Clinical trial NCT04776018
Conditions: Relapsed and/or Refractory Multiple Myeloma (RRMM)
Keywords: Drug Therapy
Sponsor: Takeda
Start date: 2021-04-20; Completion date: 2023-11-09
Enrollment: 27 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
TAK-981 is being tested in combination with anti-CD38 monoclonal antibodies (mAbs) to treat participants who have relapsed or refractory multiple myeloma (RRMM).

The main aims of the study are to evaluate the safety and efficacy of TAK-981 in combination with anti-CD38 (mAbs) and to determine the recommended Phase 2 dose (RP2D).

Participants will be on this combination treatment for 28-day cycles. They will continue with this treatment until disease progression or unacceptable toxicity.

Detailed description:
The drug being tested in this study is called TAK-981. TAK-981 in combination with an anti-CD38 monoclonal antibody (mAbs) is being tested to treat people who have RRMM. The study will include a dose escalation phase and a dose expansion phase.

The study will enroll approximately 81 participants; approximately 30 participants in the dose escalation phase (Part 1) approximately 15 participants in (Part 2) and up to 36 participants in dose expansion phase (Part 2). Participants will receive escalating doses of TAK-981 in combination with fixed doses as follows:

* Phase 1b, Part 1 - Dose Escalation: Arm A - TAK-981 Twice Weekly (BIW) + Mezagitamab
* Phase 1b, Part 1 - Dose Escalation: Arm B - TAK-981 Weekly (QW) + Mezagitamab
* Phase 1b, Part 2 - Dose Escalation: TAK-981 + Daratumumab and Hyaluronidase-fihj

Once RP2D is determined in Phase 1, participants with RRMM will be enrolled in Phase 2.

• Phase 2 - Dose Expansion: TAK-981 + Daratumumab and Hyaluronidase-fihj or Mezagitamab

This multi-center trial will be conducted in North America. The overall time to participate in this study is 2 years. Participants will make multiple visits to the clinic, and progression-free survival follow-up for maximum up to 12 months after last dose of study drug.

Arms: arm 1: Mezagitamab: A fixed dose of 600 mg subcutaneous (SC) injection once weekly in Cycles 1 and 2 (each cycle is of 28 days), followed by once every 2 weeks in Cycle 3 through 6, then every 4 weeks up to Cycle 24 or until disease progression or unacceptable toxicity, or until any other discontinuation criterion is met, whichever occurs first.

TAK-981: Escalating doses of TAK-981 BIW intravenous (IV) infusion on Days 1, 4, 8, 11 and 15 in Cycle 1 and 2 (each Cycle is of 28 days) followed by every 2 weeks in Cycles 3 through 6, followed by once every 4 weeks up to Cycle 24 or until disease progression or unacceptable toxicity, or until any other discontinuation criterion is met, whichever occurs first. arm 2: Mezagitamab: A fixed dose of 600 mg SC injection once weekly in Cycles 1 and 2 (each cycle is of 28 days), followed by once every 2 weeks from Cycle 3 through 6, then every 4 weeks up to Cycle 24 or until disease progression or unacceptable toxicity, or until any other discontinuation criterion is met, whichever occurs first.

TAK-981: Escalating doses of TAK-981 QW IV infusion on Days 1, 8, 15, and 22 in Cycles 1 and 2 (each cycle is of 28 days), followed by every 2 weeks in Cycles 3 through 6, followed by once every 4 weeks. up to Cycle 24 or until disease progression or unacceptable toxicity, or until any other discontinuation criterion is met, whichever occurs first. arm 3: Daratumumab and hyaluronidase-fihj: 1800 mg SC injection QW once weekly in Cycles 1 and 2 , (each cycle is of 28 days) followed by every 2 weeks in Cycle 3 through 6 , followed by every 4 weeks up to Cycle 24 until disease progression or unacceptable toxicity, or until any other discontinuation criterion is met, whichever occurs first.

TAK-981: As per dose and schedule of TAK-981 defined in Phase 1b Part 1. arm 4: TAK-981 at RP2D as determined in Phase 1b. Mezagitamab at a fixed dose of 600 mg SC injection or Daratumumab and Hyaluronidase-fihj at a fixed dose of 1800 mg weekly in Cycles 1 and 2 (each cycle is of 28 days), followed by every 2 weeks in Cycle 3 through 6, followed by every 4 weeks up to Cycle 24 or until disease progression unacceptable toxicity, or until any other discontinuation criterion is met, whichever occurs first.
Interventions: intervention 1: TAK-981 intervention 2: Mezagitamab intervention 3: Daratumumab and Hyaluronidase-fihj
Intervention descriptions: intervention 1: TAK-981 IV infusion. intervention 2: Mezagitamab SC injection. intervention 3: Daratumumab and Hyaluronidase-fihj SC injection.

Protocol documents:
Prot_000.pdf: 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


 
 
PROTOCOL
A Phase 1b/2 Open-Label, Multicenter Study to Evaluate the Safety and Efficacy of 
TAK-981 in Combination With Monoclonal Antibodies in Adult Patients With Relapsed 
and/or Refractory Multiple Myeloma
TAK-981 in Combination With Monoclonal Antibodies in Patients With Relapsed and/or 
Refractory Multiple Myeloma 
Sponsor:
Takeda Development Center Americas, Inc. 
95 Hayden Avenue
Lexington, MA 02421
Please note: Takeda Development Center Americas, Inc. may be referred to in this 
protocol as “sponsor” or “Takeda”.
Study Number:
TAK-981-1503
EudraCT Number:
Not applicable
Compound:
TAK-981
Date:
30 August 2021
Amendment Number:
2
Date
Amendment Number
Region
30 August 2021
Amendment 2
Global
22 December 2020 
Amendment 1
Global
03 November 2020
Initial protocol
Global
CONFIDENTIAL PROPERTY OF TAKEDA
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 except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her 
staff, and applicable institutional review committee and regulatory agencies to enable conduct of the study.
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1.0
ADMINISTRATIVE INFORMATION
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. 
Takeda Development Center–sponsored investigators per individual country requirements will 
be provided with emergency medical contact information cards to be carried by each subject.
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines 
provided to the site.
The names and contact information for the medical monitor and responsible medical officer are 
in the study manual.
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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 for Harmonisation (ICH) E6 Good Clinical Practice (GCP): 
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
 
Oncology Clinical Research
(or designee)
Date
 PhD
 
SQS Oncology
(or designee)
Date
 RN, MSN
 
Oncology Clinical Research
(or designee)
Date
 PhD
 
cology
(or designee)
Date
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INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the investigator’s brochure, 
prescribing information, 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 Council for Harmonisation, E6 GCP: Consolidated Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and
regulations.

Regulatory requirements for reporting SAE defined in Section 10.0 of this protocol.

Terms outlined in the clinical study site agreement.

