on reporting product complaints.
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.0 and relevant guidelines 
provided to the site.
Contact Type/Role
United States Contact
Serious adverse event and pregnancy reporting
See Section 10.0
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Protocol Incorporating Amendment 01
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1.2
Approval
REPRESENTATIVES OF TAKEDA 
This study will be conducted with the highest respect for the individual participants in accordance 
with the requirements of this clinical study protocol and also in accordance with the following:
The ethical principles that have their origin in the Declaration of Helsinki.
International Council on Harmonisation E6 Good Clinical Practice: Consolidated Guideline.
All applicable laws and regulations, including, without limitation, data privacy laws, clinical trial 
disclosure laws, and regulations.
SIGNATURES 
The signature of the responsible Takeda medical officer and other signatories, as applicable can be 
found on the signature page.
Electronic Signatures may be found on the last page of this document.
, MD, PhD
Global Medical Affairs
Distinguished Research Fellow Oncology
Date
, PhD
Global Statistics
Date
 
, PharmD, PhD
Quantitative Clinical Pharmacology
Date
Dec 9, 2017
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Protocol Incorporating Amendment 01
08 December 2017
INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, and any 
other product information provided by the sponsor. I agree to conduct this study in accordance 
with the requirements of this protocol and also to protect the rights, safety, privacy, and well-being 
of study subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events defined in Section 10.0 of this 
protocol.

Terms outlined in the Clinical Study Site Agreement.

Responsibilities of the Investigator
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix D of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Province)
Location of Facility (Country)
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Protocol Incorporating Amendment 01
08 December 2017
1.3
Protocol Amendment 01 Summary of Changes
Rationale for Amendment 01
This document describes the changes in reference to the protocol incorporating Amendment 01. 
The primary reason for this amendment is to incorporate changes requested by the United States
Food and Drug Administration during review of the original protocol.
Minor grammatical, editorial, formatting, and administrative changes not affecting the conduct of 
the study are included for clarification and administrative purposes only. For specific descriptions 
of text changes and where the changes are located, see Appendix G. 
Changes in Amendment 01 
1. The number of TAK-079 dose levels planned for phase 1 was changed to 6. The 400 mg dose 
level was removed, and the 300 and 600 mg dose levels were added.
2. Planned enrollment was increased to 24 patients for the phase 1 portion (42 patients overall).
3. Eligibility based on laboratory criteria for determining adequate organ function was clarified 
for patients with Gilbert’s syndrome. 
4. Inclusion criteria were modified to revise requirements for prior myeloma therapies and 
assessment of CD38 expression.
6. Exclusion criteria were modified to exclude patients with a higher risk of respiratory 
complications (chronic obstructive pulmonary disease with forced expiratory volume <80%).
7. An exclusion criterion was added to exclude patients with positive Coombs tests at screening. 
8. The description of investigational agents was revised.
9. The definition of dose-limiting toxicities (DLTs) was modified to exclude relationship in 
determining a DLT, to include Grade 4 laboratory abnormalities clearly unrelated to the 
underlying disease as DLTs, and to note that events clearly due to extraneous causes will not 
be considered DLTs.
10. The dose escalation schema was changed to a 3+3 design from a Bayesian logistic regression 
model.
11. Dose modification recommendations in the event of Grades 3 and 4 adverse events were 
modified.
12. Instructions for handling infusion reactions were added to provide further instruction 
according to reaction grade.
13. Methods for disease response imaging were clarified, including addition of a skeletal survey 
starting at Cycle 6.
14. Text was added to the safety analysis methods regarding Grade 4 or higher nonhematologic 
toxicities occurring in the Phase 2a portion of the study. 
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TABLE OF CONTENTS
1.0
ADMINISTRATIVE.......................................................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment 01 Summary of Changes ..........................................................5
2.0
STUDY SUMMARY ....................................................................................................12
3.0
STUDY REFERENCE INFORMATION ......................................................................17
3.1
List of Abbreviations ...............................................................................................18
4.0
INTRODUCTION.........................................................................................................21
4.1
Background .............................................................................................................21
4.2
Findings From Nonclinical and Clinical Studies.......................................................21
4.2.1
22
4.3
Known and Potential Benefits and Risks to Patients with TAK-079 .........................24
4.3.1
Risks..................................................................................................................24
4.3.2
Overall Benefit and Risk Assessment for This Study..........................................27
4.4
Rationale for the Proposed Study.............................................................................27
4.4.1
Rationale for the Starting Dose of TAK-079 ......................................................28
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................29
5.1
Objectives................................................................................................................29
5.1.1
Phase 1 Primary Objective .................................................................................29
5.1.2
Phase 1 Secondary Objectives............................................................................29
5.1.3
Phase 2a Primary Objective................................................................................29
5.1.4
Phase 2a Secondary Objectives ..........................................................................29
5.1.5
Phase 1 and Phase 2a Exploratory Objectives.....................................................29
5.2
Endpoints.................................................................................................................30
5.2.1
Phase 1 Primary Endpoints.................................................................................30
5.2.2
Phase 2a Primary Endpoint ................................................................................30
5.2.3
Phase 1 Secondary Endpoints.............................................................................30
5.2.4
Phase 2a Secondary Endpoints...........................................................................31
5.2.5
Exploratory Endpoints .......................................................................................31
6.0
STUDY DESIGN..........................................................................................................32
6.1
Overview of Study Design.......................................................................................32
6.2
Number of Patients ..................................................................................................33
6.3
Duration of Study ....................................................................................................33
6.3.1
Duration of an Individual Patient’s Study Participation ......................................33
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6.3.2
End of Study/Study Completion Definition and Planned Reporting....................34
6.3.3
Timeframes for Primary and Secondary Endpoints to Support Disclosures.........34
6.3.4
Total Study Duration..........................................................................................37
7.0
STUDY POPULATION................................................................................................38
7.1
Inclusion Criteria .....................................................................................................38
7.2
Exclusion Criteria ....................................................................................................40
8.0
STUDY DRUG .............................................................................................................43
8.1
Study Drug Administration......................................................................................43
8.1.1
Premedication ....................................................................................................43
8.1.2
TAK-079 Formulation and Administration.........................................................43
8.2
Definitions of DLT ..................................................................................................44
8.3
Dose-Escalation Design and Criteria........................................................................45
8.3.1
Dose Levels .......................................................................................................45
8.3.2
Escalation Schema .............................................................................................45
8.4
Dose Modification Guidelines..................................................................................48
8.4.1
Criteria for Beginning or Delaying a Subsequent Treatment Cycle.....................48
8.4.2
Criteria for Dose Reduction................................................................................48
8.4.3
Criteria for Discontinuing TAK-079 in Individual Patients (When Considering 
Dose Modification) ............................................................................................50
8.5
Excluded Concomitant Medications and Procedures ................................................50
8.6
Permitted Concomitant Medications and Procedures................................................50
8.7
Precautions and Restrictions ....................................................................................51
8.8
Management of Specific Adverse Reactions ............................................................52
8.8.1
Handling of IRs..................................................................................................52
8.8.2
Handling of Low Platelet Counts........................................................................53
8.8.3
Risk of Infection ................................................................................................53
8.8.4
Transfusion Risks...............................................................................................53
8.9
Blinding and Unblinding..........................................................................................53
8.10
Description of Investigational Agents ......................................................................53
8.11
Preparation, Reconstitution, and Dispensation..........................................................54
8.12
Packaging and Labeling...........................................................................................54
8.13
Storage, Handling, and Accountability.....................................................................54
8.13.1 Storage and Handling.........................................................................................54
8.13.2 Accountability and Destruction of Sponsor Supplied Drugs ...............................55
8.14
Investigational Drug Assignment and Dispensing Procedures ..................................56
9.0
STUDY CONDUCT......................................................................................................57
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9.1
Study Personnel and Organizations..........................................................................57
9.2
Arrangements for Recruitment of Patients................................................................57
9.3
Treatment Group Assignments.................................................................................57
9.4
Study Procedures.....................................................................................................57
9.4.1
Informed Consent...............................................................................................57
9.4.2
Patient Demographics ........................................................................................57
9.4.3
Medical History .................................................................................................57
9.4.4
Physical Examination.........................................................................................58
9.4.5
Patient Height and Weight .................................................................................58
9.4.6
Vital Signs .........................................................................................................58
9.4.7
Eligibility Criteria ..............................................................................................58
9.4.8
Pregnancy Test...................................................................................................58
9.4.9
Concomitant Medications and Procedures..........................................................59
9.4.10 AEs....................................................................................................................59
9.4.11 Enrollment .........................................................................................................59
9.4.12 ECG...................................................................................................................59
9.4.13 Clinical Laboratory Evaluations .........................................................................60
9.4.14 Disease Response Assessments ..........................................................................61
9.4.15
, PK, 
, and Immunogenicity Samples.....................64
9.5
Completion of Study Treatment (for Individual Patients) .........................................67
9.6
Completion of Study (for Individual Patients)..........................................................67
9.7
Discontinuation of Treatment With Study Drug and Patient Replacement................68
9.8
Withdrawal of Patients From Study .........................................................................69
9.9
Study Compliance....................................................................................................69
9.10
Posttreatment Follow-up Assessments (PFS and OS)...............................................69
10.0
ADVERSE EVENTS ....................................................................................................70
10.1
Definitions...............................................................................................................70
10.1.1 Pretreatment Event Definition............................................................................70
10.1.2 AE Definition ....................................................................................................70
10.1.3 SAE Definition ..................................................................................................70
10.2
Procedures for Recording and Reporting AEs and SAEs..........................................71
10.3
Monitoring of AEs and Period of Observation .........................................................72
10.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events.........72
10.5
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose) ................................................................................................................72
10.6
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities...........73
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11.0
STUDY-SPECIFIC COMMITTEES .............................................................................74
12.0
DATA HANDLING AND RECORDKEEPING............................................................75
12.1
eCRFs......................................................................................................................75
12.2
Record Retention .....................................................................................................75
13.0
STATISTICAL METHODS..........................................................................................77
13.1
Statistical and Analytical Plans ................................................................................77
13.1.1 Analysis Sets......................................................................................................77
13.1.2 Analysis of Demographics and Other Baseline Characteristics ...........................77
13.1.3 Efficacy Analysis...............................................................................................78
13.1.4 PK Analysis .......................................................................................................78
13.1.5
78
13.1.6 Immunogenicity Analyses..................................................................................78
13.1.7 Safety Analysis ..................................................................................................79
13.2
Interim Analysis and Criteria for Early Termination ................................................79
13.3
Determination of Sample Size..................................................................................79
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................81
14.1
Study Site Monitoring Visits....................................................................................81
14.2
Protocol Deviations..................................................................................................81
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................81
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................82
15.1
IRB and/or IEC Approval ........................................................................................82
15.2
Patient Information, Informed Consent, and Patient Authorization...........................83
15.3
Patient Confidentiality .............................................................................................84
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................84
15.4.1 Publication.........................................................................................................84
15.4.2 Clinical Trial Registration..................................................................................85
15.4.3 Clinical Trial Results Disclosure ........................................................................85
15.5
Insurance and Compensation for Injury....................................................................85
16.0
REFERENCES..............................................................................................................86
LIST OF IN-TEXT TABLES
Table 6.a
Primary and Secondary Endpoints for Disclosures .............................................35
Table 7.a
Required Washout Periods for Previous Treatments or Procedures Prior to 
Administration of TAK-079...............................................................................38
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Table 7.b
Laboratory Criteria for Determining Adequate Organ Function for 
Study TAK-079-1501 Eligibility........................................................................38
Table 8.a
Dose Modification Recommendations for TAK-079 Toxicities ..........................49
Table 9.a
Clinical Chemistry and Hematology Tests..........................................................61
Table 9.b
Clinical Urinalysis Tests ....................................................................................61
Table 9.c
Primary Specimen Collection.............................................................................65
Table 13.a
80% Confidence Interval Based on the Observed ORR ......................................80
LIST OF IN-TEXT FIGURES
Figure 6.a
Overall Study Schematic Diagram......................................................................33
Figure 8.a
Dose-Escalation Scheme ....................................................................................47
LIST OF APPENDICES
Appendix A
Schedule of Events.............................................................................................87
Appendix B
Pharmacokinetic Sampling Schedule..................................................................95
Appendix C
Responsibilities of the Investigator.....................................................................98
Appendix D
Investigator Consent to Use of Personal Information........................................100
Appendix E
IMWG Criteria.................................................................................................101
Appendix F
ECOG Scale for Performance Status ................................................................104
Appendix G
Detailed Description of Amendments to Text...................................................105
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2.0
STUDY SUMMARY
Name of Sponsor:
Millennium Pharmaceuticals, Inc, a wholly owned 
subsidiary of Takeda Pharmaceutical Company Limited
Compound:
TAK-079
Title of Protocol: A Phase 1/2a, Open-label, 
Dose-Escalation Study to Investigate the Safety and 
Tolerability, Efficacy, Pharmacokinetics, and 
Immunogenicity of TAK-079 Administered Subcutaneously 
as a Single Agent in Patients With Relapsed/Refractory 
Multiple Myeloma 
Study Number: TAK-079-1501
Phase: 1/2a
Study Design:
This is a multicenter, open-label, dose-escalation, single-arm, phase 1/2a study designed to determine the safety and 
tolerability of TAK-079 monotherapy in patients with relapsed or refractory (r/r) multiple myeloma (MM), and to 
provide a preliminary assessment of its activity against r/r MM. 
Once enrolled into the study, patients will receive TAK-079 via subcutaneous (SC) administration in each 28-day 
cycle of treatment, administered as once weekly for 8 weeks (8 doses), once every 2 weeks for 16 weeks (8 doses), and 
once every 4 weeks thereafter until disease progression (PD). Patients will receive ongoing treatment with TAK-079 
until PD, unacceptable toxicities, or withdrawal due to other reasons. 
The phase 1 portion of the study will evaluate administration of TAK-079 for dose-limiting toxicity (DLT) to 
determine the maximum tolerated dose (MTD) or the recommended phase 2 dose (RP2D) for further assessment in 
phase 2a. A recommended dose below the MTD may be identified based on the review of safety, pharmacokinetic 
(PK), 
, and clinical data from the phase 1 portion of the study. 
The safety and tolerability of TAK-079 will be assessed by recording and analyzing treatment-emergent adverse 
events (TEAEs), dose modifications, treatment discontinuations, vital signs, physical examinations, serum chemistry 
and hematology, urinalysis, electrocardiograms, and concomitant medications. In phase 1, approximately 6 doses of 
TAK-079 will be evaluated in ascending cohorts of 3 to 6 patients per cohort. Cohorts may be expanded by enrolling 
additional patients to further inform selection of the RP2D. In the phase 2a portion of this study, Grade 4 or higher 
nonhematologic toxicity will be monitored starting from the first 10 enrolled patients and then every 10 patients
thereafter.
It is expected that approximately 42 patients will be enrolled in the study. The estimated duration of the study is 
approximately 48 months (ie, 4 years).
Primary Objectives:
Phase 1
To determine the safety, tolerability, and the MTD/RP2D of TAK-079 monotherapy in patients with r/r MM.
Phase 2a
To provide a preliminary evaluation of the clinical activity of TAK-079 monotherapy in patients with r/r MM.
Secondary Objectives:
Phase 1

To investigate a potential MTD/RP2D of TAK-079.

To evaluate the immunogenicity of TAK-079.

To characterize the PK of TAK-079.

To provide a preliminary evaluation of the clinical activity of TAK-079.
Phase 2a

To further evaluate safety at the MTD/ RP2D.

To further evaluate the immunogenicity of TAK-079.

To further characterize the PK of TAK-079.
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Main Criteria for Inclusion:
Male and female patients, aged ≥18 years, with ECOG performance status of ≤2, requiring additional therapy as 
determined by the investigator. Patients must have received the final dose of the following treatments/procedures 
within the specified minimum intervals before the first dose of TAK-079: 120 days for antibody therapy (including 
anti-CD38), 90 days for autologous transplantation, and 30 days for chemotherapy, corticosteroid therapy (up to 
systemic equivalent of 10 mg daily prednisone allowed), radiation therapy, and major surgery. Patients must have 
adequate organ function as determined by the following laboratory values: absolute neutrophil count ≥1.0×109/L; 
platelets ≥75,000/mm3 (≥75×109/L); hemoglobin ≥7.5 g/dL; creatinine clearance ≥30 mL/min (Cockcroft-Gault 
formula); total bilirubin ≤1.5 times the upper limit of the normal range (ULN); and alanine aminotransferase/aspartate 
aminotransferase ≤2.5×ULN. Patients must have documented r/r MM per the International Myeloma Working Group 
(IMWG) criteria, with measurable disease defined as one of the following: serum M-protein ≥500 mg/dL (≥0.5 g/L) 
and urine M-protein ≥200 mg/24 hours. Patients without measurable M-protein in serum protein electrophoresis or 
urine protein electrophoresis must have a serum free light chain (FLC) assay result with involved FLC level 
≥10 mg/dL (≥100 mg/L), provided serum FLC ratio is abnormal. Patients must have evidence of r/r MM as defined by 
the IMWG criteria, previously received at least 3 lines of myeloma therapy including a PI, IMid, alkylating agent, and 
steroids. Previous exposure to anti-CD38 as single agent or in combination is allowed but is not mandatory. Patients 
must be refractory to or intolerant of at least 1 PI and 1 IMid. Patients who received a combination of PI and IMid in a 
unique treatment schedule can be included in the study after at least 2 lines of prior myeloma therapy. Prior treatment 
with an anti-CD38 monoclonal antibody (mAb) is allowed; however, CD38 expression must be significantly 
expressed on target cells for this mechanism of action to be effective. In the phase 2a portion of the study, patients 
must have been refractory to an anti-CD38 mAb therapy at any time during treatment.
Main Criteria for Exclusion:
Sensory or motor neuropathy of Grade ≥3, based on the National Cancer Institute Common Criteria for Adverse 
Events (NCI CTCAE) or not recovered from adverse reactions to prior myeloma treatments/procedures to NCI 
CTCAE Grade ≤1 or baseline; allogeneic stem cell transplant; congestive heart failure (New York Heart Association) 
Grade ≥II, cardiac myopathy, active ischemia, clinically significant arrhythmia, history of acute myocardial infarction 
within 5 months before enrollment, clinically significant uncontrolled hypertension, or any other uncontrolled cardiac 
condition or concurrent illness that would preclude study conduct and assessment; QT interval corrected by the 
Fridericia method >480 msec (Grade ≥2); history of severe allergic or anaphylactic reactions to recombinant proteins 
or excipients used in TAK-079 formulation (including patients who were previously discontinued from an anti-CD38 
treatment due to an infusion-related reaction); history of myelodysplastic syndrome or another malignancy other than 
MM; clinical signs of central nervous system involvement of MM; or active chronic hepatitis B or C infection, active 
HIV infection, or active cytomegalovirus infection. Also excluded are patients with POEMS (polyneuropathy, 
organomegaly, endocrinopathy, monoclonal gammopathy and skin changes) syndrome, monoclonal gammopathy of 
unknown significance; smoldering myeloma; solitary plasmacytoma; amyloidosis; Waldenström macroglobulinemia 
or immunoglobulin M myeloma, and patients with positive Coombs tests at screening.
Endpoints (in order of importance):
Primary: 
Phase 1

The number of patients with TEAEs overall and per dose level.
–
Patients with DLTs at each dose level.
–
Patients with Grade ≥3 TEAEs.
–
Patients with SAEs.
–
Patients who discontinue because of TEAEs.
–
Patients with dose modifications (delays, interruptions, dose reductions).
o
Clinically significant laboratory values as determined by the investigator.
o
Clinically significant vital sign measurements as determined by the investigator.
Phase 2a

Overall response rate (ORR), defined as the proportion of patients who achieved a partial response ([PR]; 50% 
tumor reduction) or better during study as defined by IMWG Uniform Response Criteria.
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Sample Size Justification:
Phase 1 of the study will follow a 3+3 dose escalation schema.
The selection of the next recommended dose will be determined based on safety, clinical, PK, 
 
data. Dose-escalation cohorts may be expanded to include additional patients to obtain a more comprehensive 
assessment of disease response before the phase 2a portion of this study is opened to enrollment. Approximately 
6 dose levels are planned. For phase 1, the number of patients is planned to be approximately 24. 
In phase 2a, approximately 18 additional patients will be treated to provide a preliminary estimate of the ORR in 
patients with r/r MM. All patients with MM must show clear evidence of PD with anti-CD38 therapy. 
Phase 2a of the study will also provide a more robust estimate of the safety profile at the MTD/RP2D.
No prospective calculations of statistical power have been made; however, the following table shows the width of the 
80% CI, based on the observed ORR in a cohort size of 18 patients, for a range of observed response rates. An 
observed ORR greater than 20% would be of interest in this r/r population.
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3.0
STUDY REFERENCE INFORMATION
Study-Related Responsibilities 
The sponsor will perform all study-related activities with the exception of those identified in the 
Study-Related Responsibilities (Appendix C). The identified vendors in the template for specific 
study-related activities will perform these activities in full or in partnership with the sponsor.
Principal Investigator
Takeda will select a Signatory Coordinating Investigator from the investigators who participate in 
the study. Selection criteria for this investigator will include significant knowledge of the study 
protocol, the study medication, their expertise in the therapeutic area and the conduct of clinical 
research as well as study participation. The Signatory Coordinating Investigator will be required to 
review and sign the clinical study report and by doing so agrees that it accurately describes the 
results of the study.
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3.1
List of Abbreviations
Abbreviation
Term
ADA
antidrug antibody
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUClast
area under the concentration-time curve from time 0 to the time of the last quantifiable 
concentration
BMA
bone marrow aspirate
CFR
Code of Federal Regulations
CLL
chronic lymphocytic leukemia
Cmax
maximum observed concentration
CMV
cytomegalovirus
CNS
central nervous system
COPD
chronic obstructive pulmonary disease
CR
complete response
CRO
contract research organization
CRS
cytokine release syndrome
CT
computed tomography
DLT
dose-limiting toxicity
DOR 
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form (refers to any media used to collect study data [ie, paper or electronic])
EOI
end of infusion
EOT
end of treatment
FDA
United States Food and Drug Administration
FIH
first-in-human
FLC
free light chain
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
HBV
hepatitis B virus
HCV
hepatitis C virus
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IEC
independent ethics committee
Ig
immunoglobulin
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Abbreviation
Term
IMiD
immunomodulatory drug
IMWG
International Myeloma Working Group
IR
injection reaction
IRB
institutional review board
IV
intravenous(ly)
LPLD
last patient, last dose
mAb
monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
MM
multiple myeloma
MR
minimal response
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NAB
neutralizing antibody
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NK
natural killer
NOAEL
no observed adverse effect level
NSAID
nonsteroidal anti-inflammatory drugs
ORR
overall response rate
OS
overall survival
PB
plasmablast
PD
progressive disease; disease progression
PET-CT
positron emission tomography–computed tomography
PFS
progression-free survival
PI
proteasome inhibitor
PK
pharmacokinetic(s)
POEMS 
syndrome
polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes
PR
partial response
QTc
QT interval corrected for heart rate
RBC
red blood cell(s)
r/r
relapsed or refractory
RP2D
recommended phase 2 dose
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
sCR
stringent complete response
SCRS
severe cytokine release syndrome
SOE
Schedule of Events
SPEP
serum protein electrophoresis
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Abbreviation
Term
SUSAR
suspected unexpected serious adverse reactions
TEAE
treatment-emergent adverse event
tmax
time of first occurrence of maximum observed concentration
TTR
time to response
ULN
upper limit of the normal range
UPEP
urine protein electrophoresis
VGPR
very good partial response
WOCBP
women of child-bearing potential
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4.3
Known and Potential Benefits and Risks to Patients with TAK-079
TAK-079 was administered only in healthy human subjects in the first-in-human (FIH) study
(TAK-079_101). Only mild or moderate AEs were observed in the FIH study in healthy subjects.
Therefore, clinical benefits and risks have not been assessed in the disease setting. 
A summary of findings is discussed in Section 4.3.1. See details for precautions and restrictions in 
Section 8.7. Additional information regarding potential risks from treatment is provided in the 
TAK-079 IB.
4.3.1
Risks
Based on the mechanism of action of TAK-079, potential risks may include infusion or injection
reactions, hematological effects, and serious infections.
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4.3.1.3
Severe Cytokine Release Syndrome 
Severe cytokine release syndrome (SCRS) is characterized by severe dyspnea, often accompanied 
by bronchospasm and hypoxia, in addition to fever, chills, rigors, urticaria, and angioedema. This 
syndrome may be associated with some features of tumor lysis syndrome such as hyperuricemia, 
hyperkalemia, hypocalcemia, hyperphosphatemia, acute renal failure, and elevated lactate 
dehydrogenase, and may be associated with acute respiratory failure and death. The acute 
respiratory failure may be accompanied by events such as pulmonary interstitial infiltration or 
edema, visible on a chest x-ray. The syndrome frequently manifests within 1 or 2 hours of 
initiating the first infusion. Patients with a history of pulmonary insufficiency or those with 
pulmonary tumor infiltration may be at greater risk of poor outcome and should be treated with 
increased caution. 
Patients who develop SCRS should have dosing interrupted immediately and should receive 
aggressive symptomatic treatment.
4.3.1.4
Hematologic Effects
Reductions in platelets, lymphocytes, and RBCs occurred in nonclinical studies in some animals 
administered doses of TAK-079 higher than the NOAEL. Subjects in clinical studies of TAK-079
should be monitored closely, including testing of hematology parameters. 
The important potential risk of these hematologic changes will be monitored throughout this 
clinical study, as described in Section 9.4.13 and Appendix A.
4.3.1.5
Serious Infections
In a GLP-compliant 13-week toxicology study, bacterial and/or viral infection secondary to 
immune suppression was observed in cynomolgus monkeys at IV doses of 3, 30, and 80 mg/kg 
administered once every 2 weeks. The NOAEL dose of 0.3 mg/kg, administered IV once every 
week, was not associated with infections.
Subjects will be monitored for any signs and symptoms of the important potential risk of serious 
infections throughout this clinical study (see Section 8.8.3).
4.3.1.6
Drug Interactions
Nonclinical drug interaction studies have not been conducted with TAK-079. However, as a fully 
human IgG1 monoclonal antibody (mAb), the risk of drug-drug interactions is low.
4.3.1.7
ADA Interactions
ADA responses were detected in most monkeys in the single-dose PK studies and the 4-week 
(non-GLP) and 13-week (GLP) toxicology studies. Strong positive ADA responses were generally 
associated with lower serum concentrations of TAK-079, and this was especially notable in the 
13-week repeat-dose toxicity studies and at lower doses.
In the single-dose healthy subject study (TAK-079_101), 5 of 54 TAK-079–treated subjects were 
positive for ADA (3 subjects with transient ADA and 2 subjects with persistent ADA). Of these, 
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1 subject was treated in the 0.06 mg IV cohort and the remaining 4 subjects were treated with 
either 0.03 mg/kg (2 subjects), 0.1 mg/kg (1 subject), or 0.6 mg/kg (1 subject) SC TAK-079.
Immunogenicity was not associated with clinically significant AEs, even in the 2 subjects with 
persistent immunogenicity.
4.3.1.8
Pregnancy and Lactation
TAK-079 has not been administered to women who are pregnant or lactating. Dedicated fertility 
and embryo-fetal development toxicology studies have not been conducted with TAK-079. 
However, there were no TAK-079–related changes in organ weights or microscopic findings noted 
in the male and female reproductive tract of monkeys following administration for up to 13 weeks. 
Women of child bearing potential (WOCBP) may be enrolled in clinical trials with appropriate 
precautions to prevent pregnancy (additional details in Section 8.7).
At this stage of development TAK-079 should not be administered to women who are pregnant or 
breastfeeding.
4.3.1.9
Overdose
TAK-079 has been administered only to healthy subjects in the FIH study. To date, there is no 
experience with overdose. If an overdose does occur, close monitoring and supportive treatment as 
required are recommended.
4.3.2
Overall Benefit and Risk Assessment for This Study
The overall clinical benefits and risks of TAK-079 have not been determined. 
Based on the mechanism of action of TAK-079, nonclinical data to date, as well as some exposure 
in healthy human subjects, risks of TAK-079 include but are not limited to IRs, CRS, 
hypersensitivity reactions, changes in hematologic parameters, and serious infections. Patients 
will be monitored closely for these risks in this clinical study.
4.4
Rationale for the Proposed Study
Although multiple therapies are available for patients with MM, this disease remains incurable; 
thus, significant unmet medical need exists for this patient population. Frequent relapses highlight 
a need for new therapies for patients in whom prior treatments have failed. 
TAK-079 binds a partially distinct epitope of CD38 and possesses a different binding profile than 
the approved cytolytic anti-CD38 therapeutic antibody daratumumab. Unlike daratumumab, 
TAK-079 does not bind to RBCs and platelets. Therefore, TAK-079 may possess higher 
tumoricidal activity than daratumumab because cytolytic effector activity is focused on CD38+ 
leukocytes/tumors and is not misdirected to RBCs and platelets. Consequently, TAK-079 may 
demonstrate higher potency (ie, activity at lower doses and exposures) and activity in 
daratumumab-refractory tumors (ie, tumors expressing lower levels of CD38) and thus be more 
efficient at eliminating tumors.
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In the FIH study (TAK-079_101), TAK-079 demonstrated pharmacodynamic effects (ie, cytolysis 
of NK cells and PBs) following single-dose administration, with no unexpected and unwanted 
clinical or hematologic effects observed.
In summary, it is feasible to investigate administration of TAK-079 in patients with relapsed or 
refractory (r/r) MM.
4.4.1
Rationale for the Starting Dose of TAK-079
In the FIH study (TAK-079_101), TAK-079 was well tolerated after SC administration of 
single-doses ranging from 0.03 to 0.6 mg/kg.
To avoid unnecessary exposure of patients to sub-therapeutic doses while preserving safety, the
starting dose for this study in patients with r/r MM will be 45 mg, the fixed-dose equivalent of 
0.6 mg/kg (assuming a body weight of 75 kg), which was the highest SC dose administered in 
Study TAK-079_101. The 0.6 mg/kg dose was well tolerated in healthy human subjects in Study 
TAK-079_101 and demonstrated depletion of peripheral blood PBs, a surrogate for tumor cells.
TAK-079 is a mAb targeting CD38, which is a cell surface molecule that is constitutively 
expressed on plasma cells, PBs, and NK cells, and is induced on activated T cells and B cells [7]. 
Therefore, the anticipated elimination routes for TAK-079 are via proteolytic catabolism and 
intracellular degradation after binding to its target. Both of these clearance mechanisms are not 
thought to be significantly influenced by body weight. Additionally, the distribution volume of 
mAbs is generally limited to the volume of the blood and extracellular fluids, such that body 
composition is a less important determinant of distribution volume as compared with small 
molecule drugs [8]. For these reasons, body weight is not expected to have a clinically significant 
effect on the disposition of TAK-079, thereby supporting the investigation of fixed-dose 
administration.
The 45 mg starting dose of TAK-079 will be tested in 3 patients with r/r MM to assess the safety 
and tolerability of TAK-079 after multiple dose administration. TAK-079 will be administered 
using the same dosing schedule as the anti-CD38 antibody, daratumumab, which is approved for 
the treatment of patients with MM [5]. Specifically, TAK-079 will be administered once weekly 
for 8 weeks (8 doses), once every 2 weeks for 16 weeks (8 doses), then once every 4 weeks until 
the patient experiences disease progression (PD), unacceptable toxicities, or withdrawal due to 
other reasons. The subsequent planned dose levels are 135, 300, 600, 1200, and 1800 mg.
Escalation to a subsequent cohort may take place after the treatment in the first cycle of the 
previous (sequential) cohort has completed.
Additional details for dose escalation are provided in Section 8.3.
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5.2
Endpoints
5.2.1
Phase 1 Primary Endpoints
The primary endpoints for phase 1 are: 

The number of patients with TEAEs overall and per dose level. 
–
Patients with dose-limiting toxicities (DLTs) at each dose level. 
–
Patients with Grade 3 TEAEs.
–
Patients with SAEs.
–
Patients who discontinue because of TEAEs.
–
Patients with dose modifications (delays, interruptions, dose reductions).
–
Clinically significant laboratory values, as determined by the investigator.
–
Clinically significant vital sign measurements, as determined by the investigator.
5.2.2
Phase 2a Primary Endpoint
The primary endpoint for phase 2a is:

ORR, defined as the proportion of patients who achieved a partial response (PR) or better 
during the study as defined by International Myeloma Working Group (IMWG) Uniform 
Response Criteria [9,10]. 
5.2.3
Phase 1 Secondary Endpoints
The secondary endpoints for phase 1 are: 

Summary statistics for the following PK parameters:
–
Maximum observed concentration (Cmax).
–
Time of first occurrence of Cmax (tmax).
–
Area under the concentration-time curve from time 0 to the time of the last quantifiable 
concentration (AUClast).

Preliminary evaluation of antitumor activity of TAK-079 will be assessed for patients with 
MM:
–
ORR, defined as the proportion of patients who achieved a PR (50% tumor reduction) or 
better during the study as defined by the IMWG Uniform Response Criteria ([9,10]; 
Appendix E).
–
Proportion of patients who achieved a minimal response (MR), defined as 25% tumor 
reduction ([9,10]; Appendix E).

Anti–TAK-079 antibody incidence and characteristics.
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6.0
STUDY DESIGN
6.1
Overview of Study Design
This is a multicenter, dose-escalation, open-label, single-arm, phase 1/2a study designed to 
determine the safety, tolerability, efficacy, PK, and immunogenicity of TAK-079 monotherapy in 
patients with r/r MM, and to provide a preliminary assessment of its activity against MM.
The phase 1 portion of the study will evaluate administration of TAK-079 for DLT(s) to determine 
the MTD/RP2D for further assessment in phase 2a. A recommended dose below the MTD may be 
identified based on safety, clinical, PK, 
 data. The safety and tolerability of 
TAK-079 will be assessed by recording and analyzing TEAEs, dose modifications, treatment 
discontinuations, vital signs, physical examinations, serum chemistry and hematology analyses, 
urinalyses, ECGs, and review of concomitant medications.
The preliminary efficacy of TAK-079 will be evaluated by measuring the ORR, defined as the 
proportion of patients who achieved a PR or better during study, as defined by IMWG
(Appendix E; [9,10]). In addition, the efficacy of TAK-079 will be assessed by measuring PFS, 
DOR, and OS; TTR will also be measured.
Once enrolled into the study, patients will receive TAK-079 via SC administration in each 28-day 
cycle of treatment, administered as once weekly for 8 weeks (8 doses), once every 2 weeks for 
16 weeks (8 doses), and once every 4 weeks thereafter until PD. Patients will receive ongoing 
treatment with TAK-079 until they experience PD, unacceptable toxicities, or withdrawal due to 
other reasons.
Phase 1 will consist of the following phases/periods: Screening, Treatment, and Follow-up:

Screening period (visit 1): Days -21 to Day -1.

Treatment period (visit 2/ongoing): Once-weekly treatment for 8 doses (Cycles 1 and 2), 
starting on Day 1, followed by treatment once every 2 weeks for 8 doses (Cycles 3-6), followed 
by treatment once every 4 weeks thereafter (Cycle 7 and beyond), continuing until patients 
experience PD, unacceptable toxicities, or withdrawal due to other reasons. 

Follow-up Period (follow-up visit): Patients who discontinue for PD will be followed for 30 
days after the last dose of study drug or until the start of subsequent alternative anticancer 
therapy to monitor safety/AEs. Patients who discontinue treatment for reasons other than PD 
will continue to be followed for PFS every 4 weeks until PD, death, loss to follow-up, consent 
withdrawal, study termination, or 12 months after the last patient has received their last dose 
(last patient, last dose [LPLD]). All patients will be followed for OS every 12 weeks until 
death, loss to follow-up, consent withdrawal, study termination, or 12 months after LPLD.
In phase 1, approximately 6 doses will be evaluated in ascending cohorts of 3-6 patients per 
cohort. Cohorts may be expanded by enrolling additional patients to further inform selection of the 
RP2D. Dose selection for phase 2a will take place after review of the available safety, efficacy, 
PK, 
 data obtained from the phase 1 portion of the study.
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It is expected that approximately 42 patients will be enrolled in total for phase 1 and 2a combined. 
The estimated duration of the study is approximately 48 months (4 years; Section 6.3).
Study procedures and assessments, with their time points, are shown in Appendix A. The study 
schematic diagram is shown in Figure 6.a.
Figure 6.a
Overall Study Schematic Diagram
Treatment Cycle
C1
C2
≤21 D
D1
D8
D15
D22
D1
D8
D15
D22
C3
C4
C5
C6
C7
C8
D1
D15
D1
D15
D1
D15
D1
D15
D1
D1
**
PD
Dose Escalation: 45, 135, 300, 600, 1200, and 1800 mg.
Cohorts in phase 1 may be expanded to further inform selection of the RP2D.
The RP2D determined in phase 1 will be further assessed in approximately 18 patients in phase 2a.
** 
=  dosing every 28 days until disease progression.
    = TAK-079 dose; C=Cycle; D=Day; R2PD=recommended phase 2 dose.
6.2
Number of Patients
For phase 1, approximately 24 patients are planned to be enrolled, including the expansion of 
additional patients in selected cohorts to further inform selection of the RP2D. For phase 2a, 
approximately 18 patients are planned. Details on the definition of evaluable patients and sample 
size are given in Section 13.1.
The study is planned to be conducted in the United States in approximately 4 investigational 
centers for phase 1 and in a total of 6 investigational centers for phase 2a.
6.3
Duration of Study
6.3.1
Duration of an Individual Patient’s Study Participation
Patients will receive TAK-079 until they experience PD as defined by IMWG for patients with 
MM ([9,10]; Appendix E), unacceptable toxicity, withdrawal of consent, death, termination of the 
study by the sponsor, until any other discontinuation criterion is met, or until 12 months after 
LPLD (additional participation details are provided in Sections 6.1, 8.4.3, 9.6, and 9.7). 
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Patients will be evaluated 30±7 days after the last dose of TAK-079 (follow-up visit) or before 
initiating subsequent systemic anticancer therapy, for detection of any delayed TEAEs.
6.3.2
End of Study/Study Completion Definition and Planned Reporting
The final data cutoff for the clinical study report will be conducted 12 months after all patients 
have been discontinued from treatment or transferred to a long-term safety study, a single-patient 
investigational new drug application, or a similar program (Table 6.a).
6.3.3
Timeframes for Primary and Secondary Endpoints to Support Disclosures
Refer to Table 6.a for disclosures information for all primary and secondary endpoints.
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6.3.4
Total Study Duration
It is anticipated that this study will last for approximately 48 months (4 years).
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7.0
STUDY POPULATION
7.1
Inclusion Criteria
Each patient must meet all the following inclusion criteria to be enrolled in the study:
1. Male or female patients aged 18 years or older.
2. Eastern Cooperative Oncology Group (ECOG) performance status of ≤2 [11].
3. Patient has received the final dose of any of the following treatments/procedures within the 
specified minimum intervals before the first dose of TAK-079 (Table 7.a):
Table 7.a
Required Washout Periods for Previous Treatments or Procedures Prior to 
Administration of TAK-079 
Previous Treatment or Procedure
Washout Period
Myeloma-specific therapy
30 days
Antibody therapy (including anti-CD38)
120 days
Corticosteroid therapy (a)
30 days
Autologous transplantation 
90 days
Radiation therapy
30 days
Major surgery
30 days
(a) Systemic corticosteroid use ≤10 mg/day (prednisone or equivalent) is allowed.
4. Patient has adequate organ function as determined by the following laboratory values
(Table 7.b):
Table 7.b
Laboratory Criteria for Determining Adequate Organ Function for 
Study TAK-079-1501 Eligibility
Laboratory Parameter
Acceptable Laboratory Criteria 
Absolute neutrophil count (a)
≥1000/mm3 (≥1.0×109/L); ≥750/mm3 (≥0.75109/L) maybe acceptable for 
patients with >50% of plasma cells in bone marrow after discussion with 
sponsor
Platelets (a)
≥75,000/mm3 (≥75×109/L); a value of ≥50,000/mm3
(≥50×109/L) may be acceptable for patients with >50% bone marrow burden 
following discussion with the sponsor
Hemoglobin 
≥7.5 g/dL (it is not permissible to transfuse a subject to reach this level)
Creatinine clearance
≥30 mL/min (Cockcroft-Gault formula)
Total serum bilirubin
≤1.5×ULN; except for patients with Gilbert’s syndrome in whom direct 
bilirubin should be <2.0×ULN 
Liver transaminases (ALT/AST)
≤2.5×ULN
ALT=alanine aminotransferase; AST=aspartate aminotransferase; ULN=upper limit of the normal range.
(a) Without ongoing growth factor or transfusion support for at least 1 week before Day 1.
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5. Female patients who:

Are WOCBP must not be pregnant or lactating. 

Are postmenopausal for at least 1 year before the screening visit, OR

Are surgically sterile, OR

If they are of childbearing potential, agree to practice 1 highly effective method of 
contraception and 1 additional effective (barrier) method at the same time, from the time of 
signing the informed consent through at least 30 days or 5 half-lives after the last dose of 
study drug, whichever time period is longest, OR

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle 
of the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, and 
postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not 
acceptable methods of contraception. Female and male condoms should not be used 
together.)
6. Male patients, even if surgically sterilized (ie, status postvasectomy), who:

Agree to practice effective barrier contraception during the entire study treatment period 
and through 120 days (or if the drug has a very long half-life, for 90 days plus 5 half-lives) 
after the last dose of study drug, OR

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle 
of the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, and 
postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not 
acceptable methods of contraception. Female and male condoms should not be used 
together.)
7. Voluntary written consent must be given before performance of any study-related procedure 
not part of standard medical care, with the understanding that consent may be withdrawn by 
the patient at any time without prejudice to future medical care.
8. The patient must be willing and able to comply with study restrictions and to remain at the 
investigational center for the required duration during the study period, and must be willing to 
return to the investigational center for the follow-up procedures and assessments specified in 
this protocol.
9. Requires additional therapy, as determined by the investigator.
10. Documentation of r/r MM as defined by the IMWG criteria (Appendix E; [9,10]).
11. For patients with MM, measurable disease defined as one of the following:

Serum M-protein ≥500 mg/dL (≥5 g/L).

Urine M-protein ≥200 mg/24 hours.
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
In patients without measurable M-protein in serum protein electrophoresis (SPEP) or urine 
protein electrophoresis (UPEP), a serum free light chain (FLC) assay result with involved 
FLC level ≥10 mg/dL (≥100 mg/L), provided serum FLC ratio is abnormal.
12. Prior therapy should meet all of the following criteria:

Patient should be previously treated with at least a PI, an IMid, an alkylating agent, and a 
steroid.

Patient should be refractory or intolerant to at least 1 PI and at least 1 IMid.

Patient should either have received ≥3 prior lines of therapy or should have received at 
least 2 prior lines of therapy if one of those lines included a combination of PI and IMid. 

Previous exposure to an anti-CD38 agent, as a single agent or in combination, is allowed 
but is not required.
13. Patients must express CD38 on target cells with a mean fluorescence intensity ≥1000 units on 
≥90% of plasma cells as determined by multicolor flow cytometry.
14. In the phase 2a portion of the study, patients with MM must also have been refractory to at 
least 1 anti-CD38 mAb therapy at any time during treatment.
NOTE:

Refractory is defined as at least a 25% increase in M-protein or PD during treatment or within 
60 days after cessation of treatment.

A line of therapy is defined as 1 or more cycles of a planned treatment program. This may 
consist of 1 or more planned cycles of single-agent therapy or combination therapy, as well as 
a sequence of treatments administered in a planned manner. A new line of therapy starts when 
a planned course of therapy is modified to include other treatment agents (alone or in 
combination) as a result of PD, relapse, or toxicity. A new line of therapy also starts when a 
planned period of observation off therapy is interrupted by a need for additional treatment for 
the disease [9].
7.2
Exclusion Criteria
Patients meeting any of the following exclusion criteria are not to be enrolled in the study:
1. Sensory or motor neuropathy of National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE) Grade ≥3 [12].
2. Patients who have received allogeneic stem cell transplant.
3. Patients who have received anti-CD38 antibody therapy and do not fulfill a 120-day washout 
period before receiving TAK-079.
4. Not recovered from adverse reactions to prior myeloma treatment or procedures 
(chemotherapy, immunotherapy, radiation therapy) to NCI CTCAE Grade ≤1 or baseline.
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5. Congestive heart failure (New York Heart Association) Grade ≥II; cardiac myopathy, active 
ischemia, or any other uncontrolled cardiac condition such as angina pectoris, clinically 
significant arrhythmia requiring therapy including anticoagulants, or clinically significant 
uncontrolled hypertension.
6. History of acute myocardial infarction within 5 months before enrollment or ECG 
abnormalities during the screening period that are deemed medically relevant by the 
investigator.
7. QT interval corrected by the Fridericia method >480 msec (Grade ≥2).
8. Concurrent illness that would preclude study conduct and assessment including, but not 
limited to, uncontrolled medical conditions, uncontrolled systemic or body organ active 
infection (considered opportunistic, life threatening, or clinically significant), uncontrolled 
risk of bleeding, uncontrolled diabetes mellitus, pulmonary disease (including obstructive 
pulmonary disease such as severe chronic obstructive pulmonary disease [COPD] with forced 
expiratory volume <80%, or persistent asthma, pulmonary fibrosis, and history of 
symptomatic bronchospasm), inflammatory bowel disease, ongoing symptomatic 
pneumonitis, alcoholic liver disease, or primary biliary cirrhosis. 
9. History of stroke or intracranial hemorrhage within 12 months of randomization; patients 
requiring anticoagulation therapy for any indication should be discussed with the medical 
monitor before screening.
10. Active autoimmune disease including autoimmune hemolytic anemia, idiopathic 
thrombocytopenic purpura, or any chronic condition requiring a higher corticosteroid systemic 
equivalent than prednisone 10 mg daily. Higher doses of corticosteroids prescribed for any 
indication must be stopped 30 days prior to randomization; exceptions may be made for 
corticosteroids prescribed specifically for management of MM symptoms after discussion with 
the medical monitor.
11. History of myelodysplastic syndrome or another malignancy other than MM, except for the 
following: any malignancy that has been in complete remission for 3 years, adequately treated 
local basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial 
bladder cancer, or asymptomatic prostate cancer without known metastatic disease and with no 
requirement for therapy or requiring only hormonal therapy and with normal prostate-specific 
antigen for 1 year before the start of study therapy.
12. Clinical signs of CNS involvement of MM.
13. Female patients who are pregnant with a positive serum pregnancy test or lactating during the 
screening period, or a positive urine pregnancy test on Day 1 before the first dose of study 
drug, if applicable. 
14. Any serious medical or psychiatric illness that could, in the investigator’s opinion, potentially 
interfere with the completion of treatment according to this protocol.
15. Active chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, active HIV, or 
cytomegalovirus (CMV) infection.
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16. History of severe allergic or anaphylactic reactions to recombinant proteins or excipients used 
in the TAK-079 formulation. This includes patients who were previously discontinued from an 
anti-CD38 treatment due to an infusion-related reaction.
17. The patient is currently participating in another antimyeloma or antileukemia clinical study, or 
has participated in another investigational clinical trial within the past 4 weeks prior to 
randomization.
18. Patients who are not able and/or willing to comply with the study requirements, rules, and 
procedures.
19. POEMS (Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin 
changes) syndrome, monoclonal gammopathy of unknown significance, smoldering myeloma, 
solitary plasmacytoma, amyloidosis, Waldenström macroglobulinemia, or IgM myeloma.
20. Patients with positive Coombs tests at screening.
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8.0
STUDY DRUG
8.1
Study Drug Administration
All protocol-specific criteria for administration of study drug must be met and documented before 
drug administration. Study drug will be administered only to eligible patients under the 
supervision of the investigator or identified subinvestigator(s).
8.1.1
Premedication
Before each injection, patients will receive the following premedications 1 to 3 hours prior to the 
start of TAK-079 administration on each dosing day:

Dexamethasone: 20 mg IV dose for the initial injection. Oral dexamethasone (20 mg) or an 
equivalent long-acting corticosteroid may be used before subsequent injections.

Antipyretics: oral acetaminophen (650 to 1000 mg).

Antihistamine: oral or IV diphenhydramine (25 to 50 mg, or equivalent).

Montelukast 10 mg (or equivalent leukotriene inhibitor) is optional for Cycle 1 Day 1.
NOTE: Patients with a higher risk of respiratory complications (eg, patients with a history of 
COPD and patients with asthma) will be treated with postinjection medication consisting of the 
following:

An antihistamine (diphenhydramine or equivalent) on the first and second days after all 
injections,

A short-acting βadrenergic receptor agonist, such as salbutamol (albuterol) aerosol, and

Control medications for lung disease (eg, inhaled corticosteroids with or without long-acting 
β2 adrenergic receptor agonists for patients with asthma; long-acting bronchodilators such as 
tiotropium or salmeterol with or without inhaled corticosteroids for patients with COPD).
Premedication will be mandatory in phase 1. The decision to premedicate in phase 2a will be 
determined based on data from phase 1.
The clinical site is responsible for sourcing any premedications outlined in the protocol.
8.1.2
TAK-079 Formulation and Administration
The strength of the TAK-079 drug product for SC use in the current study (TAK-079-1501) is 
100 mg TAK-079 in 1 mL (100 mg/mL). The drug product is supplied in clear borosilicate glass 
vials (see additional details in Section 8.10).
After patients have received premedication treatment, TAK-079 doses will be administered with 
syringes as SC injections up to a maximum volume of 2 mL per injection (ie, 200 mg/2 mL), 
injected every 30 minutes until the full scheduled dose has been administered. 
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Patients may receive low-dose methylprednisolone (< 20 mg) for the prevention of delayed 
injection related reaction, as clinically indicated. 
Refer to the Pharmacy Manual for detailed instructions regarding preparation of each dose.
8.2
Definitions of DLT
Toxicity will be evaluated according to the NCI CTCAE, Version 4.03, effective 14 June 2010 
[12]. These criteria are provided in the Study Manual. DLTs will be defined as any of the 
following events regardless of relationship, except those events that are clearly due to extraneous 
causes.

Grade 4 laboratory abnormalities, except those events that are clearly due to extraneous causes, 
will be defined as a DLT. 

Nonhematologic TEAEs of NCI CTCAE Grade 3, except those events that are clearly due to 
extraneous causes, and occurring during the first cycle will be considered DLTs (see Section 
10.2 for relatedness guidance), with the following exceptions:
–
Grade 3 nausea/vomiting that can be managed subsequently with antiemetics (Grade 3 
nausea or vomiting that persists beyond 48 hours with or without appropriate medical 
intervention will be considered a DLT).
–
Grade 3 fatigue lasting less than 72 hours.
–
Grade 3 elevation of ALT or AST that resolves to Grade ≤1 or baseline within 7 days.
–
Grade 3 IR that responds to symptomatic treatment (eg, antihistamines, nonsteroidal 
anti-inflammatory drugs (NSAIDs), narcotics, IV fluids), without recurrence of Grade 3 
symptoms.

Hematologic TEAEs of NCI CTCAE Grade ≥4, except those events that are clearly due to 
extraneous causes, and occurring during the first cycle will be considered DLTs, with the 
following exceptions:
–
Grade ≥3 hemolysis, except those events that are clearly due to extraneous causes (eg, 
negative direct Coombs test), will be included in the definition of DLT.
–
Grade 3 low platelet or higher count with clinically meaningful bleeding will be included 
in the definition of DLT.

An incomplete recovery from treatment-related toxicity causing a >2-week delay in the next
scheduled injection before the initiation of Cycle 2 will be considered a DLT.
For the purpose of dose escalation, DLTs are those events meeting the criteria above that occur 
before Cycle 2 Day 1 administration. TEAEs meeting DLT definitions occurring in later cycles 
will determine the suitability of the MTD as the RP2D.
Dose and schedule modifications for toxicity are described in Section 8.4.
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
If none of the patients in a cohort of 3 patients exhibits a DLT during the 28-day cycle, then the 
dose may be escalated for the next cohort of 3 patients.

If 1 patient in a cohort of 3 patients exhibits a DLT, then that cohort will be expanded to a total 
of 6 patients.

If ≤1 of 6 patients experiences a DLT, escalation will continue to the next higher dose level, at 
which 3 patients will be enrolled. 

If 2 or more patients (2 or more out of 3, or 2 or more out of 6) experience a DLT, dosing will 
de-escalate to the next lower dose level, at which 3 additional patients will be enrolled if 3 
patients have been treated at that dose level. If 6 patients have been enrolled at the lower level 
with 1 or less DLT out of 6, dosing may stop and the lower dose level may be considered the 
MTD.
Figure 8.a is a diagrammatical representation of the dose-escalation paradigm.
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Figure 8.a
Dose-Escalation Scheme
DLT=dose-limiting toxicity.
More conservative dose escalation, evaluation of intermediate doses, and expansion of an existing 
dose level are all permissible following discussions between the sponsor and the investigators, if 
such measures are needed for patient safety or for a better understanding of the dose-related 
toxicity, exposure, or 
.
Before initiating the dosing of the next cohort, when safety data are available for all patients in the 
current cohort, key safety data will be reviewed and evaluated by the study team consisting of 
sponsor representatives and investigators who will review the safety of all treated patients and 
make decisions regarding dose escalation. In addition, changes to the dose-escalation scheme or 
dose schedule (dosing interval) may be considered. All decisions will be documented in writing. 
Any decision to modify the dose-escalation scheme (with the exception of testing intermediate 
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dose levels) or dose schedule will be communicated to institutional review boards (IRBs), and the 
protocol will be amended accordingly.
8.4
Dose Modification Guidelines
Dose modification guidelines for toxicities are described below for TAK-079 on the basis of the 
type and severity of AEs and causality determination by investigators. Further clarification can be 
obtained in consultation with the sponsor clinician (or designee).
8.4.1
Criteria for Beginning or Delaying a Subsequent Treatment Cycle
Treatment with TAK-079 will use a cycle length of 28 days. For a new cycle of treatment to begin, 
the patient must meet the following criteria:

Absolute neutrophil count must be ≥1000/mm3.

Platelet count must be ≥75,000/mm3.

For therapy to resume, toxicity considered to be related to treatment with TAK-079 must have 
resolved to Grade 1 or baseline, or to a level considered acceptable by the physician. If the 
patient fails to meet the above-cited criteria for retreatment, initiation of the next cycle of 
treatment should be delayed for 1 week. At the end of that week, the patient should be 
re-evaluated to determine whether the criteria for re-treatment have been met. If there is a 
delay of a subsequent cycle longer than 2 weeks because of a drug-related AE, the patient may 
be withdrawn from treatment unless there is clinical benefit as assessed by the investigator, 
with agreement by the sponsor’s medical monitor. TAK-079 dosing may be continued at the 
previously established safe dose level or below.

For TAK-079 injections within the same cycle, the decision of holding treatment is left to the 
investigator’s discretion based on clinical and analytical data, and also based on the toxicity 
that the patient experienced with previous injections in the same cycle. The investigator should 
differentiate between acute toxicity (like an IR) from which the patient is recovered at the time 
of the next injection, and subacute toxicity (for example, neutropenia) that might be worsened 
upon another injection if it is not on a clear recovery path. If the dose cannot be administered 
on the scheduled day, the patient can be reviewed at the investigator’s discretion in the 
following 48 hours. If TAK-079 cannot be administered within a cycle in this 48-hour 
window, the dose will be missed and the patient scheduled for the next administration per the 
Schedule of Events (SOE; Appendix A).
8.4.2
Criteria for Dose Reduction
All toxicities that occur during the study will be actively managed following the standard of care 
unless otherwise specified in the protocol. Patients experiencing AEs attributed to TAK-079 may 
continue study treatment with the same dose, may have TAK-079 treatment held, may have their 
dose reduced, or may be permanently discontinued from the study. Patients who have study drug 
held because of treatment-related or possibly related AEs may resume study drug treatment after 
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resolution of the AE at the same dose level or at a reduced dose, depending on the nature and 
severity of the AE and whether it is the first occurrence or it is recurrent.
TEAEs that are not attributed by the investigator to the study drug may be treated as per local 
standard of care, dose-modifications, interruptions and permanent discontinuations may be 
discussed upfront with the medical monitor.
Table 8.a provides general dose modification recommendations. When the dose of TAK-079 is 
withheld on the basis of these criteria, clinical and laboratory re-evaluation should be repeated at 
least weekly or more frequently, depending on the nature of the toxicity observed, until the toxicity 
resolves to Grade ≤1 or baseline. If there are transient laboratory abnormalities that, per
investigator assessment, are not clinically significant or drug related, continuation of therapy 
without dose modification is permissible upon discussion with the sponsor. See details for 
managing specific AEs in Section 8.8.
Table 8.a
Dose Modification Recommendations for TAK-079 Toxicities
Criteria
Action
Grade 1 AEs
No dose reductions or interruptions.
Grade 2 AEs
Treat according to local practice. Whether to hold treatment or to continue it 
at the same or a reduced dose is at the discretion of the investigator.
Patients with Grade 2 AEs considered related to study treatment that are not 
easily managed or corrected and are not tolerable to the patient, or AEs that 
are not acceptable in the investigator’s judgment, should have study 
treatment interrupted until the AE resolves to Grade ≤1 or baseline, then 
restarted at the same dose or, depending on the toxicity, at the previous safe 
dose level or below.
Grade 3 AEs
Patients with Grade 3 AEs considered related to study treatment should have 
study treatment interrupted until the AE resolves to Grade ≤1 or baseline, 
then resume treatment at a reduced dose level.
Grade 4 (life-threatening) AEs
Patients with Grade 4 AEs considered related to study treatment should 
permanently discontinue treatment. 
AEs of all grades
If treatment has been held for >14 consecutive days without resolution of the 
toxicity (to baseline or Grade ≤1), consider permanently discontinuing study 
treatment unless there is clinical benefit for the patient as assessed by the 
investigator and with sponsor’s approval. Treatment can be resumed at a 
reduced dose level after resolution of AEs to Grade ≤1 or baseline.
AE=adverse event.
When a dose reduction occurs, the TAK-079 dose will be reduced to the next lower dose that has 
been established as a safe dose during dose escalation. If initial dose adjustment does not provide 
sufficient relief, the dose of TAK-079 can be further reduced if the treating physician considers 
that the patient is receiving benefit. In general, after a dose is reduced, it should not be re-escalated 
even if there is minimal or no toxicity with the reduced dose. However, if further evaluation 
reveals that the AE that led to the dose reduction was not study drug related, the dose may be 
re-escalated to the original dose level. Up to 2 dose level reductions of TAK-079 because of AE 
are generally recommended.
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If dose-reduction is not possible because the lowest dose-level has already been reached, treatment 
may be permanently discontinued.
The dose of TAK-079 will not be reduced for an individual patient during Cycle 1 unless a DLT 
has been declared and it is still possible for the patient to receive treatment within the remaining 
dosing period scheduled. In this case, the patient can complete Cycle 1 at a reduced dose level.
8.4.3
Criteria for Discontinuing TAK-079 in Individual Patients (When Considering Dose 
Modification)
TAK-079 should be discontinued in patients experiencing an AE in Cycle 1 meeting criteria for a 
DLT for which the investigator considers that re-treatment of the patient could be dangerous. For 
Grade 4 (life-threatening) TEAEs, consider permanently withdrawing the patient from the study, 
except when the investigator determines that the patient is receiving clinical benefit, there are 
opportunities to provide supportive care to mitigate risk for the Grade 4 event to reoccur, and this 
approach (ie, the specific situation and mitigation plan) has been discussed with the sponsor. In 
these circumstances, treatment may be restarted at the previously safe dose level or below when 
toxicity recovers to Grade ≤1 or baseline.
If the next cycle of TAK-079 is delayed for >14 days because of TAK-079–related toxicities, then 
the patient should have study treatment discontinued unless the investigator considers that the 
patient will receive benefit from continuing in the study. If treatment discontinuation occurs, the 
end of treatment (EOT)/early termination visit should be completed and the follow-up visit should 
occur within 30 (±7) days after the last administration of TAK-079. Additional details for study 
treatment discontinuation are provided in Section 9.7.
8.5
Excluded Concomitant Medications and Procedures
The following medications and procedures are prohibited during the study:

Chemotherapy and radiation therapy for the disease under study. Local radiotherapy for bone 
pain is permitted after agreement with the sponsor’s medical monitor and once PD is ruled out.

Systemic corticosteroid use >10 mg/day (prednisone or equivalent). 

Live vaccines.

Any investigational agent other than TAK-079, including agents that are commercially
available for indications other than MM that are under investigation for the treatment of MM.
8.6
Permitted Concomitant Medications and Procedures 

All necessary supportive care consistent with optimal patient care will be available to patients 
as necessary. All blood products and concomitant medications received from the first dose of 
the study drug regimen until 30 days after the final dose will be recorded in the electronic case 
report forms (eCRFs).

The following medications and procedures are permitted while the patient is receiving the 
study drug:
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–
Systemic corticosteroid use ≤10 mg/day (prednisone or equivalent).
–
Myeloid growth factors (eg, granulocyte colony stimulating factor, granulocyte 
macrophage-colony stimulating factor) and erythropoietin are permitted. Their use should 
follow the product label, published guidelines, and institutional practice. 
–
Transfusions with RBCs and platelets as clinically indicated; localized radiation for pain 
management for osteolytic lesions.
–
Concomitant treatment with bisphosphonates will be encouraged for all patients with 
evidence of lytic destruction of bone or with osteopenia, according to the American 
Society of Clinical Oncology Clinical Practice Guidelines or institutional practice in 
accordance with the product label, unless specifically contraindicated. If bisphosphonate 
therapy was not started before the study start, it should be initiated as soon as clinically 
indicated.
–
Topical or inhaled steroids and short-acting β2 adrenergic receptor agonists (eg, for the 
treatment of asthma) are permitted.
–
Nonresorbable corticosteroids (eg, budesonide).
–
Plasmapheresis.
8.7
Precautions and Restrictions
Fluid deficit should be corrected before initiation of treatment and during treatment.
NSAIDs should be avoided with impaired renal function given the reported NSAID-induced renal 
failure in patients with decreased renal function.
Patients should not drive, operate dangerous tools or machinery, or engage in any other potentially 
hazardous activity that requires full alertness and coordination if they experience sedation while 
enrolled in this study.
Patients are to be instructed to limit the use of alcohol while enrolled in this study.
It is not known what effects TAK-079 has on human pregnancy or development of the embryo or 
fetus; therefore, female patients participating in this study should avoid becoming pregnant, and 
male patients should avoid impregnating a female partner. Nonsterilized female patients of 
reproductive age and male patients should use effective methods of contraception through defined 
periods during and after study treatment as specified below.
Female patients must meet the following:

WOCBP must not be pregnant or lactating. 

Postmenopausal for at least 1 year before the Screening Visit, OR

Surgically sterile, OR

If they are of childbearing potential, agree to practice 1 highly effective method and 
1 additional effective (barrier) method of contraception at the same time, from the time of 
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signing of the informed consent form (ICF) through 5 half-lives after the last dose of study 
drug (whichever is longer), OR

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of 
the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, and postovulation 
methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.)
Male patients, even if surgically sterilized (ie, status postvasectomy) must agree to one of the 
following:

Agree to practice effective barrier contraception during the entire study treatment period and 
through 120 days (or if the drug has a very long half-life, for 90 days plus 5 half-lives) after the 
last dose of study drug, OR

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of 
the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, and postovulation 
methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.)
In addition, a close monitoring of serum chemistry, particularly creatinine, potassium, and uric 
acid levels must be performed. Patients with tumor lysis syndrome should be treated per
institutional practice (including correction of electrolyte abnormalities, monitoring of renal 
function and fluid balance, and administration of supportive care, including dialysis as indicated).
8.8
Management of Specific Adverse Reactions
8.8.1
Handling of IRs
Patients should be carefully observed during TAK-079 injections. Trained trial staff at the clinic 
should be prepared to intervene in case of any IRs and resources necessary for resuscitation (eg, 
agents such as epinephrine and aerosolized bronchodilators; also medical equipment such as 
oxygen tanks, tracheostomy equipment, and a defibrillator) must be available at bedside.
In case of Grade 1 or 2 infusion reactions: 

Withhold therapy (also administration of remaining SC injections when full dose was not yet 
reached) until resolution to Grade 1 or maximum to Grade 2 as per the investigator’s 
discretion. 
In case of Grade 3 infusion reactions: 

Withhold therapy (also administration of remaining SC injections when full dose was not yet 
reached and therefore skip remaining dose) until next scheduled TAK-079 SC administration, 
providing that infusion reactions have recovered to Grade ≤1 at the moment of the next 
scheduled TAK-079 dose. 

Permanently discontinue treatment after the 3rd occurrence of Grade 3 infusion reactions
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The investigator or designee must confirm that appropriate temperature conditions have been 
maintained for all TAK-079 received and that any discrepancies are reported and resolved before 
use of TAK-079.
The investigator is responsible for ensuring that deliveries of TAK-079 and other study materials 
from the sponsor are correctly received, recorded, and handled, and stored safely and properly in 
accordance with the Code of Federal Regulations (CFR) or national and local regulations, and used 
in accordance with this protocol.
Detailed dosage preparation instructions are provided in the Directions for Use section of the 
Pharmacy Manual. Complete receipt, inventory, accountability, reconciliation, and destruction 
records must be maintained for all used and unused study drug vials. Detailed instructions and the 
associated forms for these activities are in the Pharmacy Manual.
Upon receipt of study medication, the investigator or designee must verify the contents of the 
shipments against the packing list. The verifier should ensure that the quantity is correct, the 
medication is received within the labeled storage conditions, and is in good condition. If quantity 
and conditions are acceptable, investigator or designee should acknowledge the receipt of the 
shipment by signing bottom half of the packing list and faxing per instructions provided on the 
form. If there are any discrepancies between the packing list versus the actual product received, 
Takeda must be contacted to resolve the issue. The packing list should be filed in the investigator’s 
essential document file.
The sponsor must be notified immediately of any temperature excursions, shipping and handling 
or storage discrepancies.
Drug supplies will be counted and reconciled at the site before being returned to Takeda or 
designee or being destroyed.
The investigator or designee must ensure that the study medication is used in accordance with 
the approved protocol and is dispensed only to subjects enrolled in the study. To document 
appropriate use of study medication (TAK-079), the investigator must maintain records of all 
study medication delivery to the site, site inventory, use by each subject, and return to the 
sponsor or designee.
The investigator will be notified of any expiry date or retest date extension of clinical study 
material during the study conduct. On expiry date notification from the sponsor or designee, the 
site must complete all instructions outlined in the notification, including segregation of expired 
clinical study material for return to the sponsor or its designee.
Further guidance and information are provided in the Pharmacy Manual.
8.13.2 Accountability and Destruction of Sponsor Supplied Drugs
The investigator, institution, or head of the medical institution (where applicable) is responsible 
for TAK-079 accountability, reconciliation, and record maintenance (ie, receipt, reconciliation, 
and final disposition records).
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The investigator must maintain 100% accountability for all study medication (TAK-079) received 
and dispensed during his or her entire participation in the study. Proper drug accountability 
includes, but is not limited to:

Continuously monitoring expiration dates if expiry date/retest date is provided to the 
investigator.

Frequently verifying that actual inventory matches documented inventory.

Verifying that the log is completed for the drug lot used to prepare each dose.

Verifying that all containers used are documented accurately on the log.

Verifying that required fields are completed accurately and legibly.