Responsibilities of the investigator (Appendix B).
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix C 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 2 Summary of Changes and Rationale
Rationale for Amendment 2
This section describes the changes to the protocol incorporating Amendment 2.
The primary reason for this amendment was to update the translational strategy for sample 
collection for analysis of biomarkers.
Minor grammatical, editorial, formatting, and administrative changes not affecting the conduct of 
the study are included for clarification and administrative purpose only.
Protocol Amendment 2
Summary of Changes Since Last Version of the Approved Protocol
Change 
Number
Sections Affected by Change
Description of Each Change and Rationale
Location
Description
Rationale
1
Global
Updated instances of "Phase 1" to be 
"Phase 1b" for this study.
Editorial update for 
consistency.
2
Section 2.0 STUDY 
SUMMARY
Section 7.1 Inclusion Criteria
Section 8.10 Precautions and 
Restrictions
Updated text throughout the protocol to 
require patients to practice effective 
contraception through 6 months after the 
last dose of study drug (instead of 120 
days after the last dose of study drug or
6 months after last dose of TAK-981).
Compliance with local 
guidelines.
3
Section 2.0 STUDY 
SUMMARY
Section 8.5 Dose Escalation 
Rules
Section 13.3 Determination of 
Sample Size
Corrected spelling of daratumumab.
Correction.
4
Section 4.2.1 TAK-981
Section 4.4 Rationale for the 
Starting Dose and Schedule
Section 4.5.1 Potential Effects 
of TAK-981
Updated clinical sections to include 
information from the latest TAK-981 
investigator’s brochure (IB) edition 
(Edition 4, data cutoff 28 June 2021).
Updated clinical data from 
the TAK-981 IB were 
available.
5
Section 4.5.5 Coronavirus 
Disease 2019 Pandemic
Added a section on benefit-risk 
assessment of participation in the study 
during the coronavirus disease 2019 
(COVID-19) pandemic, indicating that 
the benefit/risk assessment remains 
favorable and that considerations for 
patient participation should be evaluated 
by the investigator on a patient by 
patient basis taking into consideration 
the current local situation, guidelines, 
and other recommendations.
Guidance on benefit-risk 
assessment for patient 
participation in the study 
during the COVID-19 
pandemic.
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Protocol Amendment 2
Summary of Changes Since Last Version of the Approved Protocol
Change 
Number
Sections Affected by Change
Description of Each Change and Rationale
Location
Description
Rationale
6
Section 6.5.2 End of 
Study/Study Completion 
Definition and Planned 
Reporting
Clarified that once TAK-981 has been 
discontinued, patients cannot remain on 
the monoclonal antibody as a single 
agent beyond the cycle during which 
TAK-981 was discontinued.
Clarification.
7
Section 8.1.1 TAK-981 Study 
Drug Administration
Updated text to indicate that if infusion 
reactions are observed, the length of the 
infusion can be extended up to 2 hours 
(instead of up to 4 hours) for all patients 
without requiring a protocol amendment.
Alignment with the 
TAK-981 stability data 
when at room temperature.
Added that a dose delay of up to 7 days 
is allowed to accommodate for 
COVID-19 vaccine administration after 
discussion with the sponsor.
Guidance on COVID-19 
vaccination timing and 
procedures during the 
study.
8
Section 8.7.6 COVID-19
Added a section describing criteria for 
restarting study treatment if a patient 
discontinued study treatment due to 
COVID-19 infection.
Guidance on treatment of 
patients with COVID-19.
9
Section 8.8.1 Excluded 
Concomitant Medications and 
Procedures for TAK-981
Added that vaccination during Cycle 1 is 
not permitted for patients in Phase 1b.
Vaccination during 
Cycle 1 in Phase 1b would 
confound safety evaluation 
and determination of 
dose-limiting toxicities.
10
Section 8.9 Permitted 
Concomitant Medications and 
Procedures
Added guidance on timing of 
COVID-19 vaccination during the study 
including live attenuated vaccine must 
be completed at least 4 weeks prior to 
treatment initiation, vaccination not 
permitted during Cycle 1 in Phase 1, 
vaccination to be avoided within ±3 days 
of TAK-981 administration, and 
allowing a 7-day dose delay to 
accommodate vaccination.
Guidance on COVID-19 
vaccination timing and 
procedures during the 
study.
11
Section 9.4.15
Pharmacodynamics 
Measurements
Rearranged order of specimens and 
updated the specimens collected to align 
with Table A-5 and Table A-6.
Update to align with 
translational strategy for 
biomarker sample 
collection.
12
Section 10.5 Procedures for 
Reporting Product Complaints
or Medication Errors 
(Including Overdose)
Updated contact information for 
reporting medication errors.
Administrative update.
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Protocol Amendment 2
Summary of Changes Since Last Version of the Approved Protocol
Change 
Number
Sections Affected by Change
Description of Each Change and Rationale
Location
Description
Rationale
13
Appendix A
Updated Appendix A schedule of event 
(SOE) table numbers as Tables A-1 
through A-6 instead of Tables 1 through 
6.
Updated Tables A-4, A-5, and A-6 to 
reflect streamlined PK and 
pharmacodynamic sample collection 
strategies.
Update to align with 
translational strategy for 
biomarker sample 
collection.
14
Appendix F
Drugs that 
Interact With the CYP3A 
Family of Cytochromes P450
Under strong cytochrome P450 (CYP) 
3A inhibitors deleted grapefruit. Added 
footnote b to separate sources for 
CYP3A inducers and inhibitors.
Moved table footnote text to paragraph 
above table.
Update to align with 
current Food and Drug 
Administration guidance 
and with other TAK-981 
protocols.
15
Appendix G
Examples of 
Clinical Inhibitors of 
Updated source.
Correction.
16
Appendix H
iBOIN 
Design
Updated Appendix H table numbers as 
Tables H-1 through H-3 instead of 
Tables 1 through 3.
Update for consistency 
with other protocols.
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TABLE OF CONTENTS
1.0
ADMINISTRATIVE INFORMATION ...........................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment 2 Summary of Changes and Rationale......................................5
2.0
STUDY SUMMARY ....................................................................................................16
3.0
STUDY REFERENCE INFORMATION ......................................................................22
3.1
Study-Related Responsibilities.................................................................................22
3.2
Coordinating Investigator.........................................................................................22
3.3
List of Abbreviations ...............................................................................................23
3.4
Corporate Identification ...........................................................................................25
4.0
INTRODUCTION.........................................................................................................26
4.1
Background .............................................................................................................26
4.1.1
TAK-981 .........................................................................................................27
Mechanism of Action ..............................................................................27
4.1.1.1
Nonclinical Pharmacokinetics..................................................................28
4.1.1.2
Nonclinical Toxicology ...........................................................................28
4.1.1.3
4.2
Clinical Experience..................................................................................................29
4.2.1
TAK-981 .........................................................................................................29
4.2.2
Daratumumab ..................................................................................................31
4.2.3
Mezagitamab ...................................................................................................31
4.3
Rationale for the Proposed Study.............................................................................31
4.4
Rationale for the Starting Dose and Schedule...........................................................32
4.5
Potential Risks and Benefits.....................................................................................33
4.5.1
Potential Effects of TAK-981 ..........................................................................33
4.5.2
Potential Effects of Daratumumab and Hyaluronidase-fihj...............................34
4.5.3
Potential Effects of Mezagitamab.....................................................................34
4.5.4
Overall Benefit-Risk Assessment.....................................................................34
4.5.5
Coronavirus Disease 2019 Pandemic ...............................................................35
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................35
5.1
Objectives................................................................................................................35
5.1.1
Primary Objectives ..........................................................................................35
5.1.2
Secondary Objectives ......................................................................................35
5.1.3
Exploratory Objectives ....................................................................................36
5.2
Endpoints.................................................................................................................36
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5.2.1
Primary Endpoints ...........................................................................................36
5.2.2
Secondary Endpoints .......................................................................................37
5.2.3
Exploratory Endpoints .....................................................................................37
6.0
STUDY DESIGN..........................................................................................................38
6.1
Overview of Study Design.......................................................................................38
6.2
Phase 1b Study Design.............................................................................................39
6.2.1
Phase 1b Part 1 ................................................................................................39
Selection of RP2D for TAK-981 in Combination With Mezagitamab ......40
6.2.1.1
6.2.2
Phase 1b Part 2 ................................................................................................41
Selection of RP2D for TAK-981 in Combination With Daratumumab 
6.2.2.1
and Hyaluronidase-fihj ............................................................................41
6.2.3
Selection of CD38 Antibody for Phase 2..........................................................41
6.3
Phase 2 Study Design...............................................................................................41
6.3.1
Early Stopping Rules .......................................................................................42
6.4
Number of Patients ..................................................................................................42
6.5
Duration of Study ....................................................................................................42
6.5.1
Duration of an Individual Patient’s Study Participation ....................................42
6.5.2
End of Study/Study Completion Definition and Planned Reporting..................43
6.5.3
Timeframes for Primary and Secondary Endpoints to Support Disclosures ......43
6.5.4
Total Study Duration .......................................................................................44
6.5.5
Posttrial Access ...............................................................................................45
Duration of Post-study Access .................................................................45
6.5.5.1
7.0
STUDY POPULATION................................................................................................45
7.1
Inclusion Criteria .....................................................................................................45
7.2
Exclusion Criteria ....................................................................................................47
8.0
STUDY DRUG .............................................................................................................50
8.1
Investigational Medicinal Products ..........................................................................50
8.1.1
TAK-981 Study Drug Administration ..............................................................50
TAK-981 Formulation .............................................................................51
8.1.1.1
8.1.2
Mezagitamab (TAK-079).................................................................................51
Premedications ........................................................................................53
8.1.2.1
Postmedication ........................................................................................53
8.1.2.2
Mezagitamab Formulation .......................................................................53
8.1.2.3
8.2
Standard of Care Agents ..........................................................................................54
8.2.1
Daratumumab and Hyaluronidase-fihj..............................................................54
Vital Signs...............................................................................................55
8.2.1.1
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Premedications ........................................................................................55
8.2.1.2
Postmedication ........................................................................................55
8.2.1.3
Prophylaxis for Herpes Zoster Reactivation .............................................56
8.2.1.4
8.3
Definitions of DLT ..................................................................................................56
8.4
Definition of DLT-Evaluable Patients......................................................................57
8.5
Dose Escalation Rules..............................................................................................58