A site representative, otherwise uninvolved with study conduct, will review the subject dosing 
log prior to Day 1 dosing and following dosing to ensure all subjects received the correct dose 
of study medication. This review will be documented at the site.
If any dispensing errors or discrepancies are discovered, the sponsor must be notified immediately.
Empty, partially used, and unused TAK-079 will be disposed of, retained, or returned to the 
sponsor or designee.
The investigator must maintain a current inventory (Drug Accountability Log) of all 
sponsor-supplied study medication delivered to the site, inventory at the site, and subjects’ use 
records. This log must accurately reflect the drug accountability of the study medication at all 
times. The following information will be recorded at a minimum: protocol number and title, name 
of investigator, site identifier and number, description of sponsor-supplied medication, 
expiry/retest date and amount dispensed, including the initials of the person dispensing and 
receiving the study medication. The log should include all required information as a separate entry 
for each subject to whom study medication is dispensed.
Prior to site closure or at appropriate intervals, a representative from the sponsor or its designee 
will perform clinical study material accountability and reconciliation before clinical study 
materials are returned to the sponsor or its designee or destroyed at the site, as applicable. The 
investigator will retain the original documentation regarding clinical study material accountability, 
return, and/or destruction, and copies will be sent to the sponsor or designee.
Further guidance and information are provided in the Pharmacy Manual.
8.14
Investigational Drug Assignment and Dispensing Procedures
Subjects will be assigned using an IVRS/IWRS accessible 24 hours a day to authorized users. At 
screening, the site will contact the IVRS/IWRS to register the subject into the study. During this 
contact, the investigator or designee will provide the necessary subject-identifying information. At 
drug dispensing visits, the investigator or designee will contact the IVRS/IWRS to request study 
medication assignments for a subject. Medication ID numbers (MED IDs) of the study 
medications to be dispensed will be assigned by the IVRS/IWRS. Documentation of the 
IVRS/IWRS assigned MED IDs should be included in the source documents.
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9.0
STUDY CONDUCT
This study will be conducted in compliance with the protocol, GCP, applicable regulatory 
requirements, and ICH guidelines.
9.1
Study Personnel and Organizations
The contact information for the project clinician for this study, the central laboratory, and any 
additional clinical laboratories, the coordinating investigator for each member state/country, and 
the contract research organization (CRO) team may be found in the Study Manual. A full list of 
investigators is available in the sponsor’s investigator database.
9.2
Arrangements for Recruitment of Patients
Recruitment and enrollment strategies for this study may include recruitment from the 
investigator’s local practice or referrals from other physicians. If advertisements become part of 
the recruitment strategy, they will be reviewed by the IRB/independent ethics committee (IEC). 
The screening period for this study is 21 days.
9.3
Treatment Group Assignments
All patients will receive open-label treatment with TAK-079 as indicated in respectively assigned 
treatment cohorts.
9.4
Study Procedures
Refer to the SOE (Appendix A) for timing of assessments. Additional details are provided as 
necessary in the sections that follow.
9.4.1
Informed Consent
Each patient must provide written informed consent before any study-required procedures are 
conducted, unless those procedures are performed as part of the patient’s standard care.
9.4.2
Patient Demographics
The date of birth, race, ethnicity, and sex of the patient are to be recorded during screening.
9.4.3
Medical History
During the screening period, a complete medical history will be compiled for each patient. This 
includes initial diagnosis date and MM staging at initial diagnosis using the International Staging 
System and Salmon-Durie Staging. Before dosing, the investigator should select the International 
Staging System, which should be consistently used throughout the study.
Known cytogenetic alterations should also be collected. Prior treatment regimens, with each 
treatment duration (start and stop dates), and the best response obtained with each therapy should 
be recorded. Refractoriness to previous treatments should be collected following IMWG criteria
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(Appendix E). Confirm that the patient’s current medical status does not include active chronic 
HBV, HCV, CMV, or HIV infection.
For patients who have received previous anti-CD38 therapy, the worst grade of infusion-related 
reactions should be recorded. In addition, concomitant medications will be recorded as specified in 
Section 9.4.9.
9.4.4
Physical Examination
A physical examination will be completed per standard of care at the times specified in the SOE
(Appendix A).
9.4.5
Patient Height and Weight
Height will be measured during the Screening Visit only. Weight will be measured on Day 1 of 
each treatment cycle, as indicated in Appendix A.
9.4.6
Vital Signs
Vital signs include temperature, pulse, respiratory rate, and blood pressure. Vital sign 
measurements will be made before TAK-079 injection, and include supine or seated 
measurements of diastolic and systolic blood pressure (after 3 to 5 minutes in this position). All
measurements should be performed in the same initial position, including heart rate and body 
temperature.
Blood pressure will also be measured before each injection, and at any time the patient complains 
of symptoms consistent with IR. If the patient experiences hypotension (with or without 
symptoms), intensive blood pressure monitoring according to local practice should be instituted. 
The patient should not be released from the site until blood pressure has returned to Grade 1 or 
baseline for at least 1 hour.
Vital signs will be measured at the visits specified in the SOE (Appendix A). Any vital sign value 
that is judged by the investigator as clinically significant will be recorded on both the source 
documentation and in the eCRF as an AE, and monitored as described in Section 10.2.
9.4.7
Eligibility Criteria
Eligibility criteria and confirmatory study assessments must be confirmed during the screening 
period, after a patient has signed the ICF, and before receiving study drug.
9.4.8
Pregnancy Test
WOCBP must have 2 negative pregnancy tests (human chorionic gonadotropin >5 mI/mL) prior to 
starting study drug. A serum pregnancy test will be used during the screening period (within 10 to 
14 days before the start of study drug). A serum pregnancy test must also be performed at baseline 
(within 24 hours before the start of study drug). A WOCPB is a sexually mature female who: 
1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally 
postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) 
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for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive 
months).
During the study, if a menstrual period is delayed, absence of pregnancy in WOCBP must be 
confirmed by serum pregnancy test. Pregnancy tests may also be repeated during the study upon
request by an IRB or if required by local regulations. 
A urine pregnancy test is required in WOCBP at designated treatment visits (Appendix A) and also 
at the follow-up visit. 
9.4.9
Concomitant Medications and Procedures
Any prior or concomitant medication a patient has had within 21 days before TAK-079
administration and up to 30 days after the last dose of TAK-079 (or the start of subsequent 
anticancer therapy, whichever occurs first) will be recorded on the eCRF. Trade name and 
international nonproprietary name (if available), indication, and start and end dates of the 
administered medication will be recorded. Medications used by the patient and therapeutic 
procedures completed by the patient will be recorded in the eCRF. See Section 8.5 and Section 8.6
for a list of medications and therapies that are prohibited or allowed during the study.
9.4.10 AEs
Monitoring of TEAEs, serious and nonserious, will be conducted throughout the study as specified 
in the SOE. Refer to Section 10.0 for details regarding definitions, documentation, and reporting of 
TEAEs and SAEs.
9.4.11
Enrollment
A patient is considered to be enrolled in the study at the first injection.
Procedures for completing the enrollment information are described in the Study Manual.
9.4.12
ECG
A single ECG will be collected at the screening visit for assessment of eligibility. A qualified 
person will interpret the ECG.
Time-matched triplicate 12-lead ECGs and PK samples will be collected in this study during 
Cycles 1 and 2 as specified in Appendix B. Although the number of scheduled ECG measurements 
will not be increased, the timing may be changed if emerging data indicate that an alteration in the 
ECG schedule is needed. Triplicate ECGs will be recorded electronically and transmitted to a 
central vendor for storage. 
The triplicate ECG measurements should be completed before the PK blood draw. Collection of 
triplicate ECGs should begin after the patient has rested in supine position for approximately 
5 minutes. Each ECG recording of the triplicate ECGs should occur within 3 minutes of each other 
and over a 10-minute window. It is recommended that patients refrain from eating or limit 
themselves to bland food for 1 hour before dosing and for 1 hour before each scheduled triplicate 
ECG measurement.
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Table 9.a
Clinical Chemistry and Hematology Tests
Hematology
Serum Chemistry
ANC
Hematocrit
Hemoglobin
Platelet (count) 
Reticulocyte count
RBC count
WBC count 
WBC with differential
Coagulation panel
Albumin
ALP
ALT
AST
Bilirubin (total)
BUN
Calcium
Chloride
CO2 (bicarbonate) 
Creatinine
Creatinine clearance
CRP
Glucose (nonfasting)
GGT
LDH
Phosphate
Potassium
Sodium
Total protein
Urate (uric acid)
ALP=alkaline phosphatase; ALT=alanine aminotransferase; ANC=absolute neutrophil count; AST=serine 
aminotransferase; BUN=blood urea nitrogen; CRP=C-reactive protein; GGT=γ-glutamyl transferase; LDH=lactate 
dehydrogenase RBC=red blood cell; WBC=white blood cell.
Table 9.b
Clinical Urinalysis Tests
Urinalysis
Bilirubin
Glucose
Ketones
Leukocytes
Nitrite
Occult blood
pH
Protein
Specific gravity
Turbidity and color
Urobilinogen
For estimation of creatinine clearance, the Cockcroft-Gault formula will be employed as follows:
	
 
	
 
		
= [(140 −
) • 	 () ] / [72 • 
! 
	
 (/")] 
For female patients, the result of the formula above should be multiplied by 0.85. 
9.4.13.2 Prestudy Prognostic Risk Assessment
A blood sample will be collected for serum 2 microglobulin at screening to assess patient disease 
status. Results will be analyzed locally.
9.4.14
Disease Response Assessments
Patients will be assessed for disease response according to the IMWG for MM ([9,10]; 
Appendix E).
Serum and urine response assessments will be performed no later than the first day of every 
treatment cycle, before the patient receives treatment with TAK-079.
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Imaging tests as specified in Appendix A are to be performed as defined below or when there is a 
need to document a response or a disease progression. Response and relapse categories are 
described in Appendix E. Imaging tests will be taken during the screening phase prior to treatment 
and every 6 cycles thereafter until PD or intolerance. Additional surveys (x-ray, CT, or MRI) will 
be performed at the investigator’s discretion (eg, in case of bone pain) to document a response or 
progressive disease. The same imaging technique should be used throughout the study to facilitate 
consistent disease assessment. 
CR should be confirmed with follow-up assessments of SPEP, UPEP, immunofixation of blood 
and urine, and serum FLCs as outlined in Appendix A. One BMA assessment has to occur to 
document CR; no second bone marrow confirmation is needed.
Note that to determine a response of sCR, BMA immunohistochemistry or immunofluorescence 
for kappa:lambda ratio, as well as serum FLC assay, should be performed for all patients 
suspected to be in CR to meet this response category’s requirements.
PD may be confirmed per standard clinical practice at the site. Local laboratory results may be 
used to confirm PD.
9.4.14.1 Computed Tomography/Magnetic Resonance Imaging
For patients with documented extramedullary disease, a whole body x-ray, positron emission 
tomography-computed tomography (PET-CT) scan, computed tomography (CT) scan (includes 
low-dose CT), or magnetic resonance imaging (MRI) scan will be performed at screening (if the 
patient has adequate image test performed within 5 weeks of the planned first dose of study drug, 
that image be used as baseline and does not need to be repeated as part of screening) as needed for 
evaluation of disease. If disease is documented, then a repeat PET-CT scan, CT scan, or MRI scan 
should be performed as required to document response or PD.
Scans will be performed at screening and at the EOT/early termination visit. All treatment phase 
and follow-up scans should use the same imaging modality used at screening.
Surveys (x-ray, CT, or MRI) may also be performed at the investigator’s discretion, eg, in case of 
bone pain. The screening scan may be performed up to 21 days before first dose of TAK-079. 
Radiographs will be analyzed locally and reports maintained with the patient record for retrieval 
during monitoring visits.
9.4.14.2 Quantification of Immunoglobulins
A blood sample for quantification of Ig (IgM, IgG, and IgA) will be obtained at the screening visit, 
predose on Day 1 of every cycle, and at the follow-up visit. Analysis of Ig will be performed 
locally.
9.4.14.3 Quantification of M-Protein
A predose blood and 24-hour urine sample will be obtained at the screening visit, Day 1 of every 
cycle, and at the follow-up visit. Urine sampling at designated time points is required only if urine 
M-protein is measurable at Day 1.
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The samples will be tested locally. M-protein in serum and urine will be quantified by SPEP and 
UPEP.
9.4.14.4 Serum FLC Assay
Serum and urine samples will be obtained for serum and urine immunofixation tests at the 
screening visit, predose on Day 1 of every cycle, and at the follow-up visit for the serum FLC assay 
(including quantification of kappa and lambda chains and ratio). Blood samples will be analyzed 
locally.
9.4.14.5 Immunofixation of Serum and Urine
Serum and urine samples will be obtained for serum and urine immunofixation tests at the 
screening visit, predose on Day 1 of every cycle, at the follow-up visit, and to confirm CR.
Immunofixation testing will be performed in a local laboratory.
9.4.14.6 BMAs 
BMAs will be taken during the screening period and at the beginning of designated study visits at 
Cycles 2, 4, 7, and every 6 cycles thereafter (ie, 13, 19, 25, etc.) until PD or intolerance, as 
described in Appendix A for the BMA measurements. Requirements for BMA assessments to 
confirm disease responses are defined at the beginning (Section 9.4.14).
Central Laboratory Evaluations
Molecular Analyses and Cytogenetics
The sample of BMA obtained at screening will be used for molecular analyses and for evaluation 
of cytogenetics. For response assessment purposes, when a CR is suspected on laboratory values, a 
BMA is required to confirm a CR as per routine clinical practice. At the time of this procedure, 
1 sample is analyzed locally for evaluation of disease, while a separate aspirate sample must be 
sent directly to the central laboratory on the day of collection in accordance with the procedures 
outlined in the Study Manual/Laboratory Manual. 
It is also highly encouraged (optional) to perform an aspiration procedure for the same purpose in 
patients who achieve PR as best response.
An aspirate for molecular analysis will also be collected at the time of disease relapse. This sample 
will be collected at the time of PD confirmation, before starting a new therapy, and will be sent to 
the central laboratory for analysis.
Local Laboratory Evaluations
Disease Assessment
A BMA will be obtained at screening for disease assessment and at any time a BMA sample is 
obtained to assess CR or to investigate suspected PD. This evaluation will be performed locally. 
Determination of the kappa:lambda ratio by immunohistochemistry or immunofluorescence 
should be performed to assess for sCR when CR has been documented. 
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A standard BMA drawn before consent is acceptable provided it is collected within 5 weeks prior 
to the first dose. 
Cytogenetics
If a sufficient sample is available at screening, an additional BMA or bone marrow sample may 
also be submitted for cytogenetic evaluation to be analyzed locally, according to local standards, if 
the site has the capability to perform the analysis. These analyses should be performed at screening 
using fluorescence in situ hybridization and/or conventional cytogenetics (karyotype). The central 
laboratory cytogenetic results will be used for study analysis, whereas local laboratory cytogenetic 
results (where available) will be used only in instances when central laboratory results are not 
available.
9.4.15
, PK, 
, and Immunogenicity Samples
9.4.15.1 Primary Specimen Collection for PK, 
, and 
 Assessments
Blood samples will be collected via venipuncture or indwelling catheter at the time points detailed 
in Appendix B for the measurement of serum concentrations of TAK-079 and in Appendix A for 
.
The primary specimen collection is presented in Table 9.c. Details on sample handling, storage, 
shipment, and analysis are provided in the Laboratory Manual.
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Patients will have a follow-up visit 30 days after the last dose of study drug or prior to the start of 
subsequent alternative anticancer therapy, to permit the detection of any delayed AEs. Patients 
who discontinue study treatment for reasons other than PD will continue PFS follow-up every 4 
weeks from EOT until the occurrence of PD, death, loss to follow-up, consent withdrawal, study 
termination, or 12 months after LPLD. 
Patients will be followed every 12 weeks for OS until death, loss to follow-up, consent withdrawal, 
study termination, or 12 months after LPLD.
It is anticipated that the duration of the study will be approximately 48 months (4 years).
9.7
Discontinuation of Treatment With Study Drug and Patient Replacement
Study drug must be permanently discontinued for patients meeting any of the following criteria:

Patient experiences an AE or other medical condition that indicates to the investigator that 
continued participation is not in the best interest of the patient. 

Withdrawal by patient.

Female patient has confirmed pregnancy.
Treatment with study drug may also be discontinued for any of the following reasons:

AE/SAE.

Protocol deviation.

PD. 

Symptomatic deterioration. 

Unsatisfactory therapeutic response. 

Study terminated by sponsor.

Lost to follow-up.
Once study drug has been discontinued, all study procedures outlined for the EOT/early 
termination visit will be completed as specified in the SOE. The primary reason for study drug 
discontinuation will be recorded on the eCRF.
In phase 1, patients who do not receive 4 full doses of TAK-079 within the 28-day (±2) treatment 
window or the Day 29 (ie, Cycle 2 Day 1) assessment for reasons other than a DLT will be 
replaced. In phase 2a, patients who receive 1 or more injections of study drug will not be replaced. 
Note that some patients may discontinue study drug for reasons other than PD before completing 
the full treatment course; these patients will remain in the study for posttreatment assessments as 
outlined in the SOE until PD occurs.
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9.8
Withdrawal of Patients From Study
A patient may be withdrawn from the study for any of the following reasons:

Lost to follow-up.

Study terminated by sponsor.

Withdrawal by patient (mandatory immediate discontinuation of study agent).

Death. 

PD. 
The consequence of study withdrawal is that no new information will be collected from the 
withdrawn patient and added to the existing data or any database.
9.9
Study Compliance
Study drug will be administered only to eligible patients under the supervision of the investigator 
or identified subinvestigator(s). The appropriate study personnel will maintain records of study 
drug receipt and dispensing.
9.10
Posttreatment Follow-up Assessments (PFS and OS)
Patients who stop treatment for any reason other than progressive disease will continue to have 
progression-free follow-up visits (additional details in Section 9.6). Patients who discontinue 
study treatment for reasons other than PD will continue PFS follow-up every 4 weeks from EOT 
until the occurrence of PD, death, loss to follow-up, consent withdrawal, study termination, or 
12 months after LPLD, whichever occurs first.
Patients who stop treatment due to PD will continue to have OS visits. Patients will be followed 
every 12 weeks for OS after documented PD until death, loss to follow-up, consent withdrawal, 
study termination, or 12 months after LPLD, whichever occurs first.
Survival information and death details may be collected by methods that include, but are not 
limited to, telephone, email, mail, or retrieval from online or other databases (eg, Social Security 
indexes). In addition, the start of another anticancer therapy for the disease under study will be 
collected.
See the SOE (Appendix A) for appropriate assessments during follow-up.
NOTE: All SAEs must be reported to the Takeda Global Pharmacovigilance department or 
designee. This includes deaths that the investigator considers related to study drug that occur 
during the posttreatment follow-up. Refer to Section 10.0 for details regarding definitions, 
documentation, and reporting of SAEs.
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10.0
ADVERSE EVENTS
10.1
Definitions
10.1.1 Pretreatment Event Definition
A pretreatment event is any untoward medical occurrence in a patient or subject who has signed 
informed consent to participate in a study but before administration of any study medication; it 
does not necessarily have to have a causal relationship with study participation.
10.1.2 AE Definition
AE means any untoward medical occurrence in a patient or subject administered a pharmaceutical 
product; the untoward medical occurrence does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product whether or not it is related to the medicinal product. This includes any 
newly occurring event, or a previous condition that has increased in severity or frequency since the 
administration of study drug.
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is considered 
by the investigator to be a clinically significant change from baseline.
10.1.3 SAE Definition
SAE means any untoward medical occurrence that at any dose:

Results in death.

Is life-threatening (refers to an AE in which the patient was at risk of death at the time of the 
event. It does not refer to an event which hypothetically might have caused death if it were 
more severe).

Requires inpatient hospitalization or prolongation of an existing hospitalization (see 
clarification in the paragraph in Section 10.2 on planned hospitalizations).

Results in persistent or significant disability or incapacity. (Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions).

Is a congenital anomaly/birth defect.

Is a medically important event. This refers to an AE that may not result in death, be 
immediately life threatening, or require hospitalization, but may be considered serious when, 
based on appropriate medical judgment, may jeopardize the patient, require medical or 
surgical intervention to prevent one of the outcomes listed above, or involves suspected 
transmission via a medicinal product of an infectious agent. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
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development of drug dependency or drug abuse; any organism, virus, or infectious particle 
(eg, prion protein transmitting transmissible spongiform encephalopathy), pathogenic or 
nonpathogenic, is considered an infectious agent.
In this study, intensity for each AE, including any lab abnormality, will be determined using the 
NCI CTCAE, Version 4.03, effective date 14 June 2010 [12]. Clarification should be made 
between an SAE and an AE that is considered severe in intensity (Grade 3 or 4), because the terms 
serious and severe are not synonymous. The general term severe is often used to describe the 
intensity (severity) of a specific event; the event itself, however, may be of relatively minor 
medical significance (such as a Grade 3 headache). This is not the same as serious, which is based 
on patient/event outcome or action criteria described above, and usually associated with events 
that pose a threat to a patient’s life or ability to function. A severe AE (Grade 3 or 4) does not 
necessarily need to be considered serious. For example, a white blood cell count of 1000/mm3 to 
<2000 mm3 is considered Grade 3 (severe) but may not be considered serious. Seriousness (not 
intensity) serves as a guide for defining regulatory reporting obligations.
10.2
Procedures for Recording and Reporting AEs and SAEs
All AEs spontaneously reported by the patient and/or in response to an open question from study 
personnel or revealed by observation, physical examination, or other diagnostic procedures will be 
recorded on the appropriate page of the eCRF (see Section 10.3 for the period of observation). Any 
clinically relevant deterioration in laboratory assessments or other clinical finding is considered an 
AE. When possible, signs and symptoms indicating a common underlying pathology should be 
noted as 1 comprehensive event.
Regardless of causality, SAEs and serious pretreatment events (as defined in Section 10.1) must be 
reported (see Section 10.3 for the period of observation) by the investigator to the Takeda Global 
Pharmacovigilance department or designee (contact information provided below). This should be 
done by faxing the SAE Form within 24 hours after becoming aware of the event. The SAE Form, 
created specifically by Takeda, will be provided to each clinical study site. A sample of the SAE 
Form may be found in the Study Manual. Follow-up information on the SAE or serious 
pretreatment event may be requested by Takeda. SAE report information must be consistent with 
the data provided on the eCRF.
SAE Reporting Contact Information
Cognizant
United States and Canada
Toll-free fax #: 1-800-963-6290
E-mail: takedaoncocases@cognizant.com
Planned hospital admissions or surgical procedures for an illness or disease that existed before 
study drug was given are not to be considered AEs unless the condition deteriorated in an 
unexpected manner during the trial (eg, surgery was performed earlier or later than planned).
For both serious and nonserious AEs, the investigator must determine both the severity (toxicity 
grade) of the event and the relationship of the event to study drug administration. For serious 
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pretreatment events, the investigator must determine both the severity (toxicity grade) of the event 
and the causality of the event in relation to study procedures.
Severity (toxicity grade) for each AE, including any lab abnormality, will be determined using the 
NCI CTCAE, version 4.03, effective date 14 June 2010 [12]. The criteria are provided in the Study 
Manual.
Relationship of the event to study drug administration (ie, its causality) will be determined by the 
investigator responding yes (related) or no (unrelated) to this question: “Is there a reasonable 
possibility that the AE is associated with the study drug?”
10.3
Monitoring of AEs and Period of Observation
AEs, both nonserious and serious, will be monitored throughout the study as follows:
AEs will be reported from the signing of informed consent through 30 days after administration of 
the last dose of study drug and recorded in the eCRFs. 
SAEs:

Serious pretreatment events will be reported to the Takeda Global Pharmacovigilance 
department or designee from the time of the signing of the ICF up to the first dose of study 
drug, and will also be recorded in the eCRF.

Related and unrelated treatment-emergent SAEs will be reported to the Takeda Global 
Pharmacovigilance department or designee from the first dose of study drug through 30 days 
after administration of the last dose of study drug and recorded in the eCRF. After this period, 
only related SAEs must be reported to the Takeda Global Pharmacovigilance department or 
designee. SAEs should be monitored until they are resolved or are clearly determined to be 
caused by a patient’s stable or chronic condition or intercurrent illness(es).
10.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events
If a woman becomes pregnant or suspects that she is pregnant while participating in this study, she 
must inform the investigator immediately and permanently discontinue study drug. The sponsor 
must also be contacted immediately by faxing a completed Pregnancy Form to the Takeda Global 
Pharmacovigilance department or designee (see Section 10.2). The pregnancy must be followed 
for the final pregnancy outcome.
If a female partner of a male patient becomes pregnant during the male patient’s participation in 
this study, the sponsor must also be contacted immediately by faxing a completed Pregnancy Form 
to the Takeda Global Pharmacovigilance department or designee (see Section 10.2). Every effort 
should be made to follow the pregnancy for the final pregnancy outcome.
10.5
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose)
A product complaint is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product. Individuals who 
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identify a potential product complaint situation should immediately report this via the phone 
numbers or email addresses provided below.
A medication error is a preventable event that involves an identifiable patient and that leads to 
inappropriate medication use, which may result in patient harm. Whereas overdoses and 
underdoses constitute medication errors, doses missed inadvertently by a patient do not. 
Individuals who identify a potential medication error (including overdose) situation should 
immediately report this via the phone numbers or email addresses provided below.
Product
Call Center
Phone Number
E-mail
Fax
TAK-079
DLSS
1-844-662-8532 
Non-toll-free 
number: 
1-510-740-1273 
GlobalOncologyMedinfo@takeda.com 
1-800-881-6092
Product complaints in and of themselves are not AEs. If a product complaint results in an SAE, an 
SAE Form should be completed and sent to Cognizant (refer to Section 10.2)
10.6
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, investigators, and IRBs or 
IECs as applicable, in accordance with national regulations in the countries where the study is 
conducted. Relative to the first awareness of the event by/or further provision to the sponsor or 
sponsor’s designee, SUSARs will be submitted to the regulatory authorities as an expedited report
within 7 days for fatal and life-threatening events and 15 days for other serious events, unless 
otherwise required by national regulations. The sponsor will also prepare an expedited report for 
other safety issues where these might materially alter the current benefit-risk assessment of an 
investigational medicinal product or that would be sufficient to consider changes in the 
investigational medicinal product’s administration or in the overall conduct of the trial. The 
investigational site also will forward a copy of all expedited reports to his or her IRB or IEC in 
accordance with national regulations.
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11.0
STUDY-SPECIFIC COMMITTEES
No steering committee, external data safety monitoring committee, or clinical endpoint committee 
will be used in this study.
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12.0
DATA HANDLING AND RECORDKEEPING 
The full details of procedures for data handling will be documented in the data management plan. 
If selected for coding, AEs, pretreatment events, medical history, and concurrent conditions will 
be coded using the Medical Dictionary for Regulatory Activities (MedDRA). Drugs will be coded 
using the World Health Organization Drug Dictionary.
12.1
eCRFs 
Completed eCRFs are required for each patient who signs an ICF.
The sponsor or its designee will supply investigative sites with access to eCRFs and will make 
arrangements to train appropriate site staff in the use of the eCRF. These forms are used to transmit 
the information collected in the performance of this study to the sponsor, CRO partners, and 
regulatory authorities. Investigative sites must complete eCRFs in English.
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site.
Any change of, modification of, or addition to the data on the eCRFs should be made by the 
investigator or appropriate site personnel. Corrections to eCRFs are recorded in an audit trail that 
captures the old information, the new information, identification of the person making the 
correction, the date the correction was made, and the reason for change.
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the principal investigator must retain 
full responsibility for the accuracy and authenticity of all data entered on the eCRFs.
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The sponsor or its designee will be permitted to review the patient’s medical 
and hospital records pertinent to the study to ensure accuracy of the eCRFs. The completed eCRFs 
are the sole property of the sponsor and should not be made available in any form to third parties, 
except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the sponsor.
12.2
Record Retention
The investigator agrees to keep the records stipulated in Section 12.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating patients, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated ICFs, patient authorization forms regarding the use of 
personal health information (if separate from the ICFs), electronic copy of eCRFs, including the 
audit trail, and detailed records of drug disposition to enable evaluations or audits from regulatory 
authorities, the sponsor or its designees. Any source documentation printed on degradable thermal 
sensitive paper should be photocopied by the site and filed with the original in the patient’s chart to 
ensure long-term legibility. Furthermore, ICH E6 Section 4.9.5 requires the investigator to retain 
essential documents specified in ICH E6 (Section 8) until at least 2 years after the last approval of 
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a marketing application for a specified drug indication being investigated or, if an application is 
not approved, until at least 2 years after the investigation is discontinued and regulatory authorities 
are notified. In addition, ICH E6 Section 4.9.5 states that the study records should be retained until 
an amount of time specified by applicable regulatory requirements or for a time specified in the 
Clinical Study Site Agreement between the investigator and sponsor.
Refer to the Clinical Study Site Agreement for the sponsor’s requirements on record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of any 
such documents.
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summarized. The effect of immunogenicity on PK, safety, and efficacy will be examined. NABs
may also be assessed in patients.
The immunogenicity of TAK-079 will be assessed by determining anti–TAK-079 antibody 
incidence and characteristics (eg, titer, transiently, and persistently ADA; and possible 
neutralizing activity). Analysis will be based on available data from patients with a baseline 
assessment and at least 1 postbaseline immunogenicity assessment. Summaries will be provided 
separately for each study phase and by dose, as applicable. The incidence of immunogenicity will 
be calculated. The impact of anti–TAK-079 antibodies on the PK profile, drug efficacy, and 
clinical safety will be evaluated, if possible.
13.1.7 Safety Analysis
The safety and tolerability of TAK-079 will be assessed by the recording and analysis of TEAEs 
(NCI CTCAE version 4.03; [12]), vital signs, physical examination, serum chemistry and 
hematology, urinalysis, ECG, and concomitant medications.
TEAEs will be summarized using the safety analysis set and will be coded using the MedDRA. 
Data will be summarized using preferred term and primary system organ class.
In the phase 2a portion of this study, Grade 4 or higher nonhematological toxicity will be monitored 
starting from the first 10 enrolled patients and then every 10 patients. If the stopping bounds of ≥4/10 
and ≥6/20 have been reached, accrual to the study will be suspended to allow for investigation. After 
consideration by the study team, a decision will be made as to whether accrual can be resumed. The 
bounds are based on a Bayesian strategy to monitor outcomes in clinical trials. If the stopping rule is 
met, there is 80% probability that the true toxicity rate is greater than 18% with a prior beta distribution 
with parameters 0.4 and 1.6 for the binomially distributed toxicity rate [13].
13.2
Interim Analysis and Criteria for Early Termination
No interim analysis is planned.
13.3
Determination of Sample Size
It is expected that approximately 42 patients will be enrolled in total for phase 1 and 2a combined. 
Once the RP2D is determined in phase 1, approximately 18 patients will be treated in phase 2a to 
provide a preliminary estimate of the ORR in patients with r/r MM.
A 3+3 dose escalation schema will be used for dose escalation as described in Section 8.3.2.
A group of 3 to 6 patients will be enrolled in each TAK-079 dose cohort based on safety, clinical, 
PK, 
 data. Each patient will participate in only 1 dose cohort. The actual 
dose levels may be adjusted based on the observed safety profile. 
Additional patients may be enrolled in a limited cohort expansion to confirm the safety and 
 before the phase 2a of this study is opened to enrollment. 
Approximately 6 dose levels are planned. For phase 1, the number of patients is planned to be 
approximately 24.
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In phase 2a, up to a total of 18 patients will be treated to provide a preliminary estimate of the ORR 
in patients with r/r MM. All patients must show a clear evidence of PD with anti-CD38 therapy. 
Phase 2a of the study will also provide a more robust estimate of the safety profile to determine 
whether the MTD is appropriate for future studies as the RP2D.
No prospective calculations of statistical power have been made; however, Table 13.a shows the 
width of the 80% CI, based on the observed ORR in a cohort size of 18 patients, for a range of 
observed response rates. An observed ORR greater than 20% would be of interest in this 
relapse/refractory population.
Table 13.a
80% Confidence Interval Based on the Observed ORR
N=18 patients.
ORR=overall response rate.
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14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
Study Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and institution guarantee access to source documents by the sponsor or its 
designee (CRO) and by the IRB or IEC.
All aspects of the study and its documentation will be subject to review by the sponsor or designee 
(as long as blinding is not jeopardized), including but not limited to the Investigator’s Binder, 
study medication, patient medical records, informed consent documentation, documentation of 
patient authorization to use personal health information (if separate from the ICFs), and review of 
eCRFs and associated source documents. It is important that the investigator and other study 
personnel are available during the monitoring visits and that sufficient time is devoted to the 
process.
14.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study patients. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the sponsor or 
designee (and IRB or IEC, as required) to determine the appropriate course of action. There will be 
no exemptions (a prospectively approved deviation) from the inclusion or exclusion criteria.
The site should document all protocol deviations in the patient’s source documents. In the event of 
a significant deviation, the site should notify the sponsor or its designee (and IRB or IEC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the patient, or confound interpretation of primary study 
assessment. A Protocol Deviation Form should be completed by the site and signed by the sponsor 
or designee for any significant deviation from the protocol.
14.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the FDA, the United Kingdom Medicines and Healthcare 
products Regulatory Agency, the Pharmaceuticals and Medical Devices Agency of Japan). If the 
study site is contacted for an inspection by a regulatory body, the sponsor should be notified 
immediately. The investigator and institution guarantee access for quality assurance auditors to all 
study documents as described in Section 14.1.
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15.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, patients) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct 
the study according to applicable local or regional regulatory requirements and align his or her 
conduct in accordance with the “Responsibilities of the Investigator” that are listed in Appendix C. 
The principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities.
15.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable federal/local requirements of each 
participating region. The sponsor or designee will require documentation noting all names and 
titles of members who make up the respective IRB or IEC. If any member of the IRB or IEC has 
direct participation in this study, written notification regarding his or her abstinence from voting 
must also be obtained. Those American sites unwilling to provide names and titles of all members 
due to privacy and conflict of interest concerns should instead provide a Federal Wide Assurance 
Number or comparable number assigned by the Department of Health and Human Services.
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the IB, a copy of the ICF, and if
applicable, patient recruitment materials and/or advertisements and other documents required by 
all applicable laws and regulations, must be submitted to a central or local IRB or IEC for 
approval. The IRB’s or IEC’s written approval of the protocol and patient informed consent must 
be obtained and submitted to the sponsor or designee before commencement of the study (ie, 
before shipment of the sponsor-supplied drug or study-specific screening activity). The IRB or 
IEC approval must refer to the study by exact protocol title, number, and version date; identify 
versions of other documents (eg, ICF) reviewed; and state the approval date. The sponsor will ship 
drug the sponsor has confirmed the adequacy of site regulatory documentation and, when 
applicable, the sponsor has received permission from competent authority to begin the trial. Until 
the site receives notification, no protocol activities, including screening, may occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the ICF, recruitment 
materials intended for viewing by patients, local safety reporting requirements, reports, and 
updates regarding the ongoing review of the study at intervals specified by the respective IRB or 
IEC, and submission of the investigator’s final status report to IRB or IEC. All IRB and IEC 
approvals and relevant documentation for these items must be provided to the sponsor or its 
designee.
Subject incentives should not exert undue influence for participation. Payments to patients must be 
approved by the IRB or IEC and sponsor.
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15.2
Patient Information, Informed Consent, and Patient Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The ICF, patient authorization form (if applicable), and patient
information sheet (if applicable) describe the planned and permitted uses, transfers, and 
disclosures of the patient’s personal and personal health information for purposes of conducting 
the study. The ICF and the patient information sheet (if applicable) further explain the nature of the 
study, its objectives, and potential risks and benefits, as well as the date informed consent are 
given. The ICF will detail the requirements of the participant and the fact that he or she is free to 
withdraw at any time without giving a reason and without prejudice to his or her further medical 
care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the ICF 
and if applicable, the patient authorization form. The ICF, patient authorization form (if 
applicable), and patient information sheet (if applicable) must be approved by both the IRB or IEC 
and the sponsor prior to use.
The ICF, patient authorization form (if applicable), and patient information sheet (if applicable) 
must be written in a language fully comprehensible to the prospective patient. It is the 
responsibility of the investigator to explain the detailed elements of the ICF, patient authorization 
form (if applicable), and patient information sheet (if applicable) to the patient. Information should 
be given in both oral and written form whenever possible and in the manner deemed appropriate by 
the IRB or IEC. In the event the patient is not capable of rendering adequate written informed 
consent, then the patient’s legally acceptable representative may provide such consent for the 
patient in accordance with applicable laws and regulations.
The patient, or the patient’s legally acceptable representative, must be given ample opportunity to: 
(1) inquire about details of the study and (2) decide whether or not to participate in the study. If the 
patient, or the patient’s legally acceptable representative, determines he or she will participate in 
the study, then the ICF and patient authorization form (if applicable) must be signed and dated by 
the patient, or the patient’s legally acceptable representative, at the time of consent and prior to the 
patient entering into the study. The patient or the patient’s legally acceptable representative should 
be instructed to sign using their legal names, not nicknames, using blue or black ballpoint ink. The 
investigator must also sign and date the ICF and patient authorization (if applicable) at the time of 
consent and prior to patient entering into the study; however, the sponsor may allow a designee of 
the investigator to sign to the extent permitted by applicable law.
Once signed, the original ICF, patient authorization form (if applicable), and patient information
sheet (if applicable) will be stored in the investigator’s site file. The investigator must document 
the date the patient signs the informed consent in the patient’s medical record. Copies of the signed 
ICF, the signed patient authorization form (if applicable), and patient information sheet (if 
applicable) shall be given to the patient.
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All revised ICFs must be reviewed and signed by relevant patients or the relevant patient’s legally 
acceptable representative in the same manner as the original informed consent. The date the 
revised consent was obtained should be recorded in the patient’s medical record, and the patient
should receive a copy of the revised ICF.
15.3
Patient Confidentiality
The sponsor and designees affirm and uphold the principle of the patient’s right to protection 
against invasion of privacy. Throughout this study, a patient’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited patient attributes, such as sex, age, or date 
of birth, and patient initials may be used to verify the patient and accuracy of the patient’s unique 
identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, the FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the patient’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a patient’s study participation, 
and autopsy reports. Access to a patient’s original medical records requires the specific 
authorization of the patient as part of the informed consent process (see Section 15.2).
Copies of any patient source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, patient name, address, and other identifier fields 
not collected on the patient’s eCRF).
15.4
Publication, Disclosure, and Clinical Trial Registration Policy
15.4.1 Publication 
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the Clinical Study Site Agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
this section and the Clinical Study Site Agreement. In the event of any discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail.
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15.4.2 Clinical Trial Registration
To ensure that information on clinical trials reaches the public in a timely manner and to comply 
with applicable laws, regulations and guidance, Takeda will, at a minimum register interventional 
clinical trials it sponsors anywhere in the world on ClinicalTrials.gov or other publicly accessible 
websites on or before start of study, as defined in Takeda Policy/Standard. Takeda contact 
information, along with investigator’s city, state (for America’s investigators), country, and 
recruiting status will be registered and available for public viewing. 
As needed, Takeda and investigator/site contact information may be made public to support 
participant access to trials via registries. In certain situations/registries, Takeda may assist 
participants or potential participants to find a clinical trial by helping them locate trial sites closest 
to their homes by providing the investigator name, address, and phone number via email/phone or 
other methods callers requesting trial information. Once patients receive investigator contact 
information, they may call the site requesting enrollment into the trial. The investigative sites are 
encouraged to handle the trial inquiries according to their established patient screening process. If 
the caller asks additional questions beyond the topic of trial enrollment, they should be referred to 
the sponsor. 
Any investigator who objects to Takeda providing this information to callers must provide Takeda 
with a written notice requesting that their information not be listed on the registry site. 
15.4.3 Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites (including the Takeda corporate site) and registries, as required by Takeda 
Policy/Standard, applicable laws and/or regulations.
Data Sharing
The sponsor is committed to responsible sharing of clinical data with the goal of advancing 
medical science and improving patient care. Qualified independent researchers will be permitted 
to use data collected from patients during the study to conduct additional scientific research, which 
may be unrelated to the study drug or the patient’s disease. The data provided to external 
researchers will not include information that identifies patients personally. 
15.5
Insurance and Compensation for Injury
Each patient in the study must be insured in accordance with the regulations applicable to the site 
where the patient is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to clinical study patients. 
Refer to the Clinical Study Site Agreement regarding the sponsor’s policy on patient compensation 
and treatment for injury. If the investigator has questions regarding this policy, he or she should 
contact the sponsor or sponsor’s designee.
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16.0
REFERENCES
1. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin 2014;64(1):9-29.
2. Chapman MA, Lawrence MS, Keats JJ, Cibulskis K, Sougnez C, Schinzel AC, et al. Initial 
genome sequencing and analysis of multiple myeloma. Nature 2011;471(7339):467-72.
3. Kumar SK, Lee JH, Lahuerta JJ, Morgan G, Richardson PG, Crowley J, et al. Risk of 
progression and survival in multiple myeloma relapsing after therapy with IMiDs and 
bortezomib: a multicenter international myeloma working group study. Leukemia 
2012;26(1):149-57.
4. Poh A. Multiple Myeloma Gets Three New Drugs. Cancer Discovery 2016;6(1):4.
5. DARZALEX (daratumumab) [prescribing informatoin]. USPI. Horsham, PA: Janssen 
Biotech, Inc., November, 2015.
6. Nijhof IS, Casneuf T, van Velzen J, van Kessel B, Axel AE, Syed K, et al. CD38 expression 
and complement inhibitors affect response and resistance to daratumumab therapy in 
myeloma. Blood 2016;128(7):959-70.
7. Malavasi F, Deaglio S, Funaro A, Ferrero E, Horenstein AL, Ortolan E, et al. Evolution and 
function of the ADP ribosyl cyclase/CD38 gene family in physiology and pathology. 
Physiological Reviews 2008;88(3):841-86.
8. Hendrikx J, Haanen J, Voest EE, Schellens JHM, Huitema ADR, Beijnen JH. Fixed Dosing of 
Monoclonal Antibodies in Oncology. Oncologist 2017.
9. Rajkumar SV, Harousseau JL, Durie B, Anderson KC, Dimopoulos M, Kyle R, et al. 
Consensus recommendations for the uniform reporting of clinical trials: report of the 
International Myeloma Workshop Consensus Panel 1. Blood 2011;117(18):4691-5.
10. Palumbo A, Rajkumar SV, San Miguel JF, Larocca A, Niesvizky R, Morgan G, et al. 
International myeloma working group consensus statement for the management, treatment, 
and supportive care of patients with myeloma not eligible for standard autologous stem-cell 
transplantation. J Clin Oncol 2014;32(6):587-600.
11. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. American Journal of Clinical 
Oncology 1982;5(6):649-55.
12. Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03. U.S. Department 
of Health and Human Services National Cancer Institute. 14 June 2010.
13. Thall PF, Sung HG. Some extensions and applications of a Bayesian strategy for monitoring 
multiple outcomes in clinical trials. Statistics in Medicine 1998;17(14):1563-80.
14. Rajkumar SV. Multiple myeloma: 2014 Update on diagnosis, risk-stratification, and 
management. American Journal of Hematology 2014;89(10):998-1009.
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Appendix B
Pharmacokinetic Sampling Schedule
Pharmacokinetic Assessments: Cycle 1
Cycle 1
Day 1 (a)
Day 2
Day 3
Day 4
Day 8 (a)
Day 15 (a)
Day 22 (a)
Triplicate 
ECG (b)
PK
Triplicate 
ECG (b)
PK
Triplicate 
ECG (b)
PK
Triplicate 
ECG (b)
PK
PK
PK
PK
Predose (within 1 hour before first SC 
injection)
X
X
X
X
X
5 minutes after FINAL SC injection (±2 min)
X 
(c)
4 hours after first SC injection (±30 min)
X
6 hours after first SC injection (30 min)
X
X
8 hours after first SC injection (1 hour)
X
X
24 hours after first SC injection (2 hours)
X
X
48 hours after first SC injection (2 hours)
X
X
72 hours after first SC injection (2 hours)
X
X
ECG=electrocardiogram; PK=pharmacokinetic(s); SC=subcutaneous.
When the timing of a PK or safety laboratory blood sample coincides with the timing of ECG measurements, the ECG will be completed before the collection of the 
blood sample. The triplicate ECG measurements should be completed immediately before the corresponding PK blood draw. 
(a) The timing of the morning visits should occur at approximately the same time as the morning SC administration times on previous days of the cycle.
(b) Collection of triplicate ECGs should begin after the patient has rested in supine position for approximately 5 minutes. Each ECG recording of the triplicate 
ECGs should occur within 3 minutes of each other and over a 10-minute window.
(c) If multiple SC injections are required to administer the intended dose, this PK sample should be collected after administration of the final injection. All other 
assessments should be performed in reference to the first injection.
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Pharmacokinetic Assessments: Cycle 2
Cycle 2
Day 1 (a)
Day 2
Day 3
Day 4
Day 8 (a)
Day 15 (a)
Day 22 (a)
Triplicate 
ECG (b)
PK
Triplicate 
ECG (b)
PK
Triplicate 
ECG (b)
PK
Triplicate 
ECG (b)
PK
PK
PK
PK
Predose (within 1 hour before first SC 
injection)
X
X
X
X
X
5 minutes after FINAL SC injection (±2 min)
X 
(c)
4 hours after first SC injection (±30 min)
X
6 hours after first SC injection (30 min)
X
X
8 hours after first SC injection (1 hour)
X
X
24 hours after first SC injection (2 hours)
X
X
48 hours after first SC injection (2 hours)
X
X
72 hours after first SC injection (2 hours)
X
X
ECG=electrocardiogram; PK=pharmacokinetic(s); SC=subcutaneous.
When the timing of a PK or safety laboratory blood sample coincides with the timing of ECG measurements, the ECG will be completed before the collection of the 
blood sample. The triplicate ECG measurements should be completed immediately before the corresponding PK blood draw. 
(a) The timing of the morning visits should occur at approximately the same time as the morning SC administration times on previous days of the cycle.
(b) Collection of triplicate ECGs should begin after the patient has rested in supine position for approximately 5 minutes. Each ECG recording of the triplicate 
ECGs should occur within 3 minutes of each other and over a 10-minute window.
(c) If multiple SC injections are required to administer the intended dose, this PK sample should be collected after administration of the final injection. All other 
assessments should be performed in reference to the first injection.
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Pharmacokinetic Assessments: Cycle 3 to Cycle 10
Cycle 3 to Cycle 6
Cycle 7 to Cycle 10
Day 1 (a)
Day 15 (a)
Day 1 (a)
Predose (within 1 hour before first SC 
injection)
X 
X
X
PK=pharmacokinetic; SC=subcutaneous.
(a) The timing of the morning visits should occur at approximately the same time as the morning SC administration times on previous days of the cycle.
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Appendix C
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. 
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on investigators by the FDA are 
summarized in the “Statement of Investigator” (Form FDA 1572), which must be completed and 
signed before the investigator may participate in this study.
The investigator agrees to assume the following responsibilities by signing a Form FDA 1572:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff that will assist in the protocol.
3. Ensure that study-related procedures, including study-specific (nonroutine/nonstandard panel) 
screening assessments are NOT performed on potential patients, prior to the receipt of written 
approval from relevant governing bodies/authorities.
4. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
5. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to 
21 CFR Part 56, ICH, and local regulatory requirements.
6. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to patients. Make at least yearly reports on the progress of the study to the 
IRB/IEC, and issue a final report within 3 months of study completion.
7. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH and local 
regulations, are met.
8. Obtain valid informed consent from each patient who participates in the study, and document 
the date of consent in the patient’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each ICF should contain a patient authorization section that 
describes the uses and disclosures of a patient’s personal information (including personal 
health information) that will take place in connection with the study. If an ICF does not include 
such a patient authorization, then the investigator must obtain a separate patient authorization 
form from each patient or the patient’s legally acceptable representative.
9. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents.
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10. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
11. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor.
12. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.
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Appendix D
Investigator Consent to Use of Personal Information
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, United States, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study medication.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s own 
country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.
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Appendix E
IMWG Criteria 
IMWG Definition of MM

Clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary 
plasmacytoma* and any one or more of the following myeloma-deﬁning events:
–
Evidence of end organ damage that can be attributed to the underlying plasma cell 
proliferative disorder, specifically.
–
Hypercalcemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than the upper limit of 
the normal range or >2.75 mmol/L (>11 mg/dL).
–
Renal insuﬃciency: creatinine clearance <40 mL per min† or serum creatinine 
>177 μmol/L (>2 mg/dL).
–
Anemia: hemoglobin value of >20 g/L below the lower limit of normal, or a hemoglobin 
value <100 g/L.
–
Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CT‡.

Any one or more of the following biomarkers of malignancy:
–
Clonal bone marrow plasma cell percentage* ≥60%.
–
Involved: uninvolved serum free light chain ratio§ (FLC) ≥100.
–
>1 focal lesions on MRI studies.
* Clonality should be established by showing κλ light-chain restriction on ﬂow cytometry, immunohistochemistry, or 
immunoﬂuorescence. Bone marrow plasma cell percentage should preferably be estimated from a core biopsy 
specimen; in case of a disparity between the aspirate and core biopsy, the highest value should be used.
† Measured or estimated by validated equations.
‡ If bone marrow has less than 10% clonal plasma cells, more than 1 bone lesion is required to distinguish from 
solitary plasmacytoma with minimal marrow involvement.
§ These values are based on the serum Freelite assay (The Binding Site Group, Birmingham, United Kingdom). The 
involved FLC must be ≥100 mg/L. Each focal lesion must be 5 mm or greater in size [14].
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IMWG Uniform Criteria for Response
Category of 
Response
Response Criteria
sCR
Criteria for CR as defined below, with the addition of a normal FLC ratio, and an absence of 
clonal plasma cells by immunohistochemistry or 2- to 4-color flow cytometry; 2 consecutive 
assessments of laboratory parameters are needed (a).
CR
Negative immunofixation of serum and urine, disappearance of any soft tissue plasmacytomas, 
and <5% plasma cells in bone marrow; bone marrow; in patients for whom only measurable 
disease is by serum FLC level, normal FLC ratio of 0.26 to 1.65 in addition to CR criteria is 
required; 2 consecutive assessments are needed (b).
Immunophenotypic 
CR
sCR as defined, plus absence of phenotypically aberrant plasma cells (clonal) in bone marrow 
with minimum of 1 million total bone marrow cells analyzed by multiparametric ﬂow 
cytometry (with >4 colors).
Molecular CR
CR as deﬁned, plus negative allele-speciﬁc oligonucleotide polymerase chain reaction 
(sensitivity 10-5).
VGPR
Serum and urine M-protein detectable by immunofixation but not on electrophoresis, or ≥90% 
reduction in serum M-protein plus urine M-protein <100 mg/24 hours; in patients for whom 
only measurable disease is by serum FLC level, >90% decrease in difference between involved 
and uninvolved FLC levels, in addition to VGPR criteria, is required; 2 consecutive 
assessments are needed (c).
PR
≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to 
<200 mg/24 hours.
If the serum and urine M-protein are not measurable, a ≥50% decrease in the difference 
between involved and uninvolved FLC levels is required in place of the M-protein criteria.
If serum and urine M-protein are not measurable, and serum FLC is also not measurable, ≥50% 
reduction in bone marrow plasma cells is required in place of M-protein, provided the baseline 
percentage was ≥30%.
In addition to the above criteria, if present at baseline, ≥50% reduction in the size of soft tissue 
plasmacytomas is also required.
Two consecutive assessments are needed (a) no known evidence of progressive or new bone 
lesions if radiographic studies were performed.
Minimal response 
(MR) (b)
≥25% but ≤49% reduction of serum M-protein and reduction in 24-hour urine M-protein by 
50% to 89%.
In addition to the above criteria, if present at baseline, 25% to 49% reduction in the size of soft 
tissue plasmacytomas is also required.
No increase in size or number of lytic bone lesions (development of compression fracture does 
not exclude response).
SD (c)
Does not meet the response criteria for CR (any variant), VGPR, PR, MR, or PD; no known 
evidence of progressive or new bone lesions if radiographic studies were performed.
Source: Rajkumar SV et al, 2011 and Palumbo A et al, 2014 [9,10].
CR=complete response; FLC=free light chain; IMWG=International Myeloma Working Group; MR=minimal 
response; ORR=overall response rate; PR=partial response; sCR=stringent complete response; SD=stable disease; 
VGPR=very good partial response.
(a) Clonality should be established by showing κλ light-chain restriction on ﬂow cytometry, immunohistochemistry, 
or immunoﬂuorescence. Bone marrow plasma cell percentage should preferably be estimated from a core biopsy 
specimen; in case of a disparity between the aspirate and core biopsy, the highest value should be used.
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(b) For relapse-refractory myeloma only.
(c) These categories do not contribute to the ORR.
Before the institution of any new therapy, sCR, CR, and VGPR categories require serum and urine 
studies regardless of whether disease at baseline was measurable on serum, urine, both, or neither. 
Radiographic studies are not required to satisfy these response requirements. Bone marrow 
assessments need not be conﬁrmed.
PD is defined as an increase of ≥25% from lowest response value in any of the following:
a) Serum M-protein (absolute increase must be ≥0.5 g/dL); serum M component increases 
≥1 g/dL are sufficient to deﬁne relapse if starting M component is ≥5 g/dL), and/or
b) Urine M-protein (absolute increase must be ≥200 mg/24 hour), and/or
c) Only in patients without measurable serum and urine M-protein levels: the difference between 
involved and uninvolved FLC levels (absolute increase must be >10 mg/dL).
d) Only in patients without measurable serum and urine M-protein levels and without measurable 
disease by FLC levels, bone marrow plasma cell percentage (absolute percentage must be 
≥10%).
OR
a) Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in 
the size of existing bone lesions or soft tissue plasmacytomas.
b) Development of hypercalcemia (corrected serum calcium >11.5 mg/dL) that can be attributed 
solely to the plasma cell proliferative disorder.
A diagnosis of PD must be confirmed by 2 consecutive assessments.
Clarifications to IMWG criteria for coding PD: Bone marrow criteria for PD are to be used only in 
patients without measurable disease by M-protein and by FLC levels; “25% increase” refers to 
M-protein, FLC, and bone marrow results, and does not refer to bone lesions, soft tissue 
plasmacytomas, or hypercalcemia, and the “lowest response value” does not need to be a 
confirmed value.
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Appendix F
ECOG Scale for Performance Status
Grade
Description
0
Normal activity. Fully active, able to carry on all predisease performance without restriction.
1
Symptoms but ambulatory. Restricted in physically strenuous activity, but ambulatory and able to 
carry out work of a light or sedentary nature (eg, light housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, but unable to carry out any work 
activities. Up and about more than 50% of waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair.
5
Dead.
Source: Oken MM et al, 1982 [11].
ECOG=Eastern Cooperative Oncology Group.
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Appendix G
Detailed Description of Amendments to Text
The primary sections of the protocol affected by the changes in Amendment 01 are indicated. The 
corresponding text has been revised throughout the protocol. 
Change 1: The number of TAK-079 dose levels planned for phase 1 was changed to 6. The 
400 mg dose level was removed, and the 300 and 600 mg dose levels were added.
The primary change occurs in Section 8.3.1 Dose Levels:
Initial 
wording:
Phase 1
TAK-079 injections will be escalated as follows:

45 mg, once weekly for 8 weeks (8 doses), once every 2 weeks for 16 weeks (8 
doses), and once every 4 weeks thereafter until PD, unacceptable toxicities, or 
withdrawal due to other reasons.

135 mg, once weekly for 8 weeks (8 doses), once every 2 weeks for 16 weeks (8 
doses), and once every 4 weeks thereafter until PD, unacceptable toxicities, or 
withdrawal due to other reasons.

400 mg, once weekly for 8 weeks (8 doses), once every 2 weeks for 16 weeks (8 
doses), and once every 4 weeks thereafter until PD, unacceptable toxicities, or 
withdrawal due to other reasons.

1200 mg once weekly for 8 weeks (8 doses), once every 2 weeks for 16 weeks (8 
doses), and once every 4 weeks thereafter until PD, unacceptable toxicities, or 
withdrawal due to other reasons.

1800 mg once weekly for 8 weeks (8 doses), once every 2 weeks for 16 weeks (8 
doses), and once every 4 weeks thereafter until PD, unacceptable toxicities, or 
withdrawal due to other reasons.
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Amended 
or new 
wording:
Phase 1
TAK-079 injections will be escalated as follows:

45 mg, once weekly for 8 weeks (8 doses), once every 2 weeks for 16 weeks (8 
doses), and once every 4 weeks thereafter until PD, unacceptable toxicities, or 
withdrawal due to other reasons.

135 mg, once weekly for 8 weeks (8 doses), once every 2 weeks for 16 weeks (8 
doses), and once every 4 weeks thereafter until PD, unacceptable toxicities, or 
withdrawal due to other reasons.

400 mg 300 mg, once weekly for 8 weeks (8 doses), once every 2 weeks for 16 
weeks (8 doses), and once every 4 weeks thereafter until PD, unacceptable 
toxicities, or withdrawal due to other reasons.

600 mg, once weekly for 8 weeks (8 doses), once every 2 weeks for 16 weeks (8 
doses), and once every 4 weeks thereafter until PD, unacceptable toxicities, or 
withdrawal due to other reasons.

1200 mg once weekly for 8 weeks (8 doses), once every 2 weeks for 16 weeks (8 
doses), and once every 4 weeks thereafter until PD, unacceptable toxicities, or 
withdrawal due to other reasons.

1800 mg once weekly for 8 weeks (8 doses), once every 2 weeks for 16 weeks (8 
doses), and once every 4 weeks thereafter until PD, unacceptable toxicities, or 
withdrawal due to other reasons.
Rationale for Change:
This change was made in response to regulatory feedback from FDA regarding the dose escalation 
schedule in the original protocol.
The following sections also contain this change:

Section 2.0 STUDY SUMMARY.

Section 4.4.1 Rationale for the Starting Dose of TAK-079.

Section 6.1 Overview of Study Design.

Section 13.3 Determination of Sample Size.
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Change 2: Planned enrollment was increased to 24 patients for the phase 1 portion (42 patients 
overall).
The primary change occurs in Section 6.2 Number of Patients:
Initial 
wording:
For phase 1, approximately 21 patients are planned to be enrolled, including the 
expansion of additional patients in selected cohorts to further inform selection of the 
RP2D. For phase 2a, approximately 18 patients are planned.
Amended 
or new 
wording:
For phase 1, approximately 21 24 patients are planned to be enrolled, including the 
expansion of additional patients in selected cohorts to further inform selection of the 
RP2D. For phase 2a, approximately 18 patients are planned.
Rationale for Change:
This change was made to reflect the revised number of planned dose escalation levels in the 
phase 1 portion of the study.
The following sections also contain this change:

Section 2.0 STUDY SUMMARY.

Section 6.1 Overview of Study Design.

Section 13.3 Determination of Sample Size.
Change 3: Eligibility based on laboratory criteria for determining adequate organ function was 
clarified for patients with Gilbert’s syndrome.
The primary change occurs in Section 7.1 Inclusion Criteria Table 7.b Laboratory Criteria for 
Determining Adequate Organ Function for Study TAK-079-1501 Eligibility:
Initial 
wording:
Total serum bilirubin
≤1.5×ULN; an exception for patients with Gilbert’s syndrome may be 
granted after discussion with the sponsor
Amended 
or new 
wording:
Total serum bilirubin
≤1.5×ULN; an exception except for patients with Gilbert’s syndrome may 
be granted after discussion with the sponsor in whom direct bilirubin 
should be <2.0×ULN
Rationale for Change:
This change was made to clarify the bilirubin eligibility criteria for patients with Gilbert’s 
syndrome.
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Change 4: Inclusion criteria were modified to revise requirements for prior myeloma therapies 
and assessment of CD38 expression
The primary change occurs in Section 7.1 Inclusion Criteria:
Initial 
wording:
12. Previously received at least 2 lines of standard therapy (including both an IMiD 
and a PI), and is either refractory to or intolerant of at least one of these regimens. 
Prior treatment with an anti-CD38 mAb is allowed; however, CD38 expression 
must be significantly expressed on target cells for this mechanism of action to be 
effective.
Amended 
or new 
wording:
12. Previously received at least 2 lines of standard therapy (including both an IMiD 
and a PI), and is either refractory to or intolerant of at least one of these regimens. 
Prior treatment with an anti CD38 mAb is allowed; however, CD38 expression 
must be significantly expressed on target cells for this mechanism of action to be 
effective. Prior therapy should meet all of the following criteria:

Patient should be previously treated with at least a PI, an IMid, an 
alkylating agent, and a steroid.

Patient should be refractory or intolerant to at least 1 PI and at least 1
IMid.

Patient should either have received ≥3 prior lines of therapy or should 
have received at least 2 prior lines of therapy if one of those lines included 
a combination of PI and IMid. 

Previous exposure to an anti-CD38 agent, as a single agent or in 
combination, is allowed but is not required.
13. Patients must express CD38 on target cells with a mean fluorescence intensity 
≥1000 units on ≥90% of plasma cells as determined by multicolor flow 
cytometry.
Rationale for Change:
This change was made in response to an FDA request to modify the inclusion criteria to evaluate a 
later line of prior therapy, to maintain enrollment with at least 3 lines of prior therapy given that 
single-agent lines of therapy are still available as treatment options, and to respond to an FDA 
request for further detail regarding assessment of CD38 expression.
The following sections also contain this change:

Section 2.0 STUDY SUMMARY.

Section 9.4.13 Clinical Laboratory Evaluations. 
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Change 9: The definition of dose-limiting toxicities (DLTs) was modified to exclude relationship 
in determining a DLT, to include Grade 4 laboratory abnormalities clearly unrelated to the 
underlying disease as DLTs, and to note that events clearly due to extraneous causes will not be 
considered DLTs.
The primary change occurs in Section 8.2 Definitions of DLT:
Initial 
wording:
DLT will be defined as any of the following events that are considered by the 
investigator to be at least possibly related to therapy with TAK-079.

Nonhematologic TEAEs of NCI CTCAE Grade ≥3 clearly unrelated to the 
underlying disease and occurring during the first cycle will be considered DLTs 
(see Section 10.2 for relatedness guidance), with the following exceptions:
–
Asymptomatic laboratory changes (other than renal and hepatic laboratory 
values, and Grade 4 lipase/amylase) that can be successfully supplemented 
(reversion of Grade 4 events to Grade ≤2, reversion of Grade 3 events to Grade 
≤1 or baseline) within 72 hours.
–
Grade 3 nausea/vomiting that can be managed subsequently with anti-emetics 
(Grade 3 nausea or vomiting that persists beyond 48 hours with or without 
appropriate medical intervention will be considered a DLT).
–
Grade 3 fatigue lasting less than 72 hours.
–
Grade 3 elevation of ALT or AST that resolves to Grade ≤1 or baseline within 
7 days.
–
Grade 3 IR that responds to symptomatic treatment (eg, antihistamines, 
nonsteroidal anti-inflammatory drugs (NSAIDs), narcotics, IV fluids), without 
recurrence of Grade 3 symptoms.

Hematologic TEAEs of NCI CTCAE Grade ≥4 clearly unrelated to the underlying 
disease and occurring during the first cycle will be considered DLTs, with the 
following exceptions:
–
Grade ≥3 hemolysis clearly unrelated to the underlying disease (eg, negative 
direct Coombs test) will be included in the definition of DLT.
–
Grade 3 low platelet or higher count with clinically meaningful bleeding will 
be included in the definition of DLT.
–
Grade 4 low platelet count of duration <2 weeks will not be included in the 
definition of DLT.
–
Grade 4 lymphopenia will not be included in the definition of DLT.

An incomplete recovery from treatment-related toxicity causing a >2-week delay 
in the next scheduled injection before the initiation of Cycle 2 will be considered a 
DLT.
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Amended 
or new 
wording:
DLTs will be defined as any of the following events that are considered by the 
investigator to be at least possibly related to therapy with TAK 079 regardless of 
relationship, except those events that are clearly due to extraneous causes.

Grade 4 laboratory abnormalities, except those events that are clearly due to 
extraneous causes, will be defined as a DLT.

Nonhematologic TEAEs of NCI CTCAE Grade 3 clearly unrelated to the 
underlying disease, except those events that are clearly due to extraneous 
causes, and occurring during the first cycle will be considered DLTs (see Section 
10.2 for relatedness guidance), with the following exceptions:
–
Asymptomatic laboratory changes (other than renal and hepatic laboratory 
values, and Grade 4 lipase/amylase) that can be successfully supplemented 
(reversion of Grade 4 events to Grade ≤2, reversion of Grade 3 events to Grade 
≤1 or baseline) within 72 hours.
–
Grade 3 nausea/vomiting that can be managed subsequently with anti-emetics 
(Grade 3 nausea or vomiting that persists beyond 48 hours with or without 
appropriate medical intervention will be considered a DLT).
–
Grade 3 fatigue lasting less than 72 hours.
–
Grade 3 elevation of ALT or AST that resolves to Grade ≤1 or baseline within 
7 days.
–
Grade 3 IR that responds to symptomatic treatment (eg, antihistamines, 
nonsteroidal anti-inflammatory drugs (NSAIDs), narcotics, IV fluids), without 
recurrence of Grade 3 symptoms.

Hematologic TEAEs of NCI CTCAE Grade ≥4 clearly unrelated to the underlying 
disease, except those events that are clearly due to extraneous causes, and 
occurring during the first cycle will be considered DLTs, with the following 
exceptions:
–
Grade ≥3 hemolysis clearly unrelated to the underlying disease, except those 
events that are clearly due to extraneous causes (eg, negative direct 
Coombs test), will be included in the definition of DLT.
–
Grade 3 low platelet or higher count with clinically meaningful bleeding will 
be included in the definition of DLT.
Grade 4 low platelet count of duration <2 weeks will not be included in the 
definition of DLT.
–
Grade 4 lymphopenia will not be included in the definition of DLT.

An incomplete recovery from treatment-related toxicity causing a >2-week delay 
in the next scheduled injection before the initiation of Cycle 2 will be considered a 
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DLT.
Rationale for Change:
This change was made in response to an FDA request for all AEs of specified grades to be counted 
as DLTs, regardless of investigator attribution or relatedness.
Change 10: The dose escalation schema was changed to a 3+3 design from a Bayesian logistic 
regression model.
The primary change occurs in Section 8.3.2 Escalation Schema:
Initial 
wording:
The Bayesian Logistic Regression Modeling (BLRM) method with overdose control 
will be used to inform dose escalation decisions and MTD/RP2D estimation. Initially, 
3 patients will be enrolled at the starting dose level.
The following rules will apply only for this initial dose level:

If none of the patients in a cohort of 3 patients exhibits a DLT during the 28-day 
cycle, then the dose may be escalated for the next cohort of 3 patients.

If 1 patient in a cohort of 3 patients exhibits a DLT, then that cohort will be 
expanded to a total of 6 patients.
–
If no additional patient in the expanded cohort of 6 exhibits a DLT, then the 
dose may be escalated for the next cohort of 3 patients (pending approval 
following review of available safety data).
–
If a second (or more) patient in the expanded cohort of 6 exhibits a DLT, then 
that cohort will be deemed to have exceeded the MTD, and dose escalation 
will be stopped (pending BLRM approval following review of available safety 
data).

If 2 or more patients in a cohort of 3 patients exhibit a DLT, then that cohort will 
be deemed to have exceeded the MTD, and dose escalation will be stopped.
Figure 8.a is a diagrammatical representation of the dose-escalation paradigm for the 
first cohort.
Figure 8.a
Dose-Escalation Scheme for Cohort 1
[Figure 8.a]
Once the dose is escalated above the starting dose level, BLRM will be used for all 
subsequent dose recommendations, along with consideration of other safety, clinical, 
PK, 
 data.
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Amended 
or new 
wording:
The Bayesian Logistic Regression Modeling (BLRM) method with overdose control
A 3+3 dose escalation schema will be used to inform dose escalation decisions and 
MTD/RP2D estimation. Initially, 3 patients will be enrolled at the starting dose level. 
The following rules will apply only for this initial dose level:

If none of the patients in a cohort of 3 patients exhibits a DLT during the 28-day 
cycle, then the dose may be escalated for the next cohort of 3 patients.

If 1 patient in a cohort of 3 patients exhibits a DLT, then that cohort will be 
expanded to a total of 6 patients.
If no additional patient in the expanded cohort of 6 exhibits a DLT, then the 
dose may be escalated for the next cohort of 3 patients (pending approval 
following review of available safety data).
If a second (or more) patient in the expanded cohort of 6 exhibits a DLT, then 
that cohort will be deemed to have exceeded the MTD, and dose escalation 
will be stopped (pending BLRM approval following review of available safety 
data).

If ≤1 of 6 patients experiences a DLT, escalation will continue to the next 
higher dose level, at which 3 patients will be enrolled.

If 2 or more patients in a cohort of 3 patients exhibit a DLT, then that cohort will 
be deemed to have exceeded the MTD, and dose escalation will be stopped. If 2 or 
more patients (2 or more out of 3, or 2 or more out of 6) experience a DLT, 
dosing will de-escalate to the next lower dose level, at which 3 additional 
patients will be enrolled if 3 patients have been treated at that dose level. If 6 
patients have been enrolled at the lower level with 1 or less DLT out of 6, 
dosing may stop and the lower dose level may be considered the MTD.
Figure 8.a is a diagrammatical representation of the dose-escalation paradigm for the 
first cohort.
Figure 8.a
Dose-Escalation Scheme for Cohort 1
[Figure 8.a remains unchanged]
Once the dose is escalated above the starting dose level, BLRM will be used for all 
subsequent dose recommendations, along with consideration of other safety, clinical, 
PK, 
 data.
Rationale for Change:
This change was made in response to an FDA request to revise the dose escalation schema; by 
using the traditional 3+3 dose escalation schema, the selected dose would have a toxicity rate near 
20% with range between 17% and 26% on average.
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The following sections also contain this change:

Section 2.0 STUDY SUMMARY.

Section 8.3.1 Dose Levels.

Section 13.3 Determination of Sample Size.
Change 11: Dose modification recommendations in the event of Grades 3 and 4 adverse events
were modified.
The primary change occurs in Section 8.4.2 Criteria for Dose Reduction Table 8.a Dose 
Modification Recommendations for TAK-079 Toxicities:
Initial 
wording:
Grade 3 AEs
Hold TAK-079 until resolution to Grade ≤1 or baseline, then resume 
treatment at either the same dose or a reduced dose level at the 
discretion of the investigator.
Grade 4 (life-threatening) AEs
Consider permanently withdrawing the patient from the study, except 
when the investigator determines that the patient is receiving clinical 
benefit and has discussed this with the sponsor. Treatment may be 
restarted at a reduced dose level or below when toxicity recovers to 
Grade ≤1 or baseline.
Amended 
or new 
wording:
Grade 3 AEs
Hold TAK 079 until resolution Patients with Grade 3 AEs 
considered related to study treatment should have study 
treatment interrupted until the AE resolves to Grade ≤1 or 
baseline, then resume treatment at either the same dose or a reduced 
dose level at the discretion of the investigator.
Grade 4 (life-threatening) AEs
Consider permanently withdrawing the patient from the study, except 
when the investigator determines that the patient is receiving clinical 
benefit and has discussed this with the sponsor. Treatment may be 
restarted at a reduced dose level or below when toxicity recovers to 
Grade ≤1 or baseline. Patients with Grade 4 AEs considered 
related to study treatment should permanently discontinue 
treatment.
Rationale for Change:
This change was made in response to an FDA request for the dose modification guidelines to be 
changed such that for Grade 3 nonhematologic toxicity, after resolution of the toxicity to Grade ≤1 
or baseline, TAK-079 should be reduced by 1 dose level, and for Grade 4 nonhematologic toxicity, 
TAK-079 should be permanently discontinued.
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Change 12: Instructions for handling infusion reactions were added to provide further instruction 
according to reaction grade.
The primary change occurs in Section 8.8.1 Handling of IRs:
Added text:In case of Grade 1 or 2 infusion reactions: 

Withhold therapy (also administration of remaining SC injections when full 
dose was not yet reached) until resolution to Grade 1 or maximum to Grade 2 
as per the investigator’s discretion. 
In case of Grade 3 infusion reactions: 

Withhold therapy (also administration of remaining SC injections when full 
dose was not yet reached and therefore skip remaining dose) until next 
scheduled TAK-079 SC administration, providing that infusion reactions 
have recovered to Grade ≤1 at the moment of the next scheduled TAK-079 
dose. 

Permanently discontinue treatment after the 3rd occurrence of Grade 3 
infusion reactions
In case of Grade 4 infusion reactions: 

Permanently discontinue treatment.
Rationale for Change:
This change was made to clarify the handling of IRs. 
Appendix A Schedule of Events, footnote (t), also contains this change.
Change 13: Methods for disease response imaging were clarified, including addition of a skeletal 
survey starting at Cycle 6.
The primary change occurs in 9.4.14 Disease Response Assessments.
Initial 
wording:
Imaging tests as specified in Appendix A are to be performed as defined below or 
when there is a clinical suspicion of progression. Response and relapse categories are 
described in Appendix E. Imaging tests will be taken during the screening phase 
before treatment, at the beginning of Cycles 2, 4, 7, 13, 19, 25, and every 6 cycles 
thereafter until PD or intolerance.
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Amended 
or new 
wording:
Imaging tests as specified in Appendix A are to be performed as defined below or 
when there is a clinical suspicion of need to document a response or a disease
progression. Response and relapse categories are described in Appendix E. Imaging 
tests will be taken during the screening phase before prior to treatment, at the 
beginning of Cycles 2, 4, 7, 13, 19, 25, and every 6 cycles thereafter until PD or 
intolerance. Additional surveys (x-ray, CT, or MRI) will be performed at the 
investigator’s discretion (eg, in case of bone pain) to document a response or 
progressive disease. The same imaging technique should be used throughout the 
study to facilitate consistent disease assessment.
Rationale for Change:
This change was made to correct and clarify disease assessments.
Appendix A Schedule of Events also contains this change.
Change 14: Text was added to the safety analysis methods regarding Grade 4 or higher 
nonhematologic toxicities occurring in the Phase 2a portion of the study.
The primary change occurs in 13.1.7 Safety Analysis:
Added 
text:
In the phase 2a portion of this study, Grade 4 or higher nonhematological 
toxicity will be monitored starting from the first 10 enrolled patients and then 
every 10 patients. If the stopping bounds of ≥4/10 and ≥6/20 have been reached, 
accrual to the study will be suspended to allow for investigation. After 
consideration by the study team, a decision will be made as to whether accrual 
can be resumed. The bounds are based on a Bayesian strategy to monitor 
outcomes in clinical trials. If the stopping rule is met, there is 80% probability 
that the true toxicity rate is greater than 18% with a prior beta distribution with 
parameters 0.4 and 1.6 for the binomially distributed toxicity rate [13].
Rationale for Change:
This change was made in response to an FDA request to include for the Phase 2a portion overall 
study stopping rules that (1) are based on a specified rate of unacceptable toxicity, (2) include a 
definition of unacceptable toxicity, and (3) follow statistical principles to ensure that they apply to 
the entire population at various stages of study enrollment.
Section 2.0 STUDY SUMMARY also contains this change.
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Protocol Incorporating Amendment 01
08 December 2017
Rationale for Change:
This change was made to facilitate sample collection by revising the reference injection for 
assessment purposes to the first injection, rather than the final injection, when multiple injections 
are required to administer the intended dose.
The following sections also contain this change:

Section 9.4.15.2 PK Measurements.

Section 9.4.15.3

Appendix A Schedule of Events
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PROTOCOL
A Phase 1/2a Open-label, Dose-Escalation Study to Investigate the Safety and Tolerability, 
Efficacy, Pharmacokinetics, and Immunogenicity of TAK-079 Administered 
Subcutaneously as a Single Agent in Patients With Relapsed/Refractory Multiple Myeloma
Sponsor:
Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda 
Pharmaceutical Company Limited
40 Landsdowne Street
Cambridge, MA 02139 USA
Telephone: +1 (617) 679-7000
Please note: Millennium Pharmaceuticals, Inc, a wholly owned 
subsidiary of Takeda Pharmaceutical Company Limited, may be 
referred to in this protocol as “Millennium,” “Sponsor,” or “Takeda”.
Study Number:
TAK-079-1501 
IND Number:
136,414
EudraCT Number:
Not applicable
Compound:
TAK-079
Date:
18 May 2018
Amendment Number:
02 
Amendment History: 
Date
Amendment Number
Region
12 October 2017
Initial Protocol
Global
08 December 2017
01
Global
18 May 2018
02
Global
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1.0
ADMINISTRATIVE
1.1
Contacts
A separate contact information list will be provided to each site.
Serious adverse event (SAE) and pregnancy reporting information is presented in Section 10.0, as 
is information on reporting product complaints.
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.0 and relevant guidelines 
provided to the site.
Contact Type/Role
United States Contact
SAE and pregnancy reporting
See Section 10.0
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INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, and any 
other product information provided by the sponsor. I agree to conduct this study in accordance 
with the requirements of this protocol and also to protect the rights, safety, privacy, and well-being 
of study subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting SAEs defined in Section 10.0 of this protocol.

Terms outlined in the Clinical Study Site Agreement.

Responsibilities of the Investigator
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix D of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Province)
Location of Facility (Country)
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12. Details on nonclinical studies with TAK-079 were added.
13. Details about management of IRs and injection site reactions were added.
14. The procedures for monitoring all infections were clarified. 
15. The rationale for the proposed study was revised, including presentation of results from the 
healthy subject study. 
16. The time required for highly effective contraception in women of childbearing potential 
(WOCBP) and in male patients was clarified for consistency.
17. The exclusion criterion about recovery from prior myeloma treatments was clarified to exclude 
alopecia. 
18. DLT assessments and withdrawal/replacement of patients were clarified.
19. A sentence summarizing the definition of the MTD has been added.
20. The criteria for beginning or delaying a subsequent treatment cycle were clarified.
21. Disease response assessments, including imaging and laboratory testing, were clarified.
22. “Other” was added as a reason for treatment discontinuation or withdrawal of subject from 
study. 
23. The time required to monitor ongoing adverse events (AEs) after the end of study treatment 
was clarified.
24. Investigator disease assessments were added to the Schedule of Events (SOE).
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TABLE OF CONTENTS
1.0
ADMINISTRATIVE.......................................................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment 02 Summary of Changes ..........................................................5
2.0
STUDY SUMMARY ....................................................................................................12
3.0
STUDY REFERENCE INFORMATION ......................................................................17
3.1
List of Abbreviations ...............................................................................................18
4.0
INTRODUCTION.........................................................................................................21
4.1
Background .............................................................................................................21
4.2
Findings From Nonclinical and Clinical Studies.......................................................21
4.2.1
22
4.3
Known and Potential Benefits and Risks to Patients with TAK-079 .........................25
4.3.1
Potential Risks ...................................................................................................25
4.3.2
Overall Benefit and Risk Assessment for This Study..........................................27
4.4
Rationale for the Proposed Study.............................................................................28
4.4.1
Rationale for the Starting Dose of TAK-079 ......................................................28
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................30
5.1
Objectives................................................................................................................30
5.1.1
Primary Objectives.............................................................................................30
5.1.2
Secondary Objectives.........................................................................................30
5.1.3
Exploratory Objectives.......................................................................................30
5.2
Endpoints.................................................................................................................31
5.2.1
Phase 1 Primary Endpoints.................................................................................31
5.2.2
Phase 2a Primary Endpoint ................................................................................31
5.2.3
Phase 1 Secondary Endpoints.............................................................................31
5.2.4
Phase 2a Secondary Endpoints...........................................................................32
5.2.5
Exploratory Endpoints .......................................................................................32
6.0
STUDY DESIGN..........................................................................................................34
6.1
Overview of Study Design.......................................................................................34
6.2
Number of Patients ..................................................................................................35
6.3
Duration of Study ....................................................................................................35
6.3.1
Duration of an Individual Patient’s Study Participation ......................................35
6.3.2
End of Study/Study Completion Definition and Planned Reporting....................36
6.3.3
Timeframes for Primary and Secondary Endpoints to Support Disclosures.........36
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6.3.4
Total Study Duration..........................................................................................39
7.0
STUDY POPULATION................................................................................................40
7.1
Inclusion Criteria .....................................................................................................40
7.2
Exclusion Criteria ....................................................................................................42
8.0
STUDY DRUG .............................................................................................................45
8.1
Study Drug Administration......................................................................................45
8.1.1
Predose and Postdose Medication.......................................................................45
8.1.2
TAK-079 Formulation and Administration.........................................................45
8.2
Definitions of DLT ..................................................................................................46
8.3
Dose-Escalation Design and Criteria........................................................................47
8.3.1
Dose Levels .......................................................................................................47
8.3.2
Escalation Schema .............................................................................................48
8.4
Dose Modification Guidelines..................................................................................50
8.4.1
Criteria for Beginning or Delaying a Subsequent Treatment Cycle.....................50
8.4.2
Criteria for Dose Modification ...........................................................................50
8.4.3
Criteria for Discontinuing TAK-079 in Individual Patients (When Considering 
Dose Modification) ............................................................................................53
8.5
Excluded Concomitant Medications and Procedures ................................................53
8.6
Permitted Concomitant Medications and Procedures................................................53
8.7
Precautions and Restrictions ....................................................................................54
8.8
Management of Specific Adverse Reactions ............................................................55
8.8.1
Handling of IRs..................................................................................................55
8.8.2
Injection Site Care..............................................................................................56
8.8.3
Handling of Low Platelet Counts........................................................................57
8.8.4
Risk of Infection ................................................................................................57
8.8.5
Transfusion Risks...............................................................................................57
8.9
Blinding and Unblinding..........................................................................................57
8.10
Description of Investigational Agents ......................................................................57
8.11
Preparation, Reconstitution, and Dispensation..........................................................58
8.12
Packaging and Labeling...........................................................................................58
8.13
Storage, Handling, and Accountability.....................................................................58
8.13.1 Storage and Handling.........................................................................................58
8.13.2 Accountability and Destruction of Sponsor Supplied Drugs ...............................59
8.14
Investigational Drug Assignment and Dispensing Procedures ..................................60
9.0
STUDY CONDUCT......................................................................................................61
9.1
Study Personnel and Organizations..........................................................................61
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9.2
Arrangements for Recruitment of Patients................................................................61
9.3
Treatment Group Assignments.................................................................................61
9.4
Study Procedures.....................................................................................................61
9.4.1
Informed Consent...............................................................................................61
9.4.2
Patient Demographics ........................................................................................61
9.4.3
Medical History .................................................................................................61
9.4.4
Physical Examination.........................................................................................62
9.4.5
Patient Height and Weight .................................................................................62
9.4.6
Vital Signs .........................................................................................................62
9.4.7
Eligibility Criteria ..............................................................................................62
9.4.8
Pregnancy Test...................................................................................................62
9.4.9
Concomitant Medications and Procedures..........................................................63
9.4.10 AEs....................................................................................................................63
9.4.11 Enrollment .........................................................................................................63
9.4.12 ECG...................................................................................................................63
9.4.13 Clinical Laboratory Evaluations .........................................................................64
9.4.14 Disease Response Assessments ..........................................................................65
9.4.15
, PK, 
, and Immunogenicity Samples.....................68
9.5
Completion of Study Treatment (for Individual Patients) .........................................71
9.6
Completion of Study (for Individual Patients)..........................................................71
9.7
Discontinuation of Treatment With Study Drug and Patient Replacement................72
9.8
Withdrawal of Patients From Study .........................................................................72
9.9
Study Compliance....................................................................................................73
9.10
Posttreatment Follow-up Assessments (PFS and OS)...............................................73
10.0
ADVERSE EVENTS ....................................................................................................74
10.1
Definitions...............................................................................................................74
10.1.1 Pretreatment Event Definition............................................................................74
10.1.2 AE Definition ....................................................................................................74
10.1.3 SAE Definition ..................................................................................................74
10.2
Procedures for Recording and Reporting AEs and SAEs..........................................75
10.3
Monitoring of AEs and Period of Observation .........................................................76
10.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events.........76
10.5
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose) ................................................................................................................77
10.6
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities...........77
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................78
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12.0
DATA HANDLING AND RECORDKEEPING............................................................79
12.1
eCRFs......................................................................................................................79
12.2
Record Retention .....................................................................................................79
13.0
STATISTICAL METHODS..........................................................................................81
13.1
Statistical and Analytical Plans ................................................................................81
13.1.1 Analysis Sets......................................................................................................81
13.1.2 Analysis of Demographics and Other Baseline Characteristics ...........................81
13.1.3 Efficacy Analysis...............................................................................................82
13.1.4 PK Analysis .......................................................................................................82
13.1.5
82
13.1.6 Immunogenicity Analyses..................................................................................82
13.1.7 Safety Analysis ..................................................................................................83
13.2
Interim Analysis and Criteria for Early Termination ................................................83
13.3
Determination of Sample Size..................................................................................83
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................85
14.1
Study Site Monitoring Visits....................................................................................85
14.2
Protocol Deviations..................................................................................................85
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................85
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................86
15.1
IRB and/or IEC Approval ........................................................................................86
15.2
Patient Information, Informed Consent, and Patient Authorization...........................87
15.3
Patient Confidentiality .............................................................................................88
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................88
15.4.1 Publication.........................................................................................................88
15.4.2 Clinical Trial Registration..................................................................................89
15.4.3 Clinical Trial Results Disclosure ........................................................................89
15.5
Insurance and Compensation for Injury....................................................................89
16.0
REFERENCES..............................................................................................................90
LIST OF IN-TEXT TABLES
Table 6.a
Primary and Secondary Endpoints for Disclosures .............................................37
Table 7.a
Required Washout Periods for Previous Treatments or Procedures Prior to 
Administration of TAK-079...............................................................................40
Table 7.b
Laboratory Criteria for Determining Adequate Organ Function for 
Study TAK-079-1501 Eligibility........................................................................40
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Table 8.a
Dose Modification Recommendations for TAK-079 Toxicities ..........................52
Table 8.b
TAK-079–Related Toxicity Management...........................................................52
Table 9.a
Clinical Chemistry and Hematology Tests..........................................................65
Table 9.b
Clinical Urinalysis Tests ....................................................................................65
Table 9.c
Primary Specimen Collection.............................................................................69
Table 13.a
80% Confidence Interval Based on the Observed ORR ......................................84
LIST OF IN-TEXT FIGURES
Figure 6.a
Overall Study Schematic Diagram......................................................................35
Figure 8.a
Dose-Escalation Scheme ....................................................................................49
LIST OF APPENDICES
Appendix A
Schedule of Events.............................................................................................92
Appendix B
PK Sampling Schedule.....................................................................................100
Appendix C
Responsibilities of the Investigator...................................................................103
Appendix D
Investigator Consent to Use of Personal Information........................................105
Appendix E
IMWG Criteria.................................................................................................106
Appendix F
ECOG Scale for Performance Status ................................................................109
Appendix G
Detailed Description of Amendments to Text...................................................110
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2.0
STUDY SUMMARY
Name of Sponsor:
Millennium Pharmaceuticals, Inc, a wholly owned 
subsidiary of Takeda Pharmaceutical Company Limited
Compound:
TAK-079
Title of Protocol: A Phase 1/2a, Open-label, 
Dose-Escalation Study to Investigate the Safety and 
Tolerability, Efficacy, Pharmacokinetics, and 
Immunogenicity of TAK-079 Administered Subcutaneously 
as a Single Agent in Patients With Relapsed/Refractory 
Multiple Myeloma 
Study Number: TAK-079-1501
Phase: 1/2a
Study Design:
This is a multicenter, open-label, dose-escalation, single-arm, phase 1/2a study designed to determine the safety and 
tolerability of TAK-079 monotherapy in patients with relapsed and/or refractory multiple myeloma (RRMM), and to 
provide a preliminary assessment of its activity against RRMM. 
Once enrolled into the study, patients will receive TAK-079 via subcutaneous (SC) administration in each 28-day 
cycle of treatment, administered as once weekly for 8 weeks (8 doses), once every 2 weeks for 16 weeks (8 doses), and 
once every 4 weeks thereafter until disease progression (PD). Patients will receive ongoing treatment with TAK-079 
until PD, unacceptable toxicities, or withdrawal due to other reasons. The maximum duration of treatment will be 12 
months; however, patients with clinical benefit (per investigator and as agreed upon by the sponsor’s study clinician) 
can continue on treatment beyond 1 year with the explicit approval of the sponsor’s study clinician (see Section 6.3).
The phase 1 portion of the study will evaluate administration of TAK-079 for dose-limiting toxicity (DLT) to 
determine the maximum tolerated dose (MTD) or the recommended phase 2 dose (RP2D) for further assessment in 
phase 2a. A recommended dose below the MTD may be identified based on the review of safety, pharmacokinetic 
(PK), 
, and clinical data from the phase 1 portion of the study. 
The safety and tolerability of TAK-079 will be assessed by recording and analyzing treatment-emergent adverse 
events (TEAEs), dose modifications, treatment discontinuations, vital signs, physical examinations, serum chemistry 
and hematology, urinalysis, electrocardiograms, and concomitant medications. In phase 1, approximately 6 doses of 
TAK-079 will be evaluated in ascending cohorts of 3 to 6 patients per cohort. Cohorts may be expanded by enrolling 
additional patients to further inform selection of the RP2D. In the phase 2a portion of this study, Grade 4 or higher 
nonhematologic toxicity will be monitored starting from the first 10 enrolled patients and then every 10 patients 
thereafter.
It is expected that approximately 42 patients will be enrolled in the study. The estimated duration of the study is 
approximately 36 months (ie, 3 years). 
Primary Objectives:
Phase 1
To determine the safety and tolerability of TAK-079 monotherapy in patients with RRMM.
Phase 2a
To provide a preliminary evaluation of the clinical activity of TAK-079 monotherapy in patients with RRMM.
Secondary Objectives:
Phase 1

To investigate a potential MTD/RP2D of TAK-079.

To evaluate the immunogenicity of TAK-079.

To characterize the PK of TAK-079.

To provide a preliminary evaluation of the clinical activity of TAK-079.
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Duration of Treatment:
TAK-079 will be administered until the patient experiences 
PD, unacceptable toxicities, or withdrawal due to other 
reasons. The maximum duration of treatment will be 12 
months; however, patients with clinical benefit can continue 
on treatment beyond 1 year with the explicit approval of the 
sponsor’s study clinician (see Section 6.3).
Period of Evaluation:
21 days screening, ongoing treatment to PD. 
Patients who discontinue treatment for reasons other 
than PD will continue to be followed for 
progression-free survival (PFS) every 4 weeks from 
the end-of-treatment visit until PD, death, the start of 
subsequent anticancer therapy, study termination, or 
until 12 months after discontinuation of study 
treatment, whichever occurs first. 
Overall survival (OS): Patients will be followed every 
12 weeks until death, loss to follow-up, consent 
withdrawal, or study termination.
Main Criteria for Inclusion:
Male and female patients, aged ≥18 years, with ECOG performance status of ≤2, requiring additional therapy as 
determined by the investigator. Patients must have received the final dose of the following treatments/procedures 
within the specified minimum intervals before the first dose of TAK-079: 180 days for antibody therapy (including 
anti-CD38); 90 days for autologous transplantation; 14 days for chemotherapy, radiation therapy, and major surgery; 
and 7 days for corticosteroid therapy (up to systemic equivalent of 10 mg daily prednisone allowed). Patients must 
have adequate organ function as determined by the following laboratory values: absolute neutrophil count ≥1.0×109/L; 
platelets ≥75,000/mm3 (≥75×109/L); hemoglobin ≥7.5 g/dL; creatinine clearance ≥30 mL/min (Cockcroft-Gault 
formula); total bilirubin ≤1.5 times the upper limit of the normal range (ULN); and alanine aminotransferase/aspartate 
aminotransferase ≤2.5×ULN. Patients must have documented RRMM per the International Myeloma Working Group 
(IMWG) criteria, with measurable disease defined as one of the following: serum M-protein ≥ 0.5 g/dL (≥5 g/L) and 
urine M-protein ≥200 mg/24 hours. Patients without measurable M-protein in serum protein electrophoresis or urine 
protein electrophoresis must have a serum free light chain (FLC) assay result with involved FLC level ≥10 mg/dL 
(≥100 mg/L), provided serum FLC ratio is abnormal. Patients must have evidence of RRMM as defined by the IMWG 
criteria, previously received at least 3 lines of myeloma therapy including a proteasome inhibitor (PI), 
immunomodulatory drug (IMiD), alkylating agent, and steroids. Previous exposure to anti-CD38 as single agent or in 
combination is allowed but is not mandatory. Patients must be refractory to or intolerant of at least 1 PI and 1 IMiD. 
Patients who received a combination of PI and IMiD in a unique treatment schedule can be included in the study after 
at least 2 lines of prior myeloma therapy. Prior treatment with an anti-CD38 monoclonal antibody (mAb) is allowed. 
In the phase 2a portion of the study, patients must have been refractory to an anti-CD38 mAb therapy at any time 
during treatment. 
Main Criteria for Exclusion:
Sensory or motor neuropathy of Grade ≥3, based on the National Cancer Institute Common Criteria for Adverse 
Events (NCI CTCAE) or not recovered from adverse reactions to prior myeloma treatments/procedures to NCI 
CTCAE Grade ≤1 or baseline; allogeneic stem cell transplant; congestive heart failure (New York Heart Association) 
Grade ≥II, cardiac myopathy, active ischemia, clinically significant arrhythmia, history of acute myocardial infarction 
within 5 months before enrollment, clinically significant uncontrolled hypertension, or any other uncontrolled cardiac 
condition or concurrent illness that would preclude study conduct and assessment; QT interval corrected by the 
Fridericia method >480 msec (Grade ≥2); history of severe allergic or anaphylactic reactions to recombinant proteins 
or excipients used in TAK-079 formulation (including patients who were previously discontinued from an anti-CD38 
treatment due to an infusion-related reaction); history of myelodysplastic syndrome or another malignancy other than 
MM; clinical signs of central nervous system involvement of MM; or active chronic hepatitis B or C infection, or 
active HIV infection. Also excluded are patients with POEMS (polyneuropathy, organomegaly, endocrinopathy, 
monoclonal gammopathy and skin changes) syndrome, monoclonal gammopathy of unknown significance; 
smoldering myeloma; solitary plasmacytoma; amyloidosis; Waldenström macroglobulinemia or immunoglobulin M 
myeloma, and patients with positive Coombs tests at screening.
Endpoints (in order of importance):
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3.0
STUDY REFERENCE INFORMATION
Study-Related Responsibilities 
The sponsor will perform all study-related activities with the exception of those identified in the 
Study-Related Responsibilities (Appendix C). The identified vendors in the template for specific 
study-related activities will perform these activities in full or in partnership with the sponsor.
Principal Investigator
Takeda will select a Signatory Coordinating Investigator from the investigators who participate in 
the study. Selection criteria for this investigator will include significant knowledge of the study 
protocol, the study medication, their expertise in the therapeutic area and the conduct of clinical 
research as well as study participation. The Signatory Coordinating Investigator will be required to 
review and sign the clinical study report and by doing so agrees that it accurately describes the 
results of the study.
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3.1
List of Abbreviations
Abbreviation
Term
ADA
antidrug antibody
AE
adverse event
AUClast
area under the concentration-time curve from time 0 to the time of the last quantifiable 
concentration
BMA
bone marrow aspirate
CFR
Code of Federal Regulations
CLL
chronic lymphocytic leukemia
Cmax
maximum observed concentration
CNS
central nervous system
COPD
chronic obstructive pulmonary disease
CR
complete response
CRO
contract research organization
CRS
cytokine release syndrome
CT
computed tomography
DLT
dose-limiting toxicity
DOR 
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form (refers to any media used to collect study data [ie, paper or electronic])
EOI
end of infusion
EOT
end of treatment
FDA
United States Food and Drug Administration
FIH
first-in-human
FLC
free light chain
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
HBV
hepatitis B virus
HCV
hepatitis C virus
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IEC
independent ethics committee
Ig
immunoglobulin
IMiD
immunomodulatory drug
IMWG
International Myeloma Working Group
IR
infusion reaction
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Abbreviation
Term
IRB
institutional review board
IV
intravenous(ly)
mAb
monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
MM
multiple myeloma
MR
minimal response
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NAB
neutralizing antibody
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NK
natural killer
NOAEL
no observed adverse effect level
NSAID
nonsteroidal anti-inflammatory drugs
ORR
overall response rate
OS
overall survival
PB
plasmablast
PD
progressive disease; disease progression
PET-CT
positron emission tomography–computed tomography
PFS
progression-free survival
PI
proteasome inhibitor
PK
pharmacokinetic(s)
POEMS 
syndrome
polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes
PR
partial response
QTc
QT interval corrected for heart rate
RBC
red blood cell(s)
RP2D
recommended phase 2 dose
RRMM
relapsed and/or refractory multiple myeloma
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
sCR
stringent complete response
SCRS
severe cytokine release syndrome
SOE
Schedule of Events
SPEP
serum protein electrophoresis
SUSAR
suspected unexpected serious adverse reactions
TEAE
treatment-emergent adverse event
tmax
time of first occurrence of maximum observed concentration
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Abbreviation
Term
TTR
time to response
ULN
upper limit of the normal range
UPEP
urine protein electrophoresis
VGPR
very good partial response
WOCBP
women of childbearing potential
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4.3
Known and Potential Benefits and Risks to Patients with TAK-079
TAK-079 was administered only in healthy human subjects in the first-in-human (FIH) study 
(TAK-079_101). Only mild or moderate AEs were observed in the FIH study in healthy subjects. 
Therefore, clinical benefits and risks have not been assessed in the disease setting. 
A summary of findings is discussed in Section 4.3.1. See details for precautions and restrictions in 
Section 8.7. Additional information regarding potential discomforts and risks from treatment is 
provided in the TAK-079 IB.
4.3.1
Potential Risks
Based on the mechanism of action of TAK-079, potential AEs may include infusion or injection 
site reactions, hematological effects, and infections.
4.3.1.1
Infusion and Injection Site Reactions
IRs are potentially dose-limiting AEs, not uncommonly associated with IV administration of 
biologic agents aimed at treating hematologic malignancies [5]. IRs are less frequently associated 
with SC injection of these therapies. The ‘true’ clinical hypersensitivity reactions, 
antibody-mediated occur after repeat exposure. Symptoms of hypersensitivity range from mild 
skin rash to more severe reactions, wheezing, hypotension, poor perfusion, respiratory arrest, and 
rarely death. Non-anaphylactic clinical hypersensitivity occurs within the first hour; however 
delayed responses were reported. Symptoms of anaphylaxis, a potentially life-threatening 
condition, range from swelling, angioedema, bronchospasm, respiratory distress, and shock [9]. 
There are limited nonclinical and clinical data to date for TAK-079 (Section 4.2.1). Local injection 
site abnormalities have not been observed in monkey and rat nonclinical studies after SC and/or IV 
administration of TAK-079. In the clinical study of healthy subjects (TAK-079_101), an 
infusion-related reaction was defined as a TEAE occurring within 2 hours of the start of an 
infusion; there were no IRs in this study, as no allergic or cytokine release reactions were observed 
within this time period. Mild injection site AEs were reported; AEs were Grade 1 and included 
primarily erythema or tenderness with palpitation. All injection site reactions resolved within a 
few days. 
Patients in clinical trials receiving TAK-079 will be carefully monitored for signs and symptoms 
of infusion and injection site reactions, with appropriate management of these events. Depending 
on the severity of the reaction, management may include discontinuation of SC administration of 
TAK-079 and/or the administration of appropriate medical therapy. 
See additional details for managing infusion and injection site reactions in Section 8.8.1.
4.3.1.2
Cytokine Release Syndrome
CRS represents an important IR often associated with the use of monoclonal antibodies used in 
anti-inflammatory and antitumor therapies. CRS may occur early in therapy, and often after the 
first infusion of the drug due to a high-level of activation of the immune system and engagement 
and proliferation of T-cells that can result in increased cytokine release. The CRS hallmark is 
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Subjects will be monitored for any signs and symptoms of infections throughout this clinical study 
(see Section 8.8.4).
4.3.1.5
Drug Interactions
Nonclinical drug interaction studies have not been conducted with TAK-079. However, as a fully 
human IgG1 monoclonal antibody (mAb), the risk of drug-drug interactions is low.
4.3.1.6
ADA Interactions
ADA responses were detected in most monkeys in the single-dose PK studies and the 4-week 
(non-GLP) and 13-week (GLP) toxicology studies. Strong positive ADA responses were generally 
associated with lower serum concentrations of TAK-079, and this was especially notable in the 
13-week repeat-dose toxicity studies and at lower doses.
In the single-dose healthy subject study (TAK-079_101), 5 of 54 TAK-079–treated subjects were 
positive for ADA (3 subjects with transient ADA and 2 subjects with persistent ADA). Of these, 
1 subject was treated in the 0.06 mg IV cohort and the remaining 4 subjects were treated with 
either 0.03 mg/kg (2 subjects), 0.1 mg/kg (1 subject), or 0.6 mg/kg (1 subject) SC TAK-079. 
Immunogenicity was not associated with clinically significant AEs, even in the 2 subjects with 
persistent immunogenicity.
4.3.1.7
Pregnancy and Lactation
TAK-079 has not been administered to women who are pregnant or lactating. Dedicated fertility 
and embryo-fetal development toxicology studies have not been conducted with TAK-079. 
However, there were no TAK-079–related changes in organ weights or microscopic findings noted 
in the male and female reproductive tract of monkeys following administration for up to 13 weeks. 
WOCBP may be enrolled in clinical trials with appropriate precautions to prevent pregnancy 
(additional details in Section 8.7).
At this stage of development TAK-079 should not be administered to women who are pregnant or 
breastfeeding.
4.3.1.8
Overdose
TAK-079 has been administered only to healthy subjects in the FIH study. To date, there is no 
experience with overdose. If an overdose does occur, close monitoring and supportive treatment as 
medically required are recommended.
4.3.2
Overall Benefit and Risk Assessment for This Study
The overall clinical benefits and risks of TAK-079 have not been determined. 
Based on the mechanism of action of TAK-079, nonclinical data to date, as well as some exposure 
in healthy human subjects, possible AEs of TAK-079 include but are not limited to infusion and 
injection site reactions, CRS, hypersensitivity reactions, changes in hematologic parameters, and 
infections. Patients will be monitored closely for these risks in this clinical study.
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4.4
Rationale for the Proposed Study
Although multiple therapies are available for patients with MM, this disease remains incurable; 
thus, significant unmet medical need exists for this patient population. Frequent relapses highlight 
a need for new therapies for patients in whom prior treatments have failed. 
TAK-079 binds to unique amino acids of CD38 and possesses a different binding profile than the 
approved cytolytic anti-CD38 therapeutic antibody daratumumab. 
In the FIH study (TAK-079_101), TAK-079 demonstrated pharmacodynamic effects (ie, cytolysis 
of NK cells and PBs) following single-dose administration, with no unexpected and unwanted 
clinical or hematologic effects observed. For example, NK cells were reduced >90% from baseline 
levels in all healthy subjects receiving a single 0.06 mg/kg IV dose of TAK-079 and exhibited a 
mean Cmax of 0.1 ug/mL (TAK-079_101). Comparable depletion of NK cells by daratumumab 
administered IV to a population of patients with refractory MM [12] required doses of >24 mg/kg 
and a mean Cmax of >500 ug/mL [13,14]. Consequently, TAK-079 may be significantly more 
efficient at eliminating target cells in patients, which could manifest as higher activity on tumor 
cells (ie, activity at lower doses, low-volume SC administration, and less frequent administration), 
including activity on daratumumab-refractory tumors. The potential activity of TAK-079 should 
therefore be investigated in patients with relapsed and/or refractory multiple myeloma (RRMM).
4.4.1
Rationale for the Starting Dose of TAK-079
In the FIH study (TAK-079_101), TAK-079 was well tolerated after SC administration of 
single-doses ranging from 0.03 to 0.6 mg/kg.
To avoid unnecessary exposure of patients to sub-therapeutic doses while preserving safety, the
starting dose for this study in patients with RRMM will be 45 mg, the fixed-dose equivalent of 
0.6 mg/kg (assuming a body weight of 75 kg), which was the highest SC dose administered in 
Study TAK-079_101. The 0.6 mg/kg dose was well tolerated in healthy human subjects in Study 
TAK-079_101 and demonstrated >90% depletion of peripheral blood PBs, a surrogate for 
myeloma cells in each subject (n=6).
TAK-079 is a mAb targeting CD38, which is a cell surface molecule that is constitutively 
expressed on plasma cells, PBs, and NK cells, and is induced on activated T cells and B cells [15]. 
Therefore, the anticipated elimination routes for TAK-079 are via proteolytic catabolism and 
intracellular degradation after binding to its target. Both of these clearance mechanisms are not 
thought to be significantly influenced by body weight. Additionally, the distribution volume of 
mAbs is generally limited to the volume of the blood and extracellular fluids, such that body 
composition is a less important determinant of distribution volume as compared with small 
molecule drugs [16]. For these reasons, body weight is not expected to have a clinically significant 
effect on the disposition of TAK-079, thereby supporting the investigation of fixed-dose 
administration.
The 45 mg starting dose of TAK-079 will be tested in 3 patients with RRMM to assess the safety 
and tolerability of TAK-079 after multiple dose administration. TAK-079 will be administered 
using the same dosing schedule as the anti-CD38 antibody, daratumumab, which is approved for 
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the treatment of patients with MM [5]. Specifically, TAK-079 will be administered once weekly 
for 8 weeks (8 doses), once every 2 weeks for 16 weeks (8 doses), then once every 4 weeks until 
the patient experiences disease progression (PD), unacceptable toxicities, or withdrawal due to 
other reasons. The subsequent planned dose levels are 135, 300, 600, 1200, and 1800 mg.
Escalation to a subsequent cohort may take place after the treatment in the first cycle of the 
previous (sequential) cohort has completed.
Additional details for dose escalation are provided in Section 8.3.
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6.0
STUDY DESIGN
6.1
Overview of Study Design
This is a multicenter, dose-escalation, open-label, single-arm, phase 1/2a study designed to 
determine the safety, tolerability, efficacy, PK, and immunogenicity of TAK-079 monotherapy in 
patients with RRMM, and to provide a preliminary assessment of its activity against MM. 
The phase 1 portion of the study will evaluate administration of TAK-079 for DLT(s) to determine 
the MTD/RP2D for further assessment in phase 2a. A recommended dose below the MTD may be 
identified based on safety, clinical, PK, 
 data. The safety and tolerability of 
TAK-079 will be assessed by recording and analyzing TEAEs from medical review of vital signs, 
physical examinations, serum chemistry and hematology analyses, urinalyses, ECGs, review of 
concomitant medications, dose modifications, and treatment discontinuations.
The preliminary efficacy of TAK-079 will be evaluated by measuring the ORR, defined as the 
proportion of patients who achieved a PR or better during study, as defined by IMWG 
(Appendix E; [17,18]). In addition, the efficacy of TAK-079 will be assessed by measuring MR, 
PFS, DOR, and OS; TTR will also be measured. 
Once enrolled into the study, patients will receive TAK-079 via SC administration in each 28-day 
cycle of treatment, administered as once weekly for 8 weeks (8 doses), once every 2 weeks for 
16 weeks (8 doses), and once every 4 weeks thereafter until PD. Patients will receive ongoing 
treatment with TAK-079 until they experience PD, unacceptable toxicities, or withdrawal due to 
other reasons (see Section 6.3).
Phase 1 will consist of the following phases/periods: screening, treatment, and follow-up:

Screening period (visit 1): Days -21 to Day -1.

Treatment period (visit 2/ongoing): Once-weekly treatment for 8 doses (Cycles 1 and 2), 
starting on Day 1, followed by treatment once every 2 weeks for 8 doses (Cycles 3-6), followed 
by treatment once every 4 weeks thereafter (Cycle 7 and beyond), continuing until patients 
experience PD, unacceptable toxicities, or withdrawal due to other reasons. 

Follow-up period (EOT visit): Patients who discontinue study treatment will be followed for 
approximately 30 days after the last dose of study drug or until the start of subsequent 
alternative anticancer therapy to monitor safety/AEs. Patients who discontinue treatment for 
reasons other than PD will continue to be followed for PFS every 4 weeks from the EOT visit 
until PD, death, the start of subsequent anticancer therapy, study termination, or 12 months 
after discontinuation of study treatment, whichever occurs first. Patients who discontinue for 
PD will be followed for OS after the EOT visit. All patients will be followed for OS every 
12 weeks until death, loss to follow-up, consent withdrawal, or study termination.
In phase 1, approximately 6 doses will be evaluated in ascending cohorts of 3-6 patients per 
cohort. Cohorts may be expanded by enrolling additional patients to further inform selection of the 
RP2D. Dose selection for phase 2a will take place after review of the available safety, efficacy, 
PK, 
 data obtained from the phase 1 portion of the study.
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It is expected that approximately 42 patients will be enrolled in total for phase 1 and 2a combined. 
Study procedures and assessments, with their time points, are shown in Appendix A. The study 
schematic diagram is shown in Figure 6.a.
Figure 6.a
Overall Study Schematic Diagram
Treatment Cycle
C1
C2
≤21 D
D1
D8
D15
D22
D1
D8
D15
D22
C3
C4
C5
C6
C7
C8
D1
D15
D1
D15
D1
D15
D1
D15
D1
D1
**
PD
C=Cycle; D=Day; PD=progressive disease; R2PD=recommended phase 2 dose; SC=subcutaneous. 
Dose Escalation: 45, 135, 300, 600, 1200, and 1800 mg.
Cohorts in phase 1 may be expanded to further inform selection of the RP2D.
The RP2D determined in phase 1 will be further assessed in approximately 18 patients in phase 2a.
* For dose levels where multiple SC injections are needed to administer the full prescribed dose, the Cycle 1 Day 1
dose SC injections will be given with a 30 minute interval in between each SC injection. Thereafter, if there are not 
clinically significant IRs, the SC injections may be given together without the waiting period.
** 
= dosing every 28 days until disease progression.
   = TAK-079 dose.
6.2
Number of Patients
For phase 1, approximately 24 patients are planned to be enrolled, including the expansion of 
additional patients in selected cohorts to further inform selection of the RP2D. For phase 2a, 
approximately 18 patients are planned. Details on the definition of evaluable patients and sample 
size are given in Section 13.1.
The study is planned to be conducted in the United States in approximately 4 investigational 
centers for phase 1 and in a total of 6 investigational centers for phase 2a.
6.3
Duration of Study
6.3.1
Duration of an Individual Patient’s Study Participation
Patients will receive TAK-079 until they experience PD as defined by IMWG criteria [17,18]
(Appendix E), unacceptable toxicity, or any other discontinuation criterion is met (see 
Section 8.4.3 and Section 9.7).The maximum duration of treatment is expected to be 12 months; 
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however, patients with clinical benefit (per investigator and as agreed by the sponsor’s study 
clinician) can continue on treatment beyond 1 year with the explicit approval of the sponsor’s 
study clinician. 
Patients will be evaluated 30±7 days after the last dose of TAK-079 (follow-up visit) or before 
initiating subsequent systemic anticancer therapy, for detection of any delayed TEAEs.
6.3.2
End of Study/Study Completion Definition and Planned Reporting
The final analyses for the clinical study report will be conducted after all patients enrolled in the 
study have had the opportunity to complete 12 months of treatment with TAK-079 plus the EOT 
visit or after the EOT visit of the last patient entering the study if the sponsor terminates the study 
early (Table 6.a).
6.3.3
Timeframes for Primary and Secondary Endpoints to Support Disclosures
Refer to Table 6.a for disclosures information for all primary and secondary endpoints.
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6.3.4
Total Study Duration
The final analyses for the clinical study report may be conducted after all patients enrolled in the 
study have had the opportunity to complete 12 months of treatment with TAK-079 or after the last 
patient completes the EOT visit if the sponsor terminates the study earlier.
It is anticipated that this study will last for approximately 36 months (3 years).
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7.0
STUDY POPULATION
7.1
Inclusion Criteria
Each patient must meet all the following inclusion criteria to be enrolled in the study:
1. Male or female patients aged 18 years or older.
2. Eastern Cooperative Oncology Group (ECOG) performance status of ≤2 [19].
3. Patient has received the final dose of any of the following treatments/procedures within the 
specified minimum intervals before the first dose of TAK-079 (Table 7.a):
Table 7.a
Required Washout Periods for Previous Treatments or Procedures Prior to 
Administration of TAK-079 
Previous Treatment or Procedure
Washout Period
Myeloma-specific therapy
14 days
Antibody therapy (including anti-CD38)
180 days
Corticosteroid therapy (a)
7 days
Autologous transplantation 
90 days
Radiation therapy (b)
14 days
Major surgery
14 days
(a) Systemic corticosteroid use ≤10 mg/day (prednisone or equivalent) is allowed.
(b) Prophylactic “spot” radiation for areas of pain is permitted.
4. Patient has adequate organ function as determined by the following laboratory values 
(Table 7.b):
Table 7.b
Laboratory Criteria for Determining Adequate Organ Function for 
Study TAK-079-1501 Eligibility
Laboratory Parameter
Acceptable Laboratory Criteria 
Absolute neutrophil count (a)
≥1000/mm3 (≥1.0×109/L); ≥750/mm3 (≥0.75109/L) maybe acceptable for 
patients with >50% of plasma cells in bone marrow after discussion with 
sponsor
Platelets (a)
≥75,000/mm3 (≥75×109/L); a value of ≥50,000/mm3
(≥50×109/L) may be acceptable for patients with >50% bone marrow burden 
following discussion with the sponsor
Hemoglobin 
≥7.5 g/dL (it is not permissible to transfuse a subject to reach this level)
Creatinine clearance
≥30 mL/min (Cockcroft-Gault formula)
Total serum bilirubin
≤1.5×ULN; except for patients with Gilbert’s syndrome in whom direct 
bilirubin should be <2.0×ULN 
Liver transaminases (ALT/AST)
≤2.5×ULN
ALT=alanine aminotransferase; AST=aspartate aminotransferase; ULN=upper limit of the normal range.
(a) Without ongoing growth factor or transfusion support for at least 1 week before Day 1.
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5. Female patients who: 

Are WOCBP must not be pregnant or lactating. 

Are postmenopausal for at least 1 year before the screening visit, OR

Are surgically sterile, OR

If they are of childbearing potential, agree to practice 1 highly effective method of 
contraception and 1 additional effective (barrier) method at the same time, from the time of 
signing the informed consent through at least 90 days or 5 half-lives after the last dose of 
study drug, whichever time period is longest, OR

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle 
of the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, and 
postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not 
acceptable methods of contraception. Female and male condoms should not be used 
together.)
6. Male patients, even if surgically sterilized (ie, status postvasectomy), who:

Agree to practice effective barrier contraception during the entire study treatment period 
and through 90 days (or if the drug has a very long half-life, for 90 days plus 5 half-lives) 
after the last dose of study drug, OR

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle 
of the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, and 
postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not 
acceptable methods of contraception. Female and male condoms should not be used 
together.)
7. Voluntary written consent must be given before performance of any study-related procedure 
not part of standard medical care, with the understanding that consent may be withdrawn by 
the patient at any time without prejudice to future medical care.
8. The patient must be willing and able to comply with study restrictions and to remain at the 
investigational center for the required duration during the study period, and must be willing to 
return to the investigational center for the follow-up procedures and assessments specified in 
this protocol.
9. Requires additional therapy, as determined by the investigator.
10. Documentation of RRMM as defined by the IMWG criteria (Appendix E; [17,18]).
11. For patients with MM, measurable disease defined as one of the following:

Serum M-protein ≥0.5 g/dL (≥5 g/L).

Urine M-protein ≥200 mg/24 hours.
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
In patients without measurable M-protein in serum protein electrophoresis (SPEP) or urine 
protein electrophoresis (UPEP), a serum free light chain (FLC) assay result with involved 
FLC level ≥10 mg/dL (≥100 mg/L), provided serum FLC ratio is abnormal.
12. Prior therapy, patients should meet all the following criteria:

Patient should be previously treated with at least a PI, an IMiD, an alkylating agent, and a 
steroid.

Patient should be refractory or intolerant to at least 1 PI and at least 1 IMiD.

Patient should either have received ≥3 prior lines of therapy or should have received at 
least 2 prior lines of therapy if one of those lines included a combination of PI and IMiD. 

In phase 1, previous exposure to an anti-CD38 agent, as a single agent or in combination, is 
allowed but is not required.
13. In the phase 2a portion of the study, patients with MM must also have been refractory to at 
least 1 anti-CD38 mAb therapy at any time during treatment.
NOTE: 

Refractory is defined as less than a 25% reduction in M-protein (response of stable disease
during prior therapy) or PD during treatment or within 60 days after last dose of prior therapy.

A line of therapy is defined as 1 or more cycles of a planned treatment program. This may 
consist of 1 or more planned cycles of single-agent therapy or combination therapy, as well as 
a sequence of treatments administered in a planned manner. A new line of therapy starts when 
a planned course of therapy is modified to include other treatment agents (alone or in 
combination) as a result of PD, relapse, or toxicity. A new line of therapy also starts when a 
planned period of observation off therapy is interrupted by a need for additional treatment for 
the disease [17].
7.2
Exclusion Criteria
Patients meeting any of the following exclusion criteria are not to be enrolled in the study:
1. Sensory or motor neuropathy of National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE) Grade ≥3 [20].
2. Patients who have received allogeneic stem cell transplant.
3. Patients who have received anti-CD38 antibody therapy and do not fulfill a 180-day washout 
period before receiving TAK-079.
4. Not recovered from adverse reactions to prior myeloma treatment or procedures 
(chemotherapy, immunotherapy, radiation therapy) to NCI CTCAE Grade ≤1 or baseline,
excluding alopecia.
5. Congestive heart failure (New York Heart Association) Grade ≥II; cardiac myopathy, active 
ischemia, or any other uncontrolled cardiac condition such as angina pectoris, clinically 
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significant arrhythmia requiring therapy including anticoagulants, or clinically significant 
uncontrolled hypertension.
6. History of acute myocardial infarction within 5 months before enrollment or ECG 
abnormalities during the screening period that are deemed medically relevant by the 
investigator.
7. QT interval corrected by the Fridericia method >480 msec (Grade ≥2).
8. Concurrent illness that would preclude study conduct and assessment including, but not 
limited to, uncontrolled medical conditions, uncontrolled systemic or body organ active 
infection (considered opportunistic, life threatening, or clinically significant), uncontrolled
risk of bleeding, uncontrolled diabetes mellitus, pulmonary disease (including obstructive 
pulmonary disease such as severe chronic obstructive pulmonary disease [COPD] with forced 
expiratory volume <80%, or persistent asthma, pulmonary fibrosis, and history of 
symptomatic bronchospasm), inflammatory bowel disease, ongoing symptomatic 
pneumonitis, alcoholic liver disease, or primary biliary cirrhosis. 
9. History of stroke or intracranial hemorrhage within 12 months of first dose of study drug; 
patients requiring anticoagulation therapy for any indication should be discussed with the 
medical monitor before screening.
10. Active autoimmune disease including autoimmune hemolytic anemia, idiopathic 
thrombocytopenic purpura, or any chronic condition requiring a higher corticosteroid systemic 
equivalent than prednisone 10 mg daily. Higher doses of corticosteroids prescribed for any 
indication must be stopped 7 days prior to first dose of study drug; exceptions may be made for 
corticosteroids prescribed specifically for management of MM symptoms after discussion with 
the medical monitor.
11. History of myelodysplastic syndrome or another malignancy other than MM, except for the 
following: any malignancy that has been in complete remission for 3 years, adequately treated 
local basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial 
bladder cancer, or asymptomatic prostate cancer without known metastatic disease and with no 
requirement for therapy or requiring only hormonal therapy and with normal prostate-specific 
antigen for 1 year before the start of study therapy.
12. Clinical signs of CNS involvement of MM.
13. Female patients who are pregnant with a positive serum pregnancy test or lactating during the 
screening period, or a positive urine pregnancy test on Day 1 before the first dose of study 
drug, if applicable. 
14. Any serious medical or psychiatric illness that could, in the investigator’s opinion, potentially 
interfere with the completion of treatment according to this protocol.
15. Active chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, or active HIV
infection.
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16. History of severe allergic or anaphylactic reactions to recombinant proteins or excipients used 
in the TAK-079 formulation. This includes patients who were previously discontinued from an 
anti-CD38 treatment due to an infusion-related reaction.
17. The patient is currently participating in another antimyeloma clinical study, or has participated 
in another investigational clinical trial within the 4 weeks prior to first dose of study drug.
18. Patients who are not able and/or willing to comply with the study requirements, rules, and 
procedures.
19. POEMS (Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin 
changes) syndrome, monoclonal gammopathy of unknown significance, smoldering myeloma, 
solitary plasmacytoma, amyloidosis, Waldenström macroglobulinemia, or IgM myeloma.
20. Patients with positive Coombs tests at screening. 
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8.0
STUDY DRUG
8.1
Study Drug Administration
All protocol-specific criteria for administration of study drug must be met and documented before 
drug administration. Study drug will be administered only to eligible patients under the 
supervision of the investigator or identified subinvestigator(s).
8.1.1
Predose and Postdose Medication
Predose Medication
Before each injection, patients will receive the following premedications 1 to 3 hours prior to the 
start of TAK-079 administration on each dosing day:

Dexamethasone: 20 mg IV dose for the initial injection. Oral dexamethasone (20 mg) or an 
equivalent long-acting corticosteroid may be used before subsequent injections.

Antipyretics: oral acetaminophen (650 to 1000 mg).

Antihistamine: oral or IV diphenhydramine (25 to 50 mg, or equivalent).

Montelukast 10 mg (or equivalent leukotriene inhibitor).
NOTE: For any patients with a history of COPD, consider prescribing postinfusion medications 
such as short- and long-acting bronchodilators, and inhaled corticosteroids. After the first 4
infusions, if the patient experiences no major IRs, these additional inhaled postinfusion 
medications may be discontinued.
Premedications are required in phase 1 and phase 2a. 
The clinical site is responsible for sourcing any premedications outlined in the protocol.
Postdose Medications
Postinjection site care: Apply corticosteroid cream topically to injection site(s) and apply ice 
locally for approximately 10 to 15 minutes (report the corticosteroid cream as a concomitant 
medication).
Patients may receive low-dose methylprednisolone (< 20 mg) for the prevention of delayed 
injection-related reaction as clinically indicated after an injection.
8.1.2
TAK-079 Formulation and Administration
The strength of the TAK-079 drug product for SC use in the current study (TAK-079-1501) is 
100 mg TAK-079 in 1 mL (100 mg/mL). The drug product is supplied in clear borosilicate glass 
vials (see additional details in Section 8.10).
After patients have received premedication treatment, TAK-079 doses will be administered with 
syringes as SC injections up to a maximum volume of 2 mL per injection (ie, 200 mg/2 mL). For 
dose levels where multiple SC injections are needed to administer the full prescribed dose (ie, 300 
mg dose and above), the Cycle 1 Day 1 dose will be administered by giving each SC injection 30 
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minutes apart until the full scheduled dose has been administered. On all drug administration days 
after Cycle 1 Day 1, if the patient did not have a clinically significant IR per the investigator, the 
SC injections can be given at the at the same time without a waiting period. 
When patients are to receive multiple SC injections, the injection sites need to be rotated, using the 
abdomen, thighs, arms, and upper buttock area. Time and anatomical site should be recorded for 
each SC injection.
Refer to the Pharmacy Manual for detailed instructions regarding preparation of each dose.
8.2
Definitions of DLT
Toxicity will be evaluated according to the NCI CTCAE, Version 4.03, effective 14 June 2010 
[20]. These criteria are provided in the Study Manual. DLTs will be defined as any of the 
following events regardless of relationship, except those events that are clearly due to extraneous 
causes.

Grade 4 laboratory abnormalities, except those events that are clearly due to extraneous causes, 
will be defined as a DLT. 

Nonhematologic TEAEs of NCI CTCAE Grade 3, except those events that are clearly due to 
extraneous causes, and occurring during the first cycle will be considered DLTs (see Section 
10.2 for relatedness guidance), with the following exceptions:
–
Grade 3 nausea/vomiting that can be managed subsequently with antiemetics (Grade 3 
nausea or vomiting that persists beyond 48 hours with or without appropriate medical 
intervention will be considered a DLT).
–
Grade 3 fatigue lasting less than 3 days (approximately 72 hours).
–
Grade 3 elevation of alanine aminotransferase or aspartate aminotransferase that resolves 
to Grade ≤1 or baseline within 7 days.
–
Grade 3 IR that responds to symptomatic treatment (eg, antihistamines, nonsteroidal 
anti-inflammatory drugs (NSAIDs), narcotics, IV fluids), without recurrence of Grade 3 
symptoms. See Section 8.8.1 for handling of IRs with systemic signs and symptoms.

Hematologic TEAEs of NCI CTCAE Grade ≥4, except those events that are clearly due to 
extraneous causes, and occurring during the first cycle will be considered DLTs, with the 
following exceptions:
–
Grade ≥3 hemolysis, except those events that are clearly due to extraneous causes 
(eg, negative direct Coombs test), will be included in the definition of DLT.
–
Grade ≥3 low platelet count with clinically meaningful bleeding, defined as a blood loss of 
>100 cc or the requirement of a blood transfusion, will be included in the definition of 
DLT.
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
An incomplete recovery from treatment-related toxicity causing a >2-week delay in the next 
scheduled injection before the initiation of Cycle 2 will be considered a DLT.
For the purpose of dose escalation, DLTs are those events meeting the criteria above that occur 
before Cycle 2 Day 1 administration. TEAEs meeting DLT definitions occurring in later cycles 
will determine the suitability of the MTD as the RP2D.
Patients who experience a DLT should be withdrawn from study treatment unless the sponsor 
approves subsequent treatment in a lower dose cohort; such patients will not count as a patient in 
that lower dose cohort for escalation decisions. 
In phase 1, patients who do not receive 4 full doses of TAK-079 within the 28-day (±2) treatment 
window or the Day 29 (ie, Cycle 2 Day 1) assessment for reasons other than a DLT will be 
replaced. Patients experiencing a DLT should not be replaced.
Dose and schedule modifications for toxicity are described in Section 8.4.
8.3
Dose-Escalation Design and Criteria
8.3.1
Dose Levels
Patients will be enrolled in cohorts of 3 to 6, following a 3+3 dose escalation design. 
Phase 1
TAK-079 injections will be escalated as follows:

45 mg, once weekly for 8 weeks (8 doses), once every 2 weeks for 16 weeks (8 doses), and 
once every 4 weeks thereafter until PD, unacceptable toxicities, or withdrawal due to other 
reasons.

135 mg, once weekly for 8 weeks (8 doses), once every 2 weeks for 16 weeks (8 doses), and 
once every 4 weeks thereafter until PD, unacceptable toxicities, or withdrawal due to other 
reasons.

300 mg, once weekly for 8 weeks (8 doses), once every 2 weeks for 16 weeks (8 doses), and 
once every 4 weeks thereafter until PD, unacceptable toxicities, or withdrawal due to other 
reasons.

600 mg, once weekly for 8 weeks (8 doses), once every 2 weeks for 16 weeks (8 doses), and 
once every 4 weeks thereafter until PD, unacceptable toxicities, or withdrawal due to other 
reasons.

1200 mg once weekly for 8 weeks (8 doses), once every 2 weeks for 16 weeks (8 doses), and 
once every 4 weeks thereafter until PD, unacceptable toxicities, or withdrawal due to other 
reasons.

1800 mg once weekly for 8 weeks (8 doses), once every 2 weeks for 16 weeks (8 doses), and 
once every 4 weeks thereafter until PD, unacceptable toxicities, or withdrawal due to other 
reasons.
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Figure 8.a
Dose-Escalation Scheme 
DLT=dose-limiting toxicity; MTD=maximum tolerated dose.
More conservative dose escalation, evaluation of intermediate doses, and expansion of an existing 
dose level are all permissible following discussions between the sponsor and the investigators, if 
such measures are needed for patient safety or for a better understanding of the dose-related 
toxicity, exposure,
.
Before initiating the dosing of the next cohort, when safety data are available for all patients in the 
current cohort, key safety data will be reviewed and evaluated by the study team consisting of 
sponsor representatives and investigators who will review the safety of all treated patients and 
make decisions regarding dose escalation. In addition, changes to the dose-escalation scheme or 
dose schedule (dosing interval) may be considered. All decisions will be documented in writing. 
Any decision to modify the dose-escalation scheme (with the exception of testing intermediate 
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dose levels) or dose schedule will be communicated to institutional review boards (IRBs), and the 
protocol will be amended accordingly.
8.4
Dose Modification Guidelines
Dose modification guidelines for toxicities are described below for TAK-079 on the basis of the 
type and severity of AEs and causality determination by investigators (see Section 8.4.2). Further 
clarification can be obtained in consultation with the sponsor clinician (or designee).
8.4.1
Criteria for Beginning or Delaying a Subsequent Treatment Cycle
Treatment with TAK-079 will use a cycle length of 28 days. For a new cycle of treatment to begin, 
the patient must meet the following criteria:

Absolute neutrophil count must be ≥1000/mm3.

Platelet count must be ≥75,000/mm3.

For therapy to resume, toxicity considered to be related to treatment with TAK-079 must have 
resolved to Grade 1 or baseline, or to a level considered acceptable by the physician. If the 
patient fails to meet the above-cited criteria for retreatment, initiation of the next cycle of 
treatment should be delayed for 1 week. At the end of that week, the patient should be 
re-evaluated to determine whether the criteria for re-treatment have been met. If there is a 
delay of a subsequent cycle longer than 28 days because of a drug-related AE, the patient may 
be withdrawn from treatment unless there is clinical benefit as assessed by the investigator, 
with agreement by the sponsor’s medical monitor. 

For TAK-079 injections within the same cycle, the decision of holding treatment is left to the 
investigator’s discretion based on clinical and analytical data, and also based on the toxicity 
that the patient experienced with previous injections in the same cycle. The investigator should 
differentiate between acute toxicity (like an IR) from which the patient is recovered at the time 
of the next injection, and subacute toxicity (for example, neutropenia) that might be worsened 
upon another injection if it is not on a clear recovery path. If the dose cannot be administered 
on the scheduled day, the patient can be reviewed at the investigator’s discretion in the 
following 48 hours. If TAK-079 cannot be administered within a cycle in this 48-hour 
window, the dose will be missed and the patient scheduled for the next administration per the 
Schedule of Events (SOE; Appendix A).
8.4.2
Criteria for Dose Modification
All toxicities that occur during the study will be actively managed following medical standard of 
care unless otherwise specified in the protocol. Patients experiencing AEs attributed to TAK-079 
may continue study treatment with the same dose, may have TAK-079 treatment held or may be 
permanently discontinued from the study. Patients who have study drug held because of 
treatment-related or possibly related AEs may resume study drug treatment after resolution of the 
AE at the same dose level or at a reduced dose, depending on the nature and severity of the AE and 
whether it is the first occurrence or it is recurrent.
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TEAEs that are not attributed by the investigator to the study drug may be treated as per local 
standard of care; dose-modifications, interruptions, and permanent discontinuations may be 
discussed upfront with the medical monitor. Any dose interruption of more than 28 days due to 
toxicity may result in permanent discontinuation of TAK-079.
Table 8.a provides general dose modification recommendations. When the dose of TAK-079 is 
withheld on the basis of these criteria, clinical and laboratory re-evaluation should be repeated at 
least weekly or more frequently, depending on the nature of the toxicity observed, until the toxicity 
resolves to Grade ≤1 or baseline. If there are transient laboratory abnormalities that, per 
investigator assessment, are not clinically significant or drug related, continuation of therapy 
without dose modification is permissible upon discussion with the sponsor. Toxicity is managed 
using dose interruptions, including missed doses, as is standard with administration of monoclonal 
antibodies as a means to reduce dose intensity [5,21,22]. Patients experiencing a DLT (defined in 
Section 8.2) should be withdrawn from study treatment unless the sponsor approves subsequent 
treatment in a lower dose cohort.
See details for managing specific AEs in Section 8.8.
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Table 8.a
Dose Modification Recommendations for TAK-079 Toxicities
Criteria
Action
Grade 1 AEs
No dose interruptions.
Grade 2 AEs
Treat according to local practice. Whether to hold treatment or to continue it 
at the same dose is at the discretion of the investigator.
Patients with Grade 2 AEs considered related to study treatment that are not 
easily managed or corrected and are not tolerable to the patient, or AEs that 
are not acceptable in the investigator’s judgment, should have study 
treatment interrupted until the AE resolves to Grade ≤1 or baseline, then 
restarted at the same dose.
Grade 3 AEs
Patients with Grade 3 AEs considered related to study treatment that are not 
easily managed or corrected and are not tolerable to the patient should have 
study treatment interrupted until the AE resolves to Grade ≤1 or baseline, 
then resume treatment at the same dose level. (Note Section 8.2 for AEs of 
short duration and/or that respond to medical management.) 
Note in phase 1, nonhematologic AEs Grade ≥3 may meet DLT criteria and 
as such patients should be withdrawn from further dosing unless the sponsor 
approves subsequent treatment in a lower dose cohort.
Grade 3 or higher thrombocytopenia with bleeding should result in a dose 
interruption until the AE resolves to Grade ≤1 or baseline, then resume at the 
same dose. Medical considerations should eliminate Coombs positivity 
before restarting (note Table 8.b).
Grade 4 (life-threatening) AEs
Patients with Grade 4 AEs considered related to study treatment should 
permanently discontinue treatment. Grade 4 hematologic toxicity should 
result in study treatment interruption until the AE resolves to Grade ≤1 or 
baseline, then resume at the same dose. Medical consideration should 
eliminate Coombs positivity before restarting (note Section 8.4.3 and 
Table 8.b).
AEs of all grades
If TAK-079 administration does not commence within the prespecified 
window (Table 8.b) of the scheduled administration date, then the dose will 
be considered a missed dose. Administration may resume at the next planned 
dosing date upon recovery as described above.
AE=adverse event; DLT=dose-limiting toxicity.
If initial dose interruption does not provide sufficient relief, the dose of TAK-079 should be 
considered for permanent discontinuation. 
Table 8.b
TAK-079–Related Toxicity Management
Dosing Frequency
Dose Missed
Dosing Resumption
Weekly (QW)
>3 days
Skip dose, move to next planned weekly dosing date
Biweekly (Q2W)
>7 days
Skip dose, move to next planned biweekly dosing date
Every 4 weeks (Q4W)
>21 days
Skip dose, move to next planned every 4 weeks dosing date
A TAK-079 dose held for more than 3 days from the per-protocol administration date for any 
reason other than AEs should be brought to the attention of the sponsor/designee as soon as
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possible. Subjects missing ≥3 consecutive planned doses of TAK-079 for reasons other than AEs 
should be withdrawn from treatment, unless, upon consultation with the sponsor/designee and 
review of safety and efficacy, continuation is agreed upon. A missed dose will not be made up. 
Doses of TAK-079 during every-4-weeks dosing may be delayed (interrupted) up to 4 weeks. If a 
dose is delayed (interrupted), then the dates of all subsequent doses and assessments must be 
adjusted accordingly. Any AE deemed to be related to TAK-079 that requires a dose delay 
(interruption) of more than 28 days should result in permanent discontinuation of TAK-079, unless 
both the investigator and the sponsor study clinician believe the patient is deriving clinical benefit.
8.4.3
Criteria for Discontinuing TAK-079 in Individual Patients (When Considering Dose 
Modification)
TAK-079 should be discontinued in patients experiencing an AE in Cycle 1 that meets the criteria 
for a DLT, unless the investigator considers that re-treatment of the patient not to be dangerous and 
the sponsor approves subsequent treatment in a lower dose cohort. For Grade 4 (life-threatening) 
TEAEs, consider permanently withdrawing the patient from the study, except when the 
investigator determines that the patient is receiving clinical benefit, there are opportunities to 
provide supportive care to mitigate risk for the Grade 4 event to reoccur, and this approach (ie, the 
specific situation and mitigation plan) has been discussed with the sponsor. In these circumstances, 
treatment may be restarted when toxicity recovers to Grade ≤1 or baseline (see Table 8.a and 
Table 8.b).
8.5
Excluded Concomitant Medications and Procedures
The following medications and procedures are prohibited during the study:

Chemotherapy and radiation therapy for the disease under study. Local radiotherapy for bone 
pain is permitted after agreement with the sponsor’s medical monitor and once PD is ruled out.

Systemic corticosteroid use >10 mg/day (prednisone or equivalent). 

Live vaccines.

Any investigational agent other than TAK-079, including agents that are commercially 
available for indications other than MM that are under investigation for the treatment of MM.
8.6
Permitted Concomitant Medications and Procedures 

All necessary supportive care consistent with optimal patient care will be available to patients 
as necessary. During study treatment, all blood products and concomitant medications 
received until 30 days after the final dose will be recorded in the electronic case report forms 
(eCRFs) (note additional information in Section 9.4.9 and Appendix A).

The following medications and procedures are permitted while the patient is receiving the 
study drug:
–
Systemic corticosteroid use ≤10 mg/day (prednisone or equivalent).
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–
Myeloid growth factors (eg, granulocyte colony stimulating factor, granulocyte 
macrophage-colony stimulating factor) and erythropoietin are permitted. Their use should 
follow the product label, published guidelines, and institutional practice. 
–
Transfusions with RBCs and platelets as clinically indicated; localized radiation for pain 
management for osteolytic lesions.
–
Concomitant treatment with bisphosphonates will be encouraged for all patients with 
evidence of lytic destruction of bone or with osteopenia, according to the American 
Society of Clinical Oncology Clinical Practice Guidelines or institutional practice in 
accordance with the product label, unless specifically contraindicated. If bisphosphonate 
therapy was not started before the study start, it should be initiated as soon as clinically 
indicated.
–
Topical or inhaled steroids and short-acting β2 adrenergic receptor agonists (eg, for the 
treatment of asthma) are permitted.
–
Nonresorbable corticosteroids (eg, budesonide).
–
Plasmapheresis.
8.7
Precautions and Restrictions
Fluid deficit should be corrected before initiation of treatment and during treatment.
NSAIDs should be avoided with impaired renal function given the reported NSAID-induced renal 
failure in patients with decreased renal function.
Patients should not drive, operate dangerous tools or machinery, or engage in any other potentially 
hazardous activity that requires full alertness and coordination if they experience sedation while 
enrolled in this study.
Patients are to be instructed to limit the use of alcohol while enrolled in this study.
It is not known what effects TAK-079 has on human pregnancy or development of the embryo or 
fetus; therefore, female patients participating in this study should avoid becoming pregnant, and 
male patients should avoid impregnating a female partner. Nonsterilized female patients of 
reproductive age and male patients should use effective methods of contraception through defined 
periods during and after study treatment as specified below.
Female patients must meet the following:

WOCBP must not be pregnant or lactating. 

Postmenopausal for at least 1 year before the screening visit, OR

Surgically sterile, OR

If they are of childbearing potential, agree to practice 1 highly effective method and 
1 additional effective (barrier) method of contraception at the same time, from the time of 
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signing of the informed consent form (ICF) through at least 90 days or 5 half-lives after the last 
dose of study drug (whichever is longer), OR

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of 
the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, and postovulation 
methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.)
Male patients, even if surgically sterilized (ie, status postvasectomy) must agree to one of the 
following:

Agree to practice effective barrier contraception during the entire study treatment period and 
through 90 days (or if the drug has a very long half-life, for 90 days plus 5 half-lives) after the 
last dose of study drug, OR

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of 
the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, and postovulation 
methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.)
In addition, a close monitoring of serum chemistry, particularly creatinine, potassium, and uric 
acid levels must be performed. Patients with tumor lysis syndrome should be treated per 
institutional practice (including correction of electrolyte abnormalities, monitoring of renal 
function and fluid balance, and administration of supportive care, including dialysis as indicated).
8.8
Management of Specific Adverse Reactions
8.8.1
Handling of IRs
Patients should be carefully observed during TAK-079 injections. Trained trial staff at the clinic 
should be prepared to intervene in case of any systemic IRs and resources necessary for 
resuscitation (eg, agents such as epinephrine and aerosolized bronchodilators; also medical 
equipment such as oxygen tanks, tracheostomy equipment, and a defibrillator) must be available at 
bedside.
In case of an IR (any grade), blood draws should be performed for central evaluation of 
 
, ADAs, 
. These draws must not interfere with patient care and 
blood tests necessary for the acute care of the patient. 
For additional details, refer to Section 9.4.15.3.
Grade 1 or 2 IR
In case of Grade 1 or 2 IRs (systemic signs or symptoms): 

Withhold therapy (also administration of remaining SC injections when full dose was not yet 
reached) until resolution to Grade 1 or maximum to Grade 2 as per the investigator’s 
discretion. 
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o
If a patient experiences a Grade 1 IR mid-dosing, hold subsequent SC injections, 
evaluate the patient, treat symptoms, and once the patient is stable per investigator’s 
discretion, resume SC injections to achieve the full dose level. The remaining 
injections must be given 30 minutes apart, and the patient will be evaluated for IRs
after each SC injection. 
o
If a patient experiences a Grade 2 IR mid-dosing, hold subsequent SC injections, 
evaluate the patient, treat symptoms, and once resolved to Grade 1 or resolved 
completely, per investigator’s discretion, resume SC injections to achieve the full dose 
level. The remaining injections must be given 30 minutes apart, and the patient will be 
evaluated for IRs after each SC injection.
–
Patients who experience IRs must be treated according to the investigator’s judgement and 
best clinical practice. Subsequent doses may have individual SC injections administered
more frequently at the investigator’s discretion with appropriate premedication and 
postmedication.
Grade 3 IR
In case of Grade 3 IRs (systemic signs or symptoms): 

Withhold therapy (also administration of remaining SC injections if full dose was not yet 
reached and therefore skip remaining injection[s]) until next scheduled TAK-079 SC 
administration, providing that the IR has recovered to Grade ≤1 at the time of the next 
scheduled TAK-079 dose. Patients who experience IRs must be treated according to the 
investigator’s judgement and best clinical practice. At the time of the next dose after an IR, 
patients at a dose level requiring more than 1 SC injection should receive each injection 
30 minutes apart. If no further IR, subsequent injections may be given more frequently at the 
investigator’s discretion with appropriate premedication and postmedication.