8.6
Intrapatient Dose Escalation.....................................................................................60
8.7
Dose Modification Guidelines for Phase 1b Dose Escalation and Phase 2 
Expansion Cohorts...................................................................................................61
8.7.1
Criteria for Beginning or Delaying a Subsequent Treatment Cycle...................61
8.7.2
Criteria for Dose Interruption or Dose Reduction During a Cycle ....................61
8.7.3
Dose Modification and Discontinuation Criteria for TAK-981.........................62
Dose Modification Criteria for TAK-981.................................................62
8.7.3.1
Discontinuation Criteria for TAK-981 .....................................................64
8.7.3.2
8.7.4
Dose Modification and Discontinuation Criteria for Mezagitamab ...................64
8.7.5
Dose Modification and Discontinuation Criteria for Daratumumab and 
Hyaluronidase-fihj...........................................................................................66
8.7.6
COVID-19.......................................................................................................66
8.8
Excluded Concomitant Medications and Procedures ................................................67
8.8.1
Excluded Concomitant Medications and Procedures for TAK-981...................67
8.8.2
Excluded Concomitant Medications and Procedures for Monoclonal 
Antibodies .......................................................................................................68
8.9
Permitted Concomitant Medications and Procedures ................................................68
8.10
Precautions and Restrictions ....................................................................................69
8.11
Management of Clinical Events ...............................................................................70
8.11.1
IRRs ................................................................................................................70
TAK-981.................................................................................................71
8.11.1.1
Monoclonal Antibodies............................................................................71
8.11.1.2
8.11.2
CRS.................................................................................................................72
TAK-981.................................................................................................72
8.11.2.1
Mezagitamab ...........................................................................................72
8.11.2.2
CRS Management....................................................................................73
8.11.2.3
8.11.3
Anemia, Thrombocytopenia, and Neutropenia .................................................75
8.11.4
Infusion Site Care ............................................................................................75
TAK-981.................................................................................................75
8.11.4.1
Mezagitamab ...........................................................................................75
8.11.4.2
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Daratumumab and Hyaluronidase-fihj .....................................................76
8.11.4.3
8.11.5
Nausea and Vomiting.......................................................................................76
8.11.6
Diarrhea...........................................................................................................76
8.11.7
Interference with Serologic Testing..................................................................76
8.11.8
ADA Interactions.............................................................................................77
8.12
Blinding and Unblinding..........................................................................................77
8.13
Description of Study drugs.......................................................................................77
8.13.1
TAK-981 .........................................................................................................77
Preparation, Reconstitution, and Dispensation .........................................77
8.13.1.1
Packaging and Labeling...........................................................................77
8.13.1.2
Storage, Handling, and Accountability.....................................................77
8.13.1.3
8.13.2
Mezagitamab ...................................................................................................78
Preparation, Reconstitution, and Dispensation .........................................78
8.13.2.1
Packaging and Labeling...........................................................................78
8.13.2.2
Storage and Handling ..............................................................................78
8.13.2.3
8.13.3
Non-investigational Monoclonal Antibody ......................................................79
Daratumumab and Hyaluronidase-fihj .....................................................79
8.13.3.1
8.14
Investigational Drug Assignment and Dispensing Procedures: TAK-981 and 
Mezagitamab ...........................................................................................................79
8.15
Other Protocol-Specified Materials ..........................................................................79
9.0
STUDY CONDUCT......................................................................................................79
9.1
Study Personnel and Organizations ..........................................................................79
9.2
Arrangements for Recruitment of Patients................................................................79
9.3
Treatment Group Assignments.................................................................................80
9.4
Study Procedures .....................................................................................................80
9.4.1
Informed Consent ............................................................................................80
9.4.2
Patient Demographics ......................................................................................81
9.4.3
Medical History...............................................................................................81
9.4.4
Physical Examination ......................................................................................81
9.4.5
Patient Height and Weight ...............................................................................81
9.4.6
Vital Signs.......................................................................................................81
9.4.7
Pregnancy Test ................................................................................................81
9.4.8
Concomitant Medications and Procedures........................................................82
9.4.9
Adverse Events................................................................................................82
9.4.10
Enrollment.......................................................................................................82
9.4.11
12-Lead ECG...................................................................................................82
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15.1
IRB and/or IEC Approval ......................................................................................108
15.2
Subject Information, Informed Consent, and Subject Authorization .......................109
15.3
Subject Confidentiality ..........................................................................................110
15.4
Publication, Disclosure, and Clinical Trial Registration Policy...............................110
15.4.1
Publication.....................................................................................................110
15.4.2
Clinical Trial Registration..............................................................................111
15.4.3
Clinical Trial Results Disclosure....................................................................111
15.5
Insurance and Compensation for Injury..................................................................111
16.0
REFERENCES............................................................................................................112
LIST OF IN-TEXT TABLES
Table 4.a
Most Frequent (≥10% of All Patients) TEAEs in Studies TAK-981-1002, 
TAK-981-1501, and TAK-981-1502 ..................................................................30
Table 6.a
Primary and Secondary Endpoints for Disclosures .............................................44
Table 8.a
Administration Schedule of TAK-981 and Mezagitamab (BIW TAK-981 
Schedule)...........................................................................................................52
Table 8.b
Administration Schedule of TAK-981 and Mezagitamab (QW TAK-981 
Schedule)...........................................................................................................52
Table 8.c
Administration Schedule TAK-981 and Daratumumab.......................................54
Table 8.d
Planned Dose Levels..........................................................................................60
Table 8.e
General Dose Modification Recommendations for TAK-981 Nonhematologic 
Drug-Related AEs..............................................................................................63
Table 8.f
Dose Adjustments for Hematologic Toxicities ...................................................63
Table 8.g
Dose Modification Recommendations for Mezagitamab Toxicities ....................65
Table 8.h
Mezagitamab-Related Toxicity Management .....................................................66
Table 8.i
CRS Management Recommendations and TAK-981 Dose Modifications...........73
Table 9.a
Clinical Chemistry, Hematology, and Coagulation Tests....................................83
Table 9.b
Clinical Urinalysis Tests and Creatinine Clearance.............................................83
Table 9.c
Immunosafety Determinations in Serum.............................................................84
Table 9.d
Myeloma Disease Assessments ..........................................................................84
Table 13.a
.............................................................................106
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LIST OF IN-TEXT FIGURES
Figure 4.a
Synergistic Combination of TAK-981 With Daratumumab or Mezagitamab 
(TAK-079) in the Daudi Tumor Model...............................................................28
Figure 6.a
Study Schema ....................................................................................................39
Figure 8.a
Phase 1b Dose Escalation Schema......................................................................59
LIST OF APPENDICES
Appendix A
SOEs................................................................................................................115
Appendix B
Responsibilities of the Investigator...................................................................127
Appendix C
Investigator Consent to Use of Personal Information........................................129
Appendix D
ECOG Scale for Performance Status ................................................................130
Appendix E
Methods of Contraception Considered to be Effective......................................131
Appendix F
Drugs that Interact With the CYP3A Family of Cytochromes P450..................132
Appendix G
Examples of Clinical Inhibitors of Pgp.............................................................134
Appendix H
iBOIN Design..................................................................................................135
Appendix I 
Examples of QTc Interval Prolonging Agents (During Phase 1b only) .............137
Appendix J
IMWG criteria .................................................................................................138
Appendix K
...................................................................................................139
Appendix L
......................................................146
Appendix M
......................................................................................................147
Appendix N
Protocol History...............................................................................................148
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2.0
STUDY SUMMARY
Name of Sponsor(s): Takeda Development Center 
Americas, Inc. 
Compound: TAK-981
Title of Protocol: A Phase 1b/2 Open-Label, Multicenter 
Study to Evaluate the Safety and Efficacy of TAK-981 in 
Combination With Monoclonal Antibodies in Adult 
Patients With Relapsed and/or Refractory Multiple 
Myeloma.
EudraCT No.: Not applicable
Study Number: TAK-981-1503
Phase: 1b/2
Study Design:
This study is an open-label, multicenter, Phase 1b/2 study investigating the combination of TAK-981 and 
monoclonal antibodies (mAbs) in adult patients with relapsed and/or refractory multiple myeloma (RRMM). The 
study will be conducted in 2 phases:
1.
Phase 1b dose escalation of TAK-981 guided by Bayesian Optimal Interval Design with Informative Prior 
(iBOIN) in combination with fixed doses of mezagitamab or daratumumab and hyaluronidase-fihj, respectively 
in patients with RRMM.
2.
Phase 2 study of TAK-981-based mAb combinations with multiple treatment arms in patients with RRMM.
Treatment cycle duration is 28 days. TAK-981 in combination with the mAbs will be administered for up to 
24 cycles or until disease progression or unacceptable toxicity, whichever comes first. Patients with demonstrated 
clinical benefit may continue treatment beyond 24 cycles with the agreement of the sponsor/ designee.
Patient participation will include a screening phase, a treatment phase, and a follow-up phase. The screening phase 
will be up to approximately 28 days before Cycle 1 Day 1 (C1D1). The treatment phase will extend from C1D1 until 
patients experience disease progression or unacceptable toxicity, or until any other discontinuation criterion is met.
The follow-up phase of the study begins once a patient discontinues study treatment and completes the end-of-
treatment (EOT) visit; study follow-up continues until the study ends or the patient completes overall survival (OS) 
follow-up.
Primary Objectives:
The primary objectives are:
Phase 1b:

To determine the safety and tolerability of TAK-981 in combination with mAbs in patients with RRMM.

To determine the recommended Phase 2 dose (RP2D).
Phase 2:

To evaluate the efficacy of TAK-981 in combination with mAbs in patients with RRMM.
Secondary Objectives:
The secondary objectives are:

To characterize the pharmacokinetic (PK) profile of TAK-981 in combination with anti-CD38 mAb.

To assess immunogenicity of anti-CD38 monoclonal antibodies  (mezagitamab and daratumumab) to help 
interpreting PK profile, efficacy and safety of TAK-981 in combination with monoclonal antibodies.
Phase 1b:

To evaluate preliminary efficacy of the TAK-981-mAb combination according to standard International 
Myeloma Working Group (IMWG) criteria.

To assess target engagement of TAK-981 (TAK-981- small ubiquitin-like modifier [SUMO] adduct formation) 
and SUMOylation pathway inhibition in blood.
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Phase 2:

To further characterize efficacy of TAK-981 in combination with anti-CD38 mAb in RRMM.

To evaluate the safety and tolerability of TAK-981 in combination with anti-CD38 mAb.
Subject Population: Male or female subjects aged 18 years or older with RRMM.
Number of Patients:
Approximately 81 patients will be enrolled.
Phase 1b Part 1: approximately 30 patients (approximately
15 patients in each dosing schedule).
Phase 1b Part 2: approximately 15 patients.
Phase 2: up to approximately 36 patients.
Number of Sites:
Estimated total: Approximately 15 sites in North 
America and/or globally
Dose Level(s):
TAK-981: 60, 90, and 120 mg.
Mezagitamab: 600 mg.
Daratumumab and hyaluronidase-fihj: 1800 mg 
Route of Administration:
TAK-981: Intravenous infusion.
Mezagitamab: Subcutaneous.
Daratumumab and hyaluronidase-fihj: Subcutaneous.
Duration of Treatment:
Patients will continue on the assigned therapy until disease 
progression, unacceptable toxicity, or to a maximum of 24 
cycles, whichever occurs first 
Period of Evaluation:
The expected period of evaluation for this study is 36 
to 48 months; approximately 12 months for 
enrollment for each phase and approximately 
24 months for treatment and/or follow-up.
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.
Be willing and able to provide written informed consent for the study.
3.
For patients with multiple myeloma (for Phase 1b and Phase 2):
a.
A prior diagnosis of multiple myeloma as defined by the IMWG criteria with documented disease 
progression.
b. Has 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.
c.
Has undergone stem cell transplant or is considered transplant ineligible, and

Patients with a history of autologous stem cell transplant are eligible if the transplant was 
> 100 days prior to study consent.
d.
Has failed at least 3 prior lines of anti-myeloma treatments, including an anti-CD38 antibody (eg, 
daratumumab, daratumumab and hyaluronidase-fihj, isatuximab) alone or in combination.,
e.
Is either refractory, or intolerant to at least 1 immunomodulatory drug ([IMiD]; ie, lenalidomide or 
pomalidomide [thalidomide excluded]), at least 1 proteasome inhibitor (ie, bortezomib, ixazomib or 
carfilzomib), and refractory to at least 1 anti-CD38 antibody and who have demonstrated disease 
progression with the last therapy.

Refractory myeloma is defined as disease that is nonresponsive while on therapy or progresses 
within 60 days of last therapy. Nonresponsive disease is defined as either failure to achieve at least 
minimal response or development of progressive disease (PD) while on therapy.

A line of therapy consists of ≥1 complete cycle of a single agent, a regimen consisting of a 
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combination of several drugs, or a planned sequential therapy of various regimens (eg, 3-6 cycles 
of initial therapy with bortezomib-dexamethasone followed by a stem cell transplantation, 
consolidation, and maintenance is considered 1 line).
4.
Have a performance status of 0 to 2 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale. 
5.
Have suitable venous access for safe drug administration and the study-required blood sampling, including PK 
and pharmacodynamic sampling.
6.
Have adequate organ function as specified below at screening:
a.
Platelet count ≥75, 000 mm3 (≥75 × 109/L); value of ≥50,000 mm3 (≥50 × 109/L) may be acceptable for 
patients with ≥50% bone marrow burden following discussion with the sponsor (Platelet transfusion 
will be allowed >3 days before assessment).
b.
Hemoglobin must be 8 g/dL. (red blood cell [RBC] transfusion allowed ≥14 days before assessment).
c.
Absolute neutrophil count (ANC) ≥1000 mm3 (≥1.0 × 109/L); value of ≥750 mm3 (≥0.75 × 109/L) may 
be acceptable for patients with ≥50% bone marrow burden following discussion with the sponsor.
d.
Estimated creatinine clearance using the Cockcroft-Gault formula ≥30 mL/minute for patients with 
serum creatinine concentrations above the upper limit of normal range (ULN).
e.
Aspartate aminotransferase (AST, glutamic oxaloacetic transaminase [GOT]) and alanine 
aminotransferase (ALT, GPT) ≤3.0 × ULN; bilirubin ≤1.5 × ULN. Patients with Gilbert’s syndrome 
may have a bilirubin level >1.5 × ULN, per discussion between the investigator and the medical 
monitor.
7.
Have recovered to Grade 1 or baseline from all toxicity associated with previous therapy or have the toxicity 
established as sequela.
Note: Except neuropathy Grade ≤2, any grade alopecia, or bone marrow parameters [any of Grade 1 or 2 
permitted if directly related to bone marrow involvement].
8.
Female patients who:

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 6 months after the last dose of drug in the combination. OR,

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the 
subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods], 
withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of 
contraception. Female and male condoms should not be used together.)
9.
Male patients, even if surgically sterilized (ie, status postvasectomy), who:

Agree to practice effective barrier contraception during the entire study treatment period and 
through 6 months after the last dose of drug in the combination, OR

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the 
subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods], 
withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of 
contraception. Female and male condoms should not be used together.)
10. Must be willing and able to comply with clinic visits and procedures outlined in the study protocol.
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Exclusion Criteria:
Patients meeting any of the following exclusion criteria are not to be enrolled in the study:
1.
Received treatment with systemic anticancer treatments within 14 days before the first dose of study drug or 
any investigational products (IPs) within 5 half-lives of the first dose of study drug, whichever is appropriate to 
last therapy received. (eg, non- IP IMiD, proteasome inhibitor, anti-CD38 mAb could be considered to be 
eligible if there is at least 14 days after last dose before first dose of study drug).
Note: Treatment with a single course of glucocorticoids (maximum dose of corticosteroids should not exceed 
the equivalent of 160 mg [for example, 40 mg/d for 4 days] of dexamethasone), hormonal therapy for prostate 
cancer or breast cancer (as adjuvant treatment), and treatment with bisphosphonates and receptor activator of 
nuclear factor kappa-Β ligand inhibitors are allowed.
2.
Current participation in another interventional study, including other clinical trials with investigational agents 
(including investigational vaccines or investigational medical device for disease under study) within 4 weeks of 
the first dose of TAK-981 and throughout the duration of this trial.
3.
Prior radiation therapy within 14 days of the first dose of TAK-981.
Note: Prophylactic localized (“spot”) radiation for areas of pain is allowed.
4.
Major surgery within 4 weeks before C1D1. Patients should be fully recovered from any surgically related 
complications.
Note: Kyphoplasty is not considered major surgery.
5.
Plasmapheresis within 28 days of randomization.
6.
Diagnosis of primary amyloidosis, Waldenström’s disease, monoclonal gammopathy of undetermined 
significance or smoldering multiple myeloma (SMM) per IMWG criteria or standard diagnostic criteria, plasma 
cell leukemia (according to the World Health Organization criterion: ≥20% of cells in the peripheral blood with 
an absolute plasma cell count of more than 2 × 109/L), POEMS syndrome (polyneuropathy, organomegaly, 
endocrinopathy, monoclonal protein, and skin changes), myelodysplastic syndrome, or myeloproliferative 
syndrome.
7.
With disease where the only measurable parameter is plasmacytoma.
8.
Second malignancy within the previous 3 years, except treated basal cell or localized squamous skin 
carcinomas, localized prostate cancer, cervical carcinoma in situ, resected colorectal adenomatous polyps, 
breast cancer in situ, or other malignancy for which the patient is not on active anticancer therapy.
9.
Evidence of central nervous system involvement and/or meningeal involvement of MM exhibited during 
screening.
10. Known severe allergic or anaphylactic reactions to human recombinant proteins or excipients used in the TAK-
981 formulation or the mAbs (such as daratumumab or daratumumab and hyaluronidase-fihj as per the 
prescribing information and for mezagitamab as outlined in the mezagitamab investigator's brochure).
11. History of treatment discontinuation due to treatment-related toxicity to the combination partner (daratumumab 
or daratumumab and hyaluronidase-fihj).
12. Prior treatment with more than 1 anti-CD38 antibody.
13. Chronic obstructive pulmonary disease (COPD) with forced expiratory volume in 1 second (FEV1) <50% of 
predicted normal; or diagnosis of moderate or persistent asthma within the last 2 years, or currently 
uncontrolled asthma of any classification (controlled intermittent asthma or controlled mild persistent asthma is 
allowed); pulmonary fibrosis; or history of symptomatic bronchospasm. Note that FEV1 testing is required for 
patients with known or suspected COPD or asthma and patients must have a FEV1 ≥50% of predicted normal 
during screening.
14. Any concurrent or uncontrolled medical, comorbid, or psychiatric condition or disease that is likely to interfere 
with the study procedures or results, or that in the opinion of the investigator, would constitute a hazard for 
participating in this study.
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15. History of HIV, hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.
16. Systemic infection requiring systemic antibiotic therapy or other serious infection within 14 days before the first 
dose of TAK-981 or any agent in the combination.
Note: Urinary tract infection is not considered a systemic infection.
17. History of autoimmune disease requiring systemic immunosuppressive therapy with daily doses of prednisone 
>10 mg/day or equivalent doses, or any other form of immunosuppressive therapy. Hormone therapy (eg, 
thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is 
not considered an excluded form of systemic treatment of an autoimmune disease.
18. Active or history of noninfectious pneumonitis that required steroids or a history of interstitial lung disease.
19. History of allogeneic tissue or solid organ transplant.
20. Receipt of any live vaccine (eg, varicella, pneumococcus) within 4 weeks of initiation of study treatment.
21. Receiving or requiring the continued use of medications that are known to be strong or moderate inhibitors and 
inducers of cytochrome P450 (CYP) 3A4/5 (Appendix F) or are strong P-glycoprotein (Pgp) inhibitors 
(Appendix G) at screening. To participate in this study, such patients should discontinue use of such agents for 
at least 2 weeks or 5 times the half-life (whichever is shorter) before receiving a dose of TAK-981.
22. Require the use of drugs known to prolong the corrected QT interval (during Phase 1b only) (Appendix I).
23. History of any of the following ≤6 months before first dose: congestive heart failure New York Heart 
Association Grade III or IV, unstable angina, myocardial infarction, unstable symptomatic ischemic heart 
disease, uncontrolled hypertension despite appropriate medical therapy, ongoing symptomatic cardiac 
arrhythmias >Grade 2, pulmonary embolism or symptomatic cerebrovascular events, or any other serious 
cardiac condition (eg, pericardial effusion or restrictive cardiomyopathy). Chronic atrial fibrillation on stable 
anticoagulant therapy is allowed.
24. Baseline prolongation of the QT interval with Fridericia’s correction method (QTcF) (eg, repeated 
demonstration of QTcF interval >480 ms, history of congenital long QT syndrome, or torsades de pointes). If a 
machine reading is above this value, the electrocardiogram (ECG) should be reviewed by a qualified reader and 
confirmed on a subsequent ECG.
25. Psychiatric illness/social circumstances that would limit compliance with study requirements and substantially 
increase the risk of adverse events (AEs) or has compromised ability to provide written informed consent.
26. Admission or evidence of illicit drug use, drug abuse, or alcohol abuse.
27. Female patients who are lactating and breastfeeding or have a positive serum pregnancy test during the 
screening period or a on Day 1 before first dose of TAK-981 study drug.
Main Criteria for Evaluation and Analyses:
The primary endpoints are:
Phase 1b:

Frequency and severity of treatment-emergent adverse events (TEAEs) for all dose groups.

Occurrence of dose-limiting toxicities (DLTs) in Cycle 1.
Phase 2:

Overall response rate (ORR) (response of at least partial response [PR]) based on investigator’s assessment 
according to standard IMWG disease response criteria.
The secondary endpoints are:

TAK-981 concentration-time data.

Anti-mezagitamab or anti-daratumumab antibody (ADA): negative, transient or persistent positive, high or low 
ADA titer.

Sparse PK evaluations of mezagitamab or daratumumab.
Phase 1b:
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3.0
STUDY REFERENCE INFORMATION
3.1
Study-Related Responsibilities
The sponsor will perform all study-related activities with the exception of those identified in the 
clinical supplier list in the study manual. The identified vendors will perform specific 
study-related activities either in full or in partnership with the sponsor.
3.2
Coordinating 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, and study participation. The signatory coordinating investigator will be required to 
review and sign the clinical study report (CSR) and by doing so agrees that it accurately 
describes the results of the study.
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3.3
List of Abbreviations
ADA
antidrug antibody (exchangeable terminology for anti-mezagitamab or anti-daratumumab 
antibody in this protocol)
ADCC
antibody-dependent cell-mediated cytotoxicity
ADCP
antibody-dependent cell-mediated phagocytosis
AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
BMA
bone marrow aspirate
BIW
twice weekly
C1D1
Cycle 1, Day 1
CBR
clinical benefit rate
CDC
complement dependent cytotoxicity
COPD
chronic obstructive pulmonary disease
CR
complete response
CRO
contract research organization
CRS
cytokine release syndrome
CSR
clinical study report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome P450
DC
dendritic cell
DLT
dose-limiting toxicity
DOR
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EOT
end-of-treatment
FDA
[United States] Food and Drug Administration
FEV1
forced expiratory volume in 1 second
FIH
first-in-human
FLC
free light chain
GCP
Good Clinical Practice
GOT
glutamic oxaloacetic transaminase
HBV
hepatitis B virus
HCV
hepatitis C virus
iBOIN
Bayesian Optimal Interval Design with Informative Prior
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IB
investigator's brochure
ICF
informed consent form
ICH
International Council for Harmonisation
IDMC
Independent Data Monitoring Committee
IEC
independent ethics committee
IFN
interferon
IMiD
immunomodulatory drug
IMWG
International Myeloma Working Group
IP
investigational product
IRB
institutional review board
IRR
infusion-related reaction
IRT
interactive response technology
ISS
International Staging System
IV
intravenous
IVRS/IWRS
integrated voice response system/interactive web response system
KM
Kaplan-Meier
mAb
monoclonal antibody
MCP-1
monocyte chemotactic protein-1
MedDRA
Medical Dictionary for Regulatory Activities
MED ID
medication identification
MHRA
Medicines and Healthcare products Regulatory Agency
mITT
modified intent-to-treat
MM
multiple myeloma
MOA
mechanism of action
MRD
minimal residual disease
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NDMM
newly diagnosed multiple myeloma
NGS
next-generation sequencing
NK
natural killer
ORR
overall response rate
OS
overall survival
PAD
pharmacologically active dose
PD
progressive disease
PFS
progression-free survival
Pgp
P-glycoprotein
PK
pharmacokinetic
PMDA
Pharmaceuticals and Medical Devices Agency of Japan
POEMS
polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes
PR
partial response
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QTc
corrected QT interval
QTcF
QT interval with Fridericia correction method
QW
once weekly
RANKL
receptor activator of nuclear factor kappa-Β ligand
RBC
red blood cell
RP2D
recommended Phase 2 dose
RRMM
relapsed and/or refractory multiple myeloma
SAE
serious adverse event
SAP
statistical analysis plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
sCR
stringent complete response
SLE
systemic lupus erythematosus
SMC
Safety Monitoring Committee
SMM
smoldering multiple myeloma
SOE
schedule of events
SPEP
serum protein electrophoresis
SUMO
small ubiquitin-like modifier
SUSAR
suspected unexpected serious adverse reaction
TEAE
treatment-emergent adverse event
ULN
upper limit of the normal range
TTNT
time to next treatment
TTP
time to progression
UPEP
urine protein electrophoresis
UK
United Kingdom
US
United States
VGPR
very good partial response
Vss
volume of distribution at steady state
WHO
World Health Organization
3.4
Corporate Identification
TDC Japan
Takeda Development Center Japan
TDC Asia
Takeda Development Center Asia, Pte Ltd
TDC Europe
Takeda Development Centre Europe Ltd
TDC Americas
Takeda Development Center Americas, Inc
TDC
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable
Takeda
Millennium Pharmaceuticals, Inc, TDC Japan, TDC Asia, TDC Europe and/or TDC 
Americas, as applicable
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4.0
INTRODUCTION
4.1
Background
Multiple myeloma (MM) is a plasma cell-derived malignancy that accounts for approximately 
1% of all cancers and 10% of hematologic malignant disorders [1]. It is characterized by 
proliferation of clonal malignant plasma cells in the bone marrow, lytic bone lesions, and 
immunodeficiency. Treatment of MM, especially relapsed is complicated and is characterized by 
relapses and remissions, with each remission typically lasting less than the prior one [2] MM 
Patients with successive relapses or who are refractory to immunomodulatory drugs (IMiDs), 
proteasome inhibitors, and anti-CD38 monoclonal antibody (mAb) have poor survival, 
highlighting that novel therapies and treatment combinations are urgently needed [2].
CD38 is a surface protein that is highly expressed on plasma cells, and at relatively low levels on 
normal lymphoid, myeloid cells, as well as red blood cell (RBC) and platelets [3,4]. After plasma 
cells, CD38 is most strongly expressed on natural killer (NK) cells, with weaker expression on B 
cells and T cells [3]. CD38 is highly expressed in MM in addition to a subset of hematological 
tumors such as NK/T cell lymphoma, T Cell and B Cell acute lymphoblastic leukemia, acute 
myeloid leukemia, and plasma cell dyscrasias such as Waldenström’s macroglobulinemia and 
systemic light chain amyloidosis [3].
Targeting the small ubiquitin-like modifier (SUMO) pathway may provide a novel therapeutic 
approach for hematologic malignancies. The SUMOylation pathway is often overexpressed in 
MM, as compared to normal B cells and plasma cells from healthy individuals. This 
overactivation of SUMOylation may represent a protective effect in MM cells and is associated 
with poor patient outcomes [5]. Inhibition of SUMOylation represents a novel therapeutic 
strategy in MM based on its link to type I interferon (IFN-I) regulation. Historically, IFN
treatment has played a role in the treatment of myeloma, although its use as a systemic therapy is 
limited by its toxicity and narrow therapeutic window [6]. A key role for SUMOylation in 
suppressing expression of IFN-Is was demonstrated by means of genetic knockout of the 
pathway in vivo in the myeloid compartment and ex vivo in dendritic cells (DCs), resulting in 
enhanced basal expression levels of IFN-Is and sensitization of IFN induction in response to 
pathogenic stimuli [7]. IFN-Is, such as IFNα and IFNβ are potent immunomodulatory cytokines 
induced early in the innate immune response which act upon multiple cell types to mold both 
innate and adaptive immunity. They directly enhance NK cell cytotoxicity and stimulate IL-15 
production by DCs to promote NK cell activation [8,9]. They also directly act upon T cells to
stimulate survival, clonal expansion and the development of T cell effector function [10,11]. 
IFN-Is also play a central role in propagating adaptive immune responses by promoting 
maturation of DCs and cross presentation of antigens to T cells [12,13].
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4.1.1
TAK-981
Mechanism of Action
4.1.1.1
TAK-981 is a potent and selective mechanism-based inhibitor of the SUMO-activating enzyme 
which inhibits SUMOylation by forming a covalent adduct with SUMO when it is bound to the 
SUMO-activating enzyme. Central to the antitumor mechanism of action (MOA) of TAK-981 is 
its ability to induce expression of IFN-Is. Ex vivo assays demonstrated that TAK-981 promoted 
the activation of DCs, NK cells, T cells and macrophages in a IFN-I-dependent manner. The 
ability of TAK-981 to promote activation of macrophages and NK cells provides a mechanistic 
rationale for its use in combination with anti-tumor antibodies reliant on antibody-dependent 
cell-mediated cytotoxicity (ADCC) and/or antibody-dependent cell-mediated phagocytosis 
(ADCP), such as rituximab, daratumumab, and mezagitamab. In ex vivo assays, TAK-981 
upregulated inflammatory markers on macrophages (CD80, CD86) and increased the phagocytic 
activity of monocyte-derived macrophages in both the absence and presence of the mAbs 
rituximab and daratumumab in a IFN-I-dependent manner. TAK-981 increased the activation 
marker CD69 and the degranulation marker CD107 on NK cells and enhanced the cytotoxicity of 
NK cells in both the absence and presence of rituximab. In vivo, TAK-981 showed synergy with 
the anti-CD20 antibody rituximab in OCI-Ly10 xenografts in severe combined 
immunodeficiency mice (lacking B cells and T cells but retaining an intact innate immune 
system). In vivo experiments in Daudi lymphoma xenografts, which express both CD20 and 
CD38, demonstrated synergy between TAK-981 and rituximab and between TAK-981 and the 
anti-CD38 antibodies daratumumab and mezagitamab. These studies showed that the 
combination of TAK-981 with mezagitamab or daratumumab was well tolerated with no 
synergistic toxicity. There was no treatment-related mortality or maximum mean body weight 
loss greater than 10% in the combination groups.
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Figure 4.a
Synergistic Combination of TAK-981 With Daratumumab or Mezagitamab 
(TAK-079) in the Daudi Tumor Model.
BIW: twice weekly.
TAK-981 combines synergistically with daratumumab or mezagitamab (TAK-079) in the Daudi tumor model. Eight 
week-old female CB-17 severe combined immunodeficiency mice were inoculated subcutaneously in the flank with 
2 × 106 Daudi cells. When the mean tumor volume reached approximately 100 to 200 mm3, animals were 
randomized into treatment groups (n =8/group) and dosed intravenously with TAK-981, intraperitoneally  with 
daratumumab or mezagitamab, or with the combination of TAK-981 with either daratumumab or mezagitamab at 
7.5 mg/kg twice per week for 3 weeks (D0/D5/D8/D12/D15/D19).
Nonclinical Pharmacokinetics