Permanently discontinue treatment after the third occurrence of Grade 3 IRs.
Grade 4 IRs
In case of Grade 4 IRs (systemic signs or symptoms): 

Permanently discontinue treatment.
8.8.2
Injection Site Care
Prophylactic postinjection site care:

Apply corticosteroid cream topically to injection site(s) and apply ice locally for 
approximately 10 to 15 minutes (report the corticosteroid cream as a concomitant medication).
Additional injection site care may be provided on the basis of signs and symptoms per investigator 
discretion (report any actions as a concomitant medication).
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The investigator is responsible for ensuring that deliveries of TAK-079 and other study materials 
from the sponsor are correctly received, recorded, and handled, and stored safely and properly in 
accordance with the Code of Federal Regulations (CFR) or national and local regulations, and used 
in accordance with this protocol.
Detailed dosage preparation instructions are provided in the Directions for Use section of the 
Pharmacy Manual. Complete receipt, inventory, accountability, reconciliation, and destruction 
records must be maintained for all used and unused study drug vials. Detailed instructions and the 
associated forms for these activities are in the Pharmacy Manual.
Upon receipt of study medication, the investigator or designee must verify the contents of the 
shipments against the packing list. The verifier should ensure that the quantity is correct, the 
medication is received within the labeled storage conditions, and is in good condition. If quantity 
and conditions are acceptable, investigator or designee should acknowledge the receipt of the 
shipment by signing bottom half of the packing list and faxing per instructions provided on the 
form. If there are any discrepancies between the packing list versus the actual product received, 
Takeda must be contacted to resolve the issue. The packing list should be filed in the investigator’s 
essential document file.
The sponsor must be notified immediately of any temperature excursions, shipping and handling 
or storage discrepancies.
Drug supplies will be counted and reconciled at the site before being returned to Takeda or 
designee or being destroyed.
The investigator or designee must ensure that the study medication is used in accordance with 
the approved protocol and is dispensed only to subjects enrolled in the study. To document 
appropriate use of study medication (TAK-079), the investigator must maintain records of all 
study medication delivery to the site, site inventory, use by each subject, and return to the 
sponsor or designee.
The investigator will be notified of any expiry date or retest date extension of clinical study 
material during the study conduct. On expiry date notification from the sponsor or designee, the 
site must complete all instructions outlined in the notification, including segregation of expired 
clinical study material for return to the sponsor or its designee.
Further guidance and information are provided in the Pharmacy Manual.
8.13.2 Accountability and Destruction of Sponsor Supplied Drugs
The investigator, institution, or head of the medical institution (where applicable) is responsible 
for TAK-079 accountability, reconciliation, and record maintenance (ie, receipt, reconciliation, 
and final disposition records).
The investigator must maintain 100% accountability for all study medication (TAK-079) received 
and dispensed during his or her entire participation in the study. Proper drug accountability 
includes, but is not limited to:
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
Continuously monitoring expiration dates if expiry date/retest date is provided to the 
investigator.

Frequently verifying that actual inventory matches documented inventory.

Verifying that the log is completed for the drug lot used to prepare each dose.

Verifying that all containers used are documented accurately on the log.

Verifying that required fields are completed accurately and legibly.

Per standard clinical practice, a site representative, otherwise uninvolved with study conduct, 
will review the subject dosing log prior to Day 1 dosing and following dosing to ensure all 
subjects received the correct dose of study medication. This review will be documented at the 
site.
If any dispensing errors or discrepancies are discovered, the sponsor must be notified immediately.
Empty, partially used, and unused TAK-079 will be disposed of, retained, or returned to the 
sponsor or designee, as directed by the sponsor or designee.
The investigator must maintain a current inventory (Drug Accountability Log) of all 
sponsor-supplied study medication delivered to the site, inventory at the site, and subjects’ use 
records. This log must accurately reflect the drug accountability of the study medication at all 
times. The following information will be recorded at a minimum: protocol number and title, name 
of investigator, site identifier and number, description of sponsor-supplied medication, 
expiry/retest date and amount dispensed, including the initials of the person dispensing and 
receiving the study medication. The log should include all required information as a separate entry 
for each subject to whom study medication is dispensed.
Prior to site closure or at appropriate intervals, a representative from the sponsor or its designee 
will perform clinical study material accountability and reconciliation before clinical study 
materials are returned to the sponsor or its designee or destroyed at the site, as applicable. The 
investigator will retain the original documentation regarding clinical study material accountability, 
return, and/or destruction, and copies will be sent to the sponsor or designee.
Further guidance and information are provided in the Pharmacy Manual.
8.14
Investigational Drug Assignment and Dispensing Procedures
Subjects will be assigned using an IVRS/IWRS accessible 24 hours a day to authorized users. At 
screening, the site will contact the IVRS/IWRS to register the subject into the study. During this 
contact, the investigator or designee will provide the necessary subject-identifying information. At 
drug dispensing visits, the investigator or designee will contact the IVRS/IWRS to request study 
medication assignments for a subject. Medication ID numbers (MED IDs) of the study 
medications to be dispensed will be assigned by the IVRS/IWRS. Documentation of the 
IVRS/IWRS assigned MED IDs should be included in the source documents.
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9.0
STUDY CONDUCT
This study will be conducted in compliance with the protocol, GCP, applicable regulatory 
requirements, and ICH guidelines.
9.1
Study Personnel and Organizations
The contact information for the project clinician for this study, any clinical laboratories centrally 
analyzing samples, and the contract research organization (CRO) team may be found in the Study 
Manual. A full list of investigators is available in the sponsor’s investigator database.
9.2
Arrangements for Recruitment of Patients
Recruitment and enrollment strategies for this study may include recruitment from the 
investigator’s local practice or referrals from other physicians. If advertisements become part of 
the recruitment strategy, they will be reviewed by the IRB/independent ethics committee (IEC). 
The screening period for this study is 21 days.
9.3
Treatment Group Assignments
All patients will receive open-label treatment with TAK-079 as indicated in respectively assigned 
treatment cohorts.
9.4
Study Procedures
Refer to the SOE (Appendix A) for timing of assessments. Additional details are provided as 
necessary in the sections that follow.
9.4.1
Informed Consent
Each patient must provide written informed consent before any study-required procedures are 
conducted, unless those procedures are performed as part of the patient’s standard care.
9.4.2
Patient Demographics
The date of birth, race, ethnicity, and sex of the patient are to be recorded during screening.
9.4.3
Medical History
During the screening period, a complete medical history will be compiled for each patient. This 
includes initial diagnosis date and MM staging at initial diagnosis using the International Staging 
System and Salmon-Durie Staging. Before dosing, the investigator should record the International 
Staging System as of study entry, which should be consistently used throughout the study. 
Known cytogenetic alterations should also be collected. Prior treatment regimens, with each 
treatment duration (start and stop dates), the best response obtained with each therapy, and 
date/type of disease progression should be recorded. Refractoriness to previous treatments should 
be collected following IMWG criteria (Appendix E). Confirm that the patient’s current medical 
status does not include active chronic HBV, HCV, or HIV infection.
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For patients who have received previous anti-CD38 therapy, the worst grade of infusion-related 
reactions should be recorded. In addition, concomitant medications will be recorded as specified in 
Section 9.4.9. 
Information on any subsequent anticancer therapies will be collected during the PFS/OS follow-up 
periods.
9.4.4
Physical Examination
A physical examination will be completed per standard of care at the times specified in the SOE 
(Appendix A).
9.4.5
Patient Height and Weight
Height will be measured during the screening visit only. Weight will be measured on Day 1 of each 
treatment cycle, as indicated in Appendix A.
9.4.6
Vital Signs
Vital signs include temperature, pulse, respiratory rate, and blood pressure. Vital sign 
measurements will be made before TAK-079 injection, and include supine or seated 
measurements of diastolic and systolic blood pressure (after 3 to 5 minutes in this position). All 
measurements should be performed in the same initial position, including heart rate and body 
temperature.
Blood pressure will also be measured before each injection, and at any time the patient complains 
of symptoms consistent with IR. If the patient experiences hypotension (with or without 
symptoms), intensive blood pressure monitoring according to local practice should be instituted. 
The patient should not be released from the site until blood pressure has returned to Grade 1 or 
baseline for at least 1 hour.
Vital signs will be measured at the visits specified in the SOE (Appendix A). Any vital sign value 
that is judged by the investigator as clinically significant will be recorded on both the source 
documentation and in the eCRF as an AE, and monitored as described in Section 10.2.
9.4.7
Eligibility Criteria
Eligibility criteria and confirmatory study assessments must be confirmed during the screening 
period, after a patient has signed the ICF, and before receiving study drug.
9.4.8
Pregnancy Test
WOCBP must have 2 negative pregnancy tests (human chorionic gonadotropin <5 mIU/mL) prior 
to starting study drug. A serum pregnancy test will be used during the screening period (within 
10 to 14 days before the start of study drug). A serum pregnancy test must also be performed at 
baseline (within 24 hours before the start of study drug). A WOCPB is a sexually mature female 
who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally 
postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) 
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for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive 
months).
During the study, if a menstrual period is delayed, absence of pregnancy in WOCBP must be 
confirmed by serum pregnancy test. Pregnancy tests may also be repeated during the study upon 
request by an IRB or if required by local regulations. 
A urine pregnancy test is required in WOCBP at designated treatment visits (Appendix A) and also 
at the EOT visit. 
9.4.9
Concomitant Medications and Procedures
Any prior or concomitant medication a patient has had within 21 days before TAK-079 
administration and up to 30 days after the last dose of TAK-079 (or the start of subsequent 
anticancer therapy, whichever occurs first) will be recorded on the eCRF. Trade name and 
international nonproprietary name/generic name (if available), indication, and start and end dates 
of the administered medication will be recorded. Medications used by the patient and therapeutic 
procedures completed by the patient will be recorded in the eCRF. See Section 8.5 and Section 8.6
for a list of medications and therapies that are prohibited or allowed during the study.
9.4.10 AEs
Monitoring of TEAEs, serious and nonserious, will be conducted throughout the study as specified 
in the SOE. Refer to Section 10.0 for details regarding definitions, documentation, and reporting of 
TEAEs and SAEs.
9.4.11
Enrollment
A patient is considered to be enrolled in the study at the first injection.
Procedures for completing the enrollment information are described in the Study Manual.
9.4.12
ECG
A single ECG will be collected at the screening visit for assessment of eligibility. A qualified 
person will interpret the ECG.
Time-matched triplicate 12-lead ECGs and PK samples will be collected in this study during 
Cycles 1 and 2 as specified in Appendix B. Although the number of scheduled ECG measurements 
will not be increased, the timing may be changed if emerging data indicate that an alteration in the 
ECG schedule is needed. Triplicate ECGs will be recorded electronically and transmitted to a 
central vendor for storage. 
The triplicate ECG measurements should be completed before the PK blood draw. Collection of 
triplicate ECGs should begin after the patient has rested in supine position for approximately 
5 minutes. Each ECG recording of the triplicate ECGs should occur within 3 minutes of each other 
and over a 10-minute window. It is recommended that patients refrain from eating or limit 
themselves to bland food for 1 hour before dosing and for 1 hour before each scheduled triplicate 
ECG measurement.
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Table 9.a
Clinical Chemistry and Hematology Tests
Hematology
Serum Chemistry
ANC
Hematocrit
Hemoglobin
Platelet (count) 
Reticulocyte count
RBC count
WBC count 
WBC with differential
Coagulation panel
Albumin
ALP
ALT
AST
Bilirubin (total)
BUN
Calcium
Chloride
CO2 (bicarbonate) 
Creatinine
Creatinine clearance
CRP
Glucose (nonfasting)
GGT
LDH
Phosphate
Potassium
Sodium
Total protein
Urate (uric acid)
ALP=alkaline phosphatase; ALT=alanine aminotransferase; ANC=absolute neutrophil count; AST=serine 
aminotransferase; BUN=blood urea nitrogen; CRP=C-reactive protein; GGT=γ-glutamyl transferase; LDH=lactate 
dehydrogenase; RBC=red blood cell; WBC=white blood cell.
Table 9.b
Clinical Urinalysis Tests
Urinalysis
Bilirubin
Glucose
Ketones
Leukocytes
Nitrite
Occult blood
pH
Protein
Specific gravity
Turbidity and color
Urobilinogen
For estimation of creatinine clearance, the Cockcroft-Gault formula will be employed as follows:
	
 
	
 
		
= [(140 −
) • 	 () ] / [72 • 
! 
	
 (/")] 
For female patients, the result of the formula above should be multiplied by 0.85. 
9.4.13.2 Prestudy Prognostic Risk Assessment
A blood sample will be collected for serum 2 microglobulin at screening to assess patient disease 
status. Results will be analyzed locally.
9.4.14
Disease Response Assessments
Patients will be assessed for disease response according to the IMWG criteria ([17,18]; 
Appendix E).
Serum and urine response assessments will be performed no later than the first day of every 
treatment cycle, before the patient receives treatment with TAK-079. Patients measurable by 
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SPEP only will have 24-hour urine collected at screening and EOT and to document PR, very good 
partial response (VGPR), CR, or PD. 
Imaging tests will be done per Appendix A and as described in Section 9.4.14.1. The same 
imaging technique should be used throughout the study to facilitate consistent disease assessment.
Responses should be confirmed with follow-up assessments of SPEP, UPEP, immunofixation of 
blood and urine, and serum FLCs as outlined in Appendix A. One BMA assessment has to occur to 
document CR; no second bone marrow confirmation is needed.
Note that to determine a response of sCR, BMA immunohistochemistry or immunofluorescence 
for kappa:lambda ratio, as well as serum FLC assay, should be performed for all patients 
suspected to be in CR to meet this response category’s requirements.
PD may be confirmed per standard clinical practice at the site. Local laboratory results may be 
used to confirm PD.
Blood samples, 24-hour urine sample, BMA, and imaging done for disease response assessment 
will be done locally.
9.4.14.1 Computed Tomography/Magnetic Resonance Imaging
Scans will be performed at a minimum at screening and at the EOT visit. All treatment phase and 
follow-up scans should use the same imaging modality used at screening.
For patients with documented extramedullary disease, a whole-body x-ray, positron emission 
tomography-computed tomography (PET-CT) scan, computed tomography (CT) scan (includes 
low-dose CT), or magnetic resonance imaging (MRI) scan will be performed as outlined in 
Appendix A. The screening scan may be performed up to 21 days before first dose of TAK-079; 
however, if the patient has adequate image test performed within 5 weeks of the planned first dose 
of study drug, that image can be used as baseline and does not need to be repeated as part of 
screening. If disease is documented, then a repeat PET-CT scan, CT scan, or MRI scan should be 
performed as required to document response or PD.
Additional surveys (x-ray, CT, or MRI) may also be performed at the investigator’s discretion, eg, 
in case of bone pain. Radiographs will be analyzed locally and reports maintained with the patient 
record for retrieval during monitoring visits.
9.4.14.2 Quantification of Immunoglobulins
A blood sample for quantification of Ig (IgM, IgG, and IgA) will be obtained at the screening visit, 
predose on Day 1 of every cycle, and at all visits per Appendix A. Analysis of Ig will be performed 
locally.
9.4.14.3 Quantification of M-Protein
A predose blood and 24-hour urine sample will be obtained at the screening visit, Day 1 of every 
cycle, and at all visits per Appendix A. 
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The samples will be tested locally. M-protein in serum and urine will be quantified by SPEP and 
UPEP.
9.4.14.4 Serum FLC Assay
Serum samples will be obtained predose on Day 1 of every cycle and at all visits, per Appendix A,
for the serum FLC assay (including quantification of kappa and lambda chains and ratio). Blood 
samples will be analyzed locally.
9.4.14.5 Immunofixation of Serum and Urine
Serum and urine samples will be obtained for serum and urine immunofixation tests at the 
screening visit, predose on Day 1 of every cycle, to confirm CR, and at all response assessment 
visits as per Appendix A. Immunofixation testing will be performed in a local laboratory.
9.4.14.6 BMAs 
Central Laboratory Evaluations
BMAs will be taken during the screening period and at the beginning of designated study visits at 
Cycles 2, 4, 7, and at Cycle 13, with some aspirate samples sent for central analysis (note 
Table 9.c).
Local Laboratory Evaluations
Disease Assessment
A BMA will be obtained at screening for disease assessment (if a standard BMA was drawn within 
5 weeks before consent, that BMA can be used as baseline and does not need to be repeated as part 
of screening unless cytogenetic evaluation is not available). A BMA will also be obtained at any
time to assess CR or as needed to investigate suspected PD. Requirements for BMA assessments to 
confirm disease responses are defined above and will be analyzed locally (see Section 9.4.14). 
Cytogenetics
Patients who do not have historically documented cytogenetic results for the high-risk 
abnormalities of del (17), t(4:14), and t(14:16) will have cytogenetic evaluation performed on the 
BMA sample at screening. Cytogenetic evaluation may be performed using fluorescence in situ 
hybridization or conventional cytogenetics (karyotype). At a minimum, cytogenetic markers must 
include the 3 high-risk abnormalities of del(17), t(4:14), and t(14:16). Additional abnormalities 
(ampl 1q, del13, or del1p) may also be tested. Cytogenetics will be analyzed locally, according to 
local standards.
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9.4.15
, PK, 
, and Immunogenicity Samples
9.4.15.1 Primary Specimen Collection for PK, 
, and 
 Assessments
Blood samples will be collected via venipuncture or indwelling catheter at the time points detailed 
in Appendix B for the measurement of serum concentrations of TAK-079 and in Appendix A for 
. 
The primary specimen collection is presented in Table 9.c. Details on sample handling, storage, 
shipment, and analysis are provided in the Laboratory Manual.
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Patients will be followed every 12 weeks for OS until death, loss to follow-up, consent withdrawal, 
or study termination.
It is anticipated that the duration of the study will be approximately 36 months (3 years).
9.7
Discontinuation of Treatment With Study Drug and Patient Replacement
Study drug must be permanently discontinued for patients meeting any of the following criteria:

Patient experiences an AE or other medical condition that indicates to the investigator that 
continued participation is not in the best interest of the patient. 

Withdrawal by patient.

Female patient has confirmed pregnancy.
Treatment with study drug may also be discontinued for any of the following reasons:

AE/SAE.

Protocol deviation.

PD. 

Symptomatic deterioration. 

Unsatisfactory therapeutic response. 

Study terminated by sponsor.

Lost to follow-up.

Other.
Once study drug has been discontinued, all study procedures outlined for the EOT/early 
termination visit will be completed as specified in Appendix A. The primary reason for study drug 
discontinuation will be recorded on the eCRF.
Note that some patients may discontinue study drug for reasons other than PD before completing 
the full treatment course; these patients will remain in the study for posttreatment PFS assessments 
as outlined in Appendix A until PD occurs.
9.8
Withdrawal of Patients From Study
A patient may be withdrawn from the study for any of the following reasons:

Lost to follow-up.

Study terminated by sponsor.

Withdrawal by patient (mandatory immediate discontinuation of study agent).

Death. 

PD. 
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
Other.
The consequence of study withdrawal is that no new information will be collected from the 
withdrawn patient and added to the existing data or any database.
9.9
Study Compliance
Study drug will be administered only to eligible patients under the supervision of the investigator 
or identified subinvestigator(s). The appropriate study personnel will maintain records of study 
drug receipt and dispensing.
9.10
Posttreatment Follow-up Assessments (PFS and OS)
Patients who stop treatment for any reason other than progressive disease will continue to have 
progression-free follow-up visits (additional details in Section 9.6). Patients who discontinue 
study treatment for reasons other than PD will continue PFS follow-up every 4 weeks from EOT 
until the occurrence of PD, death, the start of subsequent anticancer therapy, study termination, or 
12 months after discontinuation of study treatment, whichever occurs first.
Patients who stop treatment due to PD will continue to have OS visits. Patients will be followed
every 12 weeks for OS after documented PD until death, loss to follow-up, consent withdrawal, or 
study termination.
Survival information and death details may be collected by methods that include, but are not 
limited to, telephone, email, mail, or retrieval from online or other databases (eg, Social Security 
indexes). In addition, the start of another anticancer therapy for the disease under study will be 
collected.
See the SOE (Appendix A) for appropriate assessments during follow-up.
NOTE: All SAEs must be reported to the Takeda Global Pharmacovigilance department or 
designee. This includes deaths that the investigator considers related to study drug that occur 
during the posttreatment follow-up. Refer to Section 10.0 for details regarding definitions, 
documentation, and reporting of SAEs.
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10.0
ADVERSE EVENTS
10.1
Definitions
10.1.1 Pretreatment Event Definition
A pretreatment event is any untoward medical occurrence in a patient or subject who has signed 
informed consent to participate in a study but before administration of any study medication; it 
does not necessarily have to have a causal relationship with study participation.
10.1.2 AE Definition
AE means any untoward medical occurrence in a patient or subject administered a pharmaceutical 
product; the untoward medical occurrence does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product whether or not it is related to the medicinal product. This includes any 
newly occurring event, or a previous condition that has increased in severity or frequency since the 
administration of study drug.
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is considered 
by the investigator to be a clinically significant change from baseline.
10.1.3 SAE Definition
SAE means any untoward medical occurrence that at any dose:

Results in death.

Is life-threatening (refers to an AE in which the patient was at risk of death at the time of the 
event. It does not refer to an event which hypothetically might have caused death if it were 
more severe).

Requires inpatient hospitalization or prolongation of an existing hospitalization (see 
clarification in the paragraph in Section 10.2 on planned hospitalizations).

Results in persistent or significant disability or incapacity. (Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions).

Is a congenital anomaly/birth defect.

Is a medically important event. This refers to an AE that may not result in death, be 
immediately life threatening, or require hospitalization, but may be considered serious when, 
based on appropriate medical judgment, may jeopardize the patient, require medical or 
surgical intervention to prevent one of the outcomes listed above, or involves suspected 
transmission via a medicinal product of an infectious agent. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
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development of drug dependency or drug abuse; any organism, virus, or infectious particle 
(eg, prion protein transmitting transmissible spongiform encephalopathy), pathogenic or 
nonpathogenic, is considered an infectious agent.
In this study, intensity for each AE, including any lab abnormality, will be determined using the 
NCI CTCAE, Version 4.03, effective date 14 June 2010 [20]. Clarification should be made 
between an SAE and an AE that is considered severe in intensity (Grade 3 or 4), because the terms 
serious and severe are not synonymous. The general term severe is often used to describe the 
intensity (severity) of a specific event; the event itself, however, may be of relatively minor 
medical significance (such as a Grade 3 headache). This is not the same as serious, which is based 
on patient/event outcome or action criteria described above, and usually associated with events 
that pose a threat to a patient’s life or ability to function. A severe AE (Grade 3 or 4) does not 
necessarily need to be considered serious. For example, a white blood cell count of 1000/mm3 to 
<2000 mm3 is considered Grade 3 (severe) but may not be considered serious. Seriousness (not 
intensity) serves as a guide for defining regulatory reporting obligations.
10.2
Procedures for Recording and Reporting AEs and SAEs
All AEs spontaneously reported by the patient and/or in response to an open question from study 
personnel or revealed by observation, physical examination, or other diagnostic procedures will be 
recorded on the appropriate page of the eCRF (see Section 10.3 for the period of observation). Any 
clinically relevant deterioration in laboratory assessments or other clinical finding is considered an 
AE. When possible, signs and symptoms indicating a common underlying pathology should be 
noted as 1 comprehensive event.
Regardless of causality, SAEs and serious pretreatment events (as defined in Section 10.1) must be 
reported (see Section 10.3 for the period of observation) by the investigator to the Takeda Global 
Pharmacovigilance department or designee (contact information provided below). This should be 
done by faxing the SAE Form within 24 hours after becoming aware of the event. The SAE Form, 
created specifically by Takeda, will be provided to each clinical study site. A sample of the SAE 
Form may be found in the Study Manual. Follow-up information on the SAE or serious 
pretreatment event may be requested by Takeda. SAE report information must be consistent with 
the data provided on the eCRF.
SAE Reporting Contact Information
Cognizant
United States and Canada
Toll-free fax #: 1-800-963-6290
E-mail: takedaoncocases@cognizant.com
Planned hospital admissions or surgical procedures for an illness or disease that existed before 
study drug was given are not to be considered AEs unless the condition deteriorated in an 
unexpected manner during the trial (eg, surgery was performed earlier or later than planned).
For both serious and nonserious AEs, the investigator must determine both the severity (toxicity 
grade) of the event and the relationship of the event to study drug administration. For serious 
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pretreatment events, the investigator must determine both the severity (toxicity grade) of the event 
and the causality of the event in relation to study procedures.
Severity (toxicity grade) for each AE, including any lab abnormality, will be determined using the 
NCI CTCAE, version 4.03, effective date 14 June 2010 [20]. The criteria are provided in the Study 
Manual.
Relationship of the event to study drug administration (ie, its causality) will be determined by the 
investigator responding yes (related) or no (unrelated) to this question: “Is there a reasonable 
possibility that the AE is associated with the study drug?”
10.3
Monitoring of AEs and Period of Observation
AEs, both nonserious and serious, will be monitored throughout the study as follows:
AEs will be reported from the signing of informed consent through 30 days after administration of 
the last dose of study drug and recorded in the eCRFs. AEs ongoing at EOT should be monitored 
until they are resolved, return to baseline, are clearly determined to be due to a patient’s stable or 
chronic condition or intercurrent illness(es), the start of next-line subsequent anticancer therapy, or 
6 months after PD has occurred, whichever comes first.
SAEs:

Serious pretreatment events will be reported to the Takeda Global Pharmacovigilance 
department or designee from the time of the signing of the ICF up to the first dose of study 
drug, and will also be recorded in the eCRF.

Related and unrelated treatment-emergent SAEs will be reported to the Takeda Global 
Pharmacovigilance department or designee from the first dose of study drug through 30 days 
after administration of the last dose of study drug and recorded in the eCRF. After this period, 
only related SAEs must be reported to the Takeda Global Pharmacovigilance department or 
designee. SAEs should be monitored until they are resolved or are clearly determined to be 
caused by a patient’s stable or chronic condition or intercurrent illness(es).
10.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events
If a woman becomes pregnant or suspects that she is pregnant while participating in this study, she 
must inform the investigator immediately and permanently discontinue study drug. The sponsor 
must also be contacted immediately by faxing a completed Pregnancy Form to the Takeda Global 
Pharmacovigilance department or designee (see Section 10.2). The pregnancy must be followed 
for the final pregnancy outcome.
If a female partner of a male patient becomes pregnant during the male patient’s participation in 
this study, the sponsor must also be contacted immediately by faxing a completed Pregnancy Form 
to the Takeda Global Pharmacovigilance department or designee (see Section 10.2). Every effort 
should be made to follow the pregnancy for the final pregnancy outcome.
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10.5
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose)
A product complaint is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product. Individuals who 
identify a potential product complaint situation should immediately report this via the phone 
numbers or email addresses provided below.
A medication error is a preventable event that involves an identifiable patient and that leads to 
inappropriate medication use, which may result in patient harm. Whereas overdoses and 
underdoses constitute medication errors, doses missed inadvertently by a patient do not. 
Individuals who identify a potential medication error (including overdose) situation should 
immediately report this via the phone numbers or email addresses provided below.
Product
Call Center
Phone Number
E-mail
Fax
TAK-079
DLSS
1-844-662-8532 
Non-toll-free 
number: 
1-510-740-1273 
GlobalOncologyMedinfo@takeda.com 
1-800-881-6092
Product complaints in and of themselves are not AEs. If a product complaint results in an SAE, an 
SAE Form should be completed and sent to Cognizant (refer to Section 10.2)
10.6
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, investigators, and IRBs or 
IECs as applicable, in accordance with national regulations in the countries where the study is 
conducted. Relative to the first awareness of the event by/or further provision to the sponsor or 
sponsor’s designee, SUSARs will be submitted to the regulatory authorities as an expedited report
within 7 days for fatal and life-threatening events and 15 days for other serious events, unless 
otherwise required by national regulations. The sponsor will also prepare an expedited report for 
other safety issues where these might materially alter the current benefit-risk assessment of an 
investigational medicinal product or that would be sufficient to consider changes in the 
investigational medicinal product’s administration or in the overall conduct of the trial. The 
investigational site also will forward a copy of all expedited reports to his or her IRB or IEC in 
accordance with national regulations.
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11.0
STUDY-SPECIFIC COMMITTEES
No steering committee, external data safety monitoring committee, or clinical endpoint committee 
will be used in this study.
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12.0
DATA HANDLING AND RECORDKEEPING 
The full details of procedures for data handling will be documented in the data management plan. 
If selected for coding, AEs, pretreatment events, medical history, and concurrent conditions will 
be coded using the Medical Dictionary for Regulatory Activities (MedDRA). Drugs will be coded 
using the World Health Organization Drug Dictionary.
12.1
eCRFs 
Completed eCRFs are required for each patient who signs an ICF.
The sponsor or its designee will supply investigative sites with access to eCRFs and will make 
arrangements to train appropriate site staff in the use of the eCRF. These forms are used to transmit 
the information collected in the performance of this study to the sponsor, CRO partners, and 
regulatory authorities. Investigative sites must complete eCRFs in English.
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site.
Any change of, modification of, or addition to the data on the eCRFs should be made by the 
investigator or appropriate site personnel. Corrections to eCRFs are recorded in an audit trail that 
captures the old information, the new information, identification of the person making the 
correction, the date the correction was made, and the reason for change.
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the principal investigator must retain 
full responsibility for the accuracy and authenticity of all data entered on the eCRFs.
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The sponsor or its designee will be permitted to review the patient’s medical 
and hospital records pertinent to the study to ensure accuracy of the eCRFs. The completed eCRFs 
are the sole property of the sponsor and should not be made available in any form to third parties, 
except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the sponsor.
12.2
Record Retention
The investigator agrees to keep the records stipulated in Section 12.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating patients, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated ICFs, patient authorization forms regarding the use of 
personal health information (if separate from the ICFs), electronic copy of eCRFs, including the 
audit trail, and detailed records of drug disposition to enable evaluations or audits from regulatory 
authorities, the sponsor or its designees. Any source documentation printed on degradable thermal 
sensitive paper should be photocopied by the site and filed with the original in the patient’s chart to 
ensure long-term legibility. Furthermore, ICH E6 Section 4.9.5 requires the investigator to retain 
essential documents specified in ICH E6 (Section 8) until at least 2 years after the last approval of 
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a marketing application for a specified drug indication being investigated or, if an application is 
not approved, until at least 2 years after the investigation is discontinued and regulatory authorities 
are notified. In addition, ICH E6 Section 4.9.5 states that the study records should be retained until 
an amount of time specified by applicable regulatory requirements or for a time specified in the 
Clinical Study Site Agreement between the investigator and sponsor.
Refer to the Clinical Study Site Agreement for the sponsor’s requirements on record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of any 
such documents.
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summarized. The effect of immunogenicity on PK, safety, and efficacy will be examined. NABs 
may also be assessed in patients.
The immunogenicity of TAK-079 will be assessed by determining anti–TAK-079 antibody 
incidence and characteristics (eg, titer, transiently, and persistently ADA; and possible 
neutralizing activity). Analysis will be based on available data from patients with a baseline 
assessment and at least 1 postbaseline immunogenicity assessment. Summaries will be provided 
separately for each study phase and by dose, as applicable. The incidence of immunogenicity will 
be calculated. The impact of anti–TAK-079 antibodies on the PK profile, drug efficacy, and 
clinical safety will be evaluated, if possible.
13.1.7 Safety Analysis
The safety and tolerability of TAK-079 will be assessed by the recording and analysis of TEAEs 
(NCI CTCAE version 4.03; [20]), vital signs, physical examination, serum chemistry and 
hematology, urinalysis, ECG, and concomitant medications.
TEAEs will be summarized using the safety analysis set and will be coded using the MedDRA. 
Data will be summarized using preferred term and primary system organ class.
In the phase 2a portion of this study, Grade 4 or higher nonhematological toxicity will be monitored 
starting from the first 10 enrolled patients and then every 10 patients. If the stopping bounds of ≥4/10 
and ≥6/20 have been reached, accrual to the study will be suspended to allow for investigation. After 
consideration by the study team, a decision will be made as to whether accrual can be resumed. The 
bounds are based on a Bayesian strategy to monitor outcomes in clinical trials. If the stopping rule is 
met, there is 80% probability that the true toxicity rate is greater than 18% with a prior beta distribution 
with parameters 0.4 and 1.6 for the binomially distributed toxicity rate [23].
13.2
Interim Analysis and Criteria for Early Termination
No interim analysis is planned.
13.3
Determination of Sample Size
It is expected that approximately 42 patients will be enrolled in total for phase 1 and 2a combined. 
Once the RP2D is determined in phase 1, approximately 18 patients will be treated in phase 2a to 
provide a preliminary estimate of the ORR in patients with RRMM.
A 3+3 dose escalation schema will be used for dose escalation as described in Section 8.3.2.
A group of 3 to 6 patients will be enrolled in each TAK-079 dose cohort based on safety, clinical, 
PK, 
 data. Each patient will participate in only 1 dose cohort. The actual 
dose levels may be adjusted based on the observed safety profile. 
Additional patients may be enrolled in a limited cohort expansion to confirm the safety and 
 before the phase 2a of this study is opened to enrollment. 
Approximately 6 dose levels are planned. For phase 1, the number of patients is planned to be 
approximately 24.
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In phase 2a, up to a total of 18 patients will be treated to provide a preliminary estimate of the ORR 
in patients with RRMM. All patients must show a clear evidence of PD with anti-CD38 therapy. 
Phase 2a of the study will also provide a more robust estimate of the safety profile to determine 
whether the MTD is appropriate for future studies as the RP2D.
No prospective calculations of statistical power have been made; however, Table 13.a shows the 
width of the 80% CI, based on the observed ORR in a cohort size of 18 patients, for a range of 
observed response rates. An observed ORR greater than 20% would be of interest in this 
relapse/refractory population.
Table 13.a
80% Confidence Interval Based on the Observed ORR
N=18 patients.
ORR=overall response rate.
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14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
Study Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and institution guarantee access to source documents by the sponsor or its 
designee (CRO) and by the IRB or IEC.
All aspects of the study and its documentation will be subject to review by the sponsor or designee 
(as long as blinding is not jeopardized), including but not limited to the Investigator’s Binder, 
study medication, patient medical records, informed consent documentation, documentation of 
patient authorization to use personal health information (if separate from the ICFs), and review of 
eCRFs and associated source documents. It is important that the investigator and other study 
personnel are available during the monitoring visits and that sufficient time is devoted to the 
process.
14.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study patients. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the sponsor or 
designee (and IRB or IEC, as required) to determine the appropriate course of action. There will be 
no exemptions (a prospectively approved deviation) from the inclusion or exclusion criteria.
The site should document all protocol deviations in the patient’s source documents. In the event of 
a significant deviation, the site should notify the sponsor or its designee (and IRB or IEC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the patient, or confound interpretation of primary study 
assessment. A Protocol Deviation Form should be completed by the site and signed by the sponsor 
or designee for any significant deviation from the protocol.
14.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the FDA, the United Kingdom Medicines and Healthcare 
products Regulatory Agency, the Pharmaceuticals and Medical Devices Agency of Japan). If the 
study site is contacted for an inspection by a regulatory body, the sponsor should be notified 
immediately. The investigator and institution guarantee access for quality assurance auditors to all 
study documents as described in Section 14.1.
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15.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, patients) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct 
the study according to applicable local or regional regulatory requirements and align his or her 
conduct in accordance with the “Responsibilities of the Investigator” that are listed in Appendix C. 
The principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities.
15.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable federal/local requirements of each 
participating region. The sponsor or designee will require documentation noting all names and 
titles of members who make up the respective IRB or IEC. If any member of the IRB or IEC has 
direct participation in this study, written notification regarding his or her abstinence from voting 
must also be obtained. Those American sites unwilling to provide names and titles of all members 
due to privacy and conflict of interest concerns should instead provide a Federal Wide Assurance 
Number or comparable number assigned by the Department of Health and Human Services.
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the IB, a copy of the ICF, and if 
applicable, patient recruitment materials and/or advertisements and other documents required by 
all applicable laws and regulations, must be submitted to a central or local IRB or IEC for 
approval. The IRB’s or IEC’s written approval of the protocol and patient informed consent must 
be obtained and submitted to the sponsor or designee before commencement of the study 
(ie, before shipment of the sponsor-supplied drug or study-specific screening activity). The IRB or 
IEC approval must refer to the study by exact protocol title, number, and version date; identify 
versions of other documents (eg, ICF) reviewed; and state the approval date. The sponsor will ship 
drug the sponsor has confirmed the adequacy of site regulatory documentation and, when 
applicable, the sponsor has received permission from competent authority to begin the trial. Until 
the site receives notification, no protocol activities, including screening, may occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the ICF, recruitment 
materials intended for viewing by patients, local safety reporting requirements, reports, and 
updates regarding the ongoing review of the study at intervals specified by the respective IRB or 
IEC, and submission of the investigator’s final status report to IRB or IEC. All IRB and IEC 
approvals and relevant documentation for these items must be provided to the sponsor or its 
designee.
Subject incentives should not exert undue influence for participation. Payments to patients must be 
approved by the IRB or IEC and sponsor.
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15.2
Patient Information, Informed Consent, and Patient Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The ICF, patient authorization form (if applicable), and patient 
information sheet (if applicable) describe the planned and permitted uses, transfers, and 
disclosures of the patient’s personal and personal health information for purposes of conducting 
the study. The ICF and the patient information sheet (if applicable) further explain the nature of the 
study, its objectives, and potential risks and benefits, as well as the date informed consent are 
given. The ICF will detail the requirements of the participant and the fact that he or she is free to 
withdraw at any time without giving a reason and without prejudice to his or her further medical 
care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the ICF 
and if applicable, the patient authorization form. The ICF, patient authorization form (if 
applicable), and patient information sheet (if applicable) must be approved by both the IRB or IEC 
and the sponsor prior to use.
The ICF, patient authorization form (if applicable), and patient information sheet (if applicable) 
must be written in a language fully comprehensible to the prospective patient. It is the 
responsibility of the investigator to explain the detailed elements of the ICF, patient authorization 
form (if applicable), and patient information sheet (if applicable) to the patient. Information should 
be given in both oral and written form whenever possible and in the manner deemed appropriate by 
the IRB or IEC. In the event the patient is not capable of rendering adequate written informed 
consent, then the patient’s legally acceptable representative may provide such consent for the 
patient in accordance with applicable laws and regulations.
The patient, or the patient’s legally acceptable representative, must be given ample opportunity to: 
(1) inquire about details of the study and (2) decide whether or not to participate in the study. If the 
patient, or the patient’s legally acceptable representative, determines he or she will participate in 
the study, then the ICF and patient authorization form (if applicable) must be signed and dated by 
the patient, or the patient’s legally acceptable representative, at the time of consent and prior to the 
patient entering into the study. The patient or the patient’s legally acceptable representative should 
be instructed to sign using their legal names, not nicknames, using blue or black ballpoint ink. The 
investigator must also sign and date the ICF and patient authorization (if applicable) at the time of 
consent and prior to patient entering into the study; however, the sponsor may allow a designee of 
the investigator to sign to the extent permitted by applicable law.
Once signed, the original ICF, patient authorization form (if applicable), and patient information 
sheet (if applicable) will be stored in the investigator’s site file. The investigator must document 
the date the patient signs the informed consent in the patient’s medical record. Copies of the signed 
ICF, the signed patient authorization form (if applicable), and patient information sheet (if 
applicable) shall be given to the patient.
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All revised ICFs must be reviewed and signed by relevant patients or the relevant patient’s legally 
acceptable representative in the same manner as the original informed consent. The date the 
revised consent was obtained should be recorded in the patient’s medical record, and the patient 
should receive a copy of the revised ICF.
15.3
Patient Confidentiality
The sponsor and designees affirm and uphold the principle of the patient’s right to protection 
against invasion of privacy. Throughout this study, a patient’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited patient attributes, such as sex, age, or date 
of birth, and patient initials may be used to verify the patient and accuracy of the patient’s unique 
identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, the FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the patient’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a patient’s study participation, 
and autopsy reports. Access to a patient’s original medical records requires the specific 
authorization of the patient as part of the informed consent process (see Section 15.2).
Copies of any patient source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, patient name, address, and other identifier fields 
not collected on the patient’s eCRF).
15.4
Publication, Disclosure, and Clinical Trial Registration Policy
15.4.1 Publication 
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the Clinical Study Site Agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
this section and the Clinical Study Site Agreement. In the event of any discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail.
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15.4.2 Clinical Trial Registration
To ensure that information on clinical trials reaches the public in a timely manner and to comply 
with applicable laws, regulations and guidance, Takeda will, at a minimum register interventional 
clinical trials it sponsors anywhere in the world on ClinicalTrials.gov or other publicly accessible 
websites on or before start of study, as defined in Takeda Policy/Standard. Takeda contact 
information, along with investigator’s city, state (for America’s investigators), country, and 
recruiting status will be registered and available for public viewing. 
As needed, Takeda and investigator/site contact information may be made public to support 
participant access to trials via registries. In certain situations/registries, Takeda may assist 
participants or potential participants to find a clinical trial by helping them locate trial sites closest 
to their homes by providing the investigator name, address, and phone number via email/phone or 
other methods callers requesting trial information. Once patients receive investigator contact 
information, they may call the site requesting enrollment into the trial. The investigative sites are 
encouraged to handle the trial inquiries according to their established patient screening process. If 
the caller asks additional questions beyond the topic of trial enrollment, they should be referred to 
the sponsor. 
Any investigator who objects to Takeda providing this information to callers must provide Takeda 
with a written notice requesting that their information not be listed on the registry site. 
15.4.3 Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites (including the Takeda corporate site) and registries, as required by Takeda 
Policy/Standard, applicable laws and/or regulations.
Data Sharing
The sponsor is committed to responsible sharing of clinical data with the goal of advancing 
medical science and improving patient care. Qualified independent researchers will be permitted 
to use data collected from patients during the study to conduct additional scientific research, which 
may be unrelated to the study drug or the patient’s disease. The data provided to external 
researchers will not include information that identifies patients personally. 
15.5
Insurance and Compensation for Injury
Each patient in the study must be insured in accordance with the regulations applicable to the site 
where the patient is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to clinical study patients. 
Refer to the Clinical Study Site Agreement regarding the sponsor’s policy on patient compensation 
and treatment for injury. If the investigator has questions regarding this policy, he or she should 
contact the sponsor or sponsor’s designee.
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16.0
REFERENCES
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and complement inhibitors affect response and resistance to daratumumab therapy in 
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with Daratumumab Monotherapy in Multiple Myeloma. N Engl J Med 2015;373(13):1207-19.
13. Clemens PL, Yan X, Lokhorst HM, Lonial S, Losic N, Khan I, et al. Pharmacokinetics of 
Daratumumab Following Intravenous Infusion in Relapsed or Refractory Multiple Myeloma 
After Prior Proteasome Inhibitor and Immunomodulatory Drug Treatment. Clin 
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14. Casneuf T, Xu XS, Adams HC, 3rd, Axel AE, Chiu C, Khan I, et al. Effects of daratumumab 
on natural killer cells and impact on clinical outcomes in relapsed or refractory multiple 
myeloma. Blood Adv 2017;1(23):2105-14.
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15. Malavasi F, Deaglio S, Funaro A, Ferrero E, Horenstein AL, Ortolan E, et al. Evolution and 
function of the ADP ribosyl cyclase/CD38 gene family in physiology and pathology. 
Physiological Reviews 2008;88(3):841-86.
16. Hendrikx J, Haanen J, Voest EE, Schellens JHM, Huitema ADR, Beijnen JH. Fixed Dosing of 
Monoclonal Antibodies in Oncology. Oncologist 2017.
17. Rajkumar SV, Harousseau JL, Durie B, Anderson KC, Dimopoulos M, Kyle R, et al. 
Consensus recommendations for the uniform reporting of clinical trials: report of the 
International Myeloma Workshop Consensus Panel 1. Blood 2011;117(18):4691-5.
18. Palumbo A, Rajkumar SV, San Miguel JF, Larocca A, Niesvizky R, Morgan G, et al. 
International myeloma working group consensus statement for the management, treatment, 
and supportive care of patients with myeloma not eligible for standard autologous stem-cell 
transplantation. J Clin Oncol 2014;32(6):587-600.
19. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. American Journal of Clinical 
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20. Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03. U.S. Department 
of Health and Human Services National Cancer Institute. 14 June 2010.
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22. Herceptin (trastuzumab) [package insert]. South San Francisco (CA): Genentech, Inc., 2014.
23. Thall PF, Sung HG. Some extensions and applications of a Bayesian strategy for monitoring 
multiple outcomes in clinical trials. Statistics in Medicine 1998;17(14):1563-80.
24. Rajkumar SV. Multiple myeloma: 2014 Update on diagnosis, risk-stratification, and 
management. American Journal of Hematology 2014;89(10):998-1009.
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Appendix B
PK Sampling Schedule
PK Assessments: Cycle 1
Cycle 1
Day 1 (a)
Day 2 
Day 3
Day 4
Day 8 (a)
Day 15 (a)
Day 22 (a)
Triplicate 
ECG (b)
PK
Triplicate 
ECG (b)
PK
Triplicate 
ECG (b)
PK
Triplicate 
ECG (b)
PK
PK
PK
PK
Predose (within 1 hour before first SC 
injection)
X
X
X
X
X
5 minutes after FINAL SC injection (±2 min)
X 
(c)
4 hours after first SC injection (±30 min)
X
6 hours after first SC injection (30 min)
X
X
8 hours after first SC injection (1 hour)
X
X
24 hours after first SC injection (2 hours)
X
X
48 hours after first SC injection (2 hours)
X
X
72 hours after first SC injection (2 hours)
X
X
ECG=electrocardiogram; PK=pharmacokinetic(s); SC=subcutaneous.
When the timing of a PK or safety laboratory blood sample coincides with the timing of ECG measurements, the ECG will be completed before the collection of the blood sample. The 
triplicate ECG measurements should be completed immediately before the corresponding PK blood draw. 
(a) The timing of the morning visits should occur at approximately the same time as the morning SC administration times on previous days of the cycle.
(b) Collection of triplicate ECGs should begin after the patient has rested in supine position for approximately 5 minutes. Each ECG recording of the triplicate ECGs should occur 
within 3 minutes of each other and over a 10-minute window.
(c) If multiple SC injections are required to administer the intended dose, this PK sample should be collected after administration of the final injection. All other assessments should 
be performed in reference to the first injection.
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PK Assessments: Cycle 2
Cycle 2
Day 1 (a)
Day 2 
Day 3
Day 4
Day 8 (a)
Day 15 (a)
Day 22 (a)
Triplicate 
ECG (b)
PK
Triplicate 
ECG (b)
PK
Triplicate 
ECG (b)
PK
Triplicate 
ECG (b)
PK
PK
PK
PK
Predose (within 1 hour before first SC 
injection)
X
X
X
X
X
5 minutes after FINAL SC injection (±2 min)
X 
(c)
4 hours after first SC injection (±30 min)
X
6 hours after first SC injection (30 min)
X
X
8 hours after first SC injection (1 hour)
X
X
24 hours after first SC injection (2 hours)
X
X
48 hours after first SC injection (2 hours)
X
X
72 hours after first SC injection (2 hours)
X
X
ECG=electrocardiogram; PK=pharmacokinetic(s); SC=subcutaneous.
When the timing of a PK or safety laboratory blood sample coincides with the timing of ECG measurements, the ECG will be completed before the collection of the blood sample. The 
triplicate ECG measurements should be completed immediately before the corresponding PK blood draw. 
(a) The timing of the morning visits should occur at approximately the same time as the morning SC administration times on previous days of the cycle.
(b) Collection of triplicate ECGs should begin after the patient has rested in supine position for approximately 5 minutes. Each ECG recording of the triplicate ECGs should occur 
within 3 minutes of each other and over a 10-minute window.
(c) If multiple SC injections are required to administer the intended dose, this PK sample should be collected after administration of the final injection. All other assessments should 
be performed in reference to the first injection.
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PK Assessments: Cycle 3 to Cycle 10
Cycle 3 to Cycle 6
Cycle 7 to Cycle 10 
Day 1 (a)
Day 15 (a)
Day 1 (a)
Predose (within 1 hour before first SC 
injection)
X
X
X
PK=pharmacokinetic; SC=subcutaneous.
(a) The timing of the morning visits should occur at approximately the same time as the morning SC administration times on previous days of the cycle.
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Appendix C
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. 
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on investigators by the FDA are 
summarized in the “Statement of Investigator” (Form FDA 1572), which must be completed and 
signed before the investigator may participate in this study.
The investigator agrees to assume the following responsibilities by signing a Form FDA 1572:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff that will assist in the protocol.
3. Ensure that study-related procedures, including study-specific (nonroutine/nonstandard panel) 
screening assessments are NOT performed on potential patients, prior to the receipt of written 
approval from relevant governing bodies/authorities.
4. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
5. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to 
21 CFR Part 56, ICH, and local regulatory requirements.
6. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to patients. Make at least yearly reports on the progress of the study to the 
IRB/IEC, and issue a final report within 3 months of study completion.
7. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH and local 
regulations, are met.
8. Obtain valid informed consent from each patient who participates in the study, and document 
the date of consent in the patient’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each ICF should contain a patient authorization section that 
describes the uses and disclosures of a patient’s personal information (including personal 
health information) that will take place in connection with the study. If an ICF does not include 
such a patient authorization, then the investigator must obtain a separate patient authorization 
form from each patient or the patient’s legally acceptable representative.
9. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents.
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10. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
11. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor.
12. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.
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Appendix D
Investigator Consent to Use of Personal Information
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, United States, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study medication.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s own 
country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.
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Appendix E
IMWG Criteria 
IMWG Definition of MM [17,18,24]

Clonal bone marrow plasma cells ≥10%* or biopsy-proven bony or extramedullary 
plasmacytoma* and any one or more of the following myeloma-deﬁning events:
–
Evidence of end organ damage that can be attributed to the underlying plasma cell 
proliferative disorder, specifically.
–
Hypercalcemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than the upper limit of 
the normal range or >2.75 mmol/L (>11 mg/dL).
–
Renal insuﬃciency: creatinine clearance <40 mL per min† or serum creatinine 
>177 μmol/L (>2 mg/dL).
–
Anemia: hemoglobin value of >20 g/L below the lower limit of normal, or a hemoglobin 
value <100 g/L.
–
Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CT‡.

Any one or more of the following biomarkers of malignancy:
–
Clonal bone marrow plasma cell percentage* ≥60%.
–
Involved: uninvolved serum free light chain ratio§ (FLC) ≥100.
–
>1 focal lesions on MRI studies.
* Clonality should be established by showing κλ light-chain restriction on ﬂow cytometry, immunohistochemistry, or 
immunoﬂuorescence. Bone marrow plasma cell percentage should preferably be estimated from a core biopsy 
specimen; in case of a disparity between the aspirate and core biopsy, the highest value should be used.
† Measured or estimated by validated equations.
‡ If bone marrow has less than 10% clonal plasma cells, more than 1 bone lesion is required to distinguish from 
solitary plasmacytoma with minimal marrow involvement.
§ These values are based on the serum Freelite assay (The Binding Site Group, Birmingham, United Kingdom). The 
involved FLC must be ≥100 mg/L. Each focal lesion must be 5 mm or greater in size [24].
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IMWG Uniform Criteria for Response [17,18,24]
Category of 
Response
Response Criteria
sCR
Criteria for CR as defined below, with the addition of a normal FLC ratio, and an absence of clonal plasma 
cells by immunohistochemistry or 2- to 4-color flow cytometry; 2 consecutive assessments of laboratory 
parameters are needed (a).
CR
Negative immunofixation of serum and urine, disappearance of any soft tissue plasmacytomas, and <5% 
plasma cells in bone marrow; bone marrow; in patients for whom only measurable disease is by serum 
FLC level, normal FLC ratio of 0.26 to 1.65 in addition to CR criteria is required; 2 consecutive 
assessments are needed (b).
Immunophenotypic 
CR
sCR as defined, plus absence of phenotypically aberrant plasma cells (clonal) in bone marrow with 
minimum of 1 million total bone marrow cells analyzed by multiparametric ﬂow cytometry (with 
>4 colors).
Molecular CR
CR as deﬁned, plus negative allele-speciﬁc oligonucleotide polymerase chain reaction (sensitivity 10-5).
VGPR
Serum and urine M-protein detectable by immunofixation but not on electrophoresis, or ≥90% reduction 
in serum M-protein plus urine M-protein <100 mg/24 hours; in patients for whom only measurable 
disease is by serum FLC level, >90% decrease in difference between involved and uninvolved FLC levels, 
in addition to VGPR criteria, is required; 2 consecutive assessments are needed (c).
PR
≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to 
<200 mg/24 hours.
If the serum and urine M-protein are not measurable, a ≥50% decrease in the difference between involved 
and uninvolved FLC levels is required in place of the M-protein criteria.
If serum and urine M-protein are not measurable, and serum FLC is also not measurable, ≥50% reduction 
in bone marrow plasma cells is required in place of M-protein, provided the baseline percentage was 
≥30%.
In addition to the above criteria, if present at baseline, ≥50% reduction in the size of soft tissue 
plasmacytomas is also required.
Two consecutive assessments are needed (a) no known evidence of progressive or new bone lesions if 
radiographic studies were performed.
Minimal response 
(MR) (b)
≥25% but ≤49% reduction of serum M-protein and reduction in 24-hour urine M-protein by 50% to 89%.
In addition to the above criteria, if present at baseline, 25% to 49% reduction in the size of soft tissue 
plasmacytomas is also required.
No increase in size or number of lytic bone lesions (development of compression fracture does not exclude 
response).
SD (c)
Does not meet the response criteria for CR (any variant), VGPR, PR, MR, or PD; no known evidence of 
progressive or new bone lesions if radiographic studies were performed.
Source: Rajkumar SV et al, 2011 and Palumbo A et al, 2014 [17,18].
CR=complete response; FLC=free light chain; IMWG=International Myeloma Working Group; MR=minimal response; 
ORR=overall response rate; PR=partial response; sCR=stringent complete response; SD=stable disease; VGPR=very good partial 
response.
(a) Clonality should be established by showing κλ light-chain restriction on ﬂow cytometry, immunohistochemistry, or 
immunoﬂuorescence. Bone marrow plasma cell percentage should preferably be estimated from a core biopsy specimen; in case of 
a disparity between the aspirate and core biopsy, the highest value should be used.
(b) For relapse-refractory myeloma only.
(c) These categories do not contribute to the ORR.
Before the institution of any new therapy, sCR, CR, and VGPR categories require serum and urine 
studies regardless of whether disease at baseline was measurable on serum, urine, both, or neither. 
Radiographic studies are not required to satisfy these response requirements. Bone marrow 
assessments need not be conﬁrmed.
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PD is defined as an increase of ≥25% from lowest response value in any of the following:
a) Serum M-protein (absolute increase must be ≥0.5 g/dL); serum M component increases 
≥1 g/dL are sufficient to deﬁne relapse if starting M component is ≥5 g/dL), and/or
b) Urine M-protein (absolute increase must be ≥200 mg/24 hour), and/or
c) Only in patients without measurable serum and urine M-protein levels: the difference between 
involved and uninvolved FLC levels (absolute increase must be >10 mg/dL).
d) Only in patients without measurable serum and urine M-protein levels and without measurable 
disease by FLC levels, bone marrow plasma cell percentage (absolute percentage must be 
≥10%).
OR
a) Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in 
the size of existing bone lesions or soft tissue plasmacytomas.
b) Development of hypercalcemia (corrected serum calcium >11.5 mg/dL) that can be attributed 
solely to the plasma cell proliferative disorder.
A diagnosis of PD must be confirmed by 2 consecutive assessments.
Clarifications to IMWG criteria for coding PD: Bone marrow criteria for PD are to be used only in 
patients without measurable disease by M-protein and by FLC levels; “25% increase” refers to 
M-protein, FLC, and bone marrow results, and does not refer to bone lesions, soft tissue 
plasmacytomas, or hypercalcemia, and the “lowest response value” does not need to be a 
confirmed value.
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Appendix F
ECOG Scale for Performance Status
Grade
Description
0
Normal activity. Fully active, able to carry on all predisease performance without restriction.
1
Symptoms but ambulatory. Restricted in physically strenuous activity, but ambulatory and able to 
carry out work of a light or sedentary nature (eg, light housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, but unable to carry out any work 
activities. Up and about more than 50% of waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair.
5
Dead.
Source: Oken MM et al, 1982 [19].
ECOG=Eastern Cooperative Oncology Group. 
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Appendix G
Detailed Description of Amendments to Text
The primary sections of the protocol affected by the changes in Amendment 02 are indicated. The 
corresponding text has been revised throughout the protocol. 
Change 1: The study design was updated to reflect a maximum treatment duration of 12 months, 
unless a patient has clinical benefit that warrants continued treatment beyond 12 months.
The primary change occurs in Section 6.3.1 Duration of an Individual Patient’s Study 
Participation:
Initial 
wording:
Patients will receive TAK-079 until they experience PD as defined by IMWG for 
patients with MM ([9,10]; Appendix E), unacceptable toxicity, withdrawal of consent, 
death, termination of the study by the sponsor, until any other discontinuation criterion 
is met, or until 12 months after LPLD (additional participation details are provided in 
Sections 6.1, 8.4.3, 9.6, and 9.7). 
Amended 
or new 
wording:
Patients will receive TAK-079 until they experience PD as defined by IMWG for 
patients with MM (criteria [17,18] (Appendix E), unacceptable toxicity, withdrawal 
of consent, death, termination of the study by the sponsor, until or any other 
discontinuation criterion is met, or until 12 months after LPLD (additional 
participation details are provided in Sections 6.1, 8.4.3, 9.6, (see Section 8.4.3 and 
Section 9.7).The maximum duration of treatment is expected to be 12 months; 
however, patients with clinical benefit (per investigator and as agreed by the 
sponsor’s study clinician) can continue on treatment beyond 1 year with the 
explicit approval of the sponsor’s study clinician. 
Rationale for Change:
This change was made to clarify the duration of treatment for all patients and to require evidence 
of disease response to stay on therapy for more than 12 months.
The following sections also contain this change:

Section 2.0 STUDY SUMMARY.

Section 6.3.2 End of Study/Study Completion Definition and Planned Reporting.

Section 6.3.4 Total Study Duration.
Change 2: Maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) was clarified to 
be a secondary objective/endpoint.
The primary change occurs in Section 5.2.3 Phase 1 Secondary Endpoints:
Added text:The secondary endpoints for phase 1 are: 

RP2D based on both safety and efficacy outcomes
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wording:
has been administered). For dose levels where multiple SC injections are needed to 
administer the full prescribed dose (ie, 300 mg dose and above), the Cycle 1 Day 
1 dose will be administered by giving each SC injection 30 minutes apart until 
the full scheduled dose has been administered. On all drug administration days 
after Cycle 1 Day 1, if the patient did not have a clinically significant IR per the 
investigator, the SC injections can be given at the at the same time without a 
waiting period. 
Patients may receive low dose methylprednisolone (< 20 mg) for the prevention of 
delayed injection related reaction, as clinically indicated. 
When patients are to receive multiple SC injections, the injection sites need to be 
rotated, using the abdomen, thighs, arms, and upper buttock area. Time and 
anatomical site should be recorded for each SC injection.
Rationale for Change:
This change was made to clarify procedures in the protocol to simplify dosing for patients who do 
not experience an IR on Cycle 1 Day 1. 
The following sections also contain this change:

Section 2.0 STUDY SUMMARY.

Figure 6.a Overall Study Schematic Diagram.
Change 6: Predose and postdose medications were clarified.
The primary change occurs in Section 8.1.1 Predose and Postdose Medication (formerly titled 
Premedications):
Initial 
wording:
8.1.1 Premedication
Before each injection, patients will receive the following premedications 1 to 3 hours 
prior to the start of TAK-079 administration on each dosing day:

Dexamethasone: 20 mg IV dose for the initial injection. Oral dexamethasone 
(20 mg) or an equivalent long-acting corticosteroid may be used before 
subsequent injections.

Antipyretics: oral acetaminophen (650 to 1000 mg).

Antihistamine: oral or IV diphenhydramine (25 to 50 mg, or equivalent).

Montelukast 10 mg (or equivalent leukotriene inhibitor) is optional for Cycle 1 
Day 1.
NOTE: Patients with a higher risk of respiratory complications (eg, patients with a 
history of COPD and patients with asthma) will be treated with postinjection 
medication consisting of the following:
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
An antihistamine (diphenhydramine or equivalent) on the first and second days 
after all injections,

A short-acting βadrenergic receptor agonist, such as salbutamol (albuterol) 
aerosol, and

Control medications for lung disease (eg, inhaled corticosteroids with or without 
long-acting β2 adrenergic receptor agonists for patients with asthma; long-acting 
bronchodilators such as tiotropium or salmeterol with or without inhaled 
corticosteroids for patients with COPD).
Premedication will be mandatory in phase 1. The decision to premedicate in phase 2a 
will be determined based on data from phase 1.
The clinical site is responsible for sourcing any premedications outlined in the 
protocol.
Amended 
or new 
wording:
8.1.1 PremedicationPredose and Postdose Medication
Predose Medication
Before each injection, patients will receive the following premedications 1 to 3 hours 
prior to the start of TAK-079 administration on each dosing day:

Dexamethasone: 20 mg IV dose for the initial injection. Oral dexamethasone 
(20 mg) or an equivalent long-acting corticosteroid may be used before 
subsequent injections.

Antipyretics: oral acetaminophen (650 to 1000 mg).

Antihistamine: oral or IV diphenhydramine (25 to 50 mg, or equivalent).

Montelukast 10 mg (or equivalent leukotriene inhibitor) is optional for Cycle 1 
Day 1.
NOTE: Patients with a higher risk of respiratory complications (eg,For any patients 
with a history of COPD and patients with asthma) will be treated with postinjection 
medication consisting of the following:

An antihistamine (diphenhydramine or equivalent) on the first and second days 
after all injections,

A short acting βadrenergic receptor agonist, such as salbutamol (albuterol) 
aerosol, and
Control COPD, consider prescribing postinfusion medications for lung disease (eg, 
inhaled corticosteroids with or without long acting β2 adrenergic receptor agonists for 
patients with asthma; such as short- and long-acting bronchodilators such as 
tiotropium or salmeterol with or without, and inhaled corticosteroids. After the first 
4 infusions, if the patient experiences no major IRs, these additional inhaled 
corticosteroids for patients with COPD).postinfusion medications may be 
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discontinued.
Premedications will be mandatory are required in phase 1. The decision to 
premedicate in and phase 2a will be determined based on data from phase 1.
The clinical site is responsible for sourcing any premedications outlined in the 
protocol.
Postdose Medications
Postinjection site care: Apply corticosteroid cream topically to injection site(s)
and apply ice locally for approximately 10 to 15 minutes (report the 
corticosteroid cream as a concomitant medication).
Patients may receive low-dose methylprednisolone (<20 mg) for the prevention 
of delayed injection-related reaction as clinically indicated after an injection.
Rationale for Change:
This change was made to clarify procedures in the protocol. Required premedications were 
updated for consistency across the 2 phases of the study. Postdose prophylactic care was added to 
minimize any potential injection site reactions.
Section 2.0 STUDY SUMMARY also contains this change.
Change 7: The periods of patient evaluation at end of treatment (EOT) and for progression-free 
survival (PFS) and overall survival (OS) were clarified throughout, including the estimated 
duration of the study and end-of-study reporting.
The primary change occurs in Section 6.1 Overview of Study Design:
Initial 
wording:

Follow-up Period (follow-up visit): Patients who discontinue for PD will be 
followed for 30 days after the last dose of study drug or until the start of 
subsequent alternative anticancer therapy to monitor safety/AEs. Patients who 
discontinue treatment for reasons other than PD will continue to be followed for 
PFS every 4 weeks until PD, death, loss to follow-up, consent withdrawal, study 
termination, or 12 months after the last patient has received their last dose (last 
patient, last dose [LPLD]). All patients will be followed for OS every 12 weeks 
until death, loss to follow-up, consent withdrawal, study termination, or 12 months 
after LPLD.
…
It is expected that approximately 42 patients will be enrolled in total for phase 1 and 2a 
combined. The estimated duration of the study is approximately 48 months (4 years; 
Section 6.3).
Amended 
or new 

Follow-up Pperiod (follow-upEOT visit): Patients who discontinue for PDstudy
treatment will be followed for approximately 30 days after the last dose of study 
drug or until the start of subsequent alternative anticancer therapy to monitor 
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wording:
safety/AEs. Patients who discontinue treatment for reasons other than PD will 
continue to be followed for PFS every 4 weeks from the EOT visit until PD, 
death, loss to follow up, consent withdrawalthe start of subsequent anticancer 
therapy, study termination, or 12 months after the last patient has received their 
last dose (last patient, last dose [LPLD]).discontinuation of study treatment, 
whichever occurs first. Patients who discontinue for PD will be followed for 
OS after the EOT visit. All patients will be followed for OS every 12 weeks until 
death, loss to follow-up, consent withdrawal, or study termination, or 12 months 
after LPLD.
…
It is expected that approximately 42 patients will be enrolled in total for phase 1 and 2a 
combined. The estimated duration of the study is approximately 48 months (4 years; 
Section 6.3).
Rationale for Change:
This change was made to correct inconsistencies in the protocol. 
The following sections also contain this change:

Section 2.0 STUDY SUMMARY.

Section 6.3.1 Duration of an Individual Patient’s Study Participation.

Section 6.3.2 End of Study/Study Completion Definition and Planned Reporting.

Section 6.3.4 Total Study Duration

Section 9.4.3 Medical History.

Section 9.6 Completion of Study (for Individual Patients).

Section 9.10 Posttreatment Follow-up Assessments (PFS and OS). 

Appendix A
Schedule of Events.
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Change 11: Assessments of clinically significant laboratory values and vital signs were removed
from the phase 1 primary endpoints as these are included in the definition of treatment-emergent 
adverse events (TEAEs).
The primary change occurs in Section 5.2.1 Phase 1 Primary Endpoints:
Deleted 
text:

The number of patients with TEAEs overall and per dose level. 
–
Patients with dose-limiting toxicities (DLTs) at each dose level. 
–
Patients with Grade 3 TEAEs.
–
Patients with SAEs.
–
Patients who discontinue because of TEAEs.
–
Patients with dose modifications (delays, interruptions, dose reductions).
–
Clinically significant laboratory values, as determined by the investigator.
–
Clinically significant vital sign measurements, as determined by the 
investigator.
Rationale for Change:
Clinically significant laboratory values and vital signs will be captured as part of TEAE 
evaluation. As a result, this change was made to simplify the study objectives.
The following sections also contain this change:

Section 2.0 STUDY SUMMARY

Section 5.2.4 Phase 2a Secondary Endpoints

Table 6.a Primary and Secondary Endpoints for Disclosures.
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Change 13: Details about management of IRs and injection site reactions were added.
The primary change occurs in Section 8.8 Management of Specific Adverse Reactions: 
Initial 
wording:
8.8.1 Handling of IRs
Patients should be carefully observed during TAK-079 injections. Trained trial staff at 
the clinic should be prepared to intervene in case of any IRs and resources necessary 
for resuscitation (eg, agents such as epinephrine and aerosolized bronchodilators; also 
medical equipment such as oxygen tanks, tracheostomy equipment, and a 
defibrillator) must be available at bedside.
In case of Grade 1 or 2 infusion reactions: 

Withhold therapy (also administration of remaining SC injections when full dose 
was not yet reached) until resolution to Grade 1 or maximum to Grade 2 as per the 
investigator’s discretion. 
In case of Grade 3 infusion reactions: 

Withhold therapy (also administration of remaining SC injections when full dose 
was not yet reached and therefore skip remaining dose) until next scheduled 
TAK-079 SC administration, providing that infusion reactions have recovered to 
Grade ≤1 at the moment of the next scheduled TAK-079 dose. 

Permanently discontinue treatment after the 3rd occurrence of Grade 3 infusion 
reactions
In case of Grade 4 infusion reactions: 

Permanently discontinue treatment.
In case of an IR, blood draws should be performed for central evaluation of 
 
, ADAs, 
. These draws must not interfere with 
patient care and blood tests necessary for the acute care of the patient. 
For additional details, refer to Section 9.4.15.3
Amended 
or new 
wording:
8.8.1 Handling of IRs
Patients should be carefully observed during TAK-079 injections. Trained trial staff at 
the clinic should be prepared to intervene in case of any systemic IRs and resources 
necessary for resuscitation (eg, agents such as epinephrine and aerosolized 
bronchodilators; also medical equipment such as oxygen tanks, tracheostomy 
equipment, and a defibrillator) must be available at bedside.
In case of Grade 1 or 2 infusion reactions: In case of an IR (any grade), blood draws 
should be performed for central evaluation of 
, ADAs, 
 
. These draws must not interfere with patient care and blood tests 
necessary for the acute care of the patient. 
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For additional details, refer to Section 9.4.15.3.
Grade 1 or 2 IR
In case of Grade 1 or 2 IRs (systemic signs or symptoms): 

Withhold therapy (also administration of remaining SC injections when full dose 
was not yet reached) until resolution to Grade 1 or maximum to Grade 2 as per the 
investigator’s discretion. 
o
If a patient experiences a Grade 1 IR mid-dosing, hold subsequent SC 
injections, evaluate the patient, treat symptoms, and once the patient 
is stable per investigator’s discretion, resume SC injections to achieve 
the full dose level. The remaining injections must be given 30 minutes 
apart, and the patient will be evaluated for IRs after each SC 
injection. 
o
If a patient experiences a Grade 2 IR mid-dosing, hold subsequent SC 
injections, evaluate the patient, treat symptoms, and once resolved to 
Grade 1 or resolved completely, per investigator’s discretion, resume 
SC injections to achieve the full dose level. The remaining injections 
must be given 30 minutes apart, and the patient will be evaluated for 
IRs after each SC injection.
–
Patients who experience IRs must be treated according to the 
investigator’s judgement and best clinical practice. Subsequent doses 
may have individual SC injections administered more frequently at the 
investigator’s discretion with appropriate premedication and 
postmedication.
Grade 3 IR
In case of Grade 3 infusion reactions: IRs (systemic signs or symptoms):

Withhold therapy (also administration of remaining SC injections whenif full dose 
was not yet reached and therefore skip remaining doseinjection[s]) until next 
scheduled TAK-079 SC administration, providing that infusion reactions have the 
IR has recovered to Grade ≤1 at the momenttime of the next scheduled TAK-079 
dose. Patients who experience IRs must be treated according to the 
investigator’s judgement and best clinical practice. At the time of the next 
dose after an IR, patients at a dose level requiring more than 1 SC injection 
should receive each injection 30 minutes apart. If no further IR, subsequent 
injections may be given more frequently at the investigator’s discretion with 
appropriate premedication and postmedication.

Permanently discontinue treatment after the 3rdthird occurrence of Grade 3 
infusion reactionsIRs.
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Grade 4 IRs
In case of Grade 4 infusion reactions IRs (systemic signs or symptoms):

Permanently discontinue treatment.
8.8.2 In case of an IRInjection Site Care
Prophylactic post-injection site care:

Apply corticosteroid cream topically to injection site(s) and apply ice
locally for approximately 10 to 15 minutes (report the corticosteroid 
cream as a concomitant medication).
Additional injection site care may be provided on the basis of signs and 
symptoms per investigator discretion (report any actions as a concomitant 
medication).
Rationale for Change:
This change was made to clarify procedures in the protocol and to assist investigators in the 
management of IRs/injection site reactions that may occur.
Section 4.3.1.1 Infusion and Injection Site Reactions also contains this change.
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Change 14: The procedures for monitoring all infections were clarified.
The primary change occurs in Section 4.3.1.4 Infections:
Initial 
wording:
4.3.1.5 Serious Infections
In a GLP-compliant 13-week toxicology study, bacterial and/or viral infection 
secondary to immune suppression was observed in cynomolgus monkeys at IV doses 
of 3, 30, and 80 mg/kg administered once every 2 weeks. The NOAEL dose of 0.3 
mg/kg, administered IV once every week, was not associated with infections.
Subjects will be monitored for any signs and symptoms of the important potential risk 
of serious infections throughout this clinical study (see Section 8.8.4).
Amended 
or new 
wording:
4.3.1.5 4.3.1.4 Serious Infections
In a GLP-compliant 13-week toxicology study, bacterial and/or viral infection 
secondary to immune suppression was observed in cynomolgus monkeys at IV doses 
of 3, 30, and 80 mg/kg administered once every 2 weeks. The NOAEL dose of 0.3 
mg/kg, administered IV once every week, was not associated with infections.
Subjects will be monitored for any signs and symptoms of the important potential risk 
of serious infections throughout this clinical study (see Section 8.8.4).
Rationale for Change:
This change was made to clarify that all infections will be assessed in the study, not just serious 
infections.
The following sections also contain this change:

Section 4.3.1 Potential Risks.

Section 4.3.2 Overall Benefit and Risk Assessment for This Study.
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Change 15: The rationale for the proposed study was revised, including presentation of results 
from the healthy subject study. 
The primary change occurs in Section 4.4 Rationale for the Proposed Study:
Initial 
wording:
TAK-079 binds a partially distinct epitope of CD38 and possesses a different binding 
profile than the approved cytolytic anti-CD38 therapeutic antibody daratumumab. 
Unlike daratumumab, TAK-079 does not bind to RBCs and platelets. Therefore, 
TAK-079 may possess higher tumoricidal activity than daratumumab because 
cytolytic effector activity is focused on CD38+ leukocytes/tumors and is not 
misdirected to RBCs and platelets. Consequently, TAK-079 may demonstrate higher
potency (ie, activity at lower doses and exposures) and activity in 
daratumumab-refractory tumors (ie, tumors expressing lower levels of CD38) and 
thus be more efficient at eliminating tumors.
In the FIH study (TAK-079_101), TAK-079 demonstrated pharmacodynamic effects 
(ie, cytolysis of NK cells and PBs) following single-dose administration, with no 
unexpected and unwanted clinical or hematologic effects observed.
In summary, it is feasible to investigate administration of TAK-079 in patients with
relapsed or refractory (r/r) MM.
Amended 
or new 
wording:
TAK-079 binds a partially distinct epitopeto unique amino acids of CD38 and 
possesses a different binding profile than the approved cytolytic anti-CD38 
therapeutic antibody daratumumab. Unlike daratumumab, TAK 079 does not bind to 
RBCs and platelets. Therefore, TAK 079 may possess higher tumoricidal activity than 
daratumumab because cytolytic effector activity is focused on CD38+ 
leukocytes/tumors and is not misdirected to RBCs and platelets. Consequently, 
TAK 079 may demonstrate higher potency (ie, activity at lower doses and exposures) 
and activity in daratumumab refractory tumors (ie, tumors expressing lower levels of 
CD38) and thus be more efficient at eliminating tumors.
In the FIH study (TAK-079_101), TAK-079 demonstrated pharmacodynamic effects 
(ie, cytolysis of NK cells and PBs) following single-dose administration, with no 
unexpected and unwanted clinical or hematologic effects observed. For example, NK 
cells were reduced >90% from baseline levels in all healthy subjects receiving a 
single 0.06 mg/kg IV dose of TAK-079 and exhibited a mean Cmax of 0.1 ug/mL 
(TAK-079_101). Comparable depletion of NK cells by daratumumab 
administered IV to a population of patients with refractory MM [12] required 
doses of >24 mg/kg and a mean Cmax of >500 ug/mL [13,14]. Consequently, 
TAK-079 may be significantly more efficient at eliminating target cells in 
patients, which could manifest as higher activity on tumor cells (ie, activity at 
lower doses, low-volume SC administration, and less frequent administration), 
including activity on daratumumab-refractory tumors. The potential activity of 
TAK-079 should therefore be investigated in patients with relapsed and/or 
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refractory multiple myeloma (RRMM).
In summary, it is feasible to investigate administration of TAK 079 in patients with 
relapsed or refractory (r/r) MM.
Rationale for Change:
This change was made to provide additional details for the study rationale on the basis of newly 
learned data.
The following sections also contain this change:

Section 4.4.1 Rationale for the Starting Dose of TAK-079.

Section 4.3.1.1 Infusion and Injection Site Reactions.
Change 16: The time required for highly effective contraception in women of childbearing 
potential (WOCBP) and in male patients was clarified for consistency.
The primary change occurs in Section 8.7 Precautions and Restrictions:
Initial 
wording:
Female patients must meet the following:
…

If they are of childbearing potential, agree to practice 1 highly effective method 
and 1 additional effective (barrier) method of contraception at the same time, from 
the time of signing of the informed consent form (ICF) through 5 half-lives after 
the last dose of study drug (whichever is longer), OR

Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the patient. (Periodic abstinence [eg, calendar, ovulation, 
symptothermal, and postovulation methods], withdrawal, spermicides only, and 
lactational amenorrhea are not acceptable methods of contraception. Female and 
male condoms should not be used together.)
Male patients, even if surgically sterilized (ie, status postvasectomy) must agree to one 
of the following:

Agree to practice effective barrier contraception during the entire study treatment 
period and through 120 days (or if the drug has a very long half-life, for 90 days 
plus 5 half-lives) after the last dose of study drug, OR
Amended 
or new 
wording:
Female patients must meet the following:
…

If they are of childbearing potential, agree to practice 1 highly effective method 
and 1 additional effective (barrier) method of contraception at the same time, from 
the time of signing of the informed consent form (ICF) through at least 90 days or
5 half-lives after the last dose of study drug (whichever is longer), OR
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…
Male patients, even if surgically sterilized (ie, status postvasectomy) must agree to one 
of the following:

Agree to practice effective barrier contraception during the entire study treatment 
period and through 12090 days (or if the drug has a very long half-life, for 90 days 
plus 5 half-lives) after the last dose of study drug, OR
Rationale for Change:
This change was made to correct an inconsistency between the protocol and IB.
Section 7.1 Inclusion Criteria also contains this change.
Change 17: The exclusion criterion about recovery from prior myeloma treatments was clarified 
to exclude alopecia.
The primary change occurs in Section 7.2 Exclusion Criteria:
Added text:4. Not recovered from adverse reactions to prior myeloma treatment or procedures 
(chemotherapy, immunotherapy, radiation therapy) to NCI CTCAE Grade ≤1 or 
baseline, excluding alopecia.
Rationale for Change:
This change was made to clarify that alopecia is not a clinically significant toxicity that patients 
need to recover from before entering the study,
Change 18: DLT assessments and withdrawal/replacement of patients were clarified.
The primary change occurs in Section 8.2 Definitions of DLT:
Added text:Patients who experience a DLT should be withdrawn from study treatment 
unless the sponsor approves subsequent treatment in a lower dose cohort; such 
patients will not count as a patient in that lower dose cohort for escalation 
decisions. 
In phase 1, patients who do not receive 4 full doses of TAK-079 within the 28-day 
(±2) treatment window or the Day 29 (ie, Cycle 2 Day 1) assessment for reasons 
other than a DLT will be replaced. Patients experiencing a DLT should not be 
replaced.
Rationale for Change:
These changes were made to clarify the study procedures. 
The following sections also contain this change:

Section 8.4.1 Criteria for Beginning or Delaying a Subsequent Treatment Cycle.
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
Section 8.4.2 Criteria for Dose Modification.

Section 8.4.3 Criteria for Discontinuing TAK-079 in Individual Patients (When Considering 
Dose Modification).

Section 9.7 Discontinuation of Treatment With Study Drug and Patient Replacement.
Change 19: A sentence summarizing the definition of the MTD has been added.
The primary change occurs in Section 8.3.2 Escalation Schema:
Initial 
wording:
If 2 or more patients (2 or more out of 3, or 2 or more out of 6) experience a DLT, 
dosing will de-escalate to the next lower dose level, at which 3 additional patients will 
be enrolled if 3 patients have been treated at that dose level. If 6 patients have been 
enrolled at the lower level with 1 or less DLT out of 6, dosing may stop and the lower 
dose level may be considered the MTD.
Amended 
or new 
wording:

If 2 or more patients (2 or more out of 3, or 2 or more out of 6) experience a DLT, 
dosing will de-escalate to the next lower dose level, at which 3 additional patients 
will be enrolled if 3 patients have been treated at that dose level. If 6 patients have
been enrolled at the lower level with 1 or less DLT out of 6, dosing may stop and 
the lowerthis dose level may be considered the MTD. The MTD is defined as the 
highest dose with a cohort of 6 patients having no more than 1 patient with a 
DLT.
Rationale for Change:
The change was made to clarify the study procedures.
Change 20: The criteria for beginning or delaying a subsequent treatment cycle were clarified.
The primary change occurs in Section 8.4.2 Criteria for Dose Modification:
Initial 
wording:
8.4.2 Criteria for Dose Reduction
All toxicities that occur during the study will be actively managed following the 
standard of care unless otherwise specified in the protocol. Patients experiencing AEs 
attributed to TAK-079 may continue study treatment with the same dose, may have 
TAK-079 treatment held, may have their dose reduced, or may be permanently 
discontinued from the study. Patients who have study drug held because of 
treatment-related or possibly related AEs may resume study drug treatment after 
resolution of the AE at the same dose level or at a reduced dose, depending on the 
nature and severity of the AE and whether it is the first occurrence or it is recurrent.
TEAEs that are not attributed by the investigator to the study drug may be treated as 
per local standard of care, dose-modifications, interruptions and permanent 
discontinuations may be discussed upfront with the medical monitor.
Table 8.a provides general dose modification recommendations. When the dose of
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TAK-079 is withheld on the basis of these criteria, clinical and laboratory 
re-evaluation should be repeated at least weekly or more frequently, depending on the 
nature of the toxicity observed, until the toxicity resolves to Grade ≤1 or baseline. If 
there are transient laboratory abnormalities that, per investigator assessment, are not 
clinically significant or drug related, continuation of therapy without dose 
modification is permissible upon discussion with the sponsor. See details for 
managing specific AEs in Section 8.8.
[Table 8.a Dose Modification Recommendations for TAK-079 Toxicities]
When a dose reduction occurs, the TAK-079 dose will be reduced to the next lower 
dose that has been established as a safe dose during dose escalation. If initial dose 
adjustment does not provide sufficient relief, the dose of TAK-079 can be further 
reduced if the treating physician considers that the patient is receiving benefit. In 
general, after a dose is reduced, it should not be re-escalated even if there is minimal or 
no toxicity with the reduced dose. However, if further evaluation reveals that the AE
that led to the dose reduction was not study drug related, the dose may be re-escalated 
to the original dose level. Up to 2 dose level reductions of TAK-079 because of AE are 
generally recommended.
If dose-reduction is not possible because the lowest dose-level has already been 
reached, treatment may be permanently discontinued.
The dose of TAK-079 will not be reduced for an individual patient during Cycle 1 
unless a DLT has been declared and it is still possible for the patient to receive 
treatment within the remaining dosing period scheduled. In this case, the patient can 
complete Cycle 1 at a reduced dose level.
Amended 
or new 
wording:
8.4.2 Criteria for Dose ReductionModification
All toxicities that occur during the study will be actively managed following 
themedical standard of care unless otherwise specified in the protocol. Patients 
experiencing AEs attributed to TAK-079 may continue study treatment with the same 
dose, may have TAK-079 treatment held, may have their dose reduced, or may be 
permanently discontinued from the study. Patients who have study drug held because 
of treatment-related or possibly related AEs may resume study drug treatment after 
resolution of the AE at the same dose level or at a reduced dose, depending on the 
nature and severity of the AE and whether it is the first occurrence or it is recurrent.
TEAEs that are not attributed by the investigator to the study drug may be treated as 
per local standard of care,; dose-modifications, interruptions and permanent 
discontinuations may be discussed upfront with the medical monitor. Any dose 
interruption of more than 28 days due to toxicity may result in permanent 
discontinuation of TAK-079.
Table 8.a provides general dose modification recommendations. When the dose of 
TAK-079 is withheld on the basis of these criteria, clinical and laboratory 
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re-evaluation should be repeated at least weekly or more frequently, depending on the 
nature of the toxicity observed, until the toxicity resolves to Grade ≤1 or baseline. If 
there are transient laboratory abnormalities that, per investigator assessment, are not 
clinically significant or drug related, continuation of therapy without dose 
modification is permissible upon discussion with the sponsor. Toxicity is managed 
using dose interruptions, including missed doses, as is standard with 
administration of monoclonal antibodies as a means to reduce dose intensity 
[5,21,22]. Patients experiencing a DLT (defined in Section 8.2) should be 
withdrawn from study treatment unless the sponsor approves subsequent 
treatment in a lower dose cohort.
See details for managing specific AEs in Section 8.8.
[Table 8.a Dose Modification Recommendations for TAK-079 Toxicities: 
removed all mention of dose reductions; clarification added for assessment of DLTs 
and other AEs]
When a dose reduction occurs, the TAK 079 dose will be reduced to the next lower 
dose that has been established as a safe dose during dose escalation. If initial dose 
adjustment does not provide sufficient relief, the dose of TAK 079 can be further 
reduced if the treating physician considers that the patient is receiving benefit. In 
general, after a dose is reduced, it should not be re escalated even if there is minimal or 
no toxicity with the reduced dose. However, if further evaluation reveals that the AE 
that led to the dose reduction was not study drug related, the dose may be re escalated 
to the original dose level. Up to 2 dose level reductions of TAK 079 because of AE are 
generally recommended.
If dose reduction is not possible because the lowest dose level has already been 
reached, treatment may be permanently discontinued.
The dose of TAK 079 will not be reduced for an individual patient during Cycle 1 
unless a DLT has been declared and it is still possible for the patient to receive 
treatment within the remaining dosing period scheduled. In this case, the patient can 
complete Cycle 1 at a reduced dose level.If initial dose interruption does not 
provide sufficient relief, the dose of TAK-079 should be considered for 
permanent discontinuation. 
[New Table 8.b TAK-079 Related Toxicity Management]
A TAK-079 dose held for more than 3 days from the per-protocol administration 
date for any reason other than AEs should be brought to the attention of the 
sponsor/designee as soon as possible. Subjects missing ≥3 consecutive planned 
doses of TAK-079 for reasons other than AEs should be withdrawn from 
treatment, unless, upon consultation with the sponsor/designee and review of 
safety and efficacy, continuation is agreed upon. A missed dose will not be made 
up. Doses of TAK-079 during every-4-weeks dosing may be delayed 
(interrupted) up to 4 weeks. If a dose is delayed (interrupted), then the dates of 
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all subsequent doses and assessments must be adjusted accordingly. Any AE 
deemed to be related to TAK-079 that requires a dose delay (interruption) of 
more than 28 days should result in permanent discontinuation of TAK-079,
unless both the investigator and the sponsor study clinician believe the patient is 
deriving clinical benefit.
Rationale for Change:
The change was made to clarify that toxicity is managed by means of dose interruptions, including 
missed doses, as is standard with administration of monoclonal antibodies as a means to reduce 
dose intensity.
Section that also contain this change are:

Section 8.4.1 Criteria for Beginning or Delaying a Subsequent Treatment Cycle. 

Section 8.4.3 Criteria for Discontinuing TAK-079 in Individual Patients (When Considering 
Dose Modification).
Change 21: Disease response assessments, including imaging and laboratory testing, were 
clarified.
The primary change occurs in Section 9.4.14 Disease Response Assessments:
Initial 
wording:
Patients will be assessed for disease response according to the IMWG for MM ([9,10]; 
Appendix E).
Serum and urine response assessments will be performed no later than the first day of 
every treatment cycle, before the patient receives treatment with TAK-079.
Imaging tests as specified in Appendix A are to be performed as defined below or 
when there is a need to document a response or a disease progression. Response and 
relapse categories are described in Appendix E. Imaging tests will be taken during the 
screening phase prior to treatment and every 6 cycles thereafter until PD or 
intolerance. Additional surveys (x-ray, CT, or MRI) will be performed at the 
investigator’s discretion (eg, in case of bone pain) to document a response or 
progressive disease. The same imaging technique should be used throughout the study 
to facilitate consistent disease assessment. 
CR should be confirmed with follow-up assessments of SPEP, UPEP, immunofixation 
of blood and urine, and serum FLCs as outlined in Appendix A. One BMA assessment 
has to occur to document CR; no second bone marrow confirmation is needed.
Amended 
or new 
wording:
Patients will be assessed for disease response according to the IMWG for MMcriteria 
(9,10[17,18]; Appendix E).
Serum and urine response assessments will be performed no later than the first day of 
every treatment cycle, before the patient receives treatment with TAK-079. Patients 
measurable by SPEP only will have 24-hour urine collected at screening and 
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EOT and to document PR, VGPR, CR, or PD.
Imaging tests as specified in Appendix A are to be performed as defined below or 
when there is a need to document a response or a disease progression. Response and 
relapse categories are described in Appendix E. Imaging tests will be taken during the 
screening phase prior to treatment and every 6 cycles thereafter until PD or 
intolerance. Additional surveys (x-ray, CT, or MRI) will be performed at the 
investigator’s discretion (eg, in case of bone pain) to document a response or 
progressive disease.Imaging tests will be done per Appendix A and as described 
in Section 9.4.14.1. The same imaging technique should be used throughout the study 
to facilitate consistent disease assessment.
CR Responses should be confirmed with follow-up assessments of SPEP, UPEP, 
immunofixation of blood and urine, and serum FLCs as outlined in Appendix A. One 
BMA assessment has to occur to document CR; no second bone marrow confirmation 
is needed.
…
Blood samples, 24-hour urine sample, BMA, and imaging done for disease 
response assessment will be done locally.
Rationale for Change:
The change was made to clarify the study procedures to better align with IMWG criteria.
The following sections also contain this change:

Section 9.4.14.1 Computed Tomography/Magnetic Resonance Imaging.

Section 9.4.14.2 Quantification of Immunoglobulins.

Section 9.4.14.3 Quantification of M-Protein.

Section 9.4.14.4 Serum FLC Assay.

Section 9.4.14.5 Immunofixation of Serum and Urine.

Section 9.4.14.6 BMAs.
Change 22: “Other” was added as a reason for treatment discontinuation or withdrawal of subject 
from study.
The primary change occurs in Section 9.7 Discontinuation of Treatment With Study Drug and 
Patient Replacement:
Added text:Treatment with study drug may also be discontinued for any of the following reasons:

AE/SAE.

Protocol deviation.
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
PD. 

Symptomatic deterioration. 

Unsatisfactory therapeutic response. 

Study terminated by sponsor.

Lost to follow-up.

Other.
Rationale for Change:
The change was made to account for reasons not otherwise categorized.
Section 9.8 Withdrawal of Patients From Study also contains this change.
Change 23: The time required to monitor ongoing adverse events (AEs) after the end of study 
treatment was clarified.
The primary change occurs in Section 10.3 Monitoring of AEs and Period of Observation:
Added text:AEs will be reported from the signing of informed consent through 30 days after 
administration of the last dose of study drug and recorded in the eCRFs. AEs ongoing 
at EOT should be monitored until they are resolved, return to baseline, are 
clearly determined to be due to a patient’s stable or chronic condition or 
intercurrent illness(es), the start of next-line subsequent anticancer therapy, or 6 
months after PD has occurred, whichever comes first.
Rationale for Change:
The change was made to clarify the study procedures to allow for a longer window to monitor AEs 
after completion of treatment.
Change 24: Investigator disease assessments were added to the Schedule of Events (SOE).
The primary change occurs in Appendix A
Schedule of Events:
Description 
of change:
Added a row for “Investigator disease response” with assessments on Day 1 of every 
cycle starting at Cycle 2, at the EOT visit, and during PFS follow-up.
Rationale for Change:
The change was made to correct an error in the study procedures.
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PROTOCOL
A Phase 1/2a Open-label, Dose-Escalation Study to Investigate the Safety and Tolerability, 
Efficacy, Pharmacokinetics, and Immunogenicity of TAK-079 Administered 
Subcutaneously as a Single Agent in Patients With Relapsed/Refractory Multiple Myeloma
Sponsor:
Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda 
Pharmaceutical Company Limited
40 Landsdowne Street
Cambridge, MA 02139 USA
Telephone: +1 (617) 679-7000
Please note: Millennium Pharmaceuticals, Inc, a wholly owned 
subsidiary of Takeda Pharmaceutical Company Limited, may be 
referred to in this protocol as “Millennium,” “Sponsor,” or “Takeda.”
Study Number:
TAK-079-1501 
IND Number:
136,414
EudraCT Number:
Not applicable
Compound:
TAK-079
Date:
02 April 2019
Amendment Number:
03 
Amendment History:
Date
Amendment Number
Region
12 October 2017
Initial Protocol
Global
08 December 2017
01
Global
18 May 2018
02
Global
02 April 2019
03
Global
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1.0
ADMINISTRATIVE
1.1
Contacts
A separate contact information list will be provided to each site.
Serious adverse event (SAE) and pregnancy reporting information is presented in Section 10.0, as 
is information on reporting product complaints.
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.0 and relevant guidelines 
provided to the site.
Contact Type/Role
United States Contact
SAE and pregnancy reporting
See Section 10.0
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INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, and any 
other product information provided by the sponsor. I agree to conduct this study in accordance 
with the requirements of this protocol and also to protect the rights, safety, privacy, and well-being 
of study subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting SAEs defined in Section 10.0 of this protocol.

Terms outlined in the Clinical Study Site Agreement.

Responsibilities of the Investigator
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix D of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Province)
Location of Facility (Country)
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1.3
Protocol Amendment 03 Summary of Changes
Rationale for Amendment 03
This document describes the changes in reference to the protocol incorporating Amendment 03. 
The primary reason for this amendment is to allow for an increase in the number of patients 
enrolled to the phase 1 period to further evaluate the safety, pharmacokinetics (PK),
 
, to further inform the recommended phase 2 dose (RP2D) on the basis of
available data from the dose Escalation Cohorts. Additionally, a cohort of patients is being added 
to evaluate TAK-079 combined with the backbone regimen of pomalidomide and dexamethasone 
(PomDex) in patients with relapsed and/or refractory multiple myeloma (RRMM) who have 
received at least 2 prior therapies and are refractory to the last therapy before study entry. Data is 
emerging that treatment options are needed for patients who have been exposed or are refractory to 
lenalidomide because of its increase use as initial therapy. PomDex is approved for this patient 
population and adding an anti-CD38 monoclonal antibody to it, especially one that is given 
subcutaneously (SC), could be beneficial and convenient for patients. As a result of adding the 
cohort of TAK-079 added to PomDex, relevant details and references about the administration of 
pomalidomide, including the Pomalyst Risk Evaluation and Mitigation Strategy (REMS), have 
been added. 
Other minor changes were made throughout the protocol for clarification and to ensure 
consistency with the major changes described above.
Minor grammatical, editorial, formatting, and administrative changes not affecting the conduct of 
the study are included for clarification and administrative purposes only. 
For specific descriptions of text changes and where the changes are located, see Appendix G.
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TABLE OF CONTENTS
1.0
ADMINISTRATIVE.......................................................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment 03 Summary of Changes ..........................................................5
2.0
STUDY SUMMARY ....................................................................................................11
3.0
STUDY REFERENCE INFORMATION ......................................................................17
3.1
List of Abbreviations ...............................................................................................18
4.0
INTRODUCTION.........................................................................................................21
4.1
Background .............................................................................................................21
4.2
Findings From Nonclinical and Clinical Studies.......................................................21
4.2.1
22
4.2.2
Preliminary Findings From the Dose Escalation Period of This Study................25
4.3
Known and Potential Benefits and Risks to Patients With TAK-079 ........................25
4.3.1
Potential Risks ...................................................................................................25
4.3.2
Overall Benefit and Risk Assessment for This Study..........................................28
4.4
Rationale for the Proposed Study.............................................................................29
4.4.1
Rationale for the Starting Dose of TAK-079 ......................................................29
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................31
5.1
Objectives................................................................................................................31
5.1.1
Primary Objectives.............................................................................................31
5.1.2
Secondary Objectives.........................................................................................31
5.1.3
Exploratory Objectives.......................................................................................31
5.2
Endpoints.................................................................................................................32
5.2.1
Phase 1 Primary Endpoints.................................................................................32
5.2.2
Phase 2a Primary Endpoint ................................................................................32
5.2.3
Phase 1 Secondary Endpoints.............................................................................32
5.2.4
Phase 2a Secondary Endpoints...........................................................................33
5.2.5
Exploratory Endpoints .......................................................................................33
6.0
STUDY DESIGN..........................................................................................................35
6.1
Overview of Study Design.......................................................................................35
6.2
Number of Patients ..................................................................................................39
6.3
Duration of Study ....................................................................................................40
6.3.1
Duration of an Individual Patient’s Study Participation ......................................40
6.3.2
End of Study/Study Completion Definition and Planned Reporting....................40
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6.3.3
Timeframes for Primary and Secondary Endpoints to Support Disclosures.........40
6.3.4
Total Study Duration..........................................................................................42
6.3.5
Posttrial Access..................................................................................................43
7.0
STUDY POPULATION................................................................................................44
7.1
Inclusion Criteria .....................................................................................................44
7.2
Exclusion Criteria ....................................................................................................47
8.0
STUDY DRUG .............................................................................................................50
8.1
Study Drug Administration......................................................................................50
8.1.1
Predose and Postdose Medication.......................................................................50
8.1.2
TAK-079 Formulation and Administration.........................................................51
8.2
Definitions of DLT ..................................................................................................51
8.3
Dose-Escalation Design and Criteria........................................................................52
8.3.1
Dose Levels .......................................................................................................52
8.3.2
Escalation Schema .............................................................................................53
8.4
TAK-079 Dose in Phase 1 Dose Confirmation Cohort .............................................55
8.5
TAK-079 Dose in Phase 1 Combination Cohort.......................................................55
8.6
Dose Modification Guidelines..................................................................................56
8.6.1
Criteria for Beginning or Delaying a Subsequent Treatment Cycle.....................56
8.6.2
Criteria for Dose Modification ...........................................................................56
8.6.3
Criteria for Discontinuing TAK-079 in Individual Patients (When Considering 
Dose Modification) ............................................................................................58
8.7
Dose Modification Considerations for Patients in the Phase 1 Combination Cohort 
(TAK-079–PomDex Cohort) Only...........................................................................58
8.7.1
Dose Modification of Standard of Care Agents ..................................................59
8.8
Excluded Concomitant Medications and Procedures ................................................59
8.9
Permitted Concomitant Medications and Procedures................................................59
8.10
Precautions and Restrictions ....................................................................................60
8.11
Management of Specific Adverse Reactions ............................................................62
8.11.1 Handling of IRs..................................................................................................62
8.11.2 Injection Site Care..............................................................................................63
8.11.3 Handling of Low Platelet Counts........................................................................63
8.11.4 Risk of Infection ................................................................................................64
8.11.5 Transfusion Risks...............................................................................................64
8.12
Blinding and Unblinding..........................................................................................64
8.13
Description of Investigational Agents ......................................................................64
8.14
Preparation, Reconstitution, and Dispensation..........................................................65
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8.15
Packaging and Labeling...........................................................................................65
8.16
Storage, Handling, and Accountability.....................................................................65
8.16.1 Storage and Handling.........................................................................................65
8.16.2 Accountability and Destruction of Sponsor Supplied Drugs ...............................66
8.17
Investigational Drug Assignment and Dispensing Procedures ..................................67
8.18
Standard Drug Procurement Procedures: Patients in the Combination Cohort Only..67
8.18.1 Pomalidomide....................................................................................................67
8.18.2 Dexamethasone..................................................................................................68
8.19
Other Protocol-Specified Materials ..........................................................................68
9.0
STUDY CONDUCT......................................................................................................69
9.1
Study Personnel and Organizations..........................................................................69
9.2
Arrangements for Recruitment of Patients................................................................69
9.3
Treatment Group Assignments.................................................................................69
9.4
Study Procedures.....................................................................................................69
9.4.1
Informed Consent...............................................................................................69
9.4.2
Patient Demographics ........................................................................................69
9.4.3
Medical History .................................................................................................69
9.4.4
Physical Examination.........................................................................................70
9.4.5
Patient Height and Weight .................................................................................70
9.4.6
Vital Signs .........................................................................................................70
9.4.7
Eligibility Criteria ..............................................................................................70
9.4.8
Pregnancy Test...................................................................................................70
9.4.9
Concomitant Medications and Procedures..........................................................71
9.4.10 AEs....................................................................................................................71
9.4.11 Enrollment .........................................................................................................71
9.4.12 ECG...................................................................................................................71
9.4.13 Clinical Laboratory Evaluations .........................................................................72
9.4.14 Disease Response Assessments ..........................................................................75
9.4.15
, PK, 
, and Immunogenicity Samples.....................77
9.5
Completion of Study Treatment (for Individual Patients) .........................................80
9.6
Completion of Study (for Individual Patients)..........................................................80
9.7
Discontinuation of Treatment With Study Drug and Patient Replacement................81
9.8
Withdrawal of Patients From Study .........................................................................81
9.9
Study Compliance....................................................................................................82
9.10
Posttreatment Follow-up Assessments (PFS and OS)...............................................82
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10.0
ADVERSE EVENTS ....................................................................................................83
10.1
Definitions...............................................................................................................83
10.1.1 Pretreatment Event Definition............................................................................83
10.1.2 AE Definition ....................................................................................................83
10.1.3 SAE Definition ..................................................................................................83
10.2
Procedures for Recording and Reporting AEs and SAEs..........................................84
10.3
Monitoring of AEs and Period of Observation .........................................................85
10.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events.........85
10.5
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose) ................................................................................................................86
10.6
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities...........86
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................87
12.0
DATA HANDLING AND RECORDKEEPING............................................................88
12.1
eCRFs......................................................................................................................88
12.2
Record Retention .....................................................................................................88
13.0
STATISTICAL METHODS..........................................................................................90
13.1
Statistical and Analytical Plans ................................................................................90
13.1.1 Analysis Sets......................................................................................................90
13.1.2 Analysis of Demographics and Other Baseline Characteristics ...........................90
13.1.3 Efficacy Analysis...............................................................................................91
13.1.4 PK Analysis .......................................................................................................91
13.1.5
91
13.1.6 Immunogenicity Analyses..................................................................................91
13.1.7 Safety Analysis ..................................................................................................92
13.2
Interim Analysis and Criteria for Early Termination ................................................92
13.3
Determination of Sample Size..................................................................................92
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................94
14.1
Study Site Monitoring Visits....................................................................................94
14.2
Protocol Deviations..................................................................................................94
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................94
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................95
15.1
IRB and/or IEC Approval ........................................................................................95
15.2
Patient Information, Informed Consent, and Patient Authorization...........................96
15.3
Patient Confidentiality .............................................................................................97
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................97
15.4.1 Publication.........................................................................................................97
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15.4.2 Clinical Trial Registration..................................................................................98
15.4.3 Clinical Trial Results Disclosure ........................................................................98
15.5
Insurance and Compensation for Injury....................................................................98
16.0
REFERENCES..............................................................................................................99
LIST OF IN-TEXT TABLES
Table 6.a
Primary and Secondary Endpoints for Disclosures .............................................41
Table 7.a
Required Washout Periods for Previous Treatments or Procedures Prior to 
Administration of TAK-079...............................................................................44
Table 7.b
Laboratory Criteria for Determining Adequate Organ Function for 
Study TAK-079-1501 Eligibility........................................................................45
Table 8.a
Dose Modification Recommendations for TAK-079 Toxicities ..........................57
Table 8.b
TAK-079–Related Toxicity Management...........................................................58
Table 9.a
Clinical Chemistry and Hematology Tests for Research Purposes ......................73
Table 9.b
Clinical Urinalysis Tests for Research Purposes.................................................73
Table 9.c
Clinical Hematology and Chemistry: Standard of Care Laboratory Tests............74
Table 9.d
Clinical Hematology and Chemistry: Tests for Research Purposes .....................74
Table 9.e
Clinical Urinalysis: Tests for Research Purposes................................................74
Table 9.f
Myeloma Disease Assessments: Tests Standard of Care Tests............................75
Table 9.g
Primary Specimen Collection.............................................................................78
Table 13.a
80% Confidence Interval Based on the Observed ORR ......................................93
LIST OF IN-TEXT FIGURES
Figure 6.a
Overall Study Schematic Diagram......................................................................38
Figure 8.a
Dose-Escalation Scheme ....................................................................................54
LIST OF APPENDICES
Appendix A
Schedule of Events...........................................................................................102
Appendix B
PK Sampling Schedule.....................................................................................112
Appendix C
Responsibilities of the Investigator...................................................................115
Appendix D
Investigator Consent to Use of Personal Information........................................117
Appendix E
IMWG Criteria.................................................................................................118
Appendix F
ECOG Scale for Performance Status ................................................................121
Appendix G
Detailed Description of Amendments to Text...................................................122
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2.0
STUDY SUMMARY
Name of Sponsor:
Millennium Pharmaceuticals, Inc, a wholly owned 
subsidiary of Takeda Pharmaceutical Company Limited
Compound:
TAK-079
Title of Protocol: A Phase 1/2a, Open-label, 
Dose-Escalation Study to Investigate the Safety and 
Tolerability, Efficacy, Pharmacokinetics, and 
Immunogenicity of TAK-079 Administered Subcutaneously 
as a Single Agent in Patients With Relapsed/Refractory 
Multiple Myeloma 
Study Number: TAK-079-1501
Phase: 1/2a
Study Design:
This is a multicenter, dose-escalation, open-label, single-arm, phase 1/2a study designed to determine the safety, 
tolerability, efficacy, PK, and immunogenicity of TAK-079 monotherapy in patients relapsed and/or refractory 
multiple myeloma (RRMM), and to provide a preliminary assessment of its activity against multiple myeloma (MM).
Once enrolled into the study, patients will receive TAK-079 via subcutaneous (SC) administration in each 28-day 
cycle of treatment, administered as once weekly for 8 weeks (8 doses), once every 2 weeks for 16 weeks (8 doses), and 
once every 4 weeks thereafter until disease progression (PD). Patients will receive ongoing treatment with TAK-079 
until PD, unacceptable toxicities, or withdrawal due to other reasons. 
The phase 1 portion of the study will evaluate administration of single agent TAK-079 for dose-limiting toxicity 
(DLT) to determine the maximum tolerated dose (MTD) or the recommended phase 2 dose (RP2D) for further 
assessment in phase 2a. A recommended dose below the MTD may be identified based on the review of safety, 
pharmacokinetic (PK), 
, and clinical data from the phase 1 portion of the 
study. 
Study Schema Figure:
Dara: daratumumab; PomDex: pomalidomide and dexamethasone; PD: progressive disease; disease progression;
RP2: recommended phase 2; SC: subcutaneous.
The safety and tolerability of TAK-079 will be assessed by recording and analyzing treatment-emergent adverse 
events (TEAEs), dose modifications, treatment discontinuations, vital signs, physical examinations, serum chemistry 
and hematology, urinalysis, electrocardiograms (ECGs), and concomitant medications. In phase 1, approximately 6 
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Duration of Treatment:
TAK-079 will be administered until the patient experiences 
PD, unacceptable toxicities, or withdrawal due to other 
reasons. The maximum duration of treatment is expected to 
be 12 months for patients receiving monotherapy and 
approximately 18 months for patients in the combination 
cohort; however, patients with clinical benefit (per 
investigator and as agreed by the sponsor’s study clinician) 
can continue on treatment with the explicit approval of the 
sponsor’s study clinician.
Period of Evaluation:
21 days screening, ongoing treatment to PD. 
Patients who discontinue treatment for reasons other 
than PD will continue to be followed for 
progression-free survival (PFS) every 4 weeks from 
the end-of-treatment visit until PD, death, the start of 
subsequent anticancer therapy, study termination, or 
until 12 months after discontinuation of study 
treatment, whichever occurs first. 
Overall survival (OS): Patients will be followed every 
12 weeks until death, loss to follow-up, consent 
withdrawal, or study termination.
Main Criteria for Inclusion:
Male and female patients, aged ≥18 years, with ECOG performance status of ≤2, requiring additional therapy as 
determined by the investigator. Patients must have received the final dose of the following treatments/procedures 
within the specified minimum intervals before the first dose of TAK-079: 180 days for antibody therapy (including 
anti-CD38); 90 days for autologous transplantation; 14 days for chemotherapy, radiation therapy, and major surgery; 
and 7 days for corticosteroid therapy (up to systemic equivalent of 10 mg daily prednisone allowed). Patients must 
have adequate organ function as determined by the following laboratory values: absolute neutrophil count ≥1.0×109/L; 
platelets ≥75,000/mm3 (≥75×109/L); hemoglobin ≥7.5 g/dL; creatinine clearance ≥30 mL/min (Cockcroft-Gault 
formula); total bilirubin ≤1.5 times the upper limit of the normal range (ULN); and alanine aminotransferase/aspartate 
aminotransferase ≤2.5×ULN. Patients must have documented RRMM per the International Myeloma Working Group 
(IMWG) criteria, with measurable disease defined as one of the following: serum M-protein ≥ 0.5 g/dL (≥5 g/L) and 
urine M-protein ≥200 mg/24 hours. Patients without measurable M-protein in serum protein electrophoresis or urine 
protein electrophoresis must have a serum free light chain (FLC) assay result with involved FLC level ≥10 mg/dL 
(≥100 mg/L), provided serum FLC ratio is abnormal. Patients must have evidence of RRMM as defined by the IMWG 
criteria. For patients in the Escalation Cohort and dose Confirmation Cohort: previously received myeloma therapy 
including a proteasome inhibitor (PI), immunomodulatory drug (IMiD), and steroids; refractory or intolerant to at least 
1 PI and at least 1 IMiD; either have received ≥3 prior lines of therapy or should have received at least 2 prior lines of 
therapy if one of those lines included a combination of PI and IMiD; in phase 1, previous exposure to an anti-CD38 
agent, as a single agent or in combination, is allowed but is not required for patients in the dose Escalation Cohort. 
Patients in the Combination Cohort (TAK-079 added to PomDex cohort only): have undergone prior therapy with ≥2 
prior anti-myeloma therapies; has either relapsed or relapsed and refractory disease; have progressed on or within 60 
days of completing the last anti-myeloma therapy; patients may be either naïve or exposed to prior anti-CD38 
monoclonal antibodies; however there will be a cohort of patients refractory to at least 1 anti-CD38 mAb therapy at 
any time during treatment and one that is naïve to a prior anti-CD38 mAb. In the phase 2a portion of the study, up to 
2 cohorts of patients with RRMM may be enrolled: one that is refractory to at least 1 anti-CD38 mAb therapy at any 
time during treatment and one that is naïve to prior anti-CD38 mAb.
Main Criteria for Exclusion:
Sensory or motor neuropathy of Grade ≥3, based on the National Cancer Institute Common Criteria for Adverse 
Events (NCI CTCAE) or not recovered from adverse reactions to prior myeloma treatments/procedures to NCI 
CTCAE Grade ≤1 or baseline; allogeneic stem cell transplant; congestive heart failure (New York Heart Association) 
Grade ≥II, cardiac myopathy, active ischemia, clinically significant arrhythmia, history of acute myocardial infarction 
within 5 months before enrollment, clinically significant uncontrolled hypertension, or any other uncontrolled cardiac 
condition or concurrent illness that would preclude study conduct and assessment; QT interval corrected by the 
Fridericia method >480 msec (Grade ≥2); history of severe allergic or anaphylactic reactions to recombinant proteins 
or excipients used in TAK-079 formulation (including patients who were previously discontinued from an anti-CD38 
treatment due to an infusion-related reaction); history of myelodysplastic syndrome or another malignancy other than 
MM; clinical signs of central nervous system involvement of MM; or active chronic hepatitis B or C infection, or 
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active HIV infection. Also excluded are patients with POEMS (polyneuropathy, organomegaly, endocrinopathy, 
monoclonal gammopathy and skin changes) syndrome, monoclonal gammopathy of unknown significance; 
smoldering myeloma; solitary plasmacytoma; amyloidosis; Waldenström macroglobulinemia or immunoglobulin M 
myeloma, and patients with positive Coombs tests at screening; for patients in the Combination Cohort (TAK-079–
PomDex) only: patient has previously received pomalidomide or has hypersensitivity to thalidomide or lenalidomide. 
Endpoints (in order of importance):
Primary: 
Phase 1

The number of patients with TEAEs overall and per dose level.

Patients with DLTs at each dose level.

Patients with Grade ≥3 TEAEs.

Patients with SAEs.

Patients who discontinue because of TEAEs.

Patients with dose modifications (delays, interruptions, dose reductions).
Phase 2a 

Overall response rate (ORR), defined as the proportion of patients who achieved a partial response (PR) or better 
during study as defined by IMWG Uniform Response Criteria.
Secondary: 
Phase 1

RP2D based on both safety and efficacy outcomes as a single agent and when added to a backbone regimen of 
PomDex.

Summary statistics for the following PK parameters as a single agent and when added to a backbone regimen of 
PomDex:
–
Maximum observed concentration (Cmax).
–
Time of first occurrence of Cmax (tmax).
–
Area under the concentration-time curve from time 0 to the time of the last quantifiable concentration 
(AUClast).

Preliminary evaluation of antitumor activity of TAK-079, as single agent and in combination with PomDex, will 
be assessed for patients with MM by measuring:
–
ORR, defined as the proportion of patients who achieved a PR (50% tumor reduction) or better during the 
study as defined by the IMWG Uniform Response Criteria.
–
Proportion of patients who achieved minimal response (MR), defined as 25% tumor reduction, 
including in patients with disease measurable by serum FLCs.

Anti–TAK-079 antibody incidence and characteristics.
Phase 2a 

DLT-like frequencies and other TEAEs occurring over the course of extended treatment with TAK-079, including 
information about dose modification, treatment discontinuation, and vital signs.

Summary statistics for the following PK parameters: Cmax, tmax, and AUClast.

Anti–TAK-079 antibody incidence and characteristics.

Proportion of patients who achieved MR, defined as 25% tumor reduction, will be evaluated.

Duration of response (DOR), defined as the time from the date of the first documentation of response to the date 
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3.0
STUDY REFERENCE INFORMATION
Study-Related Responsibilities 
The sponsor will perform all study-related activities with the exception of those identified in the 
Study-Related Responsibilities (Appendix C). The identified vendors in the template for specific 
study-related activities will perform these activities in full or in partnership with the sponsor.
Principal Investigator
Takeda will select a Signatory Coordinating Investigator from the investigators who participate in 
the study. Selection criteria for this investigator will include significant knowledge of the study 
protocol, the study medication, their expertise in the therapeutic area and the conduct of clinical 
research as well as study participation. The Signatory Coordinating Investigator will be required to 
review and sign the clinical study report and by doing so agrees that it accurately describes the 
results of the study.
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3.1
List of Abbreviations
Abbreviation
Term
ADA
antidrug antibody
AE
adverse event
AML
acute myeloid leukemia
AUClast
area under the concentration-time curve from time 0 to the time of the last quantifiable 
concentration
BMA
bone marrow aspirate
CFR
Code of Federal Regulations
CLL
chronic lymphocytic leukemia
Cmax
maximum observed concentration
CNS
central nervous system
COPD
chronic obstructive pulmonary disease
CR
complete response
CRO
contract research organization
CRS
cytokine release syndrome
CT
computed tomography
DLT
dose-limiting toxicity
DOR 
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form (refers to any media used to collect study data [ie, paper or electronic])
EOI
end of infusion
EOT
end of treatment
FDA
United States Food and Drug Administration
FIH
first-in-human
FLC
free light chain
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
HBV
hepatitis B virus
HCV
hepatitis C virus
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IEC
independent ethics committee
Ig
immunoglobulin
IMiD
immunomodulatory drug
IMWG
International Myeloma Working Group
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Abbreviation
Term
IR
infusion reaction
IRB
institutional review board
IV
intravenous(ly)
mAb
monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
MM
multiple myeloma
MR
minimal response
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NAB
neutralizing antibody
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NK
natural killer
NOAEL
no observed adverse effect level
NSAID
nonsteroidal anti-inflammatory drugs
ORR
overall response rate
OS
overall survival
PB
plasmablast
PD
progressive disease; disease progression
PET-CT
positron emission tomography–computed tomography
PFS
progression-free survival
PI
proteasome inhibitor
PK
pharmacokinetic(s)
POEMS 
polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes
syndrome
PomDex
pomalidomide in combination with dexamethasone
PR
partial response
PT
Preferred Term
QTc
QT interval corrected for heart rate
RBC
red blood cell(s)
REMS
Risk Evaluation and Mitigation Strategy
RP2D
recommended phase 2 dose
RRMM
relapsed and/or refractory multiple myeloma
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
sCR
stringent complete response
SCRS
severe cytokine release syndrome
SOC
System Organ Class
SOE
schedule of events
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Abbreviation
Term
SPEP
serum protein electrophoresis
SUSAR
suspected unexpected serious adverse reactions
TEAE
treatment-emergent adverse event
tmax
time of first occurrence of maximum observed concentration
TTR
time to response
ULN
upper limit of the normal range
UPEP
urine protein electrophoresis
VGPR
very good partial response
WOCBP
women of childbearing potential
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4.2.2
Preliminary Findings From the Dose Escalation Period of This Study
As of 05 March 2018, 19 patients have been enrolled through the first 4 dose planned cohorts (45, 
135, 300, and 600 mg). In this ongoing study, the most common (in >2 patients)
treatment-emergent AEs by Medical Dictionary for Regulatory Activities (MedDRA) Preferred 
Term (PT) regardless of causality in the total population as of 05 March 2018 are anaemia (n = 5 
patients, insomnia, headache, and hypertension (n = 4 patients each), and upper respiratory tract 
infection, fatigue, and decreased appetite (n = 3 patients each). All AEs have been Grade 1 or 2; 2 
events were reported as drug-related Grade 3 AEs (decreased neutrophil count and anemia [in 1 
patient each] both of which were transient. No patient experienced dose-limiting toxicities 
(DLTs), injection site reactions, discontinued TAK-079 due to TEAEs, or died on-study; 2 patients 
experienced SAEs, none were reported as treatment related (1 event was pretreatment). No patient 
has been demonstrated to have had CRS symptoms; 1 patient in the 135 mg cohort did report 
transient facial flushing Cycle 2 Day 1, which the investigator reported as drug related. 
In the original phase 1 dose Escalation Cohorts, TAK-079 was given weekly for 8 weeks during 
Cycles 1 and 2 (8 doses), every other week during Cycles 3 to 6 (8 doses), and then once every 4 
weeks until PD. Based on a review of available clinical activity, PK, and pharmacodynamic 
findings, the dose of TAK-079 as monotherapy in the Confirmation Cohort and when added to 
PomDex in the Combination Cohort will be 300 mg in the same schedule as follows: 
Confirmation Cohort: TAK-079 will be given weekly for 8 weeks during Cycles 1 and 2 (8 doses), 
every other week during Cycles 3 to 6 (8 doses), and then once every 4 weeks until PD in 
subsequent cycles.
Combination Cohort: TAK-079 will be given weekly for 8 weeks during Cycles 1 and 2 (8 doses), 
every other week during Cycles 3 to 6 (8 doses), and then once every 4 weeks until PD in 
subsequent cycles with PomDex given according to product information (Pomalyst USPI, 
including Section 14.1).
4.3
Known and Potential Benefits and Risks to Patients With TAK-079
TAK-079 was administered only in healthy human subjects in the first-in-human (FIH) study 
(TAK-079_101). Only mild or moderate AEs were observed in the FIH study in healthy subjects. 
Therefore, clinical benefits and risks have not been assessed in the disease setting. 
TAK-079 has now been administered to patients with advanced RRMM (TAK-079-1501; this 
study). Only mild or moderate (Grade 1 or 2) TEAEs were observed as described above. 
A summary of findings is discussed in Section 4.3.1. See details for precautions and restrictions in 
Section 8.10. Additional information regarding potential discomforts and risks from treatment is 
provided in the TAK-079 IB.
4.3.1
Potential Risks
Based on the mechanism of action of TAK-079, potential AEs may include infusion or injection 
site reactions, CRS, hematological effects, and infections.
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4.3.1.1
Infusion and Injection Site Reactions
IRs are potentially dose-limiting AEs, not uncommonly associated with IV administration of 
biologic agents aimed at treating hematologic malignancies [5]. IRs are less frequently associated 
with SC injection of these therapies. The ‘true’ clinical hypersensitivity reactions, 
antibody-mediated occur after repeat exposure. Symptoms of hypersensitivity range from mild 
skin rash to more severe reactions, wheezing, hypotension, poor perfusion, respiratory arrest, and 
rarely death. Non-anaphylactic clinical hypersensitivity occurs within the first hour; however 
delayed responses were reported. Symptoms of anaphylaxis, a potentially life-threatening 
condition, range from swelling, angioedema, bronchospasm, respiratory distress, and shock [9]. 
There are limited nonclinical and clinical data to date for TAK-079 (Section 4.2.1). Local injection 
site abnormalities have not been observed in monkey and rat nonclinical studies after SC and/or IV 
administration of TAK-079. In the clinical study of healthy subjects (TAK-079_101), an 
infusion-related reaction was defined as a TEAE occurring within 2 hours of the start of an 
infusion; there were no IRs in this study, as no allergic or cytokine release reactions were observed 
within this time period. Mild injection site AEs were reported; AEs were Grade 1 and included 
primarily erythema or tenderness with palpitation. All injection site reactions resolved within a 
few days. 
In this study (TAK-079-1501) in patients with RRMM at doses up to 600 mg (given with 3 SC 
injections), no injection site reactions have been reported. 
Patients in clinical trials receiving TAK-079 will be carefully monitored for signs and symptoms 
of infusion and injection site reactions, with appropriate management of these events. Depending 
on the severity of the reaction, management may include discontinuation of SC administration of 
TAK-079 and/or the administration of appropriate medical therapy. 
See additional details for managing infusion and injection site reactions in Section 8.11.1.
4.3.1.2
Cytokine Release Syndrome
CRS represents an important IR often associated with the use of monoclonal antibodies used in 
anti-inflammatory and antitumor therapies. CRS may occur early in therapy, and often after the 
first infusion of the drug due to a high-level of activation of the immune system and engagement 
and proliferation of T-cells that can result in increased cytokine release. The CRS hallmark is 
fever. CRS also presents with rash, urticaria, headache, chills, fatigue, nausea, and/or vomiting 
[10,11]. 
Severe cytokine release syndrome (SCRS) is characterized by severe dyspnea, often accompanied 
by bronchospasm and hypoxia, in addition to fever, chills, rigors, urticaria, and angioedema. This 
syndrome may be associated with some features of tumor lysis syndrome such as hyperuricemia, 
hyperkalemia, hypocalcemia, hyperphosphatemia, acute renal failure, and elevated lactate 
dehydrogenase, and may be associated with acute respiratory failure and death. The acute 
respiratory failure may be accompanied by events such as pulmonary interstitial infiltration or 
edema, visible on a chest x-ray. The syndrome frequently manifests within 1 or 2 hours of 
initiating the first infusion. Patients with a history of pulmonary insufficiency or those with 
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reported an AE in the infection and infestation MedDRA System Organ Class (SOC); the most 
common AE reported was upper respiratory infection (n = 3); all were grade 2 and only 1 was 
reported as related to study drug.
Subjects will be monitored for any signs and symptoms of infections throughout this clinical study 
(see Section 8.11.4).
4.3.1.5
Drug Interactions
Nonclinical drug interaction studies have not been conducted with TAK-079. However, as a fully 
human IgG1 monoclonal antibody (mAb), the risk of drug-drug interactions is low.
4.3.1.6
ADA Interactions
ADA responses were detected in most monkeys in the single-dose PK studies and the 4-week 
(non-GLP) and 13-week (GLP) toxicology studies. Strong positive ADA responses were generally 
associated with lower serum concentrations of TAK-079, and this was especially notable in the 
13-week repeat-dose toxicity studies and at lower doses.
In the single-dose healthy subject study (TAK-079_101), 5 of 54 TAK-079–treated subjects were 
positive for ADA (3 subjects with transient ADA and 2 subjects with persistent ADA). Of these, 
1 subject was treated in the 0.06 mg IV cohort and the remaining 4 subjects were treated with 
either 0.03 mg/kg (2 subjects), 0.1 mg/kg (1 subject), or 0.6 mg/kg (1 subject) SC TAK-079. 
Immunogenicity was not associated with clinically significant AEs, even in the 2 subjects with 
persistent immunogenicity.
4.3.1.7
Pregnancy and Lactation
TAK-079 has not been administered to women who are pregnant or lactating. Dedicated fertility 
and embryo-fetal development toxicology studies have not been conducted with TAK-079. 
However, there were no TAK-079–related changes in organ weights or microscopic findings noted 
in the male and female reproductive tract of monkeys following administration for up to 13 weeks. 
Women of childbearing potential (WOCBP) may be enrolled in clinical trials with appropriate 
precautions to prevent pregnancy (additional details in Section 8.10).
At this stage of development TAK-079 should not be administered to women who are pregnant or 
breastfeeding.
4.3.1.8
Overdose
TAK-079 has been administered only to healthy subjects in the FIH study. To date, there is no 
experience with overdose. If an overdose does occur, close monitoring and supportive treatment as 
medically required are recommended.
4.3.2
Overall Benefit and Risk Assessment for This Study
The overall clinical benefits and risks of TAK-079 have not been determined. 
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Based on the mechanism of action of TAK-079, nonclinical data to date, as well as some exposure 
in healthy human subjects, possible AEs of TAK-079 include but are not limited to infusion and 
injection site reactions, CRS, hypersensitivity reactions, changes in hematologic parameters, and 
infections. Patients will be monitored closely for these risks in this clinical study.
The emerging preliminary safety profile, as detailed above and in the current Investigator 
Brochure, indicate that TAK-079 is generally well tolerated with manageable and reversible AEs. 
The potential toxicities can be managed by clinical monitoring and standard medical interventions. 
It is possible that TAK-079 will have toxicities that were not predicted from its evaluation in 
nonclinical studies or previously observed in ongoing clinical studies. To mitigate the inherent 
risks in clinical studies of TAK-079, patients will be carefully monitored closely for signs and 
symptoms of systemic and injection site reactions with appropriate management of these events. 
Guidance for the management of AEs are provided in Section 8.11. Depending on the severity of 
the reaction, drug dosage can be reduced by dose modification (holding or delaying) of the 
scheduled treatment within a cycle as provided in Section 8.6, and may include discontinuation of 
TAK-079.
In patients with advanced RRMM, TAK-079 has shown early signs of antitumor activity as 
evidenced by at least 50% reduction in disease burden in some patients and prolonged disease 
stabilization in others. Though additional data are needed to characterize the clinical benefit of this 
drug, the emerging data supports the ongoing development of TAK-079.
4.4
Rationale for the Proposed Study
Although multiple therapies are available for patients with MM, this disease remains incurable; 
thus, significant unmet medical need exists for this patient population. Frequent relapses highlight 
a need for new therapies for patients in whom prior treatments have failed. 
TAK-079 binds to unique amino acids of CD38 and possesses a different binding profile than the 
approved cytolytic anti-CD38 therapeutic antibody daratumumab. 
In the FIH study (TAK-079_101), TAK-079 demonstrated pharmacodynamic effects (ie, cytolysis 
of NK cells and PBs) following single-dose administration, with no unexpected and unwanted 
clinical or hematologic effects observed. For example, NK cells were reduced >90% from baseline 
levels in all healthy subjects receiving a single 0.06 mg/kg IV dose of TAK-079 and exhibited a 
mean Cmax of 0.1 ug/mL (TAK-079_101). Comparable depletion of NK cells by daratumumab 
administered IV to a population of patients with refractory MM [12] required doses of >24 mg/kg 
and a mean Cmax of >500 ug/mL [13,14]. Consequently, TAK-079 may be significantly more 
efficient at eliminating target cells in patients, which could manifest as higher activity on tumor 
cells (ie, activity at lower doses, low-volume SC administration, and less frequent administration), 
including activity on daratumumab-refractory tumors. The potential activity of TAK-079 should 
therefore be investigated in patients with relapsed and/or refractory multiple myeloma (RRMM).
4.4.1
Rationale for the Starting Dose of TAK-079
In the FIH study (TAK-079_101), TAK-079 was well tolerated after SC administration of 
single-doses ranging from 0.03 to 0.6 mg/kg.
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To avoid unnecessary exposure of patients to sub-therapeutic doses while preserving safety, the
starting dose for this study in patients with RRMM will be 45 mg, the fixed-dose equivalent of 
0.6 mg/kg (assuming a body weight of 75 kg), which was the highest SC dose administered in 
Study TAK-079_101. The 0.6 mg/kg dose was well tolerated in healthy human subjects in Study 
TAK-079_101 and demonstrated >90% depletion of peripheral blood PBs, a surrogate for 
myeloma cells in each subject (n = 6).
TAK-079 is a mAb targeting CD38, which is a cell surface molecule that is constitutively 
expressed on plasma cells, PBs, and NK cells, and is induced on activated T cells and B cells [15]. 
Therefore, the anticipated elimination routes for TAK-079 are via proteolytic catabolism and 
intracellular degradation after binding to its target. Both of these clearance mechanisms are not 
thought to be significantly influenced by body weight. Additionally, the distribution volume of 
mAbs is generally limited to the volume of the blood and extracellular fluids, such that body 
composition is a less important determinant of distribution volume as compared with small 
molecule drugs [16]. For these reasons, body weight is not expected to have a clinically significant 
effect on the disposition of TAK-079, thereby supporting the investigation of fixed-dose 
administration.
The 45 mg starting dose of TAK-079 will be tested in 3 patients with RRMM to assess the safety 
and tolerability of TAK-079 after multiple dose administration. TAK-079 will be administered 
using the same dosing schedule as the anti-CD38 antibody, daratumumab, which is approved for 
the treatment of patients with MM [5]. Specifically, TAK-079 will be administered once weekly 
for 8 weeks (8 doses), once every 2 weeks for 16 weeks (8 doses), then once every 4 weeks until 
the patient experiences PD, unacceptable toxicities, or withdrawal due to other reasons. The 
subsequent planned dose levels are 135, 300, 600, 1200, and 1800 mg.
Escalation to a subsequent cohort may take place after the treatment in the first cycle of the 
previous (sequential) cohort has completed.
Additional details for dose escalation are provided in Section 8.3.
The dose used in the Confirmation Cohort and the Combination Cohorts is the expected RP2D 
from the dose Escalation Cohorts, based on preliminary PK and PD results from the dose 
Escalation Cohort.
Relevant to the Combination Cohort, lenalidomide is established therapy in NDMM [17,18]
therefore patients for whom lenalidomide is no longer a treatment option, because of previous 
exposure, intolerance, or are refractory to lenalidomide, represent a clinically relevant population 
with unmet need. Nonclinical studies demonstrate that pomalidomide inhibits proliferation of 
lenalidomide-resistant cells [19]. Clinically, PomDex, an all oral regimen, is approved for patients 
who have previously received lenalidomide [20]. Adding an anti-CD38 monoclonal antibody to it, 
especially one that is given SC, could be beneficial and convenient to patients as compared with IV 
administered anti-CD38 monoclonal antibodies. PomDex will be given at the dose and schedule 
recommended in the product information (Pomalyst USPI including Section 14.1) while TAK-079 
will be given at the RP2D in the revised schedule described in Section 6.1.
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6.0
STUDY DESIGN
6.1
Overview of Study Design
This is a multicenter, dose-escalation, open-label, single-arm, phase 1/2a study designed to 
determine the safety, tolerability, efficacy, PK, and immunogenicity of TAK-079 monotherapy in
patients with RRMM, and to provide a preliminary assessment of its activity against MM. 
The phase 1 portion of the study will evaluate administration of single agent TAK-079 for DLT(s) 
to determine the MTD/RP2D for further assessment in phase 2a. A recommended dose below the 
MTD may be identified based on safety, clinical, PK, 
 data. The safety and 
tolerability of TAK-079 will be assessed by recording and analyzing TEAEs from medical review 
of vital signs, physical examinations, serum chemistry and hematology analyses, urinalyses, 
ECGs, review of concomitant medications, dose modifications, and treatment discontinuations.
MM is a heterogenous disease requiring treatments across multiple lines of therapy despite recent 
advances. The pace of MM treatment has been rapid in recent years and even with a shift towards 
triplet regimens from doublet regimens, patients are still relapsing from, ineligible for, or 
intolerant to such combinations. Further the treatment paradigm is fragmented due to patient 
factors as well as disease factors and acceptance of recently approved regimens is gaining but 
remains variable. Therefore, this study will continue to evaluate patients with relapsed or 
refractory disease, including those who have not progressed following daratumumab, in an effort 
to more fully understand the activity of TAK-079 in patients who represent the highly 
heterogeneous population seen in current clinical practice. Before enrolling into the phase 2a 
phase of the study, additional patients will be enrolled in a dose Confirmatory Cohort to better 
understand the safety and clinical activity of the TAK-079 RP2D based on preliminary 
PK/
data. 
More patients now receive combinations of lenalidomide, bortezomib, dexamethasone with or 
without daratumumab as first-line treatment, yet their disease still progresses. Most develop 
lenalidomide-resistant disease; thus, alternatives to lenalidomide are required in later lines of 
therapy. Pomalidomide with dexamethasone is approved for patients following therapy with 
lenalidomide and a proteasome inhibitor; however, the duration of response is short 
(7.4 months) [20]. Evidence is emerging that adding an IV administered anti-CD38 agent to 
PomDex can help prolong response duration [23]. TAK-079, a SC administered anti-CD38 
monoclonal antibody, is showing early signs of antimyeloma activity as a monotherapy in patients 
with advanced RRMM. Adding TAK-079 to the PomDex backbone could provide benefit to 
patients both in terms of improved antimyeloma activity over each agent alone, and would be more 
convenient to patients as compared with administration of IV administered anti-CD38 agents (ie, a 
TAK-079, a SC agent, added to the all oral PomDex regimen). Hence a new cohort will open to 
evaluate this combination. Information about the dose, safety, and activity of TAK-079 added to a 
standard backbone regimen of PomDex in patients with RRMM who have received at least 2 prior 
therapies and have demonstrated PD on or within 60 days of the completion of the last therapy will 
be collected. 
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The preliminary efficacy of TAK-079, as monotherapy and when added to PomDex, will be 
evaluated by measuring the ORR, defined as the proportion of patients who achieved a PR or 
better during study, as defined by IMWG (Appendix E; [21,22]). In addition, the efficacy of 
TAK-079 will be assessed by measuring MR, PFS, DOR, and OS; TTR will also be measured. 
Once enrolled into the phase 1 Dose Escalation phase, patients will receive TAK-079 via SC 
administration in each 28-day cycle of treatment, administered as once weekly for 8 weeks 
(8 doses), once every 2 weeks for 16 weeks (8 doses), and once every 4 weeks thereafter until PD. 
Patients will receive ongoing treatment with TAK-079 until they experience PD, unacceptable 
toxicities, or withdraw due to other reasons (see Section 6.3). 
In the phase 1 Confirmation Cohort Phase, patients will receive TAK-079 via SC administration in 
each 28-day cycle of treatment, administered at a dose of 300 mg once weekly for 8 weeks (8 
doses), once every 2 weeks for 16 weeks (8 doses), and then once every 4 weeks thereafter until 
PD.

In this cohort, up to 6 patients that are refractory to an anti-CD38 agent will be enrolled.

Further in this cohort, approximately 12 patients that have RRMM disease (per prior therapy 
inclusion criteria Section 7.0) and are naïve to an anti-CD38 agent will be enrolled.
In the Combination Cohort, patients will receive TAK-079 via SC administration in each 28-day 
cycle of treatment, administered at a dose of 300 mg once weekly for 8 weeks (8 doses), once 
every 2 weeks for 16 weeks (8 doses), and then once every 4 weeks thereafter until PD. PomDex
will be administered according to the product labeling (Pomalyst UPSI, including Section 14.1).

In this cohort, up to 6 patients will initially be enrolled. Safety in Cycle 1 will be reviewed in 
accordance with DLT definitions in Section 8.2.

If 0 of 6 or 1 of 6 patients develop a DLT an additional 12 patients will be tested at the initial 
dose of TAK-079 [6 patients that are naïve to a prior anti-CD38 agent and 6 patients that have 
been exposed to a prior anti-CD38 agent], for an overall total of 18 patients.

If 2 of 6 patients develop DLTs all available data will be reviewed before making decisions 
about study conduct (See details in Section 8.5). 
The Confirmation Cohort and the Combination Cohort may start in parallel and will run 
independently. 
All cohorts will consist of the following phases/periods: screening, treatment, and follow-up:

Screening period (visit 1): Days -21 to Day -1.

Treatment period (visit 2/ongoing): 

Original dose Escalation Cohort: once-weekly treatment for 8 doses (Cycles 1 and 2), starting 
on Day 1, followed by treatment once every 2 weeks for 8 doses (Cycles 3-6), followed by 
treatment once every 4 weeks thereafter (Cycle 7 and beyond), continuing until patients 
experience PD, unacceptable toxicities, or withdrawal due to other reasons. 
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
Dose Confirmation Cohort: once weekly for 8 weeks in Cycles 1 and 2 (8 doses), once every 2 
weeks for 16 weeks (8 doses) in Cycles 3 to 6, and once every 4 weeks thereafter (Cycles 7 and 
beyond) until PD.

Combination Cohort: once weekly for 8 weeks in Cycles 1 and 2 (8 doses), once every 2 weeks 
for 16 weeks (8 doses) in Cycles 3 to 6, and once every 4 weeks thereafter (Cycles 7 and 
beyond) until PD. PomDex will be administered according to the product labeling (Pomalyst 
UPSI, including Section 14.1 describing dexamethasone dosing).