4.1.1.2
TAK-981 has an acceptable nonclinical pharmacokinetic (PK) profile for continuing evaluation 
and development in humans.
In plasma, after single intravenous (IV) administration, TAK-981 showed moderate to high 
plasma clearance and volume of distribution at steady state (Vss) after IV administration in mice, 
rats, dogs, and monkeys with half-lives varying from 2 to 6 hours among species. For latest 
information, refer to the TAK-981 investigator's brochure (IB).
Nonclinical Toxicology
4.1.1.3
The nonclinical toxicology profile of TAK-981 has been fully characterized in a comprehensive 
toxicology program that included single- and repeat-dose studies in rats and dogs. Repeat daily 
dosing resulted in unacceptable toxicity due to multiorgan failure in rats and fever (increased 
body temperature) in dogs. Increased body temperature was observed in dogs after a single-dose 
of TAK-981 at ≥3 mg/kg and was dose-limiting at 12 mg/kg with body temperature reaching up 
to 40.3ºC (compared to baseline body temperature of 37.8ºC to 38.9ºC). Increased body 
temperature (0.5°C to 2.0°C) was also observed in dogs at ≥3 mg/kg in a single-dose 
cardiovascular assessment study and after repeat once-daily or once weekly (QW) dosing. 
Increased body temperature in the cardiovascular assessment study was not associated with 
effects on blood pressure or electrocardiogram (ECG) morphology but was associated with 
increased heart rate. Because intermittent dosing on a QW or twice weekly (BIW) schedule was 
demonstrated to be efficacious in mouse models, both QW and BIW schedules were examined in 
Good Laboratory Practices toxicology studies. Once per week dosing (5 doses) was associated 
with multiorgan failure in rats at ≥20 mg/kg, but was well tolerated in dogs up to the top dose of 
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6 mg/kg. However, BIW dosing (4 doses) was well tolerated in both species up to the top dose of 
10 mg/kg in rats and 4 mg/kg in dogs. Therefore, in Phase 1b Part 1 both the BIW and weekly 
schedules will be evaluated. One of the schedules will be selected for further evaluation in Phase 
1b Part 2 and Phase 2.
The primary toxicity with BIW dosing was dose-dependent mild to marked decreases in 
peripheral blood lymphocyte counts that affected T cells, T cell subsets (helper, cytotoxic, 
activated, memory, regulatory), B cells, and NK cells approximately equally. Decreases in 
lymphocyte count were associated with decreases in lymphoid cellularity in the primary and 
secondary lymphoid organs including the thymus, spleen, lymph nodes, and gut-associated 
lymphoid tissue. Decreases in other circulating cell types including neutrophils, monocytes, 
basophils, and/or eosinophils were also observed, but were of decreased severity compared to 
decreases in lymphocyte counts. Additional effects observed with BIW dosing were limited to 
myeloid hyperplasia in the bone marrow in rats at 10 mg/kg and in dogs at 4 mg/kg; modest 
increases in serum monocyte chemotactic protein-1 (MCP-1), IFN gamma-induced protein 10 
(IP-10) (rats only), and RANTES (regulated upon activation normal T cell expressed and 
secreted) (rats only) at ≥0.5 mg/kg (with no increases in cytokines typically associated with 
cytokine release syndrome [CRS]); injection site reactions in rats at ≥0.5 mg/kg; single-cell 
necrosis in the stomach in dogs at ≥2 mg/kg; and renal pelvis inflammation and fibrinoid 
vascular necrosis (without involvement of the renal parenchyma or alterations in renal 
parameters) in dogs at 4 mg/kg. Additional TAK-981-related effects after repeat daily or QW
dosing, often at nontolerated doses only, were observed in the bone marrow, liver, kidney, 
urinary bladder (dog only), gastrointestinal tract, heart, musculoskeletal system, lung, endocrine 
system, glandular organs, and reproductive tract (rat only). All target organ toxicities at tolerated 
doses were considered to be monitorable, except for inflammation and vascular necrosis in the 
renal pelvis in dogs. All target organ toxicities were completely or partially reversible.
An in vitro cytokine release assay was performed to evaluate the risk of TAK-981 to produce 
clinically significant CRS and was considered negative.
For the latest information, refer to the TAK-981 IB.
4.2
Clinical Experience
4.2.1
TAK-981
TAK-981 is being evaluated in an ongoing first-in-human (FIH) Phase 1 study evaluating safety 
in patients with advanced or refractory solid tumors or lymphomas (Study TAK-981-1002), and 
2 ongoing Phase 1b/2 clinical efficacy and safety studies; 1 in combination with rituximab in 
patients with relapsed/refractory indolent or aggressive CD20+ non Hodgkin lymphomas 
(Study TAK-981-1501) and 1 in combination with pembrolizumab in patients with select 
advanced or metastatic solid tumors (Study TAK-981-1502).
As of the 28 June 2021 data cutoff for the IB, 135 patients have been treated with TAK-981 
across 4 clinical trials; 81 patients have received single agent TAK-981 and 55 patients have 
received TAK-981 as part of a combination regimen. Overall, TAK-981 has been well tolerated 
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and the type of treatment-emergent adverse events (TEAEs) are consistent with induction of 
interferon signaling or were consistent with the patients’ underlying cancer disease (see Section 
4.5.1 and Section 8.11 for more details). The most common TEAEs (>20%) in the total 
population in Studies TAK-981-1002, TAK-981-1501, and TAK-981-1502 are fatigue, pyrexia, 
nausea, diarrhea, chills, and headache (Table 4.a). Overall, preliminary efficacy is being 
observed, and efficacy evaluations are ongoing.  (Refer to current TAk-981 IB for details).
Table 4.a
Most Frequent (≥10% of All Patients) TEAEs in Studies TAK-981-1002, 
TAK-981-1501, and TAK-981-1502
Preferred Term
Number of Patients (%)
Total (N=135)
Fatigue
49 (36.3)
Pyrexia
46 (34.1)
Nausea
45 (33.3)
Diarrhoea
39 (28.9)
Chills
36 (26.7)
Headache
35 (25.9)
Vomiting
27 (20.0)
Decreased appetite
26 (19.3)
Dyspnoea
22 (16.3)
Abdominal pain
21 (15.6)
Hypokalaemia
21 (15.6)
Anaemia
19 (14.1)
Oedema peripheral
17 (12.6)
Constipation
14 (10.4)
Source: TAK-981 Investigator’s Brochure Edition 4, Table 5.g (Data cut-off date: 28 June 2021).
TEAE: treatment-emergent adverse event.
In study TAK-981-1002, the maximum tolerated dose (MTD) was determined to be 120 mg; the 
recommended Phase 2 dose (RP2D) for single agent TAK-981 is 90 mg given BIW (Days 1, 4, 
8, 11) in a 21-day cycle. Out of the 81 patients, 4 dose-limiting toxicities (DLTs) were reported 
in the single-agent study: transient Grade 3 serum alanine aminotransferase (ALT) and aspartate 
aminotransferase (AST) elevations at 60 mg BIW, Grade 3 recurrent pneumonitis after a 
previous pneumonitis with an anti-progressive disease-1 (PD-1) inhibitor at 90 mg BIW, and 2 at 
120 mg BIW, transient Grade 3 stomatitis and transient Grade 3 cognitive disturbance with 
Grade 2 lethargy. The most common (≥20%) TEAEs in Study TAK-981-1002 across 10 dose 
levels (3 mg-120 mg) and 3 dosing schedules (Days 1, 4, 8, and 11; Days 1 and 8; and Days 1, 8, 
and 15 in a 21-day cycle) were fatigue, nausea, headache, diarrhea, pyrexia, dyspnea, vomiting, 
and decreased appetite. Reversible CRS was reported in 9 patients with 5 patients experiencing 
Grade 1 events (Grade 1 or 2 fever only) and 4 patients experiencing Grade 2 events (ie, fever 
and low peripheral oxygen saturation or low blood pressure). Grade 2 CRS was managed 
symptomatically (eg, oral antipyretics for fever, in addition to oxygen for hypoxia or IV fluids 
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for low blood pressure). No patient with CRS required vasoactive drug support or anti-IL-6 
directed therapies.
Refer to the TAK-981 IB for additional details.
4.2.2
Daratumumab
Daratumumab and hyaluronidase-fihj (Darzalex FASPRO) is an immunoglobulin GI kappa 
(IgG1ĸ) human mAb that binds to CD38 antigens and inhibits the growth of CD38 expressing 
tumor cells by inducing apoptosis, complement dependent cytotoxicity (CDC), ADCC, and 
ADCP. Daratumumab has an acceptable clinical safety profile and is approved as a monotherapy 
and in combination with standard anti-myeloma therapies for patients with MM [14,15].
4.2.3
Mezagitamab
Mezagitamab (TAK-079), is an investigational IgG1 human mAb directed against CD38. 
Compared to daratumumab, mezagitamab shows lower affinity binding to CD38 expressed on 
RBCs and platelets, and greater affinity binding to CD38 on blood B and T lymphocytes [16]. It 
depletes myeloma cells through apoptosis, ADCC, CDC, and ADCP [17]. Mezagitamab 
monotherapy has been shown to be safe, generally well tolerated, and active in patients with 
relapsed and/or refractory multiple myeloma (RRMM) through tested doses (45, 135, 300, 600, 
and 1200 mg). Clinical activity occurred early and was durable. No MTD has been identified. No 
infusion-related reactions (IRRs) and no significant hematologic toxicity has been reported. The 
RP2D is 600 mg. Progression-free survival (PFS), with a median FU of 7.5 months at the data-
cut off, is not estimable at the RP2 dose [18]. Clinical studies are ongoing in MM (relapsed/ 
refractory and newly diagnosed), systemic lupus erythematosus (SLE), myasthenia gravis, and 
primary immune thrombocytopenia purpura. Additionally a study in healthy volunteers has been 
completed. Refer to the Mezagitamab IB for additional details.
4.3
Rationale for the Proposed Study
The treatment of patients with MM is challenging even with the therapies approved in recent 
years. Patients with disease refractory to IMiDs, proteasome inhibitors, and anti-CD38 mAbs
have a poor prognosis owing to a changing biology and development of drug resistant 
phenotypes within the tumor. The role of the physical interaction between MM cells and the 
bone marrow microenvironment in myeloma pathogenesis is well documented [19]. This reality 
has driven the search for new agents and combinations that could be effective in patients with 
RRMM. Therapies that engage the immune system to treat MM may offer significant clinical 
benefit to such patients [20].
TAK-981 is a first-in-class inhibitor of SUMOylation that stimulates innate and adaptive 
immune responses and may potentially offer transformative clinical benefits to patients with 
hematologic malignancies. Ongoing Phase 1 studies have demonstrated acceptable PK 
characteristics with an acceptable and manageable safety profile. Based on its MOA, evaluation 
in patients with RRMM, patients with a high unmet medical need, is warranted.
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There is strong nonclinical evidence demonstrating that TAK-981 can synergize with mAbs 
against CD38 and other targets relevant in hematological malignancies such as CD20. TAK-981 
induces IFN-I signaling and as a consequence activates NK cells and polarizes macrophages 