Follow-up period (end of treatment [EOT] visit): Patients who discontinue study treatment will 
be followed for approximately 30 days after the last dose of study drug or until the start of 
subsequent alternative anticancer therapy to monitor safety/AEs. Patients who discontinue 
treatment for reasons other than PD will continue to be followed for PFS every 4 weeks from 
the EOT visit until PD, death, the start of subsequent anticancer therapy, study termination, or 
12 months after discontinuation of study treatment, whichever occurs first. Patients who 
discontinue for PD will be followed for OS after the EOT visit. All patients will be followed 
for OS every 12 weeks until death, loss to follow-up, consent withdrawal, or study termination.
In phase 1, approximately 6 doses will be evaluated in ascending cohorts of 3 to 6 patients per 
cohort. Cohorts may be expanded by enrolling additional patients to further inform selection of the 
RP2D. Dose selection for phase 2a will take place after review of the available safety, efficacy, 
PK, 
 data obtained from the phase 1 portion of the study.
In the phase 1 dose Confirmatory Cohort, approximately 18 patients will be enrolled at 1 dose (300 
mg); 12 patients will have been previously treated (see Section 7.0), up to 6 patients will have been 
previously treated and are refractory to an anti-CD38 therapy (see Section 7.0). In the 
Combination Cohort, approximately 18 patients will be enrolled who have received prior therapy 
and have demonstrated PD on or within 60 days of completion of the last therapy, note Section 7.0.
It is expected that approximately 100 patients will be enrolled in total for the phase 1 cohorts and 
phase 2a combined.
Study procedures and assessments, with their time points, are shown in Appendix A. The study 
schematic diagram is shown in Figure 6.a.
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Figure 6.a
Overall Study Schematic Diagram
Treatment Cycle: original phase 1 dose Escalation Cohort
C1
C2
≤21 D
D1
D8
D15
D22
D1
D8
D15
D22
C3
C4
C5
C6
C7
C8
D1
D15
D1
D15
D1
D15
D1
D15
D1
D1
**
PD
Treatment Cycle: phase 1 dose Confirmation Cohort 
C1
C2
≤21 D
D1
D8
D15
D22
D1
D8
D15
D22
TAK-079 
300 mg
C3
C4
C5
C6
C7
C8
D1
D15
D1
D15
D1
D15
D1
D15
D1
D1
**
PD
Treatment Cycle: new Combination Cohort 
C1
C2
≤21 D
D1
D8
D15
D22
D1
D8
D15
D22
Pomalidomide
TAK-079 
300 mg
Days 1-21 in a 28-day cycle***
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Details on the definition of evaluable patients and sample size are given in Section 13.1.
The study is planned to be conducted in the United States in approximately 7 investigational 
centers, although the sponsor may add more centers depending on enrollment rates. 
6.3
Duration of Study
6.3.1
Duration of an Individual Patient’s Study Participation
Patients will receive TAK-079 until they experience PD as defined by IMWG criteria [21,22]
(Appendix E), unacceptable toxicity, or any other discontinuation criterion is met (see 
Section 8.6.3 and Section 9.7). In the combination cohort, additionally patients will receive 
PomDex until they experience PD as defined by IMWG criteria. The maximum duration of 
treatment is expected to be 12 months for patients receiving monotherapy and approximately 
18 months for patients in the combination cohort; however, patients with clinical benefit (per 
investigator and as agreed by the sponsor’s study clinician) can continue on treatment with the 
explicit approval of the sponsor’s study clinician (see Section 6.3.5 for Posttrial Access). 
Patients will be evaluated 30±7 days after the last dose of TAK-079 (follow-up visit) or before 
initiating subsequent systemic anticancer therapy, for detection of any delayed TEAEs.
6.3.2
End of Study/Study Completion Definition and Planned Reporting
The final analyses for the clinical study report may be conducted after all patients enrolled in the 
study have had the opportunity to complete 12 months of treatment with single agent TAK-079, 18 
months of combination therapy, or after the last patient completes the EOT visit if the sponsor 
terminates the study earlier (Table 6.a).
6.3.3
Timeframes for Primary and Secondary Endpoints to Support Disclosures
Refer to Table 6.a for disclosures information for all primary and secondary endpoints.
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months of combination therapy, or after the last patient completes the EOT visit if the sponsor 
terminates the study earlier.
It is anticipated that this study will last for approximately 42 months (3.5 years).
6.3.5
Posttrial Access
At the conclusion or termination of the study or termination of a treatment arm in the study, if 
patients are, in the opinion of the investigator and confirmed by the sponsor, experiencing a 
clinically important benefit, TAK-079 treatment may be continued in this study or another 
extension or rollover study, if and when such a study is made available, upon request by the 
investigator and agreement by the sponsor. Continued access to TAK-079 for participants will be 
terminated for those individuals who no longer benefit from TAK-079, the benefit-risk no longer 
favors the individual, if TAK-079 becomes available either commercially or via another access 
mechanism, or when an alternative appropriate therapy becomes available. Posttrial access may be 
terminated in areas where marketing authorization has been rejected, the development of 
TAK-079 has been suspended or stopped by the sponsor, or TAK-079 can no longer be supplied. 
Only for patients enrolled into the Combination Cohort, the backbone agents ongoing at this time 
will continue to be procured by the site from commercial sources. 
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7.0
STUDY POPULATION
Phase 1 dose Confirmation Cohort: Adult patients with relapsed and/or refractory multiple 
myeloma who have been previously treated with at least a PI, an IMiD, and a steroid. Patients 
should have refractory disease or be intolerant to at least 1 PI and at least 1 IMiD, and they should 
have either received 3 or more prior therapies or received at least 2 prior therapies if one of those 
therapies included a combination of a PI and an IMiD. Patients who have had a previous 
autologous stem cell transplant will have additionally been exposed to an alkylating agent; 
however, patients who have not had a previous autologous stem cell transplant may not have been 
exposed to an alkylating agent per standard practice. Up to 6 patients will be refractory to an 
anti-CD38 agent and approximately 12 patients in this cohort should be anti-CD38 naïve. 
Combination Cohort: Adult patients with relapsed and/or refractory multiple myeloma who have 
received at least 2 prior therapies including lenalidomide and a proteasome inhibitor and have 
demonstrated PD on or within 60 days of the completion of the last therapy. The first 6 patients 
enrolled may be either naïve to a prior anti-CD38 antibody or may have been exposed to one 
previously (if exposed note washout period in Table 7.a). Once safety data have been reviewed, the 
following patients enrolled at the RP2D/MTD will be: naïve to a prior anti-CD38 monoclonal 
antibody (approximately 6 patients) or exposed to a prior anti-CD38 monoclonal antibody 
(approximately 6 patients; note washout period in Table 7.a).
7.1
Inclusion Criteria
Each patient must meet all the following inclusion criteria to be enrolled in the study:
1. Male or female patients aged 18 years or older.
2. Eastern Cooperative Oncology Group (ECOG) performance status of ≤2 [24].
3. Patient has received the final dose of any of the following treatments/procedures within the 
specified minimum intervals before the first dose of TAK-079 (Table 7.a):
Table 7.a
Required Washout Periods for Previous Treatments or Procedures Prior to 
Administration of TAK-079 
Previous Treatment or Procedure
Washout Period
Myeloma-specific therapy
14 days
Antibody therapy (including anti-CD38)
180 days
Corticosteroid therapy (a)
7 days
Autologous transplantation 
90 days
Radiation therapy (b)
14 days
Major surgery
14 days
(a) Systemic corticosteroid use ≤10 mg/day (prednisone or equivalent) is allowed.
(b) Prophylactic “spot” radiation for areas of pain is permitted.
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4. Patient has adequate organ function as determined by the following laboratory values 
(Table 7.b):
Table 7.b
Laboratory Criteria for Determining Adequate Organ Function for 
Study TAK-079-1501 Eligibility
Laboratory Parameter
Acceptable Laboratory Criteria 
Absolute neutrophil count (a)
≥1000/mm3 (≥1.0×109/L); ≥750/mm3 (≥0.75109/L) maybe acceptable for 
patients with >50% of plasma cells in bone marrow after discussion with 
sponsor
Platelets (a)
≥75,000/mm3 (≥75×109/L); a value of ≥50,000/mm3
(≥50×109/L) may be acceptable for patients with >50% bone marrow burden 
following discussion with the sponsor
Hemoglobin 
≥7.5 g/dL (it is not permissible to transfuse a subject to reach this level)
Creatinine clearance
≥30 mL/min (Cockcroft-Gault formula)
Total serum bilirubin
≤1.5×ULN; except for patients with Gilbert’s syndrome in whom direct 
bilirubin should be <2.0×ULN 
Liver transaminases (ALT/AST)
≤2.5×ULN
ALT: alanine aminotransferase; AST: aspartate aminotransferase; ULN: upper limit of the normal range.
(a) Without ongoing growth factor or transfusion support for at least 1 week before Day 1.
5. Female patients who: 

Are WOCBP must not be pregnant or lactating. 

Are postmenopausal for at least 1 year before the screening visit, OR

Are surgically sterile, OR

If they are of childbearing potential, agree to practice 1 highly effective method of 
contraception and 1 additional effective (barrier) method at the same time, from the time of 
signing the informed consent through at least 90 days or 5 half-lives after the last dose of 
study drug, whichever time period is longest (See Section 8.10), OR

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle 
of the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, and 
postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not 
acceptable methods of contraception. Female and male condoms should not be used 
together.)

Patients enrolling in the Combination Cohort (TAK-079–PomDex) only must adhere to the 
Pomalyst REMS requirements per the product label.
6. Male patients, even if surgically sterilized (ie, status postvasectomy), who:

Agree to practice effective barrier contraception during the entire study treatment period 
and through 90 days (or if the drug has a very long half-life, for 90 days plus 5 half-lives) 
after the last dose of study drug (See Section 8.10), OR
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
Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle 
of the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, and 
postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not 
acceptable methods of contraception. Female and male condoms should not be used 
together.

Patients enrolling in the Combination Cohort (TAK-079–PomDex) only must adhere to the 
Pomalyst REMS requirements per the product label.
7. Voluntary written consent must be given before performance of any study-related procedure 
not part of standard medical care, with the understanding that consent may be withdrawn by 
the patient at any time without prejudice to future medical care.
8. The patient must be willing and able to comply with study restrictions and to remain at the 
investigational center for the required duration during the study period, and must be willing to 
return to the investigational center for the follow-up procedures and assessments specified in 
this protocol.
9. Patients in the Combination Cohort (TAK-079–PomDex) only must be able to take concurrent 
prophylactic anticoagulation per standard clinical practice as directed by the investigator and 
the Pomalyst product information.
10. Documentation of RRMM as defined by the IMWG criteria (Appendix E; [21,22]).
11. For patients with MM, measurable disease defined as one of the following:

Serum M-protein ≥0.5 g/dL (≥5 g/L).

Urine M-protein ≥200 mg/24 hours.

In patients without measurable M-protein in serum protein electrophoresis (SPEP) or urine 
protein electrophoresis (UPEP), a serum FLC assay result with involved FLC level 
≥10 mg/dL (≥100 mg/L), provided serum FLC ratio is abnormal.
12. Prior therapy, patients should meet all the following criteria:
Patients in the dose Escalation Cohort (escalation phase) and patients in the dose Confirmation 
Cohort;

Patient should be previously treated with at least a PI, an IMiD, and a steroid. Note: 
Patients who have had a previous autologous stem cell transplant will have additionally 
been exposed to an alkylating agent; however, patient who have not had a previous 
autologous stem cell transplant may not have been exposed to an alkylating agent per 
standard practice. 

Patient should be refractory or intolerant to at least 1 PI and at least 1 IMiD.

Patient should either have received ≥3 prior lines of therapy or should have received at 
least 2 prior lines of therapy if one of those lines included a combination of PI and 
IMiD. 
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
In phase 1, previous exposure to an anti-CD38 agent, as a single agent or in 
combination, is allowed but is not required. [Patients in the dose Escalation Cohort]

In phase 1 dose Confirmation Cohort, 2 subgroups will be enrolled: up to 6 patients will 
be enrolled that meet above prior therapy criteria and are refractory at any time to at 
least 1 anti-CD38 agent and approximately 12 patients will be enrolled that meet above 
prior therapy criteria but are anti-CD 38 naïve.
Patients in the Combination Cohort (TAK-079 added to PomDex cohort only):

Patients have undergone prior therapy with ≥2 prior anti-myeloma therapies (line of 
therapy defined below).

Patient has either relapsed or relapsed and refractory disease. Should have progressed on or 
within 60 days of completing the last anti-myeloma therapy (refractory defined below).
13. In the phase 2a portion of the study, up to 2 cohorts of patients with RRMM may be enrolled: 1 
that is refractory to at least 1 anti-CD38 mAb therapy at any time during treatment and 1 that is 
naïve to daratumumab. Available safety and efficacy data will be used to make decisions about 
the patient cohorts to be enrolled in the phase 2a portion. The final decision on the phase 2a 
cohorts will be made by sponsor representatives following review of all available data 
considering stopping rule thresholds. (see Section 13.1.7)
NOTE: 

Refractory is defined as less than a 25% reduction in M-protein (response of stable disease 
during prior therapy) or PD during treatment or within 60 days after last dose of prior therapy.

A line of therapy is defined as 1 or more cycles of a planned treatment program. This may 
consist of 1 or more planned cycles of single-agent therapy or combination therapy, as well as 
a sequence of treatments administered in a planned manner. A new line of therapy starts when 
a planned course of therapy is modified to include other treatment agents (alone or in 
combination) as a result of PD, relapse, or toxicity. A new line of therapy also starts when a 
planned period of observation off therapy is interrupted by a need for additional treatment for 
the disease [21].
7.2
Exclusion Criteria
Patients meeting any of the following exclusion criteria are not to be enrolled in the study:
1. Sensory or motor neuropathy of National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE) Grade ≥3 [25].
2. Patients who have received allogeneic stem cell transplant.
3. Patients who have received anti-CD38 antibody therapy and do not fulfill a 180-day washout 
period before receiving TAK-079.
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4. Not recovered from adverse reactions to prior myeloma treatment or procedures 
(chemotherapy, immunotherapy, radiation therapy) to NCI CTCAE Grade ≤1 or baseline, 
excluding alopecia.
5. Congestive heart failure (New York Heart Association) Grade ≥II; cardiac myopathy, active 
ischemia, or any other uncontrolled cardiac condition such as angina pectoris, clinically 
significant arrhythmia requiring therapy including anticoagulants, or clinically significant 
uncontrolled hypertension.
6. History of acute myocardial infarction within 5 months before enrollment or ECG 
abnormalities during the screening period that are deemed medically relevant by the 
investigator.
7. QT interval corrected by the Fridericia method >480 msec (Grade ≥2).
8. Concurrent illness that would preclude study conduct and assessment including, but not 
limited to, uncontrolled medical conditions, uncontrolled systemic or body organ active 
infection (considered opportunistic, life threatening, or clinically significant), uncontrolled 
risk of bleeding, uncontrolled diabetes mellitus, pulmonary disease (including obstructive 
pulmonary disease such as severe chronic obstructive pulmonary disease [COPD] with forced 
expiratory volume <80%, or persistent asthma, pulmonary fibrosis, and history of 
symptomatic bronchospasm), inflammatory bowel disease, ongoing symptomatic 
pneumonitis, alcoholic liver disease, or primary biliary cirrhosis. 
9. History of stroke or intracranial hemorrhage within 12 months of first dose of study drug; 
patients requiring anticoagulation therapy for any indication should be discussed with the 
medical monitor before screening.
10. Active autoimmune disease including autoimmune hemolytic anemia, idiopathic 
thrombocytopenic purpura, or any chronic condition requiring a higher corticosteroid systemic 
equivalent than prednisone 10 mg daily. Higher doses of corticosteroids prescribed for any 
indication must be stopped 7 days prior to first dose of study drug; exceptions may be made for 
corticosteroids prescribed specifically for management of MM symptoms after discussion with 
the medical monitor.
11. History of myelodysplastic syndrome or another malignancy other than MM, except for the 
following: any malignancy that has been in complete remission for ≥3 years, adequately 
treated local basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ,
superficial bladder cancer, or asymptomatic prostate cancer without known metastatic disease 
and with no requirement for therapy or requiring only hormonal therapy and with normal 
prostate-specific antigen for 1 year before the start of study therapy.
12. Clinical signs of CNS involvement of MM.
13. Female patients who are pregnant with a positive serum pregnancy test or lactating during the 
screening period, or a positive urine pregnancy test on Day 1 before the first dose of study 
drug, if applicable. 
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14. Any serious medical or psychiatric illness that could, in the investigator’s opinion, potentially 
interfere with the completion of treatment according to this protocol.
15. Active chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, or active HIV 
infection.
16. History of severe allergic or anaphylactic reactions to recombinant proteins or excipients used 
in the TAK-079 formulation. This includes patients who were previously discontinued from an 
anti-CD38 treatment due to an infusion-related reaction.
17. The patient is currently participating in another antimyeloma clinical study, or has participated 
in another investigational clinical trial within the 4 weeks prior to first dose of study drug.
18. Patients who are not able and/or willing to comply with the study requirements, rules, and 
procedures.
19. POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin 
changes) syndrome, monoclonal gammopathy of unknown significance, smoldering myeloma, 
solitary plasmacytoma, amyloidosis, Waldenström macroglobulinemia, or IgM myeloma.
20. Patients with positive Coombs tests at screening. 
21. For patients in the Combination Cohort (TAK-079–PomDex) only: patient has previously 
received pomalidomide or has hypersensitivity to thalidomide or lenalidomide.
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8.0
STUDY DRUG
8.1
Study Drug Administration
All protocol-specific criteria for administration of study drug must be met and documented before 
drug administration. Study drug will be administered only to eligible patients under the 
supervision of the investigator or identified subinvestigator(s).
8.1.1
Predose and Postdose Medication
Premedications are required in phase 1 and phase 2a. 
The clinical site is responsible for sourcing any premedications outlined in the protocol.
8.1.1.1
Predose Medication: Phase 1 Dose Escalation and Dose Confirmation Cohorts 
Before each injection, patients will receive the following premedications 1 to 3 hours prior to the 
start of TAK-079 administration on each dosing day:

Dexamethasone: 20 mg IV dose for the initial injection. Oral dexamethasone (20 mg) or an 
equivalent long-acting corticosteroid may be used before subsequent injections.

Antipyretics: oral acetaminophen (650 to 1000 mg).

Antihistamine: oral or IV diphenhydramine (25 to 50 mg, or equivalent).

Montelukast 10 mg (or equivalent leukotriene inhibitor).
NOTE: For any patients with a history of COPD, consider prescribing postinfusion medications,
such as short- and long-acting bronchodilators, and inhaled corticosteroids. After the first 
4 infusions, if the patient experiences no major IRs, these additional inhaled postinfusion 
medications may be discontinued.
8.1.1.2
Predose Medications: Phase 1 Combination Cohort (TAK-079–PomDex) Only
Before each injection, patients will receive the following premedications 1 to 3 hours prior to the 
start of TAK-079 administration on each dosing day:

Antipyretics: oral acetaminophen (650 to 1000 mg).

Antihistamine: oral or IV diphenhydramine (25 to 50 mg, or equivalent).

Montelukast 10 mg (or equivalent leukotriene inhibitor).
NOTE: For any patients with a history of COPD, consider prescribing postinfusion medications,
such as short- and long-acting bronchodilators, and inhaled corticosteroids. After the first 
4 infusions, if the patient experiences no major IRs, these additional inhaled postinfusion 
medications may be discontinued.
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8.1.1.3
Postdose Medications (All Patients)
Postinjection site care: Apply corticosteroid cream topically to injection site(s) and apply ice 
locally for approximately 10 to 15 minutes (report the corticosteroid cream as a concomitant 
medication).
Patients may receive low-dose methylprednisolone (<20 mg) for the prevention of delayed 
injection-related reaction as clinically indicated after an injection.
8.1.2
TAK-079 Formulation and Administration
The strength of the TAK-079 drug product for SC use in the current study (TAK-079-1501) is 
100 mg TAK-079 in 1 mL (100 mg/mL). The drug product is supplied in clear borosilicate glass 
vials (see additional details in Section 8.13).
After patients have received premedication treatment, TAK-079 doses will be administered with 
syringes as SC injections up to a maximum volume of 2 mL per injection (ie, 200 mg/2 mL). For 
dose levels where multiple SC injections are needed to administer the full prescribed dose (ie, 300 
mg dose and above), the Cycle 1 Day 1 dose will be administered by giving each SC injection 30 
minutes apart until the full scheduled dose has been administered. On all drug administration days 
after Cycle 1 Day 1, if the patient did not have a clinically significant IR per the investigator, the 
SC injections can be given at the at the same time without a waiting period. 
When patients are to receive multiple SC injections, the injection sites need to be rotated, using the 
abdomen, thighs, arms, and upper buttock area. Time and anatomical site should be recorded for 
each SC injection.
Refer to the Pharmacy Manual for detailed instructions regarding preparation of each dose.
8.2
Definitions of DLT
Toxicity will be evaluated according to the NCI CTCAE, Version 4.03, effective 14 June 2010 
[25]. These criteria are provided in the Study Manual. DLTs will be defined as any of the 
following events regardless of relationship, except those events that are clearly due to extraneous 
causes.

Grade 4 laboratory abnormalities, except those events that are clearly due to extraneous causes, 
will be defined as a DLT. 

Nonhematologic TEAEs of NCI CTCAE Grade 3, except those events that are clearly due to 
extraneous causes, and occurring during the first cycle will be considered DLTs (see Section 
10.2 for relatedness guidance), with the following exceptions:
–
Grade 3 nausea/vomiting that can be managed subsequently with antiemetics (Grade 3 
nausea or vomiting that persists beyond 48 hours with or without appropriate medical 
intervention will be considered a DLT).
–
Grade 3 fatigue lasting less than 3 days (approximately 72 hours).
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–
Grade 3 elevation of alanine aminotransferase or aspartate aminotransferase that resolves 
to Grade ≤1 or baseline within 7 days.
–
Grade 3 IR that responds to symptomatic treatment (eg, antihistamines, nonsteroidal 
anti-inflammatory drugs (NSAIDs), narcotics, IV fluids), without recurrence of Grade 3 
symptoms. See Section 8.11.1 for handling of IRs with systemic signs and symptoms.

Hematologic TEAEs of NCI CTCAE Grade ≥4, except those events that are clearly due to 
extraneous causes, and occurring during the first cycle will be considered DLTs, with the 
following exceptions:
–
Grade ≥3 hemolysis, except those events that are clearly due to extraneous causes 
(eg, negative direct Coombs test), will be included in the definition of DLT.
–
Grade ≥3 low platelet count with clinically meaningful bleeding, defined as a blood loss of 
>100 cc or the requirement of a blood transfusion, will be included in the definition of 
DLT.

An incomplete recovery from treatment-related toxicity causing a >2-week delay in the next 
scheduled injection before the initiation of Cycle 2 will be considered a DLT.
For the purpose of dose escalation, DLTs are those events meeting the criteria above that occur 
before Cycle 2 Day 1 administration. TEAEs meeting DLT definitions occurring in later cycles 
will determine the suitability of the MTD as the RP2D.
Patients who experience a DLT should be withdrawn from study treatment unless the sponsor 
approves subsequent treatment in a lower dose cohort; such patients will not count as a patient in 
that lower dose cohort for escalation decisions. 
In phase 1, patients who do not receive 4 full doses of TAK-079 within the 28-day (±2) treatment 
window or the Day 29 (ie, Cycle 2 Day 1) assessment for reasons other than a DLT will be 
replaced. Patients experiencing a DLT should not be replaced.
Dose and schedule modifications for toxicity are described in Section 8.6.
8.3
Dose-Escalation Design and Criteria
8.3.1
Dose Levels
Patients will be enrolled in cohorts of 3 to 6, following a 3+3 dose escalation design. 
Phase 1
TAK-079 injections will be escalated as follows:

45 mg, once weekly for 8 weeks (8 doses), once every 2 weeks for 16 weeks (8 doses), and 
once every 4 weeks thereafter until PD, unacceptable toxicities, or withdrawal due to other 
reasons.
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patients have been treated at that dose level. If 6 patients have been enrolled at the lower level 
with 1 or less DLT out of 6, dosing may stop and this dose level may be considered the MTD. 
The MTD is defined as the highest dose with a cohort of 6 patients having no more than 1 
patient with a DLT.
Figure 8.a is a diagrammatical representation of the dose-escalation paradigm.
Figure 8.a
Dose-Escalation Scheme 
DLT: dose-limiting toxicity; MTD: maximum tolerated dose.
More conservative dose escalation, evaluation of intermediate doses, and expansion of an existing 
dose level are all permissible following discussions between the sponsor and the investigators, if 
such measures are needed for patient safety or for a better understanding of the dose-related 
toxicity, exposure, or 
.
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Before initiating the dosing of the next cohort, when safety data are available for all patients in the 
current cohort, key safety data will be reviewed and evaluated by the study team consisting of 
sponsor representatives and investigators who will review the safety of all treated patients and 
make decisions regarding dose escalation. In addition, changes to the dose-escalation scheme or 
dose schedule (dosing interval) may be considered. All decisions will be documented in writing. 
Any decision to modify the dose-escalation scheme (with the exception of testing intermediate 
dose levels) or dose schedule will be communicated to institutional review boards (IRBs), and the 
protocol will be amended accordingly.
8.4
TAK-079 Dose in Phase 1 Dose Confirmation Cohort

TAK-079 will be given at a fixed dose of 300 mg once weekly for 8 weeks (8 doses), once 
every 2 weeks for 16 weeks (8 doses), and once every 4 weeks thereafter until PD. 

In this cohort, safety and available efficacy, PK, 
 will be reviewed at 
least after 6 patients in each subgroup have received 1 cycle of therapy, then in an ongoing 
basis as per Takeda processes. 
8.5
TAK-079 Dose in Phase 1 Combination Cohort

TAK-079 will be given at a fixed dose of 300 mg once weekly for 8 weeks (8 doses), once 
every 2 weeks for 16 weeks (8 doses), and once every 4 weeks thereafter until PD.

PomDex are both standard of care agents and will be given in accordance with product labeling 
[Pomalyst USPI including Section 14.1; NCCN guidelines 2019].

In this cohort, up to 6 patients will initially be enrolled. Safety in Cycle 1 will be reviewed in 
accordance with DLT definitions in Section 8.2.

If 0 of 6 or 1 of 6 patients develop a DLT and additional 12 patients will be tested at the initial 
dose of TAK-079 [6 patients that are naïve to a prior anti-CD38 agent and 6 patients that have 
been exposed to a prior anti-CD38 agent], for an overall total of 18 patients.

If 2 of 6 patients develop DLTs, an additional cohort of 6 patients will be tested at a 
de-escalated dose; an intermediate or more conservative dose schedule may also be 
implemented as a means to provide an overall lower dose. A lower dose of pomalidomide may 
also be considered based on the available safety data. If 0 of 6 or 1 of 6 patients develop 
TAK-079–related DLTs at the revised dose, an additional cohort of up to 12 patients (with 
eligibility as above regarding anti-CD38 naïve or exposed) will be tested at this dose level (in 
other words a dose lower than the initial dose, one that is intermediate or more conservative 
than the initial dose) or conservative dose schedule, for an overall total of 18 patients at the 
lower dose/conservative dose schedule. If 2 of 6 patients develop DLTs at the lower dose, this 
cohort will be stopped for further evaluation.
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8.6
Dose Modification Guidelines
Dose modification guidelines for toxicities are described below for TAK-079 on the basis of the 
type and severity of AEs and causality determination by investigators (see Section 8.6.2). Further 
clarification can be obtained in consultation with the sponsor clinician (or designee).
8.6.1
Criteria for Beginning or Delaying a Subsequent Treatment Cycle
Treatment for all cohorts use a cycle length of 28 days. For a new cycle of treatment to begin, the 
patient must meet the following criteria:

Absolute neutrophil count must be ≥1000/mm3.

Platelet count must be ≥75,000/mm3.

For therapy to resume, toxicity considered to be related to treatment with TAK-079 must have 
resolved to Grade 1 or baseline, or to a level considered acceptable by the physician. If the 
patient fails to meet the above-cited criteria for retreatment, initiation of the next cycle of 
treatment should be delayed for 1 week. At the end of that week, the patient should be 
re-evaluated to determine whether the criteria for re-treatment have been met. If there is a 
delay of a subsequent cycle longer than 28 days because of a drug-related AE, the patient may 
be withdrawn from treatment unless there is clinical benefit as assessed by the investigator, 
with agreement by the sponsor’s medical monitor. 

For TAK-079 injections within the same cycle, the decision of holding treatment is left to the 
investigator’s discretion based on clinical and analytical data, and also based on the toxicity 
that the patient experienced with previous injections in the same cycle. The investigator should 
differentiate between acute toxicity (like an IR) from which the patient has recovered at the 
time of the next injection, and subacute toxicity (for example, neutropenia) that might be 
worsened upon another injection if it is not on a clear recovery path. If the dose cannot be 
administered on the scheduled day, the patient can be reviewed at the investigator’s discretion 
in the following 48 hours. If TAK-079 cannot be administered within a cycle in this 48-hour 
window, the dose will be missed and the patient scheduled for the next administration per the 
Schedule of Events (SOE; Appendix A).
8.6.2
Criteria for Dose Modification
All toxicities that occur during the study will be actively managed following medical standard of 
care unless otherwise specified in the protocol. Patients experiencing AEs attributed to TAK-079 
may continue study treatment with the same dose, may have TAK-079 treatment held or may be 
permanently discontinued from the study. Patients who have study drug held because of 
treatment-related or possibly related AEs may resume study drug treatment after resolution of the 
AE at the same dose level or at a reduced dose, depending on the nature and severity of the AE and 
whether it is the first occurrence or it is recurrent.
TEAEs that are not attributed by the investigator to the study drug may be treated as per local 
standard of care; dose-modifications, interruptions, and permanent discontinuations may be 
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discussed upfront with the medical monitor. Any dose interruption of more than 28 days due to 
toxicity may result in permanent discontinuation of TAK-079.
Table 8.a provides general dose modification recommendations. When the dose of TAK-079 is 
withheld on the basis of these criteria, clinical and laboratory re-evaluation should be repeated at 
least weekly or more frequently, depending on the nature of the toxicity observed, until the toxicity 
resolves to Grade ≤1 or baseline. If there are transient laboratory abnormalities that, per 
investigator assessment, are not clinically significant or drug related, continuation of therapy 
without dose modification is permissible upon discussion with the sponsor. Toxicity is managed 
using dose interruptions, including missed doses, as is standard with administration of monoclonal 
antibodies as a means to reduce dose intensity [5,26,27]. Patients experiencing a DLT (defined in 
Section 8.2) should be withdrawn from study treatment unless the sponsor approves subsequent 
treatment in a lower dose cohort.
See details for managing specific AEs in Section 8.11.
Table 8.a
Dose Modification Recommendations for TAK-079 Toxicities
Criteria
Action
Grade 1 AEs
No dose interruptions.
Grade 2 AEs
Treat according to local practice. Whether to hold treatment or to continue it 
at the same dose is at the discretion of the investigator.
Patients with Grade 2 AEs considered related to study treatment that are not 
easily managed or corrected and are not tolerable to the patient, or AEs that 
are not acceptable in the investigator’s judgment, should have study 
treatment interrupted until the AE resolves to Grade ≤1 or baseline, then 
restarted at the same dose.
Grade 3 AEs
Patients with Grade 3 AEs considered related to study treatment that are not 
easily managed or corrected and are not tolerable to the patient should have 
study treatment interrupted until the AE resolves to Grade ≤1 or baseline, 
then resume treatment at the same dose level. (Note Section 8.2 for AEs of 
short duration and/or that respond to medical management.) 
Note in phase 1, nonhematologic AEs Grade ≥3 may meet DLT criteria and 
as such patients should be withdrawn from further dosing unless the sponsor 
approves subsequent treatment in a lower dose cohort.
Grade 3 or higher thrombocytopenia with bleeding should result in a dose 
interruption until the AE resolves to Grade ≤1 or baseline, then resume at the 
same dose. 
Grade 4 (life-threatening) AEs
Patients with Grade 4 AEs considered related to study treatment should 
permanently discontinue treatment. Grade 4 hematologic toxicity should 
result in study treatment interruption until the AE resolves to Grade ≤1 or 
baseline, then resume at the same dose. 
AEs of all grades
If TAK-079 administration does not commence within the prespecified 
window (Table 8.b) of the scheduled administration date, then the dose will 
be considered a missed dose. Administration may resume at the next planned 
dosing date upon recovery as described above.
AE: adverse event; DLT: dose-limiting toxicity.
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If initial dose interruption does not provide sufficient relief, permanent discontinuation of 
TAK-079 should be considered.
Table 8.b
TAK-079–Related Toxicity Management
Dosing Frequency
Dose Missed
Dosing Resumption
Weekly (QW)
>3 days
Skip dose, move to next planned weekly dosing date
Biweekly (Q2W)
>7 days
Skip dose, move to next planned biweekly dosing date
Every 4 weeks (Q4W)
>21 days
Skip dose, move to next planned every 4 weeks dosing date
A TAK-079 dose held for more than 3 days from the per-protocol administration date for any 
reason other than AEs should be brought to the attention of the sponsor/designee as soon as 
possible. Subjects missing ≥3 consecutive planned doses of TAK-079 for reasons other than AEs 
should be withdrawn from treatment, unless, upon consultation with the sponsor/designee and 
review of safety and efficacy, continuation is agreed upon. A missed dose will not be made up. 
Doses of TAK-079 during every-4-weeks dosing may be delayed (interrupted) up to 4 weeks. If a 
dose is delayed (interrupted), then the dates of all subsequent doses and assessments must be 
adjusted accordingly. Any AE deemed to be related to TAK-079 that requires a dose delay 
(interruption) of more than 28 days should result in permanent discontinuation of TAK-079, unless 
both the investigator and the sponsor study clinician believe the patient is deriving clinical benefit. 
8.6.3
Criteria for Discontinuing TAK-079 in Individual Patients (When Considering Dose 
Modification)
TAK-079 should be discontinued in patients experiencing an AE in Cycle 1 that meets the criteria 
for a DLT, unless the investigator considers re-treatment of the patient not to be dangerous and the 
sponsor approves subsequent treatment in a lower dose cohort. For Grade 4 (life-threatening) 
TEAEs, consider permanently withdrawing the patient from the study, except if the investigator 
determines that the patient is receiving clinical benefit, there are opportunities to provide 
supportive care to mitigate risk for the Grade 4 event to reoccur, and this approach (ie, the specific 
situation and mitigation plan) has been discussed with the sponsor. In these circumstances, 
treatment may be restarted when toxicity recovers to Grade ≤1 or baseline (see Table 8.a and 
Table 8.b).
8.7
Dose Modification Considerations for Patients in the Phase 1 Combination Cohort 
(TAK-079–PomDex Cohort) Only 

TAK-079 (study drug) will be given as noted in Section 8.5 through 8.6.3.

Dexamethasone administered IV or orally at 40 mg/day on Days 1, 8, 15, 22, or 20 mg/day 
given on Days 1, 8, 15, and 22 for patients over 75 years of age (Pomalyst USPI, Section 14.1).

Pomalidomide is a standard of care agents and will be given in accordance with product 
labeling (Pomalyst USPI).

Treatment cycle will be 28-days as per product labeling until PD or unacceptable toxicity.
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
PomDex will be procured by the site from commercial sources.
8.7.1
Dose Modification of Standard of Care Agents

All toxicities that occur during the study will be actively managed following medical standard 
of care unless otherwise specified in the protocol.

Toxicities should be attributed, whenever possible, to a specific drug (TAK-079 study drug, or 
standard chemotherapy agents pomalidomide or dexamethasone, as applicable) so that dose 
modifications can be made rationally. Reduction of 1 agent and not others is appropriate if 
toxicity is considered to be related primarily to one of the agents. If multiple toxicities are 
attributed to an individual agent (study drug or standard chemotherapy agent), dose 
adjustments should be made according to the guidelines for the most severe toxicity. 

Toxicities attributed to pomalidomide or dexamethasone, as applicable, should be managed 
according to the relevant guidelines in the respective product information [20,28].

Once dose reduction has been implemented, unless otherwise stated specifically in the relevant 
product information and after discussion with the Sponsor Study Clinician (or designee), dose 
re-escalation should not occur. 
8.8
Excluded Concomitant Medications and Procedures
The following medications and procedures are prohibited during the study:

Chemotherapy and radiation therapy for the disease under study. Local radiotherapy for bone 
pain is permitted after agreement with the sponsor’s medical monitor and once PD is ruled out.

Systemic corticosteroid use >10 mg/day (prednisone or equivalent). 

Live vaccines.

Any investigational agent other than TAK-079, including agents that are commercially 
available for indications other than MM that are under investigation for the treatment of MM.
8.9
Permitted Concomitant Medications and Procedures 

All necessary supportive care consistent with optimal patient care will be available to patients 
as necessary. During study treatment, all blood products and concomitant medications 
received until 30 days after the final dose will be recorded in the electronic case report forms 
(eCRFs) (note additional information in Section 9.4.9 and Appendix A).

The following medications and procedures are permitted while the patient is receiving the 
study drug:
–
For patients in the Combination Cohort (TAK-079–PomDex) only: patients must adhere to 
the pregnancy prevention program (Pomalyst REMS).
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–
For patients in the Combination Cohort (TAK-079–PomDex) only: patients receiving 
pomalidomide should be on routine thromboprophylaxis according to product label, 
published guidelines, and institutional practice [20,29].
–
Systemic corticosteroid use ≤10 mg/day (prednisone or equivalent).
–
Myeloid growth factors (eg, granulocyte colony stimulating factor, granulocyte 
macrophage-colony stimulating factor) and erythropoietin are permitted. Their use should 
follow the product label, published guidelines, and institutional practice. However, 
myeloid growth factors will not be allowed in Cycle 1 unless the study is in the expansion 
phase as their prophylactic use can interfere with DLT determination.
–
Transfusions with RBCs and platelets as clinically indicated; however, platelet use will not 
be allowed in Cycle 1 unless the study is in the expansion phase because their prophylactic 
use can interfere with DLT determination.
–
Localized radiation for pain management for osteolytic lesions.
–
Concomitant treatment with bisphosphonates will be encouraged for all patients with 
evidence of lytic destruction of bone or with osteopenia, according to the American 
Society of Clinical Oncology Clinical Practice Guidelines or institutional practice in 
accordance with the product label, unless specifically contraindicated. If bisphosphonate 
therapy was not started before the study start, it should be initiated as soon as clinically 
indicated.
–
Topical or inhaled steroids and short-acting β2 adrenergic receptor agonists (eg, for the 
treatment of asthma) are permitted.
–
Nonresorbable corticosteroids (eg, budesonide).
–
Plasmapheresis.
8.10
Precautions and Restrictions
An interference with serological testing has been described with the anti-CD38 antibody 
daratumumab [23]. Daratumumab binds to CD38 on RBCs and results in a positive indirect 
antiglobulin test (Indirect Coombs test). A daratumumab-mediated positive indirect antiglobulin 
test may persist for up to 6 months after the last daratumumab infusion. Daratumumab bound to 
RBCs masks detection of antibodies to minor antigens in the patient’s serum. The determination of 
a patient’s ABO and Rh blood type are not affected. It is possible TAK-079 may affect the results 
of these blood tests; this is being evaluated. Until those tests are known, it is recommended that 
baseline type and serological screening be established before starting TAK-079. Patients should 
keep these results in case future transfusions are needed. Blood transfusion centers should also be 
informed of this interference with serological testing as necessary.
Fluid deficits should be corrected before initiation of treatment and during treatment.
NSAIDs should be avoided with impaired renal function given the reported NSAID-induced renal 
failure in patients with decreased renal function.
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Patients should not drive, operate dangerous tools or machinery, or engage in any other potentially 
hazardous activity that requires full alertness and coordination if they experience sedation while 
enrolled in this study.
Patients are to be instructed to limit the use of alcohol while enrolled in this study.
It is not known what effects TAK-079 has on human pregnancy or development of the embryo or 
fetus; therefore, female patients participating in this study should avoid becoming pregnant, and 
male patients should avoid impregnating a female partner. Nonsterilized female patients of 
reproductive age and male patients should use effective methods of contraception through defined 
periods during and after study treatment as specified below.
Female patients must meet the following:

WOCBP must not be pregnant or lactating. 

Postmenopausal for at least 1 year before the screening visit, OR

Surgically sterile, OR

If they are of childbearing potential, agree to practice 1 highly effective method and 
1 additional effective (barrier) method of contraception at the same time, from the time of 
signing of the informed consent form (ICF) through at least 90 days or 5 half-lives after the last 
dose of study drug (whichever is longer). Note the half-life of TAK-079 has not yet been 
determined. Based on conservative information in the literature regarding the half-life of IgG1 
immunoglobulins as well as other IgG1 human monoclonal antibodies [30,31], a conservative 
time frame to continue contraception would be 150 days. OR

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of 
the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, and postovulation 
methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.)
Male patients, even if surgically sterilized (ie, status postvasectomy) must agree to one of the 
following:

Agree to practice effective barrier contraception during the entire study treatment period and 
through 90 days (or if the drug has a very long half-life, for 90 days plus 5 half-lives) after the 
last dose of study drug. Note the half-life of TAK-079 has not yet been determined. Based on 
conservative information in the literature regarding the half-life of IgG1 immunoglobulins as 
well as other IgG1 human monoclonal antibodies [30,31], a conservative timeframe to 
continue contraception would be 150 days. OR

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of 
the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, and postovulation 
methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.)
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For men and women patients enrolled in the Combination (TAK-079–PomDex) Cohort only: 
patients receiving pomalidomide must adhere to the Pomalyst REMS requirements per the product 
label [20].
In addition, a close monitoring of serum chemistry, particularly creatinine, potassium, and uric 
acid levels must be performed. Patients with tumor lysis syndrome should be treated per 
institutional practice (including correction of electrolyte abnormalities, monitoring of renal 
function and fluid balance, and administration of supportive care, including dialysis as indicated).
8.11
Management of Specific Adverse Reactions
8.11.1 Handling of IRs
Patients should be carefully observed during TAK-079 injections. Trained trial staff at the clinic 
should be prepared to intervene in case of any systemic IRs and resources necessary for 
resuscitation (eg, agents such as epinephrine and aerosolized bronchodilators; also medical 
equipment such as oxygen tanks, tracheostomy equipment, and a defibrillator) must be available at 
bedside.
In case of an IR (any grade), blood draws should be performed for central evaluation of 
 
, ADAs, 
. These draws must not interfere with patient care and 
blood tests necessary for the acute care of the patient. 
For additional details, refer to Section 9.4.15.3.
Grade 1 or 2 IR
In case of Grade 1 or 2 IRs (systemic signs or symptoms): 

Withhold therapy (also administration of remaining SC injections when full dose was not yet 
reached) until resolution to Grade 1 or maximum to Grade 2 as per the investigator’s 
discretion. 
o
If a patient experiences a Grade 1 IR mid-dosing, hold subsequent SC injections, 
evaluate the patient, treat symptoms, and once the patient is stable per investigator’s 
discretion, resume SC injections to achieve the full dose level. The remaining 
injections must be given 30 minutes apart, and the patient will be evaluated for IRs 
after each SC injection. 
o
If a patient experiences a Grade 2 IR mid-dosing, hold subsequent SC injections, 
evaluate the patient, treat symptoms, and once resolved to Grade 1 or resolved 
completely, per investigator’s discretion, resume SC injections to achieve the full dose 
level. The remaining injections must be given 30 minutes apart, and the patient will be 
evaluated for IRs after each SC injection.
–
Patients who experience IRs must be treated according to the investigator’s judgement and 
best clinical practice. Subsequent doses may have individual SC injections administered 
more frequently at the investigator’s discretion with appropriate premedication and 
postmedication.
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Grade 3 IR
In case of Grade 3 IRs (systemic signs or symptoms): 

Withhold therapy (also administration of remaining SC injections if full dose was not yet 
reached and therefore skip remaining injection[s]) until next scheduled TAK-079 SC 
administration, providing that the IR has recovered to Grade ≤1 at the time of the next 
scheduled TAK-079 dose. Patients who experience IRs must be treated according to the 
investigator’s judgement and best clinical practice. At the time of the next dose after an IR, 
patients at a dose level requiring more than 1 SC injection should receive each injection 
30 minutes apart. If no further IR, subsequent injections may be given more frequently at the 
investigator’s discretion with appropriate premedication and postmedication.

Permanently discontinue treatment after the third occurrence of Grade 3 IRs.
Grade 4 IRs
In case of Grade 4 IRs (systemic signs or symptoms): 
Permanently discontinue treatment.
8.11.2 Injection Site Care
Prophylactic postinjection site care:
Apply corticosteroid cream topically to injection site(s) and apply ice locally for 
approximately 10 to 15 minutes (report the corticosteroid cream as a concomitant medication).
Additional injection site care may be provided on the basis of signs and symptoms per investigator 
discretion (report any actions as a concomitant medication).
8.11.3 Handling of Low Platelet Counts
Treatment decisions will be based on patient platelet counts assessed before any transfusion. Low 
platelet counts (Grade 4) should cause scheduled treatment to be postponed or to be permanently 
discontinued if recovery is delayed more than 14 days (see Table 8.a). If at any time the platelet 
count is less than 10×109/L, or if the patient shows a bleeding tendency considered to be due to 
thrombocytopenia occurring after initiation of TAK-079 treatment, the patient should be 
withdrawn from TAK-079 treatment. Platelet transfusion and daily monitoring of platelet counts, 
evaluation of coagulation parameters, and the Coombs test are recommended. These patients (that 
is, those who have platelets <10×109/L if recovery is delayed more than 14 days OR with bleeding 
tendency due to thrombocytopenia OR with abnormal Coombs test) should be considered as 
having experienced an SAE. 
For patients in the phase 1 Combination Cohort, thrombocytopenia is a known TEAE reported 
with pomalidomide and should be monitored and managed according to the product information 
[20].
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8.14
Preparation, Reconstitution, and Dispensation
Parenteral drug products should be inspected visually for particulate matter and discoloration 
before administration, whenever the solution and container permit.
TAK-079 is an anticancer drug; as with other potentially toxic compounds, caution should be 
exercised when handling TAK-079.
8.15
Packaging and Labeling
Supplies of TAK-079 will be labeled according to the current International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines 
on Good Clinical Practice (GCP) and Good Manufacturing Practice and will include any locally 
required statements. 
8.16
Storage, Handling, and Accountability
8.16.1 Storage and Handling
The investigator or designee must confirm that appropriate temperature conditions have been 
maintained for all TAK-079 received and that any discrepancies are reported and resolved before 
use of TAK-079.
TAK-079 must be stored according to the manufacturer’s stipulation, as specified on the label (see 
the Pharmacy Manual for additional information).
During shipping, vials will be protected from light and shipped as noted in the pharmacy manual. 
Each TAK-079 shipment will include a packing slip listing the contents of the shipment, and any 
applicable forms.
All clinical trial material must be kept in an appropriate, limited-access, secure location until used 
or returned to the sponsor or designee. All study medication must be stored under the conditions 
specified on the label, and remain in the original container until dispensed. A daily temperature log 
of the drug storage area should be maintained every day.
The investigator or designee must confirm that appropriate temperature conditions have been 
maintained for all TAK-079 received and that any discrepancies are reported and resolved before 
use of TAK-079.
The investigator is responsible for ensuring that deliveries of TAK-079 and other study materials 
from the sponsor are correctly received, recorded, and handled, and stored safely and properly in 
accordance with the Code of Federal Regulations (CFR) or national and local regulations, and used 
in accordance with this protocol.
Detailed dosage preparation instructions are provided in the Directions for Use section of the 
Pharmacy Manual. Complete receipt, inventory, accountability, reconciliation, and destruction 
records must be maintained for all used and unused study drug vials. Detailed instructions and the 
associated forms for these activities are in the Pharmacy Manual.
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Upon receipt of study medication, the investigator or designee must verify the contents of the 
shipments against the packing list. The verifier should ensure that the quantity is correct, the 
medication is received within the labeled storage conditions, and is in good condition. If quantity 
and conditions are acceptable, investigator or designee should acknowledge the receipt of the 
shipment by signing bottom half of the packing list and faxing per instructions provided on the 
form. If there are any discrepancies between the packing list versus the actual product received, 
Takeda must be contacted to resolve the issue. The packing list should be filed in the investigator’s 
essential document file.
The sponsor must be notified immediately of any temperature excursions, shipping and handling 
or storage discrepancies.
Drug supplies will be counted and reconciled at the site before being returned to Takeda or 
designee or being destroyed.
The investigator or designee must ensure that the study medication is used in accordance with 
the approved protocol and is dispensed only to subjects enrolled in the study. To document 
appropriate use of study medication (TAK-079), the investigator must maintain records of all 
study medication delivery to the site, site inventory, use by each subject, and return to the 
sponsor or designee.
The investigator will be notified of any expiry date or retest date extension of clinical study 
material during the study conduct. On expiry date notification from the sponsor or designee, the 
site must complete all instructions outlined in the notification, including segregation of expired 
clinical study material for return to the sponsor or its designee.
Further guidance and information are provided in the Pharmacy Manual.
8.16.2 Accountability and Destruction of Sponsor Supplied Drugs
The investigator, institution, or head of the medical institution (where applicable) is responsible 
for TAK-079 accountability, reconciliation, and record maintenance (ie, receipt, reconciliation, 
and final disposition records).
The investigator must maintain 100% accountability for all study medication (TAK-079) received 
and dispensed during his or her entire participation in the study. Proper drug accountability 
includes, but is not limited to:

Continuously monitoring expiration dates if expiry date/retest date is provided to the 
investigator.

Frequently verifying that actual inventory matches documented inventory.

Verifying that the log is completed for the drug lot used to prepare each dose.

Verifying that all containers used are documented accurately on the log.

Verifying that required fields are completed accurately and legibly.
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
Per standard clinical practice, a site representative, otherwise uninvolved with study conduct, 
will review the subject dosing log prior to Day 1 dosing and following dosing to ensure all 
subjects received the correct dose of study medication. This review will be documented at the 
site.
If any dispensing errors or discrepancies are discovered, the sponsor must be notified immediately.
Empty, partially used, and unused TAK-079 will be disposed of, retained, or returned to the 
sponsor or designee, as directed by the sponsor or designee.
The investigator must maintain a current inventory (Drug Accountability Log) of all 
sponsor-supplied study medication delivered to the site, inventory at the site, and subjects’ use 
records. This log must accurately reflect the drug accountability of the study medication at all 
times. The following information will be recorded at a minimum: protocol number and title, name 
of investigator, site identifier and number, description of sponsor-supplied medication, 
expiry/retest date and amount dispensed, including the initials of the person dispensing and 
receiving the study medication. The log should include all required information as a separate entry 
for each subject to whom study medication is dispensed.
Prior to site closure or at appropriate intervals, a representative from the sponsor or its designee 
will perform clinical study material accountability and reconciliation before clinical study 
materials are returned to the sponsor or its designee or destroyed at the site, as applicable. The 
investigator will retain the original documentation regarding clinical study material accountability, 
return, and/or destruction, and copies will be sent to the sponsor or designee.
Further guidance and information are provided in the Pharmacy Manual.
8.17
Investigational Drug Assignment and Dispensing Procedures
Subjects will be assigned using an IVRS/IWRS accessible 24 hours a day to authorized users. At 
screening, the site will contact the IVRS/IWRS to register the subject into the study. During this 
contact, the investigator or designee will provide the necessary subject-identifying information. At 
drug dispensing visits, the investigator or designee will contact the IVRS/IWRS to request study 
medication assignments for a subject. Medication ID numbers (MED IDs) of the study 
medications to be dispensed will be assigned by the IVRS/IWRS. Documentation of the 
IVRS/IWRS assigned MED IDs should be included in the source documents.
8.18
Standard Drug Procurement Procedures: Patients in the Combination Cohort Only
8.18.1 Pomalidomide
Pomalidomide will be procured by the site from commercial sources. Additional details are 
provided in the product information [20]. Patients receiving pomalidomide must adhere to the 
Pomalyst REMS program per the product label.
Pomalidomide capsules should be stored at temperatures in accordance with the instructions 
provided in the manufacturers product information.
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8.18.2 Dexamethasone
Dexamethasone will be procured by the site from commercial sources. Additional details are 
provided in the product information (Decadron USPI).
Dexamethasone tablets should be stored according to the instructions provided in the 
manufacture’s product information. 
8.19
Other Protocol-Specified Materials
TAK-079 will be supplied for use in this clinical study. No other drugs (including PomDex in the 
Combination Cohort) or ancillary materials are supplied for use in this study. 
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9.0
STUDY CONDUCT
This study will be conducted in compliance with the protocol, GCP, applicable regulatory 
requirements, and ICH guidelines.
9.1
Study Personnel and Organizations
The contact information for the project clinician for this study, any clinical laboratories centrally 
analyzing samples, and the contract research organization (CRO) team may be found in the Study 
Manual. A full list of investigators is available in the sponsor’s investigator database.
9.2
Arrangements for Recruitment of Patients
Recruitment and enrollment strategies for this study may include recruitment from the 
investigator’s local practice or referrals from other physicians. If advertisements become part of 
the recruitment strategy, they will be reviewed by the IRB/independent ethics committee (IEC). 
The screening period for this study is 21 days.
9.3
Treatment Group Assignments
All patients will receive open-label treatment with TAK-079 as indicated in respectively assigned 
treatment cohorts.
For phase 1 Combination Cohort (TAK-079–PomDex) Cohort only: patients must meet 
prespecified inclusion/exclusion criteria in Section 7.0 to be assigned to this cohort. 
9.4
Study Procedures
Refer to the SOE (Appendix A) for timing of assessments. Additional details are provided as 
necessary in the sections that follow.
9.4.1
Informed Consent
Each patient must provide written informed consent before any study-required procedures are 
conducted, unless those procedures are performed as part of the patient’s standard care.
9.4.2
Patient Demographics
The date of birth, race, ethnicity, and sex of the patient are to be recorded during screening.
9.4.3
Medical History
During the screening period, a complete medical history will be compiled for each patient. This 
includes initial diagnosis date and MM staging at initial diagnosis using the International Staging 
System and Salmon-Durie Staging. Before dosing, the investigator should record the International 
Staging System as of study entry, which should be consistently used throughout the study. 
Known cytogenetic alterations should also be collected. Prior treatment regimens, with each 
treatment duration (start and stop dates), the best response obtained with each therapy, and 
date/type of PD should be recorded. Refractoriness to previous treatments should be collected 
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following IMWG criteria (Appendix E). Confirm that the patient’s current medical status does not 
include active chronic HBV, HCV, or HIV infection.
For patients who have received previous anti-CD38 therapy, the worst grade of infusion-related 
reactions should be recorded. In addition, concomitant medications will be recorded as specified in 
Section 9.4.9. 
Information on any subsequent anticancer therapies will be collected during the PFS/OS follow-up 
periods.
9.4.4
Physical Examination
A physical examination will be completed per standard of care at the times specified in the SOE 
(Appendix A).
9.4.5
Patient Height and Weight
Height will be measured during the screening visit only. Weight will be measured on Day 1 of each 
treatment cycle, as indicated in Appendix A.
9.4.6
Vital Signs
Vital signs include temperature, pulse, respiratory rate, and blood pressure. Vital sign 
measurements will be made before TAK-079 injection, and include supine or seated 
measurements of diastolic and systolic blood pressure (after 3 to 5 minutes in this position). All 
measurements should be performed in the same initial position, including heart rate and body 
temperature.
Blood pressure will also be measured before each injection, and at any time the patient complains 
of symptoms consistent with IR. If the patient experiences hypotension (with or without 
symptoms), intensive blood pressure monitoring according to local practice should be instituted. 
The patient should not be released from the site until blood pressure has returned to Grade 1 or 
baseline for at least 1 hour.
Vital signs will be measured at the visits specified in the SOE (Appendix A). Any vital sign value 
that is judged by the investigator as clinically significant will be recorded on both the source 
documentation and in the eCRF as an AE, and monitored as described in Section 10.2.
9.4.7
Eligibility Criteria
Eligibility criteria and confirmatory study assessments must be confirmed during the screening 
period, after a patient has signed the ICF, and before receiving study drug.
9.4.8
Pregnancy Test
WOCBP must have 2 negative pregnancy tests (human chorionic gonadotropin <5 mIU/mL) prior 
to starting study drug. A serum pregnancy test will be used during the screening period (within 
10 to 14 days before the start of study drug). A serum pregnancy test must also be performed at 
baseline (within 24 hours before the start of study drug). A WOCPB is a sexually mature female 
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who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally 
postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) 
for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive 
months).
During the study, if a menstrual period is delayed, absence of pregnancy in WOCBP must be 
confirmed by serum pregnancy test. Pregnancy tests may also be repeated during the study upon 
request by an IRB or if required by local regulations. 
A urine pregnancy test is required in WOCBP at designated treatment visits (Appendix A) and also 
at the EOT visit. 
Patients receiving pomalidomide in the Combination Cohort (TAK-079–PomDex) must adhere to 
the Pomalyst REMS program per the product label. Pregnancy tests may also be repeated during 
the study as per request of the IEC/IRBs or required by local regulations. 
9.4.9
Concomitant Medications and Procedures
Any prior or concomitant medication a patient has had within 21 days before TAK-079 
administration and up to 30 days after the last dose of TAK-079 (or the start of subsequent 
anticancer therapy, whichever occurs first) will be recorded on the eCRF. Trade name and 
international nonproprietary name/generic name (if available), indication, and start and end dates 
of the administered medication will be recorded. Medications used by the patient and therapeutic 
procedures completed by the patient will be recorded in the eCRF. See Section 8.8 and Section 8.9
for a list of medications and therapies that are prohibited or allowed during the study.
9.4.10 AEs
Monitoring of TEAEs, serious and nonserious, will be conducted throughout the study as specified 
in the SOE. Refer to Section 10.0 for details regarding definitions, documentation, and reporting of 
TEAEs and SAEs.
9.4.11
Enrollment
A patient is considered to be enrolled in the study at the first injection.
Procedures for completing the enrollment information are described in the Study Manual.
9.4.12
ECG
A single ECG will be collected at the screening visit for assessment of eligibility. A qualified 
person will interpret the ECG.
Time-matched triplicate 12-lead ECGs and PK samples will be collected in this study during 
Cycles 1 and 2 as specified in Appendix B. Although the number of scheduled ECG measurements 
will not be increased, the timing may be changed if emerging data indicate that an alteration in the 
ECG schedule is needed. Triplicate ECGs will be recorded electronically and transmitted to a 
central vendor for storage. 
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For Patients in Cohorts Receiving TAK-079 monotherapy:
Table 9.a
Clinical Chemistry and Hematology Tests for Research Purposes 
Hematology
Serum Chemistry
ANC
Hematocrit
Hemoglobin
Platelet (count) 
Reticulocyte count
RBC count
WBC count with differential
Coagulation panel
Albumin
ALP
ALT
AST
Bilirubin (total)
BUN
Calcium
Chloride
CO2 (bicarbonate) 
Creatinine 
Creatinine clearance
CRP
Glucose (nonfasting)
GGT
LDH
Phosphate
Potassium
Sodium
Total protein
Urate (uric acid)
ALP: alkaline phosphatase; ALT: alanine aminotransferase; ANC: absolute neutrophil count; AST: serine 
aminotransferase; BUN: blood urea nitrogen; CRP: C-reactive protein; GGT: γ-glutamyl transferase; LDH: lactate 
dehydrogenase; RBC: red blood cell; WBC: white blood cell.
Table 9.b
Clinical Urinalysis Tests for Research Purposes
Urinalysis
Bilirubin
Glucose
Ketones
Leukocytes
Nitrite
Occult blood
pH
Protein
Specific gravity
Turbidity and color
Urobilinogen
For estimation of creatinine clearance, the Cockcroft-Gault formula will be employed as follows:
	
 
	
 
		
= [(140 −
) • 	 () ] / [72 • 
! 
	
 (/")] 
For female patients, the result of the formula above should be multiplied by 0.85. 
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For patients in the phase 1 Combination Cohort (TAK-079–PomDex) Cohort only:
Table 9.c
Clinical Hematology and Chemistry: Standard of Care Laboratory Tests
Hematology
Chemistry
Leukocytes with complete differential (total 
neutrophils [ANC], lymphocytes, monocytes, 
eosinophils, and monocytes)
Albumin
CO2 (bicarbonate)
Platelet count
ALP
Creatinine
Hemoglobin
ALT
Estimated glomerular 
filtration rate
Serum pregnancy test
AST
Glucose
B2- microglobulin
LDH
Bilirubin (direct and indirect)
Potassium
Calcium
Sodium
Chloride
Urate
ALP: alkaline phosphatase; ALT: alanine aminotransferase; ANC: absolute neutrophil count; AST: serine 
aminotransferase; LDH: lactate dehydrogenase.
Table 9.d
Clinical Hematology and Chemistry: Tests for Research Purposes
Clinical Hematology or Chemistry
Serology antibody titers
Coagulation panel (PT, PTT, INR)
Hepatitis B
Indirect and direct coombs
Hepatitis C
C-reactive protein
HIV
INR: international normalized ratio; PT: prothrombin time; PTT: partial thromboplastin time.
Table 9.e
Clinical Urinalysis: Tests for Research Purposes
Urinalysis
Bilirubin
pH
Glucose
Protein
Ketones
Specific gravity
Leukocytes
Turbidity, appearance, and color
Nitrite
Urobilinogen
Occult blood
Microscopic assessment (a)
(a) Microscopic analyses will be performed only as clinically indicated: bacteria, RBCs, WBCs, casts, and crystals.
All procedures and tests should be done as outlined in the SOE (Appendix A). After 24 months on treatment, the 
patient may be monitored according to standard clinical practice per the treating physician.
9.4.13.2 Prestudy Prognostic Risk Assessment
A blood sample will be collected for serum 2 microglobulin at screening to assess patient disease 
status. Results will be analyzed locally.
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9.4.14
Disease Response Assessments
Patients will be assessed for disease response according to the IMWG criteria ([21,22]; 
Appendix E). In addition, in patients that have myeloma measurable by serum free light chains, 
MR will be defined as a reduction of ≥25 but ≤49% in the difference between involved and 
uninvolved FLC levels.
For patients in the phase 1 Combination Cohort (TAK-079–PomDex) Cohort only:
Table 9.f
Myeloma Disease Assessments: Tests Standard of Care Tests
Serum/Urine
Bone Marrow/Imaging
SPEP
Bone marrow biopsy and/or aspirate (a)
UPEP
Cytogenetics [presence of del (17), t(4:14), and t(14:16) at a 
minimum]
Immunofixation (serum and urine)
Imaging (skeletal survey, CT scan, PET/CT scan, MRI)
Quantification immunoglobulin levels
Serum FLC
CT: computed tomography; MRI: magnetic resonance imaging; PET: positron emission tomography.
(a) The BMAs only at Cycle 2D1, C4D1, C7D1, and C13D1 are for research purposes unless these align with a 
suspected CR then this procedure would be Standard of Care.
For all patients: 
After 24 cycles on treatment, the patient may be monitored according to standard clinical practice 
per the treating physician.
Serum and urine response assessments will be performed no later than the first day of every 
treatment cycle, before the patient receives treatment with TAK-079. Patients with myeloma 
measurable by SPEP only will have 24-hour urine collected at screening and EOT and to document 
PR, very good partial response (VGPR), CR, or PD.
Imaging tests will be done per Appendix A and as described in Section 9.4.14.1. The same 
imaging technique should be used throughout the study to facilitate consistent disease assessment.
Responses should be confirmed with follow-up assessments of SPEP, UPEP, immunofixation of 
blood and urine, and serum FLCs as outlined in Appendix A. One BMA assessment has to occur to 
document CR; no second bone marrow confirmation is needed.
Note that to determine a response of sCR, BMA immunohistochemistry or immunofluorescence 
for kappa:lambda ratio, as well as serum FLC assay, should be performed for all patients 
suspected to be in CR to meet this response category’s requirements.
PD may be confirmed per standard clinical practice at the site. Local laboratory results may be 
used to confirm PD.
Blood samples, 24-hour urine sample, BMA, and imaging done for disease response assessment 
will be done locally.
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9.4.14.1 Computed Tomography/Magnetic Resonance Imaging
Scans will be performed at a minimum at screening and at the EOT visit. All treatment phase and 
follow-up scans should use the same imaging modality used at screening.
For patients with documented extramedullary disease, a whole-body x-ray, positron emission 
tomography-computed tomography (PET-CT) scan, computed tomography (CT) scan (includes 
low-dose CT), or magnetic resonance imaging (MRI) scan will be performed as outlined in 
Appendix A. The screening scan may be performed up to 21 days before first dose of TAK-079; 
however, if the patient has adequate image test performed within 5 weeks of the planned first dose 
of study drug, that image can be used as baseline and does not need to be repeated as part of 
screening. If disease is documented, then a repeat PET-CT scan, CT scan, or MRI scan should be 
performed as required to document response or PD.
Additional surveys (x-ray, CT, or MRI) may also be performed at the investigator’s discretion, eg, 
in case of bone pain. Radiographs will be analyzed locally and reports maintained with the patient 
record for retrieval during monitoring visits.
9.4.14.2 Quantification of Immunoglobulins
A blood sample for quantification of Ig (IgM, IgG, and IgA) will be obtained at the screening visit, 
predose on Day 1 of every cycle, and at all visits per Appendix A. Analysis of Ig will be performed 
locally.
9.4.14.3 Quantification of M-Protein
A predose blood and 24-hour urine sample will be obtained at the screening visit, Day 1 of every 
cycle, and at all visits per Appendix A. 
The samples will be tested locally. M-protein in serum and urine will be quantified by SPEP and 
UPEP.
9.4.14.4 Serum FLC Assay
Serum samples will be obtained predose on Day 1 of every cycle and at all visits, per Appendix A, 
for the serum FLC assay (including quantification of kappa and lambda chains and ratio). Blood 
samples will be analyzed locally.
9.4.14.5 Immunofixation of Serum and Urine
Serum and urine samples will be obtained for serum and urine immunofixation tests at the 
screening visit, predose on Day 1 of every cycle, to confirm CR, and at all response assessment 
visits as per Appendix A. Immunofixation testing will be performed in a local laboratory.
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9.4.14.6 BMAs 
Central Laboratory Evaluations
BMAs will be taken during the screening period and at the beginning of designated study visits at 
Cycles 2, 4, 7, and at Cycle 13, with some aspirate samples sent for central analysis (note 
Table 9.g).
Local Laboratory Evaluations
Disease Assessment
A BMA will be obtained at screening for disease assessment (if a standard BMA was drawn within 
5 weeks before consent, that BMA can be used as baseline and does not need to be repeated as part 
of screening unless cytogenetic evaluation is not available). A BMA will also be obtained at any 
time to assess CR or as needed to investigate suspected PD. Requirements for BMA assessments to 
confirm disease responses are defined above and will be analyzed locally (see Section 9.4.14). 
Cytogenetics
Patients who do not have historically documented cytogenetic results for the high-risk 
abnormalities of del (17), t(4:14), and t(14:16) will have cytogenetic evaluation performed on the 
BMA sample at screening. Cytogenetic evaluation may be performed using fluorescence in situ 
hybridization or conventional cytogenetics (karyotype). At a minimum, cytogenetic markers must 
include the 3 high-risk abnormalities of del(17), t(4:14), and t(14:16). Additional abnormalities 
(ampl 1q, del13, or del1p) may also be tested. Cytogenetics will be analyzed locally, according to 
local standards.
9.4.15
, PK, 
, and Immunogenicity Samples
9.4.15.1 Primary Specimen Collection for PK, 
, and 
 Assessments
Blood samples will be collected via venipuncture or indwelling catheter at the time points detailed 
in Appendix B for the measurement of serum concentrations of TAK-079 and in Appendix A for 
. 
The primary specimen collection is presented in Table 9.g. Details on sample handling, storage, 
shipment, and analysis are provided in the Laboratory Manual.
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Patients will be followed every 12 weeks for OS until death, loss to follow-up, consent withdrawal, 
or study termination.
It is anticipated that the duration of the study will be approximately 42 months (3.5 years).
9.7
Discontinuation of Treatment With Study Drug and Patient Replacement
Study drug must be permanently discontinued for patients meeting any of the following criteria:

Patient experiences an AE or other medical condition that indicates to the investigator that 
continued participation is not in the best interest of the patient. 

Withdrawal by patient.

Female patient has confirmed pregnancy.
Treatment with study drug may also be discontinued for any of the following reasons:

AE/SAE.

Protocol deviation.

PD. 

Symptomatic deterioration. 

Unsatisfactory therapeutic response. 

Study terminated by sponsor.

Lost to follow-up.

Other.
Once study drug has been discontinued, all study procedures outlined for the EOT/early 
termination visit will be completed as specified in Appendix A. The primary reason for study drug 
discontinuation will be recorded on the eCRF.
Note that some patients may discontinue study drug for reasons other than PD before completing 
the full treatment course; these patients will remain in the study for posttreatment PFS assessments 
as outlined in Appendix A until PD occurs.
9.8
Withdrawal of Patients From Study
A patient may be withdrawn from the study for any of the following reasons:

Lost to follow-up.

Study terminated by sponsor.

Withdrawal by patient (mandatory immediate discontinuation of study agent).

Death. 

PD. 
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
Other.
The consequence of study withdrawal is that no new information will be collected from the 
withdrawn patient and added to the existing data or any database.
9.9
Study Compliance
Study drug will be administered only to eligible patients under the supervision of the investigator 
or identified subinvestigator(s). The appropriate study personnel will maintain records of study 
drug receipt and dispensing.
9.10
Posttreatment Follow-up Assessments (PFS and OS)
Patients who stop treatment for any reason other than progressive disease will continue to have 
progression-free follow-up visits (additional details in Section 9.6). Patients who discontinue 
study treatment for reasons other than PD will continue PFS follow-up every 4 weeks from EOT 
until the occurrence of PD, death, the start of subsequent anticancer therapy, study termination, or 
12 months after discontinuation of study treatment, whichever occurs first.
Patients who stop treatment due to PD will continue to have OS visits. Patients will be followed 
every 12 weeks for OS after documented PD until death, loss to follow-up, consent withdrawal, or 
study termination.
Survival information and death details may be collected by methods that include, but are not 
limited to, telephone, email, mail, or retrieval from online or other databases (eg, Social Security 
indexes). In addition, the start of another anticancer therapy for the disease under study will be 
collected.
See the SOE (Appendix A) for appropriate assessments during follow-up.
NOTE: All SAEs must be reported to the Takeda Global Pharmacovigilance department or 
designee. This includes deaths that the investigator considers related to study drug that occur 
during the posttreatment follow-up. Refer to Section 10.0 for details regarding definitions, 
documentation, and reporting of SAEs.
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10.0
ADVERSE EVENTS
10.1
Definitions
10.1.1 Pretreatment Event Definition
A pretreatment event is any untoward medical occurrence in a patient or subject who has signed 
informed consent to participate in a study but before administration of any study medication; it 
does not necessarily have to have a causal relationship with study participation.
10.1.2 AE Definition
AE means any untoward medical occurrence in a patient or subject administered a pharmaceutical 
product; the untoward medical occurrence does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product whether or not it is related to the medicinal product. This includes any 
newly occurring event, or a previous condition that has increased in severity or frequency since the 
administration of study drug.
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is considered 
by the investigator to be a clinically significant change from baseline.
10.1.3 SAE Definition
SAE means any untoward medical occurrence that at any dose:

Results in death.

Is life-threatening (refers to an AE in which the patient was at risk of death at the time of the 
event. It does not refer to an event which hypothetically might have caused death if it were 
more severe).

Requires inpatient hospitalization or prolongation of an existing hospitalization (see 
clarification in the paragraph in Section 10.2 on planned hospitalizations).

Results in persistent or significant disability or incapacity. (Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions).

Is a congenital anomaly/birth defect.

Is a medically important event. This refers to an AE that may not result in death, be 
immediately life threatening, or require hospitalization, but may be considered serious when, 
based on appropriate medical judgment, may jeopardize the patient, require medical or 
surgical intervention to prevent one of the outcomes listed above, or involves suspected 
transmission via a medicinal product of an infectious agent. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
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development of drug dependency or drug abuse; any organism, virus, or infectious particle 
(eg, prion protein transmitting transmissible spongiform encephalopathy), pathogenic or 
nonpathogenic, is considered an infectious agent.
In this study, intensity for each AE, including any lab abnormality, will be determined using the 
NCI CTCAE, Version 4.03, effective date 14 June 2010 [25]. Clarification should be made 
between an SAE and an AE that is considered severe in intensity (Grade 3 or 4), because the terms 
serious and severe are not synonymous. The general term severe is often used to describe the 
intensity (severity) of a specific event; the event itself, however, may be of relatively minor 
medical significance (such as a Grade 3 headache). This is not the same as serious, which is based 
on patient/event outcome or action criteria described above, and usually associated with events 
that pose a threat to a patient’s life or ability to function. A severe AE (Grade 3 or 4) does not 
necessarily need to be considered serious. For example, a white blood cell count of 1000/mm3 to 
<2000 mm3 is considered Grade 3 (severe) but may not be considered serious. Seriousness (not 
intensity) serves as a guide for defining regulatory reporting obligations.
10.2
Procedures for Recording and Reporting AEs and SAEs
All AEs spontaneously reported by the patient and/or in response to an open question from study 
personnel or revealed by observation, physical examination, or other diagnostic procedures will be 
recorded on the appropriate page of the eCRF (see Section 10.3 for the period of observation). Any 
clinically relevant deterioration in laboratory assessments or other clinical finding is considered an 
AE. When possible, signs and symptoms indicating a common underlying pathology should be 
noted as 1 comprehensive event.
Regardless of causality, SAEs and serious pretreatment events (as defined in Section 10.1) must be 
reported (see Section 10.3 for the period of observation) by the investigator to the Takeda Global 
Pharmacovigilance department or designee (contact information provided below). This should be 
done by faxing the SAE Form within 24 hours after becoming aware of the event. The SAE Form, 
created specifically by Takeda, will be provided to each clinical study site. A sample of the SAE 
Form may be found in the Study Manual. Follow-up information on the SAE or serious 
pretreatment event may be requested by Takeda. SAE report information must be consistent with 
the data provided on the eCRF.
SAE Reporting Contact Information
Cognizant
United States and Canada
Toll-free fax #: 1-800-963-6290
E-mail: takedaoncocases@cognizant.com
Planned hospital admissions or surgical procedures for an illness or disease that existed before 
study drug was given are not to be considered AEs unless the condition deteriorated in an 
unexpected manner during the trial (eg, surgery was performed earlier or later than planned).
For both serious and nonserious AEs, the investigator must determine both the severity (toxicity 
grade) of the event and the relationship of the event to study drug administration. For serious 
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pretreatment events, the investigator must determine both the severity (toxicity grade) of the event 
and the causality of the event in relation to study procedures.
Severity (toxicity grade) for each AE, including any lab abnormality, will be determined using the 
NCI CTCAE, version 4.03, effective date 14 June 2010 [25]. The criteria are provided in the Study 
Manual.
Relationship of the event to study drug administration (ie, its causality) will be determined by the 
investigator responding yes (related) or no (unrelated) to this question: “Is there a reasonable 
possibility that the AE is associated with the study drug?”
10.3
Monitoring of AEs and Period of Observation
AEs, both nonserious and serious, will be monitored throughout the study as follows:
AEs will be reported from the signing of informed consent through 30 days after administration of 
the last dose of study drug and recorded in the eCRFs. AEs ongoing at EOT should be monitored 
until they are resolved, return to baseline, are clearly determined to be due to a patient’s stable or 
chronic condition or intercurrent illness(es), the start of next-line subsequent anticancer therapy, or 
6 months after PD has occurred, whichever comes first.
SAEs:

Serious pretreatment events will be reported to the Takeda Global Pharmacovigilance 
department or designee from the time of the signing of the ICF up to the first dose of study 
drug, and will also be recorded in the eCRF.

Related and unrelated treatment-emergent SAEs will be reported to the Takeda Global 
Pharmacovigilance department or designee from the first dose of study drug through 30 days 
after administration of the last dose of study drug and recorded in the eCRF. After this period, 
only related SAEs must be reported to the Takeda Global Pharmacovigilance department or 
designee. SAEs should be monitored until they are resolved or are clearly determined to be 
caused by a patient’s stable or chronic condition or intercurrent illness(es).
10.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events
If a woman becomes pregnant or suspects that she is pregnant while participating in this study, she 
must inform the investigator immediately and permanently discontinue study drug. The sponsor 
must also be contacted immediately by faxing a completed Pregnancy Form to the Takeda Global 
Pharmacovigilance department or designee (see Section 10.2). The pregnancy must be followed 
for the final pregnancy outcome.
If a female partner of a male patient becomes pregnant during the male patient’s participation in 
this study, the sponsor must also be contacted immediately by faxing a completed Pregnancy Form 
to the Takeda Global Pharmacovigilance department or designee (see Section 10.2). Every effort 
should be made to follow the pregnancy for the final pregnancy outcome.
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10.5
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose)
A product complaint is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product. Individuals who 
identify a potential product complaint situation should immediately report this via the phone 
numbers or email addresses provided below.
A medication error is a preventable event that involves an identifiable patient and that leads to 
inappropriate medication use, which may result in patient harm. Whereas overdoses and 
underdoses constitute medication errors, doses missed inadvertently by a patient do not. 
Individuals who identify a potential medication error (including overdose) situation should 
immediately report this via the phone numbers or email addresses provided below.
Product
Call Center
Phone Number
E-mail
Fax
TAK-079
DLSS
1-844-662-8532 
Non-toll-free 
number: 
1-510-740-1273 
GlobalOncologyMedinfo@takeda.com 
1-800-881-6092
Product complaints in and of themselves are not AEs. If a product complaint results in an SAE, an 
SAE Form should be completed and sent to Cognizant (refer to Section 10.2)
10.6
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, investigators, and IRBs or 
IECs as applicable, in accordance with national regulations in the countries where the study is 
conducted. Relative to the first awareness of the event by/or further provision to the sponsor or 
sponsor’s designee, SUSARs will be submitted to the regulatory authorities as an expedited report
within 7 days for fatal and life-threatening events and 15 days for other serious events, unless 
otherwise required by national regulations. The sponsor will also prepare an expedited report for 
other safety issues where these might materially alter the current benefit-risk assessment of an 
investigational medicinal product or that would be sufficient to consider changes in the 
investigational medicinal product’s administration or in the overall conduct of the trial. The 
investigational site also will forward a copy of all expedited reports to his or her IRB or IEC in 
accordance with national regulations.
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11.0
STUDY-SPECIFIC COMMITTEES
No steering committee, external data safety monitoring committee, or clinical endpoint committee 
will be used in this study.
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12.0
DATA HANDLING AND RECORDKEEPING 
The full details of procedures for data handling will be documented in the data management plan. 
If selected for coding, AEs, pretreatment events, medical history, and concurrent conditions will 
be coded using MedDRA. Drugs will be coded using the World Health Organization Drug 
Dictionary.
12.1
eCRFs 
Completed eCRFs are required for each patient who signs an ICF.
The sponsor or its designee will supply investigative sites with access to eCRFs and will make 
arrangements to train appropriate site staff in the use of the eCRF. These forms are used to transmit 
the information collected in the performance of this study to the sponsor, CRO partners, and 
regulatory authorities. Investigative sites must complete eCRFs in English.
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site.
Any change of, modification of, or addition to the data on the eCRFs should be made by the 
investigator or appropriate site personnel. Corrections to eCRFs are recorded in an audit trail that 
captures the old information, the new information, identification of the person making the 
correction, the date the correction was made, and the reason for change.
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the principal investigator must retain 
full responsibility for the accuracy and authenticity of all data entered on the eCRFs.
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The sponsor or its designee will be permitted to review the patient’s medical 
and hospital records pertinent to the study to ensure accuracy of the eCRFs. The completed eCRFs 
are the sole property of the sponsor and should not be made available in any form to third parties, 
except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the sponsor.
12.2
Record Retention
The investigator agrees to keep the records stipulated in Section 12.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating patients, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated ICFs, patient authorization forms regarding the use of 
personal health information (if separate from the ICFs), electronic copy of eCRFs, including the 
audit trail, and detailed records of drug disposition to enable evaluations or audits from regulatory 
authorities, the sponsor or its designees. Any source documentation printed on degradable thermal 
sensitive paper should be photocopied by the site and filed with the original in the patient’s chart to 
ensure long-term legibility. Furthermore, ICH E6 Section 4.9.5 requires the investigator to retain 
essential documents specified in ICH E6 (Section 8) until at least 2 years after the last approval of 
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a marketing application for a specified drug indication being investigated or, if an application is 
not approved, until at least 2 years after the investigation is discontinued and regulatory authorities 
are notified. In addition, ICH E6 Section 4.9.5 states that the study records should be retained until 
an amount of time specified by applicable regulatory requirements or for a time specified in the 
Clinical Study Site Agreement between the investigator and sponsor.
Refer to the Clinical Study Site Agreement for the sponsor’s requirements on record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of any 
such documents.
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summarized. The effect of immunogenicity on PK, safety, and efficacy will be examined. NABs 
may also be assessed in patients.
The immunogenicity of TAK-079 will be assessed by determining anti–TAK-079 antibody 
incidence and characteristics (eg, titer, transiently, and persistently ADA; and possible 
neutralizing activity). Analysis will be based on available data from patients with a baseline 
assessment and at least 1 postbaseline immunogenicity assessment. Summaries will be provided 
separately for each study phase and by dose, as applicable. The incidence of immunogenicity will 
be calculated. The impact of anti–TAK-079 antibodies on the PK profile, drug efficacy, and 
clinical safety will be evaluated, if possible.
13.1.7 Safety Analysis
The safety and tolerability of TAK-079 will be assessed by the recording and analysis of TEAEs 
(NCI CTCAE version 4.03; [25]), vital signs, physical examination, serum chemistry and 
hematology, urinalysis, ECG, and concomitant medications.
TEAEs will be summarized using the safety analysis set and will be coded using the MedDRA. 
Data will be summarized using PT and primary SOC.
In the phase 2a portion of this study, Grade 4 or higher nonhematological toxicity will be monitored 
starting from the first 10 enrolled patients and then every 10 patients. If the stopping bounds of ≥4/10 
and ≥6/20 have been reached, accrual to the study will be suspended to allow for investigation. After 
consideration by the study team, a decision will be made as to whether accrual can be resumed. The 
bounds are based on a Bayesian strategy to monitor outcomes in clinical trials. If the stopping rule is 
met, there is 80% probability that the true toxicity rate is greater than 18% with a prior beta distribution 
with parameters 0.4 and 1.6 for the binomially distributed toxicity rate [32].
13.2
Interim Analysis and Criteria for Early Termination
No interim analysis is planned.
13.3
Determination of Sample Size
It is expected that approximately 100 patients will be enrolled in total for phase 1 and 2a combined. 
Once the RP2D is determined in phase 1, approximately 48 patients will be treated in phase 2a to 
provide a preliminary estimate of the ORR in patients with RRMM.
A 3+3 dose escalation schema will be used for dose escalation as described in Section 8.3.2.
A group of 3 to 6 patients will be enrolled in each TAK-079 dose cohort based on safety, clinical, 
PK, 
 data. Each patient will participate in only 1 dose cohort. The actual 
dose levels may be adjusted based on the observed safety profile. 
Additional patients may be enrolled in a limited cohort expansion to confirm the safety and 
 before the phase 2a of this study is opened to enrollment. In the 
phase 1 dose Confirmatory Cohort, approximately 18 patients will be enrolled at 1 dose and 
schedule: 12 patients with RRMM that is anti-CD38 naive and up to 6 patients with RRMM that is 
refractory to an anti-CD38 therapy. In the Combination Cohort, approximately 18 patients with 
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RRMM that has been previously treated with at least 2 prior therapies and that is refractory to the 
last therapy will be enrolled. 
In phase 2a, up to a total of 48 patients will be treated to provide a preliminary estimate of the ORR 
in 2 expansion cohorts of patients with RRMM: up to 24 patients with RRMM that is anti-CD38 
naive and up to 24 patients with RRMM that is refractory to an anti-CD38 therapy. Phase 2a of the 
study will also provide a more robust estimate of the safety profile to determine whether the MTD 
is appropriate for future studies as the RP2D.
No prospective calculations of statistical power have been made; however, Table 13.a shows the 
width of the 80% CI, based on the observed ORR in a cohort size of 24 patients, for a range of 
observed response rates. 
Table 13.a
80% Confidence Interval Based on the Observed ORR
N = 24 patients.
ORR: overall response rate.
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14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
Study Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and institution guarantee access to source documents by the sponsor or its 
designee (CRO) and by the IRB or IEC.
All aspects of the study and its documentation will be subject to review by the sponsor or designee 
(as long as blinding is not jeopardized), including but not limited to the Investigator’s Binder, 
study medication, patient medical records, informed consent documentation, documentation of 
patient authorization to use personal health information (if separate from the ICFs), and review of 
eCRFs and associated source documents. It is important that the investigator and other study 
personnel are available during the monitoring visits and that sufficient time is devoted to the 
process.
14.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study patients. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the sponsor or 
designee (and IRB or IEC, as required) to determine the appropriate course of action. There will be 
no exemptions (a prospectively approved deviation) from the inclusion or exclusion criteria.
The site should document all protocol deviations in the patient’s source documents. In the event of 
a significant deviation, the site should notify the sponsor or its designee (and IRB or IEC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the patient, or confound interpretation of primary study 
assessment. A Protocol Deviation Form should be completed by the site and signed by the sponsor 
or designee for any significant deviation from the protocol.
14.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the FDA, the United Kingdom Medicines and Healthcare 
products Regulatory Agency, the Pharmaceuticals and Medical Devices Agency of Japan). If the 
study site is contacted for an inspection by a regulatory body, the sponsor should be notified 
immediately. The investigator and institution guarantee access for quality assurance auditors to all 
study documents as described in Section 14.1.
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15.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, patients) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct 
the study according to applicable local or regional regulatory requirements and align his or her 
conduct in accordance with the “Responsibilities of the Investigator” that are listed in Appendix C. 
The principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities.
15.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable federal/local requirements of each 
participating region. The sponsor or designee will require documentation noting all names and 
titles of members who make up the respective IRB or IEC. If any member of the IRB or IEC has 
direct participation in this study, written notification regarding his or her abstinence from voting 
must also be obtained. Those American sites unwilling to provide names and titles of all members 
due to privacy and conflict of interest concerns should instead provide a Federal Wide Assurance 
Number or comparable number assigned by the Department of Health and Human Services.
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the IB, a copy of the ICF, and if 
applicable, patient recruitment materials and/or advertisements and other documents required by 
all applicable laws and regulations, must be submitted to a central or local IRB or IEC for 
approval. The IRB’s or IEC’s written approval of the protocol and patient informed consent must 
be obtained and submitted to the sponsor or designee before commencement of the study 
(ie, before shipment of the sponsor-supplied drug or study-specific screening activity). The IRB or 
IEC approval must refer to the study by exact protocol title, number, and version date; identify 
versions of other documents (eg, ICF) reviewed; and state the approval date. The sponsor will ship 
drug the sponsor has confirmed the adequacy of site regulatory documentation and, when 
applicable, the sponsor has received permission from competent authority to begin the trial. Until 
the site receives notification, no protocol activities, including screening, may occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the ICF, recruitment 
materials intended for viewing by patients, local safety reporting requirements, reports, and 
updates regarding the ongoing review of the study at intervals specified by the respective IRB or 
IEC, and submission of the investigator’s final status report to IRB or IEC. All IRB and IEC 
approvals and relevant documentation for these items must be provided to the sponsor or its 
designee.
Subject incentives should not exert undue influence for participation. Payments to patients must be 
approved by the IRB or IEC and sponsor.
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15.2
Patient Information, Informed Consent, and Patient Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The ICF, patient authorization form (if applicable), and patient 
information sheet (if applicable) describe the planned and permitted uses, transfers, and 
disclosures of the patient’s personal and personal health information for purposes of conducting 
the study. The ICF and the patient information sheet (if applicable) further explain the nature of the 
study, its objectives, and potential risks and benefits, as well as the date informed consent are 
given. The ICF will detail the requirements of the participant and the fact that he or she is free to 
withdraw at any time without giving a reason and without prejudice to his or her further medical 
care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the ICF 
and if applicable, the patient authorization form. The ICF, patient authorization form (if 
applicable), and patient information sheet (if applicable) must be approved by both the IRB or IEC 
and the sponsor prior to use.
The ICF, patient authorization form (if applicable), and patient information sheet (if applicable) 
must be written in a language fully comprehensible to the prospective patient. It is the 
responsibility of the investigator to explain the detailed elements of the ICF, patient authorization 
form (if applicable), and patient information sheet (if applicable) to the patient. Information should 
be given in both oral and written form whenever possible and in the manner deemed appropriate by 
the IRB or IEC. In the event the patient is not capable of rendering adequate written informed 
consent, then the patient’s legally acceptable representative may provide such consent for the 
patient in accordance with applicable laws and regulations.
The patient, or the patient’s legally acceptable representative, must be given ample opportunity to: 
(1) inquire about details of the study and (2) decide whether or not to participate in the study. If the 
patient, or the patient’s legally acceptable representative, determines he or she will participate in 
the study, then the ICF and patient authorization form (if applicable) must be signed and dated by 
the patient, or the patient’s legally acceptable representative, at the time of consent and prior to the 
patient entering into the study. The patient or the patient’s legally acceptable representative should 
be instructed to sign using their legal names, not nicknames, using blue or black ballpoint ink. The 
investigator must also sign and date the ICF and patient authorization (if applicable) at the time of 
consent and prior to patient entering into the study; however, the sponsor may allow a designee of 
the investigator to sign to the extent permitted by applicable law.
Once signed, the original ICF, patient authorization form (if applicable), and patient information 
sheet (if applicable) will be stored in the investigator’s site file. The investigator must document 
the date the patient signs the informed consent in the patient’s medical record. Copies of the signed 
ICF, the signed patient authorization form (if applicable), and patient information sheet (if 
applicable) shall be given to the patient.
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All revised ICFs must be reviewed and signed by relevant patients or the relevant patient’s legally 
acceptable representative in the same manner as the original informed consent. The date the 
revised consent was obtained should be recorded in the patient’s medical record, and the patient 
should receive a copy of the revised ICF.
15.3
Patient Confidentiality
The sponsor and designees affirm and uphold the principle of the patient’s right to protection 
against invasion of privacy. Throughout this study, a patient’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited patient attributes, such as sex, age, or date 
of birth, and patient initials may be used to verify the patient and accuracy of the patient’s unique 
identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, the FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the patient’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a patient’s study participation, 
and autopsy reports. Access to a patient’s original medical records requires the specific 
authorization of the patient as part of the informed consent process (see Section 15.2).
Copies of any patient source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, patient name, address, and other identifier fields 
not collected on the patient’s eCRF).
15.4
Publication, Disclosure, and Clinical Trial Registration Policy
15.4.1 Publication 
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the Clinical Study Site Agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
this section and the Clinical Study Site Agreement. In the event of any discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail.
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15.4.2 Clinical Trial Registration
To ensure that information on clinical trials reaches the public in a timely manner and to comply 
with applicable laws, regulations and guidance, Takeda will, at a minimum register interventional 
clinical trials it sponsors anywhere in the world on ClinicalTrials.gov or other publicly accessible 
websites on or before start of study, as defined in Takeda Policy/Standard. Takeda contact 
information, along with investigator’s city, state (for America’s investigators), country, and 
recruiting status will be registered and available for public viewing. 
As needed, Takeda and investigator/site contact information may be made public to support 
participant access to trials via registries. In certain situations/registries, Takeda may assist 
participants or potential participants to find a clinical trial by helping them locate trial sites closest 
to their homes by providing the investigator name, address, and phone number via email/phone or 
other methods callers requesting trial information. Once patients receive investigator contact 
information, they may call the site requesting enrollment into the trial. The investigative sites are 
encouraged to handle the trial inquiries according to their established patient screening process. If 
the caller asks additional questions beyond the topic of trial enrollment, they should be referred to 
the sponsor. 
Any investigator who objects to Takeda providing this information to callers must provide Takeda 
with a written notice requesting that their information not be listed on the registry site. 
15.4.3 Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites (including the Takeda corporate site) and registries, as required by Takeda 
Policy/Standard, applicable laws and/or regulations.
Data Sharing
The sponsor is committed to responsible sharing of clinical data with the goal of advancing 
medical science and improving patient care. Qualified independent researchers will be permitted 
to use data collected from patients during the study to conduct additional scientific research, which 
may be unrelated to the study drug or the patient’s disease. The data provided to external 
researchers will not include information that identifies patients personally. 
15.5
Insurance and Compensation for Injury
Each patient in the study must be insured in accordance with the regulations applicable to the site 
where the patient is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to clinical study patients. 
Refer to the Clinical Study Site Agreement regarding the sponsor’s policy on patient compensation 
and treatment for injury. If the investigator has questions regarding this policy, he or she should 
contact the sponsor or sponsor’s designee.
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16.0
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30. Mankarious S, Lee M, Fischer S, Pyun KH, Ochs HD, Oxelius VA, et al. The half-lives of IgG 
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Screening, Baseline, Treatment Period Cycles 1 and 2
Study Period (Phases 1 and 2a)
Screen-
ing (a)
Treatment Phase (Weekly)
Cycle 1
Cycle 2
Cycle Day
C1D1
C1D8
C1D15
C1D22
C2D1
C2D8
C2D15
C2D22
Window Allowed
±2 days
±2 days
±2 days
±2 days
±2 days
±2 days
±2 days
±2 days
Serum sample for immunogenicity 
(ADA/titer) (s)
X
X
X
Serum sample for direct and indirect Coombs 
test
X
X
X
Footnotes appear on last page of SOE tables.
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Treatment Period Continued: Cycles 7 to Follow-up and Overall Survival Follow-up
Study Period (Phases 1 and 2a)
Treatment Phase
(Monthly; Every 4 Weeks; to PD)
Follow-Up Phase
Cycle 7
Cycle 8 and beyond
EOT/Early Termination
PFS Follow-Up
Every 4 Weeks
OS 
Follow-Up 
Every 12 Weeks
Cycle Day
C7D1
C8D1, CXD1
Up to 30 days After Last 
Dose
--------
--------
Window Allowed
±2 days
±2 days
±7 days
7 days
7 days
Subsequent anticancer therapy 
X
X
Survival (u)
X
Footnotes begin on the next page.
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Appendix B
PK Sampling Schedule
PK Assessments: Cycle 1
Cycle 1
Day 1 (a)
Day 2 
Day 3
Day 4
Day 8 (a)
Day 15 (a)
Day 22 (a)
Triplicate 
ECG (b)
PK
Triplicate 
ECG (b)
PK
Triplicate 
ECG (b)
PK
Triplicate 
ECG (b)
PK
PK
PK
PK
Predose (within 1 hour before first SC 
injection)
X
X
X
X
X
5 minutes after FINAL SC injection (±2 min)
X 
(c)
4 hours after first SC injection (±30 min)
X
6 hours after first SC injection (30 min)
X
X
8 hours after first SC injection (1 hour)
X
X
24 hours after first SC injection (2 hours)
X
X
48 hours after first SC injection (2 hours)
X
X
72 hours after first SC injection (2 hours)
X
X
ECG: electrocardiogram; PK: pharmacokinetic(s); SC: subcutaneous.
When the timing of a PK or safety laboratory blood sample coincides with the timing of ECG measurements, the ECG will be completed before the collection of the blood sample. The 
triplicate ECG measurements should be completed immediately before the corresponding PK blood draw. 
(a) The timing of the morning visits should occur at approximately the same time as the morning SC administration times on previous days of the cycle.
(b) Collection of triplicate ECGs should begin after the patient has rested in supine position for approximately 5 minutes. Each ECG recording of the triplicate ECGs should occur 
within 3 minutes of each other and over a 10-minute window.
(c) If multiple SC injections are required to administer the intended dose, this PK sample should be collected after administration of the final injection. All other assessments should 
be performed in reference to the first injection.
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PK Assessments: Cycle 2
Cycle 2
Day 1 (a)
Day 2 
Day 3
Day 4
Day 8 (a)
Day 15 (a)
Day 22 (a)
Triplicate 
ECG (b)
PK
Triplicate 
ECG (b)
PK
Triplicate 
ECG (b)
PK
Triplicate 
ECG (b)
PK
PK
PK
PK
Predose (within 1 hour before first SC 
injection)
X
X
X
X
X
5 minutes after FINAL SC injection (±2 min)
X 
(c)
4 hours after first SC injection (±30 min)
X
6 hours after first SC injection (30 min)
X
X
8 hours after first SC injection (1 hour)
X
X
24 hours after first SC injection (2 hours)
X
X
48 hours after first SC injection (2 hours)
X
X
72 hours after first SC injection (2 hours)
X
X
ECG: electrocardiogram; PK: pharmacokinetic(s); SC: subcutaneous.
When the timing of a PK or safety laboratory blood sample coincides with the timing of ECG measurements, the ECG will be completed before the collection of the blood sample. The 
triplicate ECG measurements should be completed immediately before the corresponding PK blood draw. 
(a) The timing of the morning visits should occur at approximately the same time as the morning SC administration times on previous days of the cycle.
(b) Collection of triplicate ECGs should begin after the patient has rested in supine position for approximately 5 minutes. Each ECG recording of the triplicate ECGs should occur 
within 3 minutes of each other and over a 10-minute window.
(c) If multiple SC injections are required to administer the intended dose, this PK sample should be collected after administration of the final injection. All other assessments should 
be performed in reference to the first injection.
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PK Assessments: Cycle 3 to Cycle 10
Cycle 3 to Cycle 6
Cycle 7 to Cycle 10 
Day 1 (a)
Day 15 (a)
Day 1 (a)
Predose (within 1 hour before first SC 
injection)
X
X
X
PK: pharmacokinetic; SC: subcutaneous.
(a) The timing of the morning visits should occur at approximately the same time as the morning SC administration times on previous days of the cycle.
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Appendix C
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. 
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on investigators by the FDA are 
summarized in the “Statement of Investigator” (Form FDA 1572), which must be completed and 
signed before the investigator may participate in this study.
The investigator agrees to assume the following responsibilities by signing a Form FDA 1572:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff that will assist in the protocol.
3. Ensure that study-related procedures, including study-specific (nonroutine/nonstandard panel) 
screening assessments are NOT performed on potential patients, prior to the receipt of written 
approval from relevant governing bodies/authorities.
4. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
5. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to 
21 CFR Part 56, ICH, and local regulatory requirements.
6. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to patients. Make at least yearly reports on the progress of the study to the 
IRB/IEC, and issue a final report within 3 months of study completion.
7. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH and local 
regulations, are met.
8. Obtain valid informed consent from each patient who participates in the study, and document 
the date of consent in the patient’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each ICF should contain a patient authorization section that 
describes the uses and disclosures of a patient’s personal information (including personal 
health information) that will take place in connection with the study. If an ICF does not include 
such a patient authorization, then the investigator must obtain a separate patient authorization 
form from each patient or the patient’s legally acceptable representative.
9. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents.
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10. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
11. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor.
12. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.
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Appendix D
Investigator Consent to Use of Personal Information
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, United States, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study medication.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s own 
country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.
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Appendix E
IMWG Criteria 
IMWG Definition of MM [21,22,33]

Clonal bone marrow plasma cells ≥10%* or biopsy-proven bony or extramedullary 
plasmacytoma* and any one or more of the following myeloma-deﬁning events:
–
Evidence of end organ damage that can be attributed to the underlying plasma cell 
proliferative disorder, specifically.
–
Hypercalcemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than the upper limit of 
the normal range or >2.75 mmol/L (>11 mg/dL).
–
Renal insuﬃciency: creatinine clearance <40 mL per min† or serum creatinine 
>177 μmol/L (>2 mg/dL).
–
Anemia: hemoglobin value of >20 g/L below the lower limit of normal, or a hemoglobin 
value <100 g/L.
–
Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CT‡.

Any one or more of the following biomarkers of malignancy:
–
Clonal bone marrow plasma cell percentage* ≥60%.
–
Involved: uninvolved serum free light chain ratio§ (FLC) ≥100.
–
>1 focal lesions on MRI studies.
* Clonality should be established by showing κλ light-chain restriction on ﬂow cytometry, immunohistochemistry, or 
immunoﬂuorescence. Bone marrow plasma cell percentage should preferably be estimated from a core biopsy 
specimen; in case of a disparity between the aspirate and core biopsy, the highest value should be used.
† Measured or estimated by validated equations.
‡ If bone marrow has less than 10% clonal plasma cells, more than 1 bone lesion is required to distinguish from 
solitary plasmacytoma with minimal marrow involvement.
§ These values are based on the serum Freelite assay (The Binding Site Group, Birmingham, United Kingdom). The 
involved FLC must be ≥100 mg/L. Each focal lesion must be 5 mm or greater in size [33].
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IMWG Uniform Criteria for Response [21,22,33]
Category of 
Response
Response Criteria
sCR
Criteria for CR as defined below, with the addition of a normal FLC ratio, and an absence of clonal plasma 
cells by immunohistochemistry or 2- to 4-color flow cytometry; 2 consecutive assessments of laboratory 
parameters are needed (a).
CR
Negative immunofixation of serum and urine, disappearance of any soft tissue plasmacytomas, and <5% 
plasma cells in bone marrow; bone marrow; in patients for whom only measurable disease is by serum 
FLC level, normal FLC ratio of 0.26 to 1.65 in addition to CR criteria is required; 2 consecutive 
assessments are needed (b).
Immunophenotypic 
CR
sCR as defined, plus absence of phenotypically aberrant plasma cells (clonal) in bone marrow with 
minimum of 1 million total bone marrow cells analyzed by multiparametric ﬂow cytometry (with 
>4 colors).
Molecular CR
CR as deﬁned, plus negative allele-speciﬁc oligonucleotide polymerase chain reaction (sensitivity 10-5).
VGPR
Serum and urine M-protein detectable by immunofixation but not on electrophoresis, or ≥90% reduction 
in serum M-protein plus urine M-protein <100 mg/24 hours; in patients for whom only measurable 
disease is by serum FLC level, >90% decrease in difference between involved and uninvolved FLC levels, 
in addition to VGPR criteria, is required; 2 consecutive assessments are needed (c).
PR
≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to 
<200 mg/24 hours.
If the serum and urine M-protein are not measurable, a ≥50% decrease in the difference between involved 
and uninvolved FLC levels is required in place of the M-protein criteria.
If serum and urine M-protein are not measurable, and serum FLC is also not measurable, ≥50% reduction 
in bone marrow plasma cells is required in place of M-protein, provided the baseline percentage was 
≥30%.
In addition to the above criteria, if present at baseline, ≥50% reduction in the size of soft tissue 
plasmacytomas is also required.
Two consecutive assessments are needed (a) no known evidence of progressive or new bone lesions if 
radiographic studies were performed.
Minimal response 
(MR) (b)
≥25% but ≤49% reduction of serum M-protein and reduction in 24-hour urine M-protein by 50% to 89%.
In addition to the above criteria, if present at baseline, 25% to 49% reduction in the size of soft tissue 
plasmacytomas is also required.
No increase in size or number of lytic bone lesions (development of compression fracture does not exclude 
response).
In this study, in patients that have myeloma measurable by serum free light chains, MR will be defined as 
a reduction of ≥25 but ≤49% in the difference between involved and uninvolved FLC levels.
SD (c)
Does not meet the response criteria for CR (any variant), VGPR, PR, MR, or PD; no known evidence of 
progressive or new bone lesions if radiographic studies were performed.
Source: Rajkumar SV et al, 2011 and Palumbo A et al, 2014 [21,22]
CR: complete response; FLC: free light chain; IMWG: International Myeloma Working Group; MR minimal response; ORR: 
overall response rate; PR: partial response; sCR: stringent complete response; SD: stable disease; VGPR: very good partial 
response.
(a) Clonality should be established by showing κλ light-chain restriction on ﬂow cytometry, immunohistochemistry, or 
immunoﬂuorescence. Bone marrow plasma cell percentage should preferably be estimated from a core biopsy specimen; in case of 
a disparity between the aspirate and core biopsy, the highest value should be used.
(b) For relapse-refractory myeloma only.
(c) These categories do not contribute to the ORR.
Before the institution of any new therapy, sCR, CR, and VGPR categories require serum and urine 
studies regardless of whether disease at baseline was measurable on serum, urine, both, or neither. 
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Radiographic studies are not required to satisfy these response requirements. Bone marrow 
assessments need not be conﬁrmed.
PD is defined as an increase of ≥25% from lowest response value in any of the following:
a) Serum M-protein (absolute increase must be ≥0.5 g/dL); serum M component increases 
≥1 g/dL are sufficient to deﬁne relapse if starting M component is ≥5 g/dL), and/or
b) Urine M-protein (absolute increase must be ≥200 mg/24 hour), and/or
c) Only in patients without measurable serum and urine M-protein levels: the difference between 
involved and uninvolved FLC levels (absolute increase must be >10 mg/dL).
d) Only in patients without measurable serum and urine M-protein levels and without measurable 
disease by FLC levels, bone marrow plasma cell percentage (absolute percentage must be 
≥10%).
OR
a) Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in 
the size of existing bone lesions or soft tissue plasmacytomas.
b) Development of hypercalcemia (corrected serum calcium >11.5 mg/dL) that can be attributed 
solely to the plasma cell proliferative disorder.
A diagnosis of PD must be confirmed by 2 consecutive assessments.
Clarifications to IMWG criteria for coding PD: Bone marrow criteria for PD are to be used only in 
patients without measurable disease by M-protein and by FLC levels; “25% increase” refers to 
M-protein, FLC, and bone marrow results, and does not refer to bone lesions, soft tissue 
plasmacytomas, or hypercalcemia, and the “lowest response value” does not need to be a 
confirmed value.
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Appendix F
ECOG Scale for Performance Status
Grade
Description
0
Normal activity. Fully active, able to carry on all predisease performance without restriction.
1
Symptoms but ambulatory. Restricted in physically strenuous activity, but ambulatory and able to 
carry out work of a light or sedentary nature (eg, light housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, but unable to carry out any work 
activities. Up and about more than 50% of waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair.
5
Dead.
Source: Oken et al,1982 [24]
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Appendix G
Detailed Description of Amendments to Text
All changes made in the protocol, other than typographical and formatting changes, are listed 
below in the order they appear in the protocol. Changes are listed by sections, only the sections 
with modifications are listed and only the paragraphs containing changes within the section are 
represented. All changes made in the body of the protocol are also reflected in the Study Summary.
Changes to the Study Summary are not listed here.
Note: All deletions have been identified by strikethrough.
All revisions have been identified as bold red text.
All moved text has been identified as underlined green text and the previous location is 
identified as green strikethrough
REVISED PROTOCOL SECTIONS
3.1
List of Abbreviations
Abbreviation
Term
AML
acute myeloid leukemia
POEMS 
syndrome
polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes
syndrome
PomDex
pomalidomide in combination with dexamethasone
PT
Preferred Term
REMS
Risk Evaluation and Mitigation Strategy
SOC
System Organ Class
SOE
Scheduleschedule of Eventsevents
4.0
INTRODUCTION
4.2.2
Preliminary Findings From the Dose Escalation Period of This Study
As of 05 March 2018, 19 patients have been enrolled through the first 4 dose planned cohorts 
(45, 135, 300, and 600 mg). In this ongoing study, the most common (in >2 patients) 
treatment-emergent AEs by Medical Dictionary for Regulatory Activities (MedDRA)
Preferred Term (PT) regardless of causality in the total population as of 05 March 2018 are 
anaemia (n = 5 patients, insomnia, headache, and hypertension (n = 4 patients each), and 
upper respiratory tract infection, fatigue, and decreased appetite (n = 3 patients each). All 
AEs have been Grade 1 or 2; 2 events were reported as drug-related Grade 3 AEs (decreased 
neutrophil count and anemia [in 1 patient each] both of which were transient. No patient 
experienced dose-limiting toxicities (DLTs), injection site reactions, discontinued TAK-079 
due to TEAEs, or died on-study; 2 patients experienced SAEs, none were reported as 
treatment related (1 event was pretreatment). No patient has been demonstrated to have had 
CRS symptoms; 1 patient in the 135 mg cohort did report transient facial flushing Cycle 2 
Day 1, which the investigator reported as drug related. 
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In the original phase 1 dose Escalation Cohorts, TAK-079 was given weekly for 8 weeks 
during Cycles 1 and 2 (8 doses), every other week during Cycles 3 to 6 (8 doses), and then 
once every 4 weeks until PD. Based on a review of available clinical activity, PK, and 
pharmacodynamic findings, the dose of TAK-079 as monotherapy in the Confirmation 
Cohort and when added to PomDex in the Combination Cohort will be 300 mg in the same 
schedule as follows: 
Confirmation Cohort: TAK-079 will be given weekly for 8 weeks during Cycles 1 and 2 (8 
doses), every other week during Cycles 3 to 6 (8 doses), and then once every 4 weeks until PD 
in subsequent cycles.
Combination Cohort: TAK-079 will be given weekly for 8 weeks during Cycles 1 and 2 (8 
doses), every other week during Cycles 3 to 6 (8 doses), and then once every 4 weeks until PD 
in subsequent cycles with PomDex given according to product information (Pomalyst USPI, 
including Section 14.1). 
4.3
Known and Potential Benefits and Risks to Patients withWith TAK-079
…..
TAK-079 has now been administered to patients with advanced RRMM (TAK-079-1501; 
this study). Only mild or moderate (Grade 1 or 2) TEAEs were observed as described above. 
…..
4.3.1
Potential Risks
Based on the mechanism of action of TAK-079, potential AEs may include infusion or injection 
site reactions, CRS, hematological effects, and infections.
4.3.1.1 Infusion and Injection Site Reactions
….
In this study (TAK-079-1501) in patients with RRMM at doses up to 600 mg (given with 3 
SC injections), no injection site reactions have been reported. 
…..
4.3.1.2 Cytokine Release Syndrome
…..
In the FIH study conducted in healthy human subjects, rarely-observed symptoms consistent with 
mild CRS were reported particularly at higher doses, and they did not require dose adjustment or 
interruption. In this study (TAK-079-1501) in patients with RRMM at doses up to 600 mg, 1 
transient event on Cycle 2 Day 1 of drug-related flushing in a single patient in the 135 mg 
cohort could conservatively be a symptom of a systemic infusion reaction; however, no other 
symptoms have been reported in this or other patients. 
….
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4.3.1.3 Hematologic Effects
Reductions in platelets, lymphocytes, and RBCs occurred in nonclinical studies in some animals 
administered doses of TAK-079 higher than the NOAEL of 0.3 mg/kg. The NOAEL was based 
on occurrence of thrombocytopenia in 1 of 14 monkeys and is believed to be species specific. 
In the TAK-079 FIH (TAK-079_101) and RRMM (this study TAK-079-1501) at doses up to 
600 mg, no decrease in platelet counts below the lower limit of normal related to TAK-079 
were seen (note 1 event of grade 3 thrombocytopenia was reported as related to progression 
of the underlying advanced myeloma in study TAK-079-1501). 
…
4.3.1.4 Infections
…
In the TAK-079 FIH study, mild infections, specifically nasopharyngitis was reported. In the 
study in patients with RRMM (TAK-079-1501, this study), 4 of 19 patients treated at doses 
up to 600 mg reported an AE in the infection and infestation MedDRA System Organ Class 
(SOC); the most common AE reported was upper respiratory infection (n = 3); all were 
grade 2 and only 1 was reported as related to study drug.
…
4.3.2
Overall Benefit and Risk Assessment for This Study
…
The emerging preliminary safety profile, as detailed above and in the current Investigator 
Brochure, indicate that TAK-079 is generally well tolerated with manageable and reversible 
AEs. The potential toxicities can be managed by clinical monitoring and standard medical 
interventions. It is possible that TAK-079 will have toxicities that were not predicted from 
its evaluation in nonclinical studies or previously observed in ongoing clinical studies. To 
mitigate the inherent risks in clinical studies of TAK-079, patients will be carefully 
monitored closely for signs and symptoms of systemic and injection site reactions with 
appropriate management of these events. Guidance for the management of AEs are 
provided in Section 8.11. Depending on the severity of the reaction, drug dosage can be 
reduced by dose modification (holding or delaying) of the scheduled treatment within a cycle 
as provided in Section 8.6, and may include discontinuation of TAK-079.
In patients with advanced RRMM, TAK-079 has shown early signs of antitumor activity as 
evidenced by at least 50% reduction in disease burden in some patients and prolonged 
disease stabilization in others. Though additional data are needed to characterize the clinical 
benefit of this drug, the emerging data supports the ongoing development of TAK-079.
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4.4.1
Rationale for the Starting Dose of TAK-079
…..
The dose used in the Confirmation Cohort and the Combination Cohorts is the expected 
RP2D from the dose Escalation Cohorts, based on preliminary PK and PD results from the 
dose Escalation Cohort.
Relevant to the Combination Cohort, lenalidomide is established therapy in NDMM [17,18] 
therefore patients for whom lenalidomide is no longer a treatment option, because of 
previous exposure, intolerance, or are refractory to lenalidomide, represent a clinically 
relevant population with unmet need. Nonclinical studies demonstrate that pomalidomide 
inhibits proliferation of lenalidomide-resistant cells [19]. Clinically, PomDex, an all oral 
regimen, is approved for patients who have previously received lenalidomide [20]. Adding 
an anti-CD38 monoclonal antibody to it, especially one that is given SC, could be beneficial 
and convenient to patients as compared with IV administered anti-CD38 monoclonal 
antibodies. PomDex will be given at the dose and schedule recommended in the product 
information (Pomalyst USPI including Section 14.1) while TAK-079 will be given at the 
RP2D in the revised schedule described in Section 6.1.
5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives 
5.1.1
Primary Objectives
Phase 1
The primary objective of the phase 1 portion of the study is to determine the safety and tolerability 
of TAK-079 monotherapy and when combined with a backbone regimen of PomDex in 
patients with RRMM.
…
5.1.2
Secondary Objectives
Phase 1
The Phasephase 1 secondary objectives are:

To investigate a potential MTD/RP2D of TAK-079.079 as a single agent and when added to 
a backbone regimen of PomDex. 

To evaluate the immunogenicity of TAK-079.079 as a single agent and when added to a 
backbone regimen of PomDex.

To characterize the PK of TAK-079.079 as a single agent and when added to a backbone 
regimen of PomDex.

To provide a preliminary evaluation of the clinical activity of TAK-079.079 as a single agent 
and when added to a backbone regimen of PomDex.
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…..
5.2.3
Phase 1 Secondary Endpoints
The secondary endpoints for phase 1 are: 

RP2D based on both safety and efficacy outcomes as a single agent and when added to a 
backbone regimen of PomDex.

Summary statistics for the following PK parameters as a single agent and when added to a 
backbone regimen of PomDex:
Maximum observed concentration (Cmax).
Time of first occurrence of Cmax (tmax).
Area under the concentration-time curve from time 0 to the time of the last quantifiable 
concentration (AUClast).

Preliminary evaluation of antitumor activity of TAK-079079, as single agent and in 
combination with PomDex, will be assessed for patients with MM by measuring:
ORR, defined as the proportion of patients who achieved a PR (50% tumor reduction) or 
better during the study as defined by the IMWG Uniform Response Criteria ([17,1821,22]; 
Appendix E).
Proportion of patients who achieved a minimal response (MR), defined as 25% tumor 
reduction ([17,18, including in patients with disease measurable by serum free light 
chains (FLCs) ([21,22]; Appendix E).

Anti–TAK-079 antibody incidence and characteristics.
5.2.4
Phase 2a Secondary Endpoints
The secondary endpoints for phase 2a are:

DLT-like frequencies and other TEAEs occurring over the course of extended treatment with 
TAK-079, including information about dose modification, treatment discontinuation, and vital 
signs.

Summary statistics for the following PK parameters: Cmax, tmax, and AUClast.

Anti–TAK-079 antibody incidence and characteristics.

Proportion of patients who achieved MR, defined as 25% tumor reduction.

Duration of response (DOR), defined as the time from the date of the first documentation of 
response to the date of the first documented PD.

Progression-free survival (PFS), defined as the time from the date of the first dose until the 
earliest date of PD, defined by IMWG criteria, or the date of death due to any cause 
([17,1821,22]; Appendix E). 
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
Overall survival (OS), defined as the time from the date of first dose to the date of death due 
to any cause.

Time to response (TTR), defined as the time from the date of the first dose to the date of the 
first documentation of response (PR or better).
6.0
STUDY DESIGN
6.1
Overview of Study Design
...
The phase 1 portion of the study will evaluate administration of single agent TAK-079 for DLT(s) 
to determine the MTD/RP2D for further assessment in phase 2a. A recommended dose below the 
MTD may be identified based on safety, clinical, PK, 
 data. The safety and 
tolerability of TAK-079 will be assessed by recording and analyzing TEAEs from medical review 
of vital signs, physical examinations, serum chemistry and hematology analyses, urinalyses, 
ECGs, review of concomitant medications, dose modifications, and treatment discontinuations.
MM is a heterogenous disease requiring treatments across multiple lines of therapy despite 
recent advances. The pace of MM treatment has been rapid in recent years and even with a 
shift towards triplet regimens from doublet regimens, patients are still relapsing from, 
ineligible for, or intolerant to such combinations. Further the treatment paradigm is 
fragmented due to patient factors as well as disease factors and acceptance of recently 
approved regimens is gaining but remains variable. Therefore, this study will continue to 
evaluate patients with relapsed or refractory disease, including those who have not 
progressed following daratumumab, in an effort to more fully understand the activity of 
TAK-079 in patients who represent the highly heterogeneous population seen in current 
clinical practice. Before enrolling into the phase 2a phase of the study, additional patients 
will be enrolled in a dose Confirmatory Cohort to better understand the safety and clinical 
activity of the TAK-079 RP2D based on preliminary PK/
 data. 
More patients now receive combinations of lenalidomide, bortezomib, dexamethasone with 
or without daratumumab as first-line treatment, yet their disease still progresses. Most 
develop lenalidomide-resistant disease; thus, alternatives to lenalidomide are required in 
later lines of therapy. Pomalidomide with dexamethasone is approved for patients following 
therapy with lenalidomide and a proteasome inhibitor; however, the duration of response is 
short (7.4 months) [20]. Evidence is emerging that adding an IV administered anti-CD38 
agent to PomDex can help prolong response duration [23]. TAK-079, a SC administered 
anti-CD38 monoclonal antibody, is showing early signs of antimyeloma activity as a 
monotherapy in patients with advanced RRMM. Adding TAK-079 to the PomDex backbone 
could provide benefit to patients both in terms of improved antimyeloma activity over each 
agent alone, and would be more convenient to patients as compared with administration of 
IV administered anti-CD38 agents (ie, a TAK-079, a SC agent, added to the all oral PomDex 
regimen). Hence a new cohort will open to evaluate this combination. Information about the 
dose, safety, and activity of TAK-079 added to a standard backbone regimen of PomDex in 
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patients with RRMM who have received at least 2 prior therapies and have demonstrated 
PD on or within 60 days of the completion of the last therapy will be collected. 
The preliminary efficacy of TAK-079079, as monotherapy and when added to PomDex, will be 
evaluated by measuring the ORR, defined as the proportion of patients who achieved a PR or 
better during study, as defined by IMWG (Appendix E; [17,1821,22]). In addition, the efficacy of 
TAK-079 will be assessed by measuring MR, PFS, DOR, and OS; TTR will also be measured. 
Once enrolled into the studyphase 1 Dose Escalation phase, patients will receive TAK-079 via 
SC administration in each 28-day cycle of treatment, administered as once weekly for 8 weeks (8 
doses), once every 2 weeks for 16 weeks (8 doses), and once every 4 weeks thereafter until PD. 
Patients will receive ongoing treatment with TAK-079 until they experience PD, unacceptable 
toxicities, or withdrawalwithdraw due to other reasons (see Section 6.3). 
In the phase 1 Confirmation Cohort Phase, patients will receive TAK-079 via SC 
administration in each 28-day cycle of treatment, administered at a dose of 300 mg once 
weekly for 8 weeks (8 doses), once every 2 weeks for 16 weeks (8 doses), and then once every 
4 weeks thereafter until PD.

In this cohort, up to 6 patients that are refractory to an anti-CD38 agent will be enrolled.

Further in this cohort, approximately 12 patients that have RRMM disease (per prior 
therapy inclusion criteria Section 7.0) and are naïve to an anti-CD38 agent will be 
enrolled.
In the Combination Cohort, patients will receive TAK-079 via SC administration in each 
28-day cycle of treatment, administered at a dose of 300 mg once weekly for 8 weeks (8 
doses), once every 2 weeks for 16 weeks (8 doses), and then once every 4 weeks thereafter 
until PD. PomDex will be administered according to the product labeling (Pomalyst UPSI, 
including Section 14.1).

In this cohort, up to 6 patients will initially be enrolled. Safety in Cycle 1 will be 
reviewed in accordance with DLT definitions in Section 8.2.

If 0 of 6 or 1 of 6 patients develop a DLT an additional 12 patients will be tested at the 
initial dose of TAK-079 [6 patients that are naïve to a prior anti-CD38 agent and 6 patients 
that have been exposed to a prior anti-CD38 agent], for an overall total of 18 patients.

If 2 of 6 patients develop DLTs all available data will be reviewed before making 
decisions about study conduct (See details in Section 8.5). 
The Confirmation Cohort and the Combination Cohort may start in parallel and will run 
independently. 
Phase 1All cohorts will consist of the following phases/periods: screening, treatment, and 
follow-up:

Screening period (visit 1): Days -21 to Day -1.

Treatment period (visit 2/ongoing): Once
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
Original dose Escalation Cohort: once-weekly treatment for 8 doses (Cycles 1 and 2), 
starting on Day 1, followed by treatment once every 2 weeks for 8 doses (Cycles 3-6), followed by 
treatment once every 4 weeks thereafter (Cycle 7 and beyond), continuing until patients 
experience PD, unacceptable toxicities, or withdrawal due to other reasons. 

Dose Confirmation Cohort: once weekly for 8 weeks in Cycles 1 and 2 (8 doses), once 
every 2 weeks for 16 weeks (8 doses) in Cycles 3 to 6, and once every 4 weeks thereafter 
(Cycles 7 and beyond) until PD.

Combination Cohort: once weekly for 8 weeks in Cycles 1 and 2 (8 doses), once every 
2 weeks for 16 weeks (8 doses) in Cycles 3 to 6, and once every 4 weeks thereafter (Cycles 7 
and beyond) until PD. PomDex will be administered according to the product labeling 
(Pomalyst UPSI, including Section 14.1 describing dexamethasone dosing).

Follow-up period (end of treatment [EOT] visit): Patients who discontinue study 
treatment will be followed for approximately 30 days after the last dose of study drug or until 
the start of subsequent alternative anticancer therapy to monitor safety/AEs. Patients who 
discontinue treatment for reasons other than PD will continue to be followed for PFS every 4 
weeks from the EOT visit until PD, death, the start of subsequent anticancer therapy, study 
termination, or 12 months after discontinuation of study treatment, whichever occurs first. 
Patients who discontinue for PD will be followed for OS after the EOT visit. All patients will 
be followed for OS every 12 weeks until death, loss to follow-up, consent withdrawal, or study 
termination.
In phase 1, approximately 6 doses will be evaluated in ascending cohorts of 3 to 6 patients per 
cohort. Cohorts may be expanded by enrolling additional patients to further inform selection of the 
RP2D. Dose selection for phase 2a will take place after review of the available safety, efficacy, 
PK, 
 data obtained from the phase 1 portion of the study.
In the phase 1 dose Confirmatory Cohort, approximately 18 patients will be enrolled at 1 
dose (300 mg); 12 patients will have been previously treated (see Section 7.0), up to 6 patients 
will have been previously treated and are refractory to an anti-CD38 therapy (see Section 
7.0). In the Combination Cohort, approximately 18 patients will be enrolled who have 
received prior therapy and have demonstrated PD on or within 60 days of completion of the 
last therapy, note Section 7.0.
It is expected that approximately 42100 patients will be enrolled in total for the phase 1 cohorts 
and phase 2a combined. 
Study procedures and assessments, with their time points, are shown in Appendix A. The study 
schematic diagram is shown in Figure 6.a.
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Figure 6.a
Overall Study Schematic Diagram
Treatment Cycle: original phase 1 dose Escalation Cohort
C1
C2
≤21 D
D1
D8
D15
D22
D1
D8
D15
D22
C3
C4
C5
C6
C7
C8
D1
D15
D1
D15
D1
D15
D1
D15
D1
D1
**
PD
Treatment Cycle: phase 1 dose Confirmation Cohort 
C1
C2
≤21 D
D1
D8
D15
D22
D1
D8
D15
D22
TAK-079 
300 mg
C3
C4
C5
C6
C7
C8
D1
D15
D1
D15
D1
D15
D1
D15
D1
D1
**
PD
Treatment Cycle: new Combination Cohort 
C1
C2
≤21 D
D1
D8
D15
D22
D1
D8
D15
D22
Pomalidomide
TAK-079 
300 mg
Days 1-21 in a 28-day cycle***
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The study is planned to be conducted in the United States in approximately 47 investigational 
centers for phase 1 and in a total of 6 investigational centers for phase 2a., although the sponsor 
may add more centers depending on enrollment rates. 
6.3
Duration of Study
6.3.1
Duration of an Individual Patient’s Study Participation
Patients will receive TAK-079 until they experience PD as defined by IMWG criteria [17,1821,22] 
(Appendix E), unacceptable toxicity, or any other discontinuation criterion is met (see Section 
8.4.38.6.3 and Section 9.7). In the combination cohort, additionally patients will receive 
PomDex until they experience PD as defined by IMWG criteria. The maximum duration of 
treatment is expected to be 12 months for patients receiving monotherapy and approximately 
18 months for patients in the combination cohort; however, patients with clinical benefit (per 
investigator and as agreed by the sponsor’s study clinician) can continue on treatment beyond 1 
year with the explicit approval of the sponsor’s study clinician (see Section 6.3.5 for Posttrial 
Access). 
Patients will be evaluated 30±7 days after the last dose of TAK-079 (follow-up visit) or before 
initiating subsequent systemic anticancer therapy, for detection of any delayed TEAEs.
6.3.2
End of Study/Study Completion Definition and Planned Reporting
The final analyses for the clinical study report willmay be conducted after all patients enrolled in 
the study have had the opportunity to complete 12 months of treatment with TAK 079 plus the 
EOT visitsingle agent TAK-079, 18 months of combination therapy, or after the EOT visit of 
the last patient enteringcompletes the studyEOT visit if the sponsor terminates the study 
earlyearlier (Table 6.a).
6.3.4
Total Study Duration
The final analyses for the clinical study report may be conducted after all patients enrolled in the 
study have had the opportunity to complete 12 months of treatment with TAK-079single agent 
TAK-079, 18 months of combination therapy, or after the last patient completes the EOT visit if 
the sponsor terminates the study earlier.
It is anticipated that this study will last for approximately 36
42 months (33.5 years).
6.3.5
Posttrial Access
At the conclusion or termination of the study or termination of a treatment arm in the study, 
if patients are, in the opinion of the investigator and confirmed by the sponsor, experiencing 
a clinically important benefit, TAK-079 treatment may be continued in this study or another 
extension or rollover study, if and when such a study is made available, upon request by the 
investigator and agreement by the sponsor. Continued access to TAK-079 for participants 
will be terminated for those individuals who no longer benefit from TAK-079, the 
benefit-risk no longer favors the individual, if TAK-079 becomes available either 
commercially or via another access mechanism, or when an alternative appropriate therapy 
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becomes available. Posttrial access may be terminated in areas where marketing 
authorization has been rejected, the development of TAK-079 has been suspended or 
stopped by the sponsor, or TAK-079 can no longer be supplied. Only for patients enrolled 
into the Combination Cohort, the backbone agents ongoing at this time will continue to be 
procured by the site from commercial sources. 
7.0
STUDY POPULATION
Phase 1 dose Confirmation Cohort: Adult patients with relapsed and/or refractory multiple 
myeloma who have been previously treated with at least a PI, an IMiD, and a steroid. 
Patients should have refractory disease or be intolerant to at least 1 PI and at least 1 IMiD, 
and they should have either received 3 or more prior therapies or received at least 2 prior 
therapies if one of those therapies included a combination of a PI and an IMiD. Patients who 
have had a previous autologous stem cell transplant will have additionally been exposed to 
an alkylating agent; however, patients who have not had a previous autologous stem cell 
transplant may not have been exposed to an alkylating agent per standard practice. Up to 6 
patients will be refractory to an anti-CD38 agent and approximately 12 patients in this 
cohort should be anti-CD38 naïve. 
Combination Cohort: Adult patients with relapsed and/or refractory multiple myeloma who 
have received at least 2 prior therapies including lenalidomide and a proteasome inhibitor 
and have demonstrated PD on or within 60 days of the completion of the last therapy. The 
first 6 patients enrolled may be either naïve to a prior anti-CD38 antibody or may have been 
exposed to one previously (if exposed note washout period in Table 7.a).  Once safety data 
have been reviewed, the following patients enrolled at the RP2D/MTD will be: naïve to a 
prior anti-CD38 monoclonal antibody (approximately 6 patients) or exposed to a prior 
anti-CD38 monoclonal antibody (approximately 6 patients; note washout period in Table 
7.a). 
7.1
Inclusion Criteria
…
5.
Female patients who: 

Are WOCBP must not be pregnant or lactating. 

Are postmenopausal for at least 1 year before the screening visit, OR

Are surgically sterile, OR

If they are of childbearing potential, agree to practice 1 highly effective method of 
contraception and 1 additional effective (barrier) method at the same time, from the time of 
signing the informed consent through at least 90 days or 5 half-lives after the last dose of 
study drug, whichever time period is longest (See Section 8.10), OR

Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, and 
postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not 
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acceptable methods of contraception. Female and male condoms should not be used 
together.)

Patients enrolling in the Combination Cohort (TAK-079–PomDex) only must 
adhere to the Pomalyst REMS requirements per the product label.
6. Male patients, even if surgically sterilized (ie, status postvasectomy), who:

Agree to practice effective barrier contraception during the entire study treatment 
period and through 90 days (or if the drug has a very long half-life, for 90 days plus 5 
half-lives) after the last dose of study drug (See Section 8.10), OR

Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, and 
postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not 
acceptable methods of contraception. Female and male condoms should not be used 
together.)

Patients enrolling in the Combination Cohort (TAK-079–PomDex) only must 
adhere to the Pomalyst REMS requirements per the product label.
7. Voluntary written consent must be given before performance of any study-related procedure 
not part of standard medical care, with the understanding that consent may be withdrawn by 
the patient at any time without prejudice to future medical care.
8. The patient must be willing and able to comply with study restrictions and to remain at the 
investigational center for the required duration during the study period, and must be willing to 
return to the investigational center for the follow-up procedures and assessments specified in 
this protocol.
9. Requires additional therapy, as determined by the investigator.Patients in the Combination 
Cohort (TAK-079–PomDex) only must be able to take concurrent prophylactic 
anticoagulation per standard clinical practice as directed by the investigator and the 
Pomalyst product information.
10. Documentation of RRMM as defined by the IMWG criteria (Appendix E; [17,1821,22]).
11. For patients with MM, measurable disease defined as one of the following:

Serum M-protein ≥0.5 g/dL (≥5 g/L).

Urine M-protein ≥200 mg/24 hours.

In patients without measurable M-protein in serum protein electrophoresis (SPEP) 
or urine protein electrophoresis (UPEP), a serum free light chain (FLC) assay result with 
involved FLC level ≥10 mg/dL (≥100 mg/L), provided serum FLC ratio is abnormal.
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12. Prior therapy, patients should meet all the following criteria:
Patients in the dose Escalation Cohort (escalation phase) and patients in the dose 
Confirmation Cohort;

Patient should be previously treated with at least a PI, an IMiD, and a steroid. 
Note: Patients who have had a previous autologous stem cell transplant will have 
additionally been exposed to an alkylating agent, and a steroid.; however, patient 
who have not had a previous autologous stem cell transplant may not have been 
exposed to an alkylating agent per standard practice. 

Patient should be refractory or intolerant to at least 1 PI and at least 1 IMiD.

Patient should either have received ≥3 prior lines of therapy or should have 
received at least 2 prior lines of therapy if one of those lines included a combination of 
PI and IMiD. 

In phase 1, previous exposure to an anti-CD38 agent, as a single agent or in 
combination, is allowed but is not required. [Patients in the dose Escalation Cohort]

In phase 1 dose Confirmation Cohort, 2 subgroups will be enrolled: up to 6 
patients will be enrolled that meet above prior therapy criteria and are refractory 
at any time to at least 1 anti-CD38 agent and approximately 12 patients will be 
enrolled that meet above prior therapy criteria but are anti-CD 38 naïve.
Patients in the Combination Cohort (TAK-079 added to PomDex cohort only):

Patients have undergone prior therapy with ≥2 prior anti-myeloma therapies 
(line of therapy defined below).

Patient has either relapsed or relapsed and refractory disease. Should have 
progressed on or within 60 days of completing the last anti-myeloma therapy 
(refractory defined below).
13. In the phase 2a portion of the study, up to 2 cohorts of patients with MM must also have 
beenRRMM may be enrolled: 1 that is refractory to at least 1 anti-CD38 mAb therapy at any 
time during treatment. and 1 that is naïve to daratumumab. Available safety and efficacy 
data will be used to make decisions about the patient cohorts to be enrolled in the phase 
2a portion. The final decision on the phase 2a cohorts will be made by sponsor 
representatives following review of all available data considering stopping rule 
thresholds. (see Section 13.1.7)
...
7.2
Exclusion Criteria
19. POEMS (Polyneuropathypolyneuropathy, organomegaly, endocrinopathy, monoclonal 
gammopathy and skin changes) syndrome, monoclonal gammopathy of unknown significance, 
smoldering myeloma, solitary plasmacytoma, amyloidosis, Waldenström macroglobulinemia, 
or IgM myeloma.
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20. ….
21.
For patients in the Combination Cohort (TAK-079–PomDex) only: patient has 
previously received pomalidomide or has hypersensitivity to thalidomide or lenalidomide.
8.0
STUDY DRUG
8.1
Study Drug Administration
…
8.1.1
Predose and Postdose Medication
Premedications are required in phase 1 and phase 2a. 
The clinical site is responsible for sourcing any premedications outlined in the protocol.
8.1.1.1 Predose Medication: Phase 1 Dose Escalation and Dose Confirmation Cohorts 
Before each injection, patients will receive the following premedications 1 to 3 hours prior to the 
start of TAK-079 administration on each dosing day:

Dexamethasone: 20 mg IV dose for the initial injection. Oral dexamethasone (20 mg) or an 
equivalent long-acting corticosteroid may be used before subsequent injections.

Antipyretics: oral acetaminophen (650 to 1000 mg).

Antihistamine: oral or IV diphenhydramine (25 to 50 mg, or equivalent).

Montelukast 10 mg (or equivalent leukotriene inhibitor). 
NOTE: For any patients with a history of COPD, consider prescribing postinfusion medications,
such as short- and long-acting bronchodilators, and inhaled corticosteroids. After the first 4 
infusions, if the patient experiences no major IRs, these additional inhaled postinfusion 
medications may be discontinued.
Premedications are required in phase 1 and phase 2a. 
The clinical site is responsible for sourcing any premedications outlined in the protocol
8.1.1.2 Predose Medications: Phase 1 Combination Cohort (TAK-079–PomDex) Only
Before each injection, patients will receive the following premedications 1 to 3 hours prior to 
the start of TAK-079 administration on each dosing day:

Antipyretics: oral acetaminophen (650 to 1000 mg).

Antihistamine: oral or IV diphenhydramine (25 to 50 mg, or equivalent).

Montelukast 10 mg (or equivalent leukotriene inhibitor). 
NOTE: For any patients with a history of COPD, consider prescribing postinfusion 
medications, such as short- and long-acting bronchodilators, and inhaled corticosteroids. 
After the first 4 infusions, if the patient experiences no major IRs, these additional inhaled 
postinfusion medications may be discontinued.
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8.1.1.3 Postdose Medications (All Patients)
...
8.4
TAK-079 Dose in Phase 1 Dose Confirmation Cohort

TAK-079 will be given at a fixed dose of 300 mg once weekly for 8 weeks (8 doses), 
once every 2 weeks for 16 weeks (8 doses), and once every 4 weeks thereafter until PD. 

In this cohort, safety and available efficacy, PK, 
 will be 
reviewed at least after 6 patients in each subgroup have received 1 cycle of therapy, then 
in an ongoing basis as per Takeda processes. 
8.5
TAK-079 Dose in Phase 1 Combination Cohort

TAK-079 will be given at a fixed dose of 300 mg once weekly for 8 weeks (8 doses), 
once every 2 weeks for 16 weeks (8 doses), and once every 4 weeks thereafter until PD.

PomDex are both standard of care agents and will be given in accordance with 
product labeling [Pomalyst USPI including Section 14.1; NCCN guidelines 2019].

In this cohort, up to 6 patients will initially be enrolled. Safety in Cycle 1 will be 
reviewed in accordance with DLT definitions in Section 8.2.

If 0 of 6 or 1 of 6 patients develop a DLT and additional 12 patients will be tested at 
the initial dose of TAK-079 [6 patients that are naïve to a prior anti-CD38 agent and 
6 patients that have been exposed to a prior anti-CD38 agent], for an overall total of 
18 patients.

If 2 of 6 patients develop DLTs, an additional cohort of 6 patients will be tested at a 
de-escalated dose; an intermediate or more conservative dose schedule may also be 
implemented as a means to provide an overall lower dose. A lower dose of 
pomalidomide may also be considered based on the available safety data. If 0 of 6 or 1 
of 6 patients develop TAK-079–related DLTs at the revised dose, an additional 
cohort of up to 12 patients (with eligibility as above regarding anti-CD38 naïve or 
exposed) will be tested at this dose level (in other words a dose lower than the initial 
dose, one that is intermediate or more conservative than the initial dose) or 
conservative dose schedule, for an overall total of 18 patients at the lower 
dose/conservative dose schedule. If 2 of 6 patients develop DLTs at the lower dose, 
this cohort will be stopped for further evaluation. 
8.6
8.4 Dose Modification Guidelines
...
8.6.1
8.4.1 Criteria for Beginning or Delaying a Subsequent Treatment Cycle
Treatment with TAK 079 willfor all cohorts use a cycle length of 28 days. For a new cycle of 
treatment to begin, the patient must meet the following criteria:
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...
8.6.2
8.4.2 Criteria for Dose Modification
....
Table 8.a
Dose Modification Recommendations for TAK-079 Toxicities
Criteria
Action
Grade 1 AEs
No dose interruptions.
Grade 2 AEs
Treat according to local practice. Whether to hold treatment or to continue it 
at the same dose is at the discretion of the investigator.
Patients with Grade 2 AEs considered related to study treatment that are not 
easily managed or corrected and are not tolerable to the patient, or AEs that 
are not acceptable in the investigator’s judgment, should have study 
treatment interrupted until the AE resolves to Grade ≤1 or baseline, then 
restarted at the same dose.
Grade 3 AEs
Patients with Grade 3 AEs considered related to study treatment that are not 
easily managed or corrected and are not tolerable to the patient should have 
study treatment interrupted until the AE resolves to Grade ≤1 or baseline, 
then resume treatment at the same dose level. (Note Section 8.2 for AEs of 
short duration and/or that respond to medical management.) 
Note in phase 1, nonhematologic AEs Grade ≥3 may meet DLT criteria and 
as such patients should be withdrawn from further dosing unless the sponsor 
approves subsequent treatment in a lower dose cohort.
Grade 3 or higher thrombocytopenia with bleeding should result in a dose 
interruption until the AE resolves to Grade ≤1 or baseline, then resume at the 
same dose. Medical considerations should eliminate Coombs positivity 
before restarting (note Table 8.b).
Grade 4 (life-threatening) AEs
Patients with Grade 4 AEs considered related to study treatment should 
permanently discontinue treatment. Grade 4 hematologic toxicity should 
result in study treatment interruption until the AE resolves to Grade ≤1 or 
baseline, then resume at the same dose. Medical consideration should 
eliminate Coombs positivity before restarting (note Section 8.4.3 and Table 
8.b).
AEs of all grades
If TAK-079 administration does not commence within the prespecified 
window (Table 8.b) of the scheduled administration date, then the dose will 
be considered a missed dose. Administration may resume at the next planned 
dosing date upon recovery as described above.
AE=: adverse event; DLT=: dose-limiting toxicity.
8.7
Dose Modification Considerations for Patients in the Phase 1 Combination Cohort 
(TAK-079–PomDex Cohort) Only

TAK-079 (study drug) will be given as noted in Section 8.5 through 8.6.3.

Dexamethasone administered IV or orally at 40 mg/day on Days 1, 8, 15, 22, or 20 
mg/day given on Days 1, 8, 15, and 22 for patients over 75 years of age (Pomalyst USPI, 
Section 14.1).
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
Pomalidomide is a standard of care agents and will be given in accordance with 
product labeling (Pomalyst USPI).

Treatment cycle will be 28-days as per product labeling until PD or unacceptable 
toxicity.

PomDex will be procured by the site from commercial sources.
8.7.1
Dose Modification of Standard of Care Agents

All toxicities that occur during the study will be actively managed following medical 
standard of care unless otherwise specified in the protocol.

Toxicities should be attributed, whenever possible, to a specific drug (TAK-079 study 
drug, or standard chemotherapy agents pomalidomide or dexamethasone, as applicable) 
so that dose modifications can be made rationally. Reduction of 1 agent and not others is 
appropriate if toxicity is considered to be related primarily to one of the agents. If 
multiple toxicities are attributed to an individual agent (study drug or standard 
chemotherapy agent), dose adjustments should be made according to the guidelines for 
the most severe toxicity. 

Toxicities attributed to pomalidomide or dexamethasone, as applicable, should be 
managed according to the relevant guidelines in the respective product information 
[20,28].

Once dose reduction has been implemented, unless otherwise stated specifically in the 
relevant product information and after discussion with the Sponsor Study Clinician (or 
designee), dose re-escalation should not occur. 
8.9
8.6 Permitted Concomitant Medications and Procedures 

All necessary supportive care consistent with optimal patient care will be available to 
patients as necessary. During study treatment, all blood products and concomitant medications 
received until 30 days after the final dose will be recorded in the electronic case report forms 
(eCRFs) (note additional information in Section 9.4.9 and Appendix A).

The following medications and procedures are permitted while the patient is receiving the 
study drug:
–
For patients in the Combination Cohort (TAK-079–PomDex) only: patients 
must adhere to the pregnancy prevention program (Pomalyst REMS).
–
For patients in the Combination Cohort (TAK-079–PomDex) only: patients 
receiving pomalidomide should be on routine thromboprophylaxis according to 
product label, published guidelines, and institutional practice [20,29].
–
Systemic corticosteroid use ≤10 mg/day (prednisone or equivalent).
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–
Myeloid growth factors (eg, granulocyte colony stimulating factor, granulocyte 
macrophage-colony stimulating factor) and erythropoietin are permitted. Their use should 
follow the product label, published guidelines, and institutional practice. However, 
myeloid growth factors will not be allowed in Cycle 1 unless the study is in the 
expansion phase as their prophylactic use can interfere with DLT determination.
–
Transfusions with RBCs and platelets as clinically indicated; localizedhowever, 
platelet use will not be allowed in Cycle 1 unless the study is in the expansion phase 
because their prophylactic use can interfere with DLT determination.
–
Localized radiation for pain management for osteolytic lesions.
–
…
8.10
8.7 Precautions and Restrictions
An interference with serological testing has been described with the anti-CD38 antibody 
daratumumab [23]. Daratumumab binds to CD38 on RBCs and results in a positive indirect 
antiglobulin test (Indirect Coombs test). A daratumumab-mediated positive indirect 
antiglobulin test may persist for up to 6 months after the last daratumumab infusion. 
Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the 
patient’s serum. The determination of a patient’s ABO and Rh blood type are not affected. 
It is possible TAK-079 may affect the results of these blood tests; this is being evaluated. 
Until those tests are known, it is recommended that baseline type and serological screening 
be established before starting TAK-079. Patients should keep these results in case future 
transfusions are needed. Blood transfusion centers should also be informed of this 
interference with serological testing as necessary.
Fluid deficitdeficits should be corrected before initiation of treatment and during treatment.

…..

If they are of childbearing potential, agree to practice 1 highly effective method and 1 
additional effective (barrier) method of contraception at the same time, from the time of 
signing of the informed consent form (ICF) through at least 90 days or 5 half-lives after the last 
dose of study drug (whichever is longer),. Note the half-life of TAK-079 has not yet been 
determined. Based on conservative information in the literature regarding the half-life of 
IgG1 immunoglobulins as well as other IgG1 human monoclonal antibodies [30,31], a 
conservative time frame to continue contraception would be 150 days. OR

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of 
the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, and postovulation
methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.)
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Male patients, even if surgically sterilized (ie, status postvasectomy) must agree to one of the 
following:

Agree to practice effective barrier contraception during the entire study treatment period 
and through 90 days (or if the drug has a very long half-life, for 90 days plus 5 half-lives) after 
the last dose of study drug,. Note the half-life of TAK-079 has not yet been determined. 
Based on conservative information in the literature regarding the half-life of IgG1 
immunoglobulins as well as other IgG1 human monoclonal antibodies [30,31], a 
conservative timeframe to continue contraception would be 150 days. OR

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle 
of the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, and postovulation 
methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.)
For men and women patients enrolled in the Combination (TAK-079–PomDex) Cohort 
only: patients receiving pomalidomide must adhere to the Pomalyst REMS requirements 
per the product label [20].
In addition, a close monitoring of serum chemistry, particularly creatinine, potassium, and uric 
acid levels must be performed. Patients with tumor lysis syndrome should be treated per 
institutional practice (including correction of electrolyte abnormalities, monitoring of renal 
function and fluid balance, and administration of supportive care, including dialysis as indicated).
8.11
8.8 Management of Specific Adverse Reactions
8.11.3 8.8.3 Handling of Low Platelet Counts
….
For patients in the phase 1 Combination Cohort, thrombocytopenia is a known TEAE 
reported with pomalidomide and should be monitored and managed according to the 
product information [20].
8.11.4 8.8.4 Risk of Infection
….
For patients in the phase 1 Combination Cohort, neutropenia is a known adverse drug 
reaction reported with pomalidomide and should be monitored and managed according to 
the product information [20].
8.16
8.13 Storage, Handling, and Accountability
8.16.1 8.13.1 Storage and Handling
….
During shipping, vials will be protected from light and maintained below -15°C (5°F)shipped as 
noted in the pharmacy manual. Each TAK-079 shipment will include a packing slip listing the 
contents of the shipment, and any applicable forms.
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All clinical trial material must be kept in an appropriate, limited-access, secure location until used 
or returned to the sponsor or designee. All study medication must be stored under the conditions 
specified on the label, and remain in the original container until dispensed. A daily temperature log 
of the drug storage area mustshould be maintained every day.
…
8.18
Standard Drug Procurement Procedures: Patients in the Combination Cohort Only
8.18.1 Pomalidomide
Pomalidomide will be procured by the site from commercial sources. Additional details are 
provided in the product information [20]. Patients receiving pomalidomide must adhere to 
the Pomalyst REMS program per the product label.
Pomalidomide capsules should be stored at temperatures in accordance with the 
instructions provided in the manufacturers product information.
8.18.2 Dexamethasone
Dexamethasone will be procured by the site from commercial sources. Additional details are 
provided in the product information (Decadron USPI).
Dexamethasone tablets should be stored according to the instructions provided in the 
manufacture’s product information. 
8.19
Other Protocol-Specified Materials
TAK-079 will be supplied for use in this clinical study. No other drugs (including PomDex in 
the Combination Cohort) or ancillary materials are supplied for use in this study. 
9.3
Treatment Group Assignments
...
For phase 1 Combination Cohort (TAK-079–PomDex) Cohort only: patients must meet 
prespecified inclusion/exclusion criteria in Section 7.0 to be assigned to this cohort. 
9.4
Study Procedures
.... 
Patients receiving pomalidomide in the Combination Cohort (TAK-079–PomDex) must 
adhere to the Pomalyst REMS program per the product label. Pregnancy tests may also be 
repeated during the study as per request of the IEC/IRBs or required by local regulations. 
9.4.12 ECG
... 
The triplicate ECG measurements should be completed before the PK blood draw. Collection of 
triplicate ECGs should begin after the patient has rested in supine position for approximately 5 
minutes. Each ECG recording of the triplicate ECGs should occur within 3 minutes of each other 
and over a 10-minute window. It is recommended that patients refrain from eating or limit 
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themselves to bland food for 1 hour before dosing and for 1 hour before each scheduled triplicate 
ECG measurementbe done according to institutional standards.
….
9.4.13.1
Clinical Chemistry, Hematology, and Urinalysis
Blood samples for analysis of the clinical chemistry and hematological parameters shown in Table 
9.a and urine samplessample parameters for analysis of the parametersare shown in Table 9.bthe 
tables below. Samples will be obtained as specified in the SOE (Appendix A). They will be 
performed locally only.
For Patients in Cohorts Receiving TAK-079 monotherapy:
Table 9.a
Clinical Chemistry and Hematology Tests for Research Purposes
Hematology
Serum Chemistry
ANC
Hematocrit
Hemoglobin
Platelet (count) 
Reticulocyte count
RBC count
WBC count 
WBC with differential
Coagulation panel
Albumin
ALP
ALT
AST
Bilirubin (total)
BUN
Calcium
Chloride
CO2 (bicarbonate) 
Creatinine 
Creatinine clearance
CRP
Glucose (nonfasting)
GGT
LDH
Phosphate
Potassium
Sodium
Total protein
Urate (uric acid)
ALP=: alkaline phosphatase; ALT=: alanine aminotransferase; ANC=: absolute neutrophil count; AST=: serine 
aminotransferase; BUN=: blood urea nitrogen; CRP=: C-reactive protein; GGT=: γ-glutamyl transferase; LDH=: 
lactate dehydrogenase; RBC=: red blood cell; WBC=: white blood cell.
Table 9.b
Clinical Urinalysis Tests for Research Purposes
Urinalysis
Bilirubin
Glucose
Ketones
Leukocytes
Nitrite
Occult blood
pH
Protein
Specific gravity
Turbidity and color
Urobilinogen
For estimation of creatinine clearance, the Cockcroft-Gault formula will be employed as follows:
For female patients, the result of the formula above should be multiplied by 0.85. 
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For patients in the phase 1 Combination Cohort (TAK-079–PomDex) Cohort only:
Table 9.c 
Clinical Hematology and Chemistry: Standard of Care Laboratory Tests
Hematology
Chemistry
Leukocytes with complete differential (total 
neutrophils [ANC], lymphocytes, 
monocytes, eosinophils, and monocytes)
Albumin
CO2 (bicarbonate)
Platelet count
ALP
Creatinine
Hemoglobin
ALT
Estimated glomerular 
filtration rate
Serum pregnancy test
AST
Glucose
B2- microglobulin
LDH
Bilirubin (direct and indirect)
Potassium
Calcium
Sodium
Chloride
Urate
ALP: alkaline phosphatase; ALT: alanine aminotransferase; ANC: absolute neutrophil count; AST: serine 
aminotransferase; LDH: lactate dehydrogenase.
Table 9.d Clinical Hematology and Chemistry: Tests for Research Purposes
Clinical Hematology or Chemistry
Serology antibody titers
Coagulation panel (PT, PTT, INR)
Hepatitis B
Indirect and direct coombs
Hepatitis C
C-reactive protein
HIV
INR: international normalized ratio; PT: prothrombin time; PTT: partial thromboplastin time. 
Table 9.e  Clinical Urinalysis: Tests for Research Purposes
Urinalysis
Bilirubin
pH
Glucose
Protein
Ketones
Specific gravity
Leukocytes
Turbidity, appearance, and color
Nitrite
Urobilinogen
Occult blood
Microscopic assessment (a)
(a) Microscopic analyses will be performed only as clinically indicated: bacteria, RBCs, WBCs, casts, and 
crystals.
All procedures and tests should be done as outlined in the SOE (Appendix A). After 24 months on treatment, 
the patient may be monitored according to standard clinical practice per the treating physician.
9.4.14 Disease Response Assessments
Patients will be assessed for disease response according to the IMWG criteria ([17,18]; Appendix 
E).21,22]; Appendix E). In addition, in patients that have myeloma measurable by serum 
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free light chains, MR will be defined as a reduction of ≥25 but ≤49% in the difference 
between involved and uninvolved FLC levels.
For patients in the phase 1 Combination Cohort (TAK-079–PomDex) Cohort only:
Table 9.f
Myeloma Disease Assessments: Tests Standard of Care Tests
Serum/Urine
Bone Marrow/Imaging
SPEP
Bone marrow biopsy and/or aspirate (a)
UPEP
Cytogenetics [presence of del (17), t(4:14), and t(14:16) at a 
minimum]
Immunofixation (serum and urine)
Imaging (skeletal survey, CT scan, PET/CT scan, MRI)
Quantification immunoglobulin levels
Serum FLC
CT: computed tomography; MRI: magnetic resonance imaging; PET: positron emission tomography.
(a) The BMAs only at Cycle 2D1, C4D1, C7D1, and C13D1 are for research purposes unless these align with a 
suspected CR then this procedure would be Standard of Care.
For all patients: 
After 24 cycles on treatment, the patient may be monitored according to standard clinical 
practice per the treating physician.
9.6
Completion of Study (for Individual Patients)
…
It is anticipated that the duration of the study will be approximately 3642 months (33.5 years).
13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
13.1.1 Analysis Sets
All-enrolled analysis set: The all-enrolled analysis set will include all patients enrolled into the 
study, regardless of whether they received any dose of TAK 079.any study drug.
…
Safety analysis set: The safety analysis set will include all enrolled patients who receive at least 1 
dose of TAK-079.any study drug.
…
13.1.3 Efficacy Analysis
…
The preliminary efficacy of TAK-079 for MM will be evaluated by measuring the ORR (defined 
as the proportion of patients who achieved a PR or better during study;) and the composition of 
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sCR, CR, VGPR, and PR as defined by the IMWG Uniform Response Criteria (see Appendix E). 
In addition, MR will be analyzed (see Section 9.4.14 and Appendix E).
...
13.3
Determination of Sample Size
It is expected that approximately 42100 patients will be enrolled in total for phase 1 and 2a 
combined. Once the RP2D is determined in phase 1, approximately 1848 patients will be treated in 
phase 2a to provide a preliminary estimate of the ORR in patients with RRMM.
A 3+3 dose escalation schema will be used for dose escalation as described in Section 8.3.2.
A group of 3 to 6 patients will be enrolled in each TAK-079 dose cohort based on safety, clinical, 
PK, 
 data. Each patient will participate in only 1 dose cohort. The actual 
dose levels may be adjusted based on the observed safety profile. 
Additional patients may be enrolled in a limited cohort expansion to confirm the safety and 
 before the phase 2a of this study is opened to enrollment. 
Approximately 6 dose levels are planned. For phase 1, the number of patients is planned to be 
approximately 24.In the phase 1 dose Confirmatory Cohort, approximately 18 patients will 
be enrolled at 1 dose and schedule: 12 patients with RRMM that is anti-CD38 naive and up 
to 6 patients with RRMM that is refractory to an anti-CD38 therapy. In the Combination 
Cohort, approximately 18 patients with RRMM that has been previously treated with at 
least 2 prior therapies and that is refractory to the last therapy will be enrolled. 
In phase 2a, up to a total of 1848 patients will be treated to provide a preliminary estimate of the 
ORR in 2 expansion cohorts of patients with RRMM. All: up to 24 patients must show a clear 
evidence of PD with RRMM that is anti-CD38 naive and up to 24 patients with RRMM that 
is refractory to an anti-CD38 therapy. Phase 2a of the study will also provide a more robust 
estimate of the safety profile to determine whether the MTD is appropriate for future studies as the 
RP2D.
No prospective calculations of statistical power have been made; however, Table 13.a shows the 
width of the 80% CI, based on the observed ORR in a cohort size of 1824 patients, for a range of 
observed response rates. An observed ORR greater than 20% would be of interest in this 
relapse/refractory population.
Table 13.a
80% Confidence Interval Based on the Observed ORR
N =18 24 patients.
ORR=: overall response rate.
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16.0
REFERENCES
…
17.
Moreau P, San Miguel J, Sonneveld P, Mateos MV, Zamagni E, Avet-Loiseau H, et 
al. Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment 
and follow-up. Ann Oncol 2017;28(suppl_4):iv52-iv61.
18.
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Multiple 
Myeloma (Version 2.2019). National Comprehensive Cancer Network. November 16, 
2018.
19.
Rychak E, Mendy D, Shi T, Ning Y, Leisten J, Lu L, et al. Pomalidomide in 
combination with dexamethasone results in synergistic anti-tumour responses in 
pre-clinical models of lenalidomide-resistant multiple myeloma. Br J Haematol 
2016;172(6):889-901.
20.
POMALYST (pomalidomide) capsules, for oral use [package insert]. Summit, NJ: 
Celgene Corporation, 2014.
21.
Rajkumar SV, Harousseau JL, Durie B, Anderson KC, Dimopoulos M, Kyle R, et al. 
Consensus recommendations for the uniform reporting of clinical trials: report of the 
International Myeloma Workshop Consensus Panel 1. Blood 2011;117(18):4691-5.
18.22. Palumbo A, Rajkumar SV, San Miguel JF, Larocca A, Niesvizky R, Morgan G, et al. 
International myeloma working group consensus statement for the management, treatment, 
and supportive care of patients with myeloma not eligible for standard autologous 
stem-cell transplantation. J Clin Oncol 2014;32(6):587-600.
23.
Darzalex (daratumumab) [package insert]. Horsham, PA: Janssen Biotech, Inc.
19.24. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity 
and response criteria of the Eastern Cooperative Oncology Group. American Journal of 
Clinical Oncology 1982;5(6):649-55.
20.25. Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03. U.S. 
Department of Health and Human Services National Cancer Institute. 14 June 2010.
21.26. RITUXAN (rituximab) [prescribing information]. San Francisco, CA: Genentech, Inc., 
2013.
22.27. Herceptin (trastuzumab) [package insert]. South San Francisco (CA): Genentech, Inc., 
2014.
28.
DECADRON [package insert]. Whitehouse Station, NJ: Merck & Co., Inc., January 
2007.
29.
Schunemann HJ, Cushman M, Burnett AE, Kahn SR, Beyer-Westendorf J, Spencer 
FA, et al. American Society of Hematology 2018 guidelines for management of 
venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical 
patients. Blood Adv 2018;2(22):3198-225.
30.
Mankarious S, Lee M, Fischer S, Pyun KH, Ochs HD, Oxelius VA, et al. The 
half-lives of IgG subclasses and specific antibodies in patients with primary 
immunodeficiency who are receiving intravenously administered immunoglobulin. J 
Lab Clin Med 1988;112(5):634-40.
31.
Suzuki T, Ishii-Watabe A, Tada M, Kobayashi T, Kanayasu-Toyoda T, Kawanishi T, 
et al. Importance of neonatal FcR in regulating the serum half-life of therapeutic 
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proteins containing the Fc domain of human IgG1: a comparative study of the 
affinity of monoclonal antibodies and Fc-fusion proteins to human neonatal FcR. J 
Immunol 2010;184(4):1968-76.
23.32. Thall PF, Sung HG. Some extensions and applications of a Bayesian strategy for 
monitoring multiple outcomes in clinical trials. Statistics in Medicine 
1998;17(14):1563-80.
24.33. Rajkumar SV. Multiple myeloma: 2014 Update on diagnosis, risk-stratification, and 
management. American Journal of Hematology 2014;89(10):998-1009.
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Appendix A
Schedule of Events
Screening, Baseline, Treatment Period Cycles 1 and 2
Study Period (Phases 1 and 2a)
Screen-
ing (a)
Treatment Phase (Weekly)
Cycle 1
Cycle 2
Cycle Day
C1D1
C1D8
C1D15
C1D22
C2D1
C2D8
C2D15
C2D22
Window Allowed
±2 days
±2 days
±2 days
±2 days
±2 days
±2 days
±2 days
±2 days
Informed consent (b)
X
Eligibility criteria
X
Demographics
X
Medical history
X
Prior medication and treatment history
X
HBV, HCV, and HIV
X
Height and weight (c)
X
X
X
ECOG performance status 
X
X
X
ECG (d)
X
X
X
ECG measurements additionally on Days 2, 3, and 4 for Cycles 1 and 2 (see Section 9.4.12).
Physical examination 
X
X
X
X
X
X
X
X
X
Vital signs (e)
X
X
X
X
X
X
X
X
X
Monitoring of concomitant medication and 
procedures
Recorded from up to 21 days before the first dose of TAK-079 through 30 days after last dose of study drug or the start of subsequent 
anticancer therapy, whichever occurs first.
AE reporting
Recorded from signing of the ICF through 30 days after the last dose of study drug (Section 10.3).
SAEs (includes pretreatment, and related and unrelated treatment-emergent events) will be reported from signing of the ICF through 
30 days after last dose of study drug, even if the patient starts nonprotocol therapy (Section 10.3).
Dosing for Phase 1 Dose Escalation Cohort
Pre-injection medication
X
X
X
X
X
X
X
X
TAK-079 injection (f)
X
X
X
X
X
X
X
X
Dosing Patients in Dose Confirmation Cohort
Pre-injection medication
X
X
X
X
X
X
X
X
TAK-079 SC injection (f)
X
X
X
X
X
X
X
X
Dosing Patients in Combination Cohort Only
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Screening, Baseline, Treatment Period Cycles 1 and 2
Study Period (Phases 1 and 2a)
Screen-
ing (a)
Treatment Phase (Weekly)
Cycle 1
Cycle 2
Cycle Day
C1D1
C1D8
C1D15
C1D22
C2D1
C2D8
C2D15
C2D22
Window Allowed
±2 days
±2 days
±2 days
±2 days
±2 days
±2 days
±2 days
±2 days
Pre-injection medication
X
X
X
X
X
X
X
X
TAK-079 SC injection (f)
X
X
X
X
X
X
X
X
Pomalidomide
Day 1-21 in each cycle
Dexamethasone
Day 1, 8, 15, and 22 in each cycle
Laboratory assessments
Serum chemistry (g) 
X
X
X
X
X
X
X
X
X
Hematology (h)
X
X
X
X
X
X
X
X
X
Urinalysis (i)
X
X
X
Pregnancy test (j) (k)
X
X
X
Response assessments for MM
Investigator disease assessment (t)
X
Serum M-protein 
X
X
X
Urine M-protein (l) 
X
X
X
Serum FLC assay (m)
X
X
X
Immunofixation - serum and urine (n)
X
X
X
Quantification of Ig 
X
X
X
Skeletal survey: WB x-ray, CT, low-dose CT, 
PET-CT, or MRI scan (o)
X
Biological assessments
Bone marrow aspiration (BMA) (p)
X
X
Serum sample for TAK-079 PK (q) 
X
X
X
X
X
X
X
X
PK sampling additionally on Days 2, 3, and 4 for Cycles 1 and 2.
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TAK-079
Study No. TAK-079-1501
Page 151 of 160
Protocol Incorporating Amendment 03
02 April 2019
Screening, Baseline, Treatment Period Cycles 1 and 2
Study Period (Phases 1 and 2a)
Screen-
ing (a)
Treatment Phase (Weekly)
Cycle 1
Cycle 2
Cycle Day
C1D1
C1D8
C1D15
C1D22
C2D1
C2D8
C2D15
C2D22
Window Allowed
±2 days
±2 days
±2 days
±2 days
±2 days
±2 days
±2 days
±2 days
Serum sample for immunogenicity 
(ADA/titer) (s)
X
X
X
Serum sample for direct and indirect Coombs 
test
X
X
X
Footnotes appear on last page of SOE tables.
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TAK-079
Study No. TAK-079-1501
Page 152 of 160
Protocol Incorporating Amendment 03
02 April 2019
Treatment Period Continued: Cycles 3 Through 6
Study Period 
(Phases 1 and 2a)
Treatment Phase (Every 2 Weeks)
Cycle 3
Cycle 4
Cycle 5
Cycle 6
Cycle Day
C3D1
C3D15
C4D1
C4D15
C5D1
C5D15
C6D1
C6D15
Window Allowed
±2 days
±2 days
±2 days
±2 days
±2 days
±2 days
±2 days
±2 days
Height and weight (c)
X
X
X
X
ECOG performance status
X
X
X
X
ECG (d)
X
X
X
X
Physical examination
X
X
X
X
X
X
X
X
Vital signs (e)
X
X
X
X
X
X
X
X
Monitoring of concomitant medication and 
procedures
Recorded up to 21 days before the first dose of TAK-079 through 30 days after the last dose of study drug or the start of subsequent 
anticancer therapy, whichever occurs first.
AE reporting
Recorded from signing of the ICF through 30 days after the last dose of study drug (Section 10.3).
SAEs (includes pretreatment, and related and unrelated treatment-emergent events) will be reported from signing of the ICF through 
30 days after last dose of study drug, even if the patient starts nonprotocol therapy (Section 10.3).
Dosing Patients in Dose Escalation Cohort
Pre-injection medication
X
X
X
X
X
X
X
X
TAK-079 injection (f)
X
X
X
X
X
X
X
X
Dosing Patients in Dose Confirmation Cohort
Pre-injection medication
X
X
X
X
X
X
X
X
TAK-079 SC injection (f)
X
X
X
X
X
X
X
X
Dosing Patients in Combination Cohort Only
Pre-injection medication
X
X
X
X
X
X
X
X
TAK-079 SC injection (f)
X
X
X
X
X
X
X
X
Pomalidomide
Day 1-21 in each cycle
Dexamethasone
Day 1, 8, 15, and 22 in each cycle
Laboratory assessments
Serum chemistry (g)
X
X
X
X
X
X
X
X
Hematology (h)
X
X
X
X
X
X
X
X
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TAK-079
Study No. TAK-079-1501
Page 153 of 160
Protocol Incorporating Amendment 03
02 April 2019
Treatment Period Continued: Cycles 3 Through 6
Study Period 
(Phases 1 and 2a)
Treatment Phase (Every 2 Weeks)
Cycle 3
Cycle 4
Cycle 5
Cycle 6
Cycle Day
C3D1
C3D15
C4D1
C4D15
C5D1
C5D15
C6D1
C6D15
Window Allowed
±2 days
±2 days
±2 days
±2 days
±2 days
±2 days
±2 days
±2 days
Urinalysis (i) 
X
X
X
X
Pregnancy test (j) (k)
X
X
X
X
Response assessments for MM
Investigator disease assessment (t)
X
X
X
X
Serum M-protein 
X
X
X
X
Urine M-protein (l)
X
X
X
X
Serum FLC assay (m) 
X
X
X
X
Immunofixation - serum and urine (n)
X
X
X
X
Quantification of Ig 
X
X
X
X
Skeletal survey: WB x-ray, CT, low-dose 
CT, PET-CT, or MRI scan (o)
X
Biological assessments
Bone marrow aspiration (BMA) (p)
X
Serum sample for TAK-079 PK (q) 
X
X
X
X
X
X
X
X
Serum sample for immunogenicity 
(ADA/titer) (s)
X
X
X
X
Serum sample for direct and indirect 
Coombs test 
X
X
X
X
Footnotes appear on last page of SOE tables.
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TAK-079
Study No. TAK-079-1501
Page 154 of 160
Protocol Incorporating Amendment 03
02 April 2019
Treatment Period Continued: Cycles 7 to Follow-up and Overall Survival Follow-up
Study Period (Phases 1 and 2a)
Treatment Phase
(Monthly; Every 4 Weeks; to PD)
Follow-Up Phase
Cycle 7
Cycle 8 and beyond
EOT/Early Termination
PFS Follow-Up
Every 4 Weeks
OS 
Follow-Up 
Every 12 Weeks
Cycle Day
C7D1
C8D1, CXD1
Up to 30 days After Last 
Dose
--------
--------
Window Allowed
±2 days
±2 days
±7 days
7 days
7 days
Laboratory assessments 
Height and weight (c)
X
X
X
ECOG performance status
X
X
X
ECG (d)
X
X
X
Physical examination
X
X
X
Vital signs (e)
X
X
X
Monitoring of concomitant medication and 
procedures
AE reporting
Recorded from up to 21 days before the first dose of TAK 079 through 30 days after the last dose of study drug or the start of 
subsequent anticancer therapy, whichever occurs first.
Recorded from signing of the ICF through 30 days after the last dose of study drug (Section 10.3).
SAEs (includes pretreatment, and related and unrelated treatment-emergent events) will be reported from signing of the ICF 
through 30 days after last dose of study drug, even if the patient starts nonprotocol therapy (Section 10.3).
AE reporting
Dosing Patients in Dose Escalation Cohort
Pre-injection medication
X
X
TAK-079 injection (f)
X
X
Dosing Patients in Dose Confirmation Cohort
Pre-injection medication
X
X
TAK-079 SC injection (f)
X
X
Dosing Patients in Combination Cohort Only
Pre-injection medication
X
X
TAK-079 SC injection (f)
X
X
Pomalidomide
Day 1-21 each cycle
Dexamethasone
Day 1, 8, 15, and 22 each cycle
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TAK-079
Study No. TAK-079-1501
Page 155 of 160
Protocol Incorporating Amendment 03
02 April 2019
Treatment Period Continued: Cycles 7 to Follow-up and Overall Survival Follow-up
Study Period (Phases 1 and 2a)
Treatment Phase
(Monthly; Every 4 Weeks; to PD)
Follow-Up Phase
Cycle 7
Cycle 8 and beyond
EOT/Early Termination
PFS Follow-Up
Every 4 Weeks
OS 
Follow-Up 
Every 12 Weeks
Cycle Day
C7D1
C8D1, CXD1
Up to 30 days After Last 
Dose
--------
--------
Window Allowed
±2 days
±2 days
±7 days
7 days
7 days
Laboratory assessments
Serum chemistry (g) 
X
X
X
Hematology (h)
X
X
X
Urinalysis (i)
X
X
X
Pregnancy test (j) (k) 
X
X
X
Response assessments for MM
Investigator disease assessment (t)
X
X
X
X
Serum M-protein 
X
X
X
X
Urine M-protein (l)
X
X
X
X
Serum FLC assay (m) 
X
X
X
X
Immunofixation - serum and urine (n)
X
X
X
Quantification of Ig 
X
X
X
Skeletal survey: WB X-ray, CT, low dose CT, 
PET-CT, or MRI scan (o)
X
Biological assessments
Bone marrow aspiration (BMA) (p)
X
X (Cycle 13 only)
Serum sample for TAK-079 PK (q) 
X
X
X
Serum sample for immunogenicity (ADA/titer) (s)
X
X
X
Serum sample for direct and indirect Coombs test
X
X
X
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TAK-079
Study No. TAK-079-1501
Page 156 of 160
Protocol Incorporating Amendment 03
02 April 2019
Treatment Period Continued: Cycles 7 to Follow-up and Overall Survival Follow-up
Study Period (Phases 1 and 2a)
Treatment Phase
(Monthly; Every 4 Weeks; to PD)
Follow-Up Phase
Cycle 7
Cycle 8 and beyond
EOT/Early Termination
PFS Follow-Up
Every 4 Weeks
OS 
Follow-Up 
Every 12 Weeks
Cycle Day
C7D1
C8D1, CXD1
Up to 30 days After Last 
Dose
--------
--------
Window Allowed
±2 days
±2 days
±7 days
7 days
7 days
Subsequent anticancer therapy 
X
X
Survival (u)
X
Footnotes begin on the next page.
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TAK-079
Study No. TAK-079-1501
Page 159 of 160
Protocol Incorporating Amendment 03
02 April 2019
Appendix E
IMWG Criteria 
…..
IMWG Uniform Criteria for Response [17,18,2421,22,33]
Category of 
Response
Response Criteria
sCR
Criteria for CR as defined below, with the addition of a normal FLC ratio, and an absence of clonal plasma 
cells by immunohistochemistry or 2- to 4-color flow cytometry; 2 consecutive assessments of laboratory 
parameters are needed (a).
CR
Negative immunofixation of serum and urine, disappearance of any soft tissue plasmacytomas, and <5% 
plasma cells in bone marrow; bone marrow; in patients for whom only measurable disease is by serum 
FLC level, normal FLC ratio of 0.26 to 1.65 in addition to CR criteria is required; 2 consecutive 
assessments are needed (b).
Immunophenotypic 
CR
sCR as defined, plus absence of phenotypically aberrant plasma cells (clonal) in bone marrow with 
minimum of 1 million total bone marrow cells analyzed by multiparametric ﬂow cytometry (with >4 
colors).
Molecular CR
CR as deﬁned, plus negative allele-speciﬁc oligonucleotide polymerase chain reaction (sensitivity 10-5).
VGPR
Serum and urine M-protein detectable by immunofixation but not on electrophoresis, or ≥90% reduction 
in serum M-protein plus urine M-protein <100 mg/24 hours; in patients for whom only measurable disease 
is by serum FLC level, >90% decrease in difference between involved and uninvolved FLC levels, in 
addition to VGPR criteria, is required; 2 consecutive assessments are needed (c).
PR
≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to <200 
mg/24 hours.
If the serum and urine M-protein are not measurable, a ≥50% decrease in the difference between involved 
and uninvolved FLC levels is required in place of the M-protein criteria.
If serum and urine M-protein are not measurable, and serum FLC is also not measurable, ≥50% reduction 
in bone marrow plasma cells is required in place of M-protein, provided the baseline percentage was 
≥30%.
In addition to the above criteria, if present at baseline, ≥50% reduction in the size of soft tissue 
plasmacytomas is also required.
Two consecutive assessments are needed (a) no known evidence of progressive or new bone lesions if 
radiographic studies were performed.
Minimal response 
(MR) (b)
≥25% but ≤49% reduction of serum M-protein and reduction in 24-hour urine M-protein by 50% to 89%.
In addition to the above criteria, if present at baseline, 25% to 49% reduction in the size of soft tissue 
plasmacytomas is also required.
No increase in size or number of lytic bone lesions (development of compression fracture does not exclude 
response).
In this study, in patients that have myeloma measurable by serum free light chains, MR will be 
defined as a reduction of ≥25 but ≤49% in the difference between involved and uninvolved FLC 
levels.
SD (c)
Does not meet the response criteria for CR (any variant), VGPR, PR, MR, or PD; no known evidence of 
progressive or new bone lesions if radiographic studies were performed.
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Study No. TAK-079-1501
Page 160 of 160
Protocol Incorporating Amendment 03
02 April 2019
Source: Rajkumar SV et al, 2011 and Palumbo A et al, 2014 [17,1821,22].
CR=: complete response; FLC=: free light chain; IMWG=: International Myeloma Working Group; MR=:minimal response; 
ORR=: overall response rate; PR=: partial response; sCR=: stringent complete response; SD=: stable disease; VGPR=: very good 
partial response.
(a) Clonality should be established by showing κλ light-chain restriction on ﬂow cytometry, immunohistochemistry, or 
immunoﬂuorescence. Bone marrow plasma cell percentage should preferably be estimated from a core biopsy specimen; in case of 
a disparity between the aspirate and core biopsy, the highest value should be used.
(b) For relapse-refractory myeloma only.
(c) These categories do not contribute to the ORR.
……
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SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN
NCT Number:
Study Title:
SAP Versions and Date:
Version 1.0: 11 January 2021 
NCT03439280
A Phase 1/2a Open-label, Dose-Escalation Study to Investigate 
the Safety and Tolerability, Efficacy, Pharmacokinetics, and 
Immunogenicity of TAK-079 Administered Subcutaneously as a 
Single Agent in Patients With Relapsed/Refractory Multiple 
Myeloma
TAK-079-1501
Study Number:
Property of Takeda: For non-commercial use only and subject to the applicable 
ple
ble
ple
Terms 
as a 
Te
as a 
of Use


STATISTICAL ANALYSIS PLAN
STUDY NUMBER: TAK-079-1501
A Phase 1/2a Open-label, Dose-Escalation Study to Investigate the Safety and Tolerability, 
Efficacy, Pharmokinetics, and Immunogenicity of TAK-079 Administered 
Subcutaneously as a Single Agent in Patients with Relapsed/Refractory Multiple Myeloma
PHASE 1/2a
Version: V1.0
Date: 11 January 2021
Prepared by:
, PhD
Based on:
Protocol Version: 03
Protocol Date: 02 April 2019
CONFIDENTIAL PROPERTY OF TAKEDA
Property of Takeda
or non-commercial use only and subject to the applicable Terms of Use
he Safet
the 
he Safet
AK
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AK-
o
-079 
o th
079 
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11 Janu
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Prot
f T
Prot


TAK-079
Study No. TAK-079-1501
Page 2 of 28
Statistical Analysis Plan
11 January 2021
This document is a confidential communication of Takeda. Acceptance of this document 
constitutes the agreement by the recipient that no information contained herein will be published 
or disclosed without written authorization from Takeda.
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f




TAK-079
Study No. TAK-079-1501
Page 4 of 28
Statistical Analysis Plan
11 January 2021
2.0
TABLE OF CONTENTS
1.0
TITLE PAGE ..................................................................................................................1
1.1
Approval Signatures ............................................................................................... .3
2.0
TABLE OF CONTENTS........................................................................................... .....4
3.0
LIST OF ABBREVIATIONS..........................................................................................6
4.0
OBJECTIVES ............................................................................................. ...................8
4.1
Primary Objective.............................................................................. . .....................8
4.2
Secondary Objectives.................................................................. .... .........................8
4.3
Exploratory Objectives ........................................................... .................................9
4.4
Study Design ................................................................... .........................................9
5.0
ANALYSIS ENDPOINTS.............................................................................................12
5.1
Primary Endpoint................................................... . ...............................................12
5.2
Secondary Endpoints .......................................... ....................................................12
5.3
Exploratory Endpoint................................. .. .........................................................13
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................14
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................15
7.1
General Principles...................... . . .........................................................................15
7.1.1 Study Definitions..................... ..................................................................................15
7.1.2 Definition of Study Days .... .......................................................................................15
7.1.3 Definition of Study Visit Windows.............................................................................15
7.1.4 Conventions for Missing Adverse Event Dates ...........................................................15
7.1.5 Conventions for Missing Concomitant Medication Dates............................................16
7.2
Analysis Sets ..........................................................................................................17
7.3
Disposition of Subjects ............................................................................................17
7.4
Demographic and Other Baseline Characteristics.....................................................18
7.5
Medical History and Concurrent Medical Conditions...............................................19
7.6
Medication History and Concomitant Medications...................................................19
7.7
Study Drug Exposure and Compliance.....................................................................20
7.8
Efficacy Analysis.....................................................................................................20
7.9
Pharmacokinetic/
 Analysis ..........................................................22
7.9.1
Pharmacokinetic Analysis ..................................................................................22
7.9.2
22
7.10
Other Outcomes.......................................................................................................23
7.10.1 Immunogenicity Analyses..................................................................................23
7.11
Safety Analysis........................................................................................................23
For non-commercial use only and subject to the applicable Terms of Use
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Study No. TAK-079-1501
Page 5 of 28
Statistical Analysis Plan
11 January 2021
7.11.1 Adverse Events ..................................................................................................23
7.11.2 Clinical Laboratory Evaluations .........................................................................25
7.11.3 Vital Signs ........................................................................................................ 26
7.11.4 12-Lead ECGs .............................................................................................. ....26
7.11.5 Other Observations Related to Safety....................................................... .........26
7.12
Interim Analysis ................................................................................... . ...............26
7.13
Changes in the Statistical Analysis Plan............................................ .. ...................27
8.0
REFERENCES................................................................................. . . ........................28
pplicable Terms of Use
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Property of Takeda: For non-commercial use only and subject to the app
. . . ..
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TAK-079
Study No. TAK-079-1501
Page 6 of 28
Statistical Analysis Plan
11 January 2021
3.0
LIST OF ABBREVIATIONS
AE
adverse event
ANC
absolute neutrophil count
CI
confidence interval
CMH
Cochran-Mantel-Haenszel
CR
complete response 
del
deletion
DOR
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EOT
End of Treatment (visit)
FA
final analysis
FDA
United States Food and Drug Administration
GCP
Good Clinical Practice
HR
Hazard Ratio
HU
health utilization
IA
interim analysis
IDMC
independent data monitoring committee
IMiD
immunomodulatory drug
IMWG
International Myeloma Working Group
IRC
independent review committee
ITT
intent-to-treat
K-M
Kaplan-Meier
line of therapy
1or more cycles of a planned treatment program; this may consist of 1 or more 
planned cycles of single-agent therapy or combination therapy, as well as a 
sequence of treatments administered in a planned manner (eg, a planned 
treatment approach of induction therapy followed by autologous SCT, followed 
by maintenance is considered 1 line of therapy).[1]  Typically each line of 
therapy is separated by progressive disease.
MedDRA
Medical Dictionary for Regulatory Activities
MID
minimally important difference
MM
multiple myeloma
MTD
Maximum tolerated dose
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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TAK-079
Study No. TAK-079-1501
Page 7 of 28
Statistical Analysis Plan
11 January 2021
NCI
National Cancer Institute
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
ORR
overall response rate
OS
overall survival
PD
progressive disease (disease progression)
PFS
progression-free survival
PK
pharmacokinetic(s)
PN
peripheral neuropathy
PR
partial response 
PRO
patient-reported outcome
PSMB1
Proteasome subunit beta type-1
QTc
rate-corrected QT interval (millisec) of electrocardiograph
RP2D
recommended phase 2 dose
RRMM
relapsed and/or refractory multiple myeloma
SAE
serious adverse event
SAP
statistical analysis plan
sCR
stringent complete response
SD
stable disease
t
translocation
TTP
time to progression
VGPR
very good partial response
WHO
World Health Organization
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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TAK-079
Study No. TAK-079-1501
Page 8 of 28
Statistical Analysis Plan
11 January 2021
4.0
OBJECTIVES
4.1
Primary Objective
Phase 1
The primary objective of the phase 1 portion of the study is to determine the safety and 
tolerability of TAK-079 monotherapy and when combined with a backbone regimen of PomDex
in patients with RRMM.
Phase 2a
The primary objective of the phase 2a portion of the study is to provide a preliminary evaluation 
of the clinical activity of TAK-079 monotherapy in patients with RRMM.
4.2
Secondary Objectives
Phase 1
The phase 1 secondary objectives are:

To investigate a potential MTD/RP2D of TAK-079 as a single agent and when added to a 
backbone regimen of PomDex. 

To evaluate the immunogenicity of TAK-079 as a single agent and when added to a 
backbone regimen of PomDex.

To characterize the PK of TAK-079 as a single agent and when added to a backbone regimen 
of PomDex.

To provide a preliminary evaluation of the clinical activity of TAK-079 as a single agent and 
when added to a backbone regimen of PomDex.
Phase 2a
The phase 2a secondary objectives are:

To further evaluate safety at the MTD/RP2D.

To provide a preliminary evaluation of time-to-event measures.

To further evaluate the immunogenicity of TAK-079.

To further characterize the PK of TAK-079.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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TAK-079
Study No. TAK-079-1501
Page 10 of 28
Statistical Analysis Plan
11 January 2021
lenalidomide-resistant disease; thus, alternatives to lenalidomide are required in later lines of 
therapy. Pomalidomide with dexamethasone is approved for patients following therapy with
lenalidomide and a proteasome inhibitor; however, the duration of response is short (7.4 months) 
[20]. Evidence is emerging that adding an IV administered anti-CD38 agent to PomDex can help 
prolong response duration [23]. TAK-079, a SC administered anti-CD38 monoclonal antibody, is 
showing early signs of antimyeloma activity as a monotherapy in patients with advanced 
RRMM. Adding TAK-079 to the PomDex backbone could provide benefit to patients both in 
terms of improved antimyeloma activity over each agent alone, and would be more convenient to 
patients as compared with administration of IV administered anti-CD38 agents (ie, a TAK-079, a 
SC agent, added to the all oral PomDex regimen). Hence a new cohort will open to evaluate this 
combination. Information about the dose, safety, and activity of TAK-079 added to a standard 
backbone regimen of PomDex in patients with RRMM who have received at least 2 prior 
therapies and have demonstrated PD on or within 60 days of the completion of the last therapy
will be collected. 
The preliminary efficacy of TAK-079, as monotherapy and when added to PomDex, will be 
evaluated by measuring the ORR, defined as the proportion of patients who achieved a PR or 
better during study, as defined by IMWG (Appendix E; [21,22]). In addition, the efficacy of 
TAK-079 will be assessed by measuring MR, PFS, DOR, and OS; TTR will also be measured. 
Once enrolled into the phase 1 Dose Escalation phase, patients will receive TAK-079 via SC 
administration in each 28 day cycle of treatment, administered as once weekly for 8 weeks (8 
doses), once every 2 weeks for 16 weeks (8 doses), and once every 4 weeks thereafter until PD. 
Patients will receive ongoing treatment with TAK-079 until they experience PD, unacceptable 
toxicities, or withdraw due to other reasons (see Section 6.3). 
In the phase 1 Confirmation Cohort Phase, patients will receive TAK-079 via SC administration 
in each 28-day cycle of treatment, administered at a dose of 300 mg once weekly for 8 weeks (8 
doses), once every 2 weeks for 16 weeks (8 doses), and then once every 4 weeks thereafter until 
PD.
•
In this cohort, up to 6 patients that are refractory to an anti-CD38 agent will be enrolled.
•
Further in this cohort, approximately 12 patients that have RRMM disease (per prior 
therapy inclusion criteria Section 7.0) and are naïve to an anti-CD38 agent will be enrolled.
In the Combination Cohort, patients will receive TAK-079 via SC administration in each 28-day
cycle of treatment, administered at a dose of 300 mg once weekly for 8 weeks (8 doses), once 
every 2 weeks for 16 weeks (8 doses), and then once every 4 weeks thereafter until PD. PomDex 
will be administered according to the product labeling (Pomalyst UPSI, including Section 14.1).
•
In this cohort, up to 6 patients will initially be enrolled. Safety in Cycle 1 will be 
reviewed in accordance with DLT definitions in Section 8.2.
•
If 0 of 6 or 1 of 6 patients develop a DLT an additional 12 patients will be tested at the 
initial dose of TAK-079 [6 patients that are naïve to a prior anti-CD38 agent and 6 patients that 
have been exposed to a prior anti-CD38 agent], for an overall total of 18 patients.
•
If 2 of 6 patients develop DLTs all available data will be reviewed before making 
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TAK-079
Study No. TAK-079-1501
Page 11 of 28
Statistical Analysis Plan
11 January 2021
decisions about study conduct (See details in Section 8.5). 
The Confirmation Cohort and the Combination Cohort may start in parallel and will run 
independently. 
All cohorts will consist of the following phases/periods: screening, treatment, and follow-up:
•
Screening period (visit 1): Days -21 to Day -1.
•
Treatment period (visit 2/ongoing): 
•
Original dose Escalation Cohort: once-weekly treatment for 8 doses (Cycles 1 and 2), 
starting on Day 1, followed by treatment once every 2 weeks for 8 doses (Cycles 3-6), followed 
by treatment once every 4 weeks thereafter (Cycle 7 and beyond), continuing until patients 
experience PD, unacceptable toxicities, or withdrawal due to other reasons. 
•
Dose Confirmation Cohort: once weekly for 8 weeks in Cycles 1 and 2 (8 doses), once 
every 2 weeks for 16 weeks (8 doses) in Cycles 3 to 6, and once every 4 weeks thereafter (Cycles 
7 and beyond) until PD.
•
Combination Cohort: once weekly for 8 weeks in Cycles 1 and 2 (8 doses), once every 2 
weeks for 16 weeks (8 doses) in Cycles 3 to 6, and once every 4 weeks thereafter (Cycles 7 and 
beyond) until PD. PomDex will be administered according to the product labeling (Pomalyst 
UPSI, including Section 14.1 describing dexamethasone dosing).
•
Follow-up period (end of treatment [EOT] visit): Patients who discontinue study
treatment will be followed for approximately 30 days after the last dose of study drug or until the 
start of subsequent alternative anticancer therapy to monitor safety/AEs. Patients who 
discontinue treatment for reasons other than PD will continue to be followed for PFS every 4 
weeks from the EOT visit until PD, death, the start of subsequent anticancer therapy, study
termination, or 12 months after discontinuation of study treatment, whichever occurs first. 
Patients who discontinue for PD will be followed for OS after the EOT visit. All patients will be 
followed for OS every 12 weeks until death, loss to follow-up, consent withdrawal, or study
termination.
In phase 1, approximately 6 doses will be evaluated in ascending cohorts of 3 to 6 patients per 
cohort. Cohorts may be expanded by enrolling additional patients to further inform selection of 
the RP2D. Dose selection for phase 2a will take place after review of the available safety,
efficacy, PK, 
 data obtained from the phase 1 portion of the study.
In the phase 1 dose Confirmatory Cohort, approximately 18 patients will be enrolled at 1 dose 
(300 mg); 12 patients will have been previously treated (see Section 7.0), up to 6 patients will 
have been previously treated and are refractory to an anti-CD38 therapy (see Section 7.0). In the 
Combination Cohort, approximately 18 patients will be enrolled who have received prior therapy 
and have demonstrated PD on or within 60 days of completion of the last therapy, note Section 
7.0.
It is expected that approximately 100 patients will be enrolled in total for the phase 1 cohorts and 
phase 2a combined.
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TAK-079
Study No. TAK-079-1501
Page 14 of 28
Statistical Analysis Plan
11 January 2021
6.0
DETERMINATION OF SAMPLE SIZE
It is expected that approximately 100 patients will be enrolled in total for phase 1 and 2a 
combined. Once the RP2D is determined in phase 1, approximately 48 patients will be treated in 
phase 2a to provide a preliminary estimate of the ORR in patients with RRMM.
A 3+3 dose escalation schema will be used for dose escalation as described in Section 4 4
A group of 3 to 6 patients will be enrolled in each TAK-079 dose cohort based on safety, 
clinical, PK,
 data. Each patient will participate in only 1 dose cohort. The 
actual dose levels may be adjusted based on the observed safety profile. 
Additional patients may be enrolled in a limited cohort expansion to confirm the safety and 
receptor occupancy on tumor cells before the phase 2a of this study is opened to enrollment. In 
the phase 1 dose Confirmatory Cohort, approximately 18 patients will be enrolled at 1 dose and 
schedule: 12 patients with RRMM that is anti-CD38 naive and up to 6 patients with RRMM that 
is refractory to an anti-CD38 therapy. In the Combination Cohort, approximately 18 patients 
with RRMM that has been previously treated with at least 2 prior therapies and that is refractory
to the last therapy will be enrolled. 
In phase 2a, up to a total of 48 patients will be treated to provide a preliminary estimate of the 
ORR in 2 expansion cohorts of patients with RRMM: up to 24 patients with RRMM that is anti-
CD38 naive and up to 24 patients with RRMM that is refractory to an anti-CD38 therapy. Phase 
2a of the study will also provide a more robust estimate of the safety profile to determine 
whether the MTD is appropriate for future studies as the RP2D.
No prospective calculations of statistical power have been made; however, Table 6.a shows the 
width of the 80% CI, based on the observed ORR in a cohort size of 24 patients, for a range of 
observed response rates. 
Table 6.a
80% Confidence Interval Based on the Observed ORR
N = 24 patients.
ORR: overall response rate.
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TAK-079
Study No. TAK-079-1501
Page 15 of 28
Statistical Analysis Plan
11 January 2021
7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
General Principles 
All statistical analyses will be conducted using SAS® Version 9.2, or higher.
Where appropriate, variables will be summarized descriptively by study visit. For categorical 
variables, the count and proportions of each possible value will be tabulated by treatment group. 
The denominator for the proportion will be based on the number of subjects who provided non-
missing responses to the categorical variable. For continuous variables, the number of subjects 
with non-missing values, mean, median, standard deviation (SD), minimum, and maximum 
values will be presented by treatment group. For time-to-event data, the Kaplan-Meier survival 
curves and 25th, 50th (median), and 75th percentiles will be provided along with their
confidence intervals (CIs).
Means and medians will be presented to 1 more decimal place than the recorded data. SDs and 
CIs about a parameter estimate will be presented to 2 more decimal places than the recorded 
data.
All confidence intervals, statistical tests, and resulting P-values will be reported as 2-sided and 
will be assessed at α=0.05 significance level unless otherwise stated. P-values will be rounded to 
3 decimal places prior to assessment of statistical significance. 
The summary tables will be presented for each dose cohort, combination cohorts, pooled cohorts 
in phase 1 portion, RP2D cohort, and all patients.  
Baseline values are defined as the last observed value before the first dose of study medication. 
7.1.1 Study Definitions
7.1.2 Definition of Study Days
Study Day 1 is defined as the date on which a subject is administered their first full dose of the 
medication. Other study days are defined relative to Study Day 1 with Day 1 being Study Day 1 
and Day -1 being the day prior to Study Day 1.
7.1.3 Definition of Study Visit Windows
All data will be categorized on the basis of the visit at which they are collected.  Visit
designators are predefined values that appear as part of the visit tab in the electronic case report 
form (eCRF). Summaries will be provided for scheduled visits only.
7.1.4 Conventions for Missing Adverse Event Dates
           Adverse events with start dates that are completely or partially missing will be imputed as 
follows:

If month and year are known but day is missing 
oIf month and year are the same as month and year of 1st dose date, then 1st dose date will 
be imputed.
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TAK-079
Study No. TAK-079-1501
Page 16 of 28
Statistical Analysis Plan
11 January 2021
oIf month and year are different than month and year of 1st dose date, then 1st date of the 
month will be imputed.

If year is known but day and month are missing 
oIf year is same as year of 1st dose date, then 1st dose date will be imputed.
oIf year is different than year of 1st dose date, then 1st of January of the year will be 
imputed.

If all is missing, then 1st dose date will be imputed.
Imputing missing AE start date is mandatory. After imputation, all imputed dates are checked 
against the stop dates to ensure that start dates do not occur after stop dates. If an imputed start date 
occurs after the stop date, then change the imputed start date to be the same as the stop date. 
Adverse events with stop dates that are completely or partially missing will be imputed as follows:

If “ongoing” is checked, no imputation is necessary.

If month and year are known but day is missing, the last day of the month will be imputed.

If year is known, but day and month are missing
o
If YYYY < year of last dose, then 31st of December will be imputed.
o
If YYYY = year of last dose, then 31st of December will be imputed.
o
If YYYY > year of last dose, then 1st of January will be imputed.

If all are missing, then 31st of December in the year of last dose will be imputed. 
Imputing missing AE stop date is not mandatory if AE is regarded as ongoing. However if it 
is to be done, the rules are outlined above. If subject dies, then use death date for AE stop date. 
After imputation, all imputed dates are checked against start dates to ensure that stop dates do not 
occur before start dates. If an imputed stop date occurs prior to the start date, then change the 
imputed stop date to be the same as the start date. 
7.1.5 Conventions for Missing Concomitant Medication Dates
Subsequent therapies recorded as concomitant medications with missing/partial start dates will 
be imputed as follows:

When month and year are present and the day of the month is missing, 
o
If the month and year of the start date are the same as the month and year of
treatment termination, the day of treatment termination or the day-component of the 
stop date, whichever comes first, is imputed.  
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TAK-079
Study No. TAK-079-1501
Page 18 of 28
Statistical Analysis Plan
11 January 2021
7.4
Demographic and Other Baseline Characteristics
Demographics
Demographics will be summarized by each dose cohort in a descriptive fashion in the ITT 
population. Demographic data at study entry to be evaluated will include age, sex, race, 
ethnicity, height, weight and ECOG status.
Disease Specific History
Disease specific history will be summarized to include type of immunoglobulin at diagnosis, 
Durie-Salmon stage at diagnosis, International Stage System (ISS) at diagnosis, evidence of lytic 
bone disease and extramedullary disease, prior therapies (number of patients with prior therapy, 
lines of prior therapies,  best hematological response to prior therapy, type of prior therapy in the 
format of therapy contained, number of patients who received anti-CD38 monoclonal antibody 
[e.g., daratumumab, isatuximab] as the last line of prior therapy, number of patients refractory to 
any line of prior therapy, prior radiation site and dose, prior surgery), and months from prior 
diagnosis to the first dose of TAK-079. Disease specific history will be summarized and listed by 
cohorts and for all patients if there is sufficient data for analysis. The months from prior 
diagnosis to the first dose of TAK-079 is calculated by 
first dose date - date of diagnosis 
365.25/12
Disease specific characteristics will be presented in by-patient listings.
Baseline characteristics
Baseline disease characteristics will be summarized by cohorts and for all patients including 
serum M-protein, urine M-protein, serum free light chain, serum free light chain ratio, 
2
-
microglobulin and its category (i.e., < 2.5, 2.5-5.5, > 5.5 mg/L), serum creatinine and its 
category, (<=2, >2 mg/dL), calculated creatinine clearance and its category (<30, 30-<60, 60-
<90, >=90 mL/min), serum albumin by category (i.e., <3.5,  >=3.5 g/dL), corrected calcium, 
hemoglobin, platelet count, neutrophil count, LDH and Eastern Cooperative Oncology Group 
(ECOG) performance status. 
Creatinine clearance will be calculated using the Cockcroft-Gault formulas as follows:
For male patients: 
For female patients:
Integer values will be used. 
[mg/dL])
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(serum
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TAK-079
Study No. TAK-079-1501
Page 19 of 28
Statistical Analysis Plan
11 January 2021
For patients with heavy chain, the patient’s type of myeloma is determined by the combination of 
heavy chain type (IgG, IgA, IgM, IgD, and other) and light chain type (Kappa, Lambda, and 
biclonal). In descriptive summaries, the disease will be categorized by the heavy chain type first, 
then within each of these categories, patients will be further classified according to their light 
chain type. For patients with light chain only, patients will be classified according to their light 
chain type.
Extent of disease and bone marrow cytogenetic results at baseline
The extent of disease at baseline will be summarized including number of patients with a bone 
marrow aspirate, bone marrow aspirate results (% plasma cells), number of patients with a bone 
marrow biopsy, bone marrow biopsy results (% plasma cells, % cellularity, type of cellularity, % 
Kappa/Lambda ratio performed), skeletal survey results (normal, abnormal not clinically 
significant, abnormal clinically significant, and not done) and imaging including magnetic 
resonance imaging (MRI) / computed tomography (CT) results (normal, abnormal not clinically
significant, abnormal clinically significant, and not done), number and percentage of lytic bone 
lesions present,  number of extramedullary plasmacytoma present, size of measurable 
plasmacytoma (longest diameter and longest perpendicular) and site of extramedullary 
plasmacytoma. 
Bone marrow cytogenetic results at baseline from the conventional/karyotype and 
molecular/FISH cytogenetic analyses methods will be displayed. The results will be categorized 
as “Normal”, “Abnormal” and “Indeterminate”. The percentage of each category will be 
summarized.  Abnormal types of interest, including but not limited to, del 13, del 17, t(4;14), 
t(11;14), t(14;16), -13q, -17p, hyperdiploidy, hypodiploidy and high risk cytogenetics group (del
17, -17p, t(4,14) or t(14,16)), will also be tabulated. 
By-patient listings for these baseline characteristics will also be presented.
7.5
Medical History and Concurrent Medical Conditions
General medical history data including prior therapies, prior radiation, prior surgery and prior 
transplant will be summazied. A by-patient listing will also be presented. 
7.6
Medication History and Concomitant Medications
Concomitant medications will be coded by generic term using the World Health Organization 
(WHO) Drug Dictionary.  The number and percentage of patients taking concomitant 
medications will be tabulated by WHO drug generic term from the first dose of study treatment 
through 30 days after the last dose of study medication. Concomitant procedures will not be 
coded.
Concomitant medications and procedures will be presented in by-patient listings and summazied 
table.
non-commercial use only and subject to the applicable Terms of Use
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TAK-079
Study No. TAK-079-1501
Page 20 of 28
Statistical Analysis Plan
11 January 2021
7.7
Study Drug Exposure and Compliance
A patient will be considered as treated in a cycle as long as this patient received any amount of
study drug in that cycle. A treatment cycle is defined as a cycle in which the patient received any 
amount of study drug. 
Relative dose intensity is defined as 100*(dose intensity (mg/week)/ planned dose intensity 
(mg/week)), where dose intensity is defined as (total amount of dose taken (mg) / treatment 
duration (weeks)) and planned dose intensity = (total planned amount of dose taken (mg) / 
planned treatment duration (weeks)). An RDI of 100% indicates that the drug was administered 
at the right dose within the planned timeframe (e.g. every 28 days). 
The exposure to study drug will be summarized including the extent of exposure in days, number 
of cycles, total amount of dose taken (in mg), total number of doses taken, number and 
percentages of patients by treatment cycles, and relative dose intensity. Aggregate summary of
numbers and percentages of patients who had 1-6, 7-12, and ≥13 treatment cycles will also be 
presented in the same table. Test dose will be excluded from exposure calculations and 
summaries.
The number of patients with 100% relative dose intensity, 80% to < 100%, 50% to <80%, and 
<50% will be summarized by dose level and for all patients. 
All the summazied tables will be presented by TAK-079, Pomalidomide and Dexamethasone 
separately. Dosing data will also be presented in a by-patient listing.
7.8
Efficacy Analysis
All available efficacy data will be included in data listings and tabulated by each dose cohort, 
combination cohorts, pooled cohorts in phase 1 portion, RP2D cohort, and all patients. Data that 
are potentially spurious or erroneous will be examined according to standard data management 
operating procedures. In general, missing data will be treated as missing, and no data imputation 
will be applied, unless otherwise specified. 
Response will be assessed according to the International Myeloma Working Group (IMWG)
criteria for all patients. Best M-Protein Response to Treatment is defined as the percent change
from baseline to best (lowest) value post-baseline in serum M-protein for subjects with
measurable serum M-protein at baseline; for subjects with non-measurable serum M-protein but
measurable urine M-protein, it is the percent change from baseline to best (lowest) value post-
baseline in urine M-protein. Best M-Protein Response to Treatment will be tabulated by
categories of % reduction (e.g., 100 % reduction, >=90% reduction, >=50% reduction, 90%-
100% reduction, 75-90% reduction, 50%-75% reduction, 25%-50% reduction, <25% Reduction 
to <25% Increase, >=25% Increase). No Post-Baseline Assessment of Measurable M-Protein will
also be tabulated.
Overall Response Rate
The ORR is defined as the proportion of patients who achieved a confirmed PR or better during 
study per investigator assessment; sCR, CR, VGPR, and PR as defined by IMWG Uniform 
keda: For non-commercial use only and subject to the applicable Terms of Use
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TAK-079
Study No. TAK-079-1501
Page 21 of 28
Statistical Analysis Plan
11 January 2021
Response Criteria [1]. The ORR is determined from the start of the study treatment until the end 
of treatment, taking into account any requirement for confirmation. To calculate the confirmed 
response, 1 visit after end of treatment (EOT) is used to confirm the assessment at EOT. ORR 
will be summarized by frequencies and percentages.
Duration of Response (DOR)
Duration of response is defined as the time from the date of first documentation of a confirmed 
PR or better to the date of first documentation of PD for responders. Responders without 
documentation of PD will be censored at the date of their last response assessment that is SD or 
better and prior to initiation of alternative therapy. 
Progression Free Survival (PFS)
PFS is defined as the time from the date of first dose until the sooner of the date of PD, defined 
by IMWG criteria, or the date of death due to any cause. Patients without documentation of PD 
or death will be censored at the date of the last response assessment that is SD or better prior to 
the date of initiation of alternative therapy. Patients with no response assessment will be 
censored at the date of first dose. 
Overall Survival (OS)
OS is defined as the date of first dose to the date of death due to any cause. Patients without 
documentation of death at the time of analysis will be censored at the date last known to be alive.
Time to Response (TTR)
Time to response is defined as the time from first dose to the date of first documentation of 
response (PR or better).
Time to Best Response
Time to response is defined as the time from first dose to the date of first instance of confirmed 
best response.
Time to Progression (TTP)
TTP is defined as the time from first dose to time of progressive disease.
In general, time-to-event data will be summarized by 25th, 50th (median), and 75th percentiles 
with associated 2-sided 95% confidence intervals, as well as the KM estimate at 6, 9, 12, 18 and 
24 months. In addition, the percent of censored observations with reasons will also be 
summarized.
The response rates, DOR, time to response, and time to best response will be analyzed based on 
Response-Evaluable analysis sets. PFS and OS will be analyzed based on safety analysis sets. 
Time-to-event endpoints will be analyzed using standard survival analysis techniques based on 
Kaplan-Meier estimates. 
a: For non-commercial use only and subject to the applicable Terms of Use
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TAK-079
Study No. TAK-079-1501
Page 23 of 28
Statistical Analysis Plan
11 January 2021
7.10
Other Outcomes
7.10.1 Immunogenicity Analyses
The proportion of subjects with positive ADA (transient and persistent) during the study will be 
summarized. The proportion of patients in phase 2a with positive neutralizing ADA during the 
study may be summarized. The effect of immunogenicity on PK, safety, and efficacy will be 
examined. NABs may also be assessed in patients.
The immunogenicity of TAK-079 will be assessed by determining anti–TAK-079 antibody
incidence and characteristics (eg, titer, transiently, and persistently ADA, and possibly 
neutralizing activity). Analysis will be based on available data from patients with a baseline 
assessment and at least 1 post-baseline immunogenicity assessment (from the immunogenicity 
analysis set). Summaries will be provided separately for each study phase and by dose, as 
applicable. The incidence of immunogenicity will be calculated. The impact of anti–TAK-079
antibodies on the PK profile, drug efficacy, and clinical safety will be evaluated, if possible. 
These analyses will be exploratory in nature, and all results will be descriptive in nature. 
7.11
Safety Analysis
7.11.1 Adverse Events
Adverse events
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). AEs will be reported from the first dose of study drug through 30 days after 
administration of the last dose of study drug. Treatment-emergent is defined as any AE that 
occurs after administration of the first dose of any study treatment through 30 days after the last 
dose of any study treatment. 
All AEs will be presented in a by-patient listing. AEs will be tabulated according to the 
MedDRA by system organ class, high level terms and preferred terms. Summary tabulations by 
each dose cohort, combination cohorts, pooled cohorts in phase 1 portion, RP2D cohort, and all 
patients will be provided for the following categories: 

Treatment-emergent AEs

Drug-related treatment-emergent AEs

Grade 3 or higher treatment-emergent AEs (also grade 3 only and 4 only will be reported 
separately)

Grade 3 or higher drug-related treatment-emergent AEs (also grade 3 only and 4 only will 
be reported separately)

The most commonly reported treatment-emergent AEs (i.e., those events reported by
>= 10% of all patients)

Serious adverse events related and regardless of relationship
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TAK-079
Study No. TAK-079-1501
Page 24 of 28
Statistical Analysis Plan
11 January 2021

Treatment-emergent AEs resulting in study drug reduction

Treatment-emergent AEs resulting in any study drug discontinuation
Patients with the same AE more than once will have that event counted only once within each 
body system, once within each high level term, and once within each preferred term. Patients 
with the same AE more than once will have the maximum intensity of that event counted once 
within each body system, once within each high level term, and once within each preferred term.
Drug-related treatment-emergent AEs will also be summarized by the National Cancer Institute 
Common Toxicity Criteria (NCI CTCAE) version 4.03 AE [2]. 
Most commonly reported (at least 10% of all patients) treatment-emergent AEs will be presented 
by preferred term only.  Patients with the same AE more than once will have that event counted 
only once within each preferred term.
An overall summary AE table will include numbers and percentages of patients who had any AE, 
drug-related AE, grade 3 or higher AE, grade 3 or higher drug-related AE, serious AE (SAE), 
drug-related SAE, AE resulting in any drug discontinuation, AE resulting in any dose reduction, 
AE resulting in any dose modification (defined as delay, interruption, reduction or
discontinuation), and on-study deaths. On-study death is defined as the death that occurs between 
the first dose of study drug and up to 30 days after the last dose.
Serious Adverse Events
The number and percentage of patients experiencing at least one treatment-emergent SAE will be 
summarized by MedDRA primary system organ class, high level term, and preferred term. Drug-
related SAEs will be summarized similarly.
In addition, a by-patient listing of the SAEs will be presented (the patient listing will contain all 
SAEs regardless of treatment-emergent AE status).
Deaths
A by-patient listing of the on-study deaths will be presented.  On-study death is defined as the 
death that occurs between the first dose of study drug up to 30 days after the last dose of study
drug.
Adverse Events Resulting in Discontinuation of Study Drug
The number and percentage of patients experiencing at least one adverse event resulting in 
discontinuation of any study drug will be summarized by MedDRA system organ class, high 
level term, and preferred term.
A by-patient listing of treatment-emergent AEs resulting in discontinuation of any study drug 
will be presented.  All AEs resulting in discontinuation of any study drug occurring on-study will 
be displayed.
of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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TAK-079
Study No. TAK-079-1501
Page 26 of 28
Statistical Analysis Plan
11 January 2021

Hematology: ANC, hemoglobin, platelets, 

Serum chemistry: ALT, AST, ALP, creatinine, total bilirubin, calcium, magnesium, 
potassium, sodium, and phosphate.
Summary statistics will also be presented for shift from urinalysis values at study entry.

Urinalysis: Turbidity and Color, pH, specific gravity, protein, ketones, bilirubin, occult 
blood, nitrite, urobilinogen, glucose, leukocytes, microscopic analysis
Mean laboratory values and box plots over time for key lab parameters will be produced, 
including but not limited to ANC, platelets, and liver function tests (ALT, AST, alkaline 
phosphatase, and total bilirubin).
By-patient listings to be presented include hematology, serum chemistry, urinalysis, urine total 
protein, and urine creatinine.
7.11.3 Vital Signs
The actual values of vital sign parameters including temperature, blood pressure, heart rate, and 
body weight, will be summarized over time by cohort, dose level, and overall.  Change from
baseline will also be presented.  
A by-patient listing will also be presented.
7.11.4 12-Lead ECGs
Descriptive statistics for the actual values and changes from baseline in ECGs will be listed by 
time point and summarized by cohort, dose level, and overall. Standard and triplicate ECGs will 
be summarized separately.
Rate-corrected QT interval (millisec) of electrocardiograph (QTc) interval will be calculated 
using Bazett’s correction and Fridericia’s correction.  The formulas are:
QTc (Bazett) = QT / (RR0.5)
QTc (Fridericia) = QT / (RR0.33)
where RR = 60 / heart rate (bpm)
7.11.5 Other Observations Related to Safety
Eastern Cooperative Oncology Group performance status and shifts from baseline to post-
baseline assessment over time, and ECOG score frequency table over time will be summarized
by cohort, dose level, and overall.  Shifts from baseline to the worst post-baseline score will be 
tabulated by cohort, dose level, and overall. Injection related reaction evaluation and severity 
will be summarized by table using safety analysis set and be listed. Pregnancy testing results will 
be presented in a by-patient listing.
7.12
Interim Analysis
An interim analysis of phase I part may be conducted as needed. 
f Takeda: For non-commercial use only and subject to the applicable Terms of Use
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TAK-079
Study No. TAK-079-1501
Page 27 of 28
Statistical Analysis Plan
11 January 2021
7.13
Changes in the Statistical Analysis Plan 
{None}
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-079
Study No. TAK-079-1501
Page 28 of 28
Statistical Analysis Plan
11 January 2021
8.0
REFERENCES
1. Durie BG, Harousseau JL, Miguel JS, Blade J, Barlogie B, Anderson K, et al. International 
uniform response criteria for multiple myeloma. Leukemia 2006; 20(9): 1467-73. 
2. U.S. Department of Health and Human Services, National Institutes of Health National 
Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE). Version 4.03. 
14 June 2010.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
nal
er
nal
Version 
Te
Version