towards an M1 phenotype, which enhances ADCC and ADCP. These antibody-dependent 
effector mechanisms are a major contributor to the antitumor effects of IgG1 mAbs, providing a 
mechanistic rationale for the use of TAK-981 in combination. Preclinical studies have 
demonstrated combination benefit in vitro and in vivo with the therapeutic mAbs rituximab, 
daratumumab, and mezagitamab. An additional rationale for the use of TAK-981 in combination 
with anti-CD38 mAbs is that CD38 expression levels can increase in response to IFN-I signaling 
[21], which could restore or promote sensitivity to anti-CD38 mAbs in cases where its 
expression is low. Clinical trials are underway with TAK-981 as a single agent in patients with 
advanced solid tumors and relapsed/refractory hematological malignancies (NCT03648372), 
with TAK-981 in combination with rituximab in patients with relapsed/refractory CD20+ 
lymphoma (NCT04074330), and with TAK-981 in combination with the checkpoint inhibitor 
pembrolizumab in patients with advanced solid tumors [NCT04381650]. This Phase 1b/2 trial 
proposes to study the combination of TAK-981 with the anti-CD38 mAbs daratumumab and 
mezagitamab in patients with CD38 positive hematologic malignancies, ie, RRMMs.
4.4
Rationale for the Starting Dose and Schedule
TAK-981 has been extensively characterized in preclinical studies (Refer to the TAK-981 IB for 
the latest information) and is in the early stages of clinical investigation. The initial dose of 
TAK-981 was selected from the dose escalation portion of the FIH study TAK-981-1002, a 
Phase 1/2 study of TAK-981 in patients with advanced or metastatic solid tumors or 
relapsed/refractory hematologic malignancies. As of the IB data cutoff at the time of the initial 
TAK-981-1503 protocol development (28 June 2020), Study TAK-981-1002 enrolled 31 patients 
and had completed dose escalation across 7 dose cohorts (3, 6, 10, 15, 25, 40, and 60 mg) with 
enrollment ongoing in cohort 8 (90 mg) on Days 1, 4, 8, and 11 (every 3 weeks). Across the 
doses tested at that time, the PK of TAK-981 was linear and indicated minimal or no 
accumulation [current TAK-981 IB], the MTD had not been reached, and the most common 
TEAE reported was fatigue.
Two DLTs had been observed; 1 each at the 60 and 90 mg dose levels. The DLT observed at 60 
mg consisted of a transient Grade 2 serum ALT and AST evaluation with normal bilirubin after 
the third dose of TAK-981. The patient did not have a history of liver metastasis or fatty liver, 
and was not taking confounding concomitant medications. The ALT and AST elevations 
resolved within 72 hours, TAK-981 was resumed at 40 mg, and no further alterations of the liver 
function tests were observed in the subsequent TAK-981 doses. The DLT observed at 90 mg 
consisted of Grade 3 pneumonitis. The patient was previously treated with 3 check point 
inhibitor-containing regimens and had a previous episode of immune-related pneumonitis that 
led to dual anti-CTLA-4 and anti-PD-1 blockade discontinuation 6 months before the initiation 
of TAK-981 treatment. The patient reported fever and increasing fatigue; Grade 4 lymphopenia 
with C-reactive protein of 149.6 mg/L were observed. Blood cultures for bacterial infection in 
addition to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) polymerase chain 
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reaction test were negative. Computed tomography (CT) scan of the chest confirmed ground 
glass opacities compatible with recurrent pneumonitis. The patient was discharged after 12 days 
of treatment with IV steroids and subsequent oral prednisone tapering with mild residual 
opacities in the radiology evaluation.
Based on the available safety, pharmacodynamic, and PK data at the time of this protocol 
development, the starting dose of TAK-981 will be 60 mg. This starting dose level of TAK-981 
is 1 dose level below the monotherapy dose that cleared the DLT period (90 mg) and 2 dose 
levels below the current dose escalation cohort (120 mg) in the ongoing FIH single agent study 
(Study TAK-981-1002). Early pharmacodynamic studies of patient samples collected in 
TAK-981-1002 provide evidence of dose-dependent target engagement (TAK-981-SUMO 
adduct) in blood and skin, evidence of SUMO pathway inhibition in blood and skin, and 
induction of a IFN-I response at 60 mg assessed by several complementary methods (gene 
expression in blood, increase in plasma cytokines and chemokines, and increased CD69 
expression on NK cells).
The individual mAbs included in this study are given in a 28-day cycle. Therefore, the TAK-981 
schedule will also be adapted to a 28-day cycle. TAK-981 will be given on Days 1, 4, 8, 11, and 
15, in Cycles 1 and 2, followed by 1 dose every 2 weeks in Cycle 3 to 6, and then once every 
4 weeks dosing thereafter (See Section 8.0). The adapted TAK-981 BIW dosing schedule allows 
for >10 days of hematopoietic recovery in the event that lymphocytopenia emerges as a DLT in 
the 28-day cycle. To date, reductions in lymphocyte counts have been mild and transient with 
full recovery over 72 hours with TAK-981 dosing on Day 1, Day 4, Day 8, and Day 11 of a 
15-day cycle. This approach will allow this study to start safely at a dosing schedule of 5 doses 
in a 28-day cycle; a total dose that is lower than that already safely evaluated in study 
TAK-981-1002 where 6 doses are delivered over the course of the first 28 days. A second 
schedule will evaluate TAK-981 given weekly in a 28-day cycle during cycle 1 and 2. The 
weekly schedule, TAK-981 administration on Day 1 and Day 8 of a 21-day cycle, is being 
explored in Study TAK-981-1002 and TAK-981-1501 to assess the impact of dose schedule 
intensity on safety and pharmacodynamic endpoints. The dose of 90 mg weekly on Day 1 and 8 
has cleared the DLT period and the 120 mg cohort is now open for enrollment.
During the CD38 mAb taper from weekly dosing for C1 and C2 to twice monthly dosing for 
C3 to C6 and once every 4 weeks dosing thereafter, the schedule of TAK-981 administration was 
aligned with CD38 mAb administration and was primarily driven by practical considerations 
with regards to the treatment burden in MM patients. Overall, the emerging safety, efficacy, 
pharmacodynamic and PK data will guide the selection of the RP2D and schedule.
4.5
Potential Risks and Benefits
4.5.1
Potential Effects of TAK-981
The potential AEs/risks of TAK-981 are based on findings from the nonclinical studies with 
TAK-981 and the emerging safety data from ongoing clinical studies: hematologic effects 
(lymphocytopenia with/without associated opportunistic infection; anemia, thrombocytopenia, 
neutropenia); injection site reactions; IRRs and potential for CRS; changes in renal function 
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(Refer to Section 8.11). Safety data (as of 28 June 2021) obtained from the dose escalation 
cohorts across all ongoing studies demonstrated that the most common TEAEs (>20%) are 
fatigue, pyrexia, nausea, diarrhea, chills, and headache; TEAEs consistent with induction of IFN 
signaling. The only serious adverse reaction considered expected for safety reporting purposes 
across the ongoing TAK-981 studies is pyrexia. The single agent MTD (in 
Study TAK-981-1002) has been identified as 120 mg with evaluation continuing in the ongoing 
studies of TAK-981 in combination with rituximab or pembrolizumab (studies TAK-981-1501 
and TAK-981-1502, respectively). For additional details, refer to the TAK-981 IB.
4.5.2
Potential Effects of Daratumumab and Hyaluronidase-fihj
The most frequently reported adverse reactions (incidence ≥20%) were: upper respiratory 
infection, neutropenia, IRRs, thrombocytopenia, anemia, leukopenia, and lymphocytopenia [15]. 
Refer to Section 8.11 and daratumumab and hyaluronidase-fihj Prescribing Information for more 
details.
4.5.3
Potential Effects of Mezagitamab
The potential effects of mezagitamab are based on findings from the nonclinical studies with 
mezagitamab and the emerging safety data from ongoing clinical studies. The most common (in 
≥ 15% of patients receiving monotherapy) TEAEs by preferred terms regardless of causality as 
of 20 March 2021 data cut off are fatigue and upper respiratory tract infection (27% each), 
insomnia and back pain (20% each), diarrhea, nausea, and anemia (16% each). Very limited 
injection site reactions have been reported (0.21%; including mild pruritis, moderate swelling at 
site). Thrombocytopenia/decrease in platelet count has been generally low grade and not 
clinically important. No DLTs have been reported with monotherapy. The MTD was not 
identified. No systemic infusion reactions, including documented CRS or anaphylaxis, have been 
reported. Refer to Section 8.11 and Mezagitamab IB for additional details.
4.5.4
Overall Benefit-Risk Assessment
The emerging preliminary safety profile, as summarized in Section 8.11, with further details in 
the current IBs, indicate that TAK-981 and mezagitamab are generally well tolerated with 
manageable and reversible AEs. Daratumumab and hyaluronidase-fihj has an acceptable clinical 
safety profile and is approved for patients with MM. The potential toxicities of all agents can be 
managed by clinical monitoring and standard medical interventions. It is possible that TAK-981 
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-981, patients will be carefully monitored closely for signs and symptoms of IRRs, CRS, 
hematologic toxicity, lymphopenia and opportunistic infections, and infusion site reactions with 
appropriate management of these events (see Section 8.11). Depending on the severity of the 
reaction, the TAK-981 drug dosage can be modified (ie, dose hold, delay or discontinued within 
a cycle) as outlined in Section 8.7.3.
In the ongoing clinical studies, TAK-981 has shown early signs of antitumor activity as a single 
agent and in combination with rituximab.
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Though additional data are needed to characterize the clinical benefit of this drug, the emerging 
data supports the ongoing development of TAK-981.
4.5.5
Coronavirus Disease 2019 Pandemic
The coronavirus disease 2019 (COVID-19) pandemic has affected health care and specifically 
cancer care broadly across the globe. Based on current knowledge, the benefit-risk assessment 
for patient participation in this study remains favorable. The benefit-risk considerations for 
patient participation should be evaluated by the investigator on a patient-by-patient basis taking 
into consideration the current local situation, guidelines, and recommendations. Investigators 
should follow local recommendations and guidelines with regards to COVID-19 precautions, 
vaccination, and treatment.
5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objectives
The primary objectives are:
Phase 1b:

To determine the safety and tolerability of TAK-981 in combination with mAbs in patients 
with RRMM.

To determine the RP2D.
Phase 2:

To evaluate the efficacy of TAK-981 in combination with mAbs in patients with RRMM.
5.1.2
Secondary Objectives
The secondary objectives are:

To characterize the PK profile of TAK-981 in combination with anti-CD38 mAb.

To assess immunogenicity of anti-CD38 monoclonal antibodies  (mezagitamab and 
daratumumab) to help interpreting PK profile, efficacy and safety of TAK-981 in 
combination with monoclonal antibodies.
Phase 1b:

To evaluate preliminary efficacy of the TAK-981-mAb combination according to standard 
International Myeloma Working Group (IMWG) criteria.

To assess target engagement of TAK-981 (TAK-981-SUMO adduct formation) and 
SUMOylation pathway inhibition in blood.
Phase 2:

To further characterize efficacy of TAK-981 in combination with anti-CD38 mAb in RRMM 
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Figure 6.a
Study Schema
Patient participation will include a screening phase, a treatment phase, and a follow-up phase 
(see Section 9.0). The screening phase will be up to approximately 28 days before Cycle 1, 
Day 1 (C1D1). The treatment phase will extend from C1D1 until patients experience disease 
progression or unacceptable toxicity, or until any other discontinuation criterion is met (Refer to 
Section 9.7). The follow-up phase of the study begins once a patient discontinues study treatment 
and completes the end-of-treatment (EOT) visit; study follow-up continues until the study ends 
or the patient completes OS follow-up (Refer to Section 9.10).
6.2
Phase 1b Study Design
The Phase 1b part of the study will enroll patients with RRMM with the purpose of defining the 
RP2D and schedule of TAK-981 in combination with mezagitamab and daratumumab and 
hyaluronidase-fihj, respectively. The first part of the Phase 1b will determine the dose and 
schedule of TAK-981 in combination with a fixed dose and schedule of mezagitamab for 
expansion in Phase 2. The second part of the Phase 1b will determine the dose of TAK-981 for 
the combination with daratumumab and hyaluronidase-fihj. 
6.2.1
Phase 1b Part 1
Dose escalation of TAK-981 will be guided by a iBOIN (see Section 8.5 and Appendix H for 
details). Up to approximately 15 patients will be enrolled to each of the TAK-981 schedules until 
either MTD or a pharmacologically active dose (PAD) is identified: 

Arm A: TAK-981 given IV BIW on Days 1, 4, 8, 11, and 15 in Cycles 1 and 2 followed by 
every 2 weeks in Cycles 3 through 6, then once every 4 weeks. TAK-981 will be given in 
combination with mezagitamab (Further details in Section 8.0). 
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
Arm B: TAK-981 given IV weekly (QW) on Days 1, 8, 15, and 22 in Cycles 1 and 2 
followed by every 2 weeks in Cycles 3 through 6, then once every 4 weeks. TAK-981 will be 
given in combination with mezagitamab (Further details in Section 8.0).
The starting dose for TAK-981 will be 60 mg; the rationale for the initial TAK-981 dose is 
provided in Section 4.4. The dose of mezagitamab is the established RP2D at 600 mg.
Once enrolled into the study, patients will be assigned to a treatment arm in a nonrandomized, 
sequential manner based upon the recruitment status of the TAK-981 arm schedule, as 
communicated by the sponsor/ designee. A minimum of 3 patients will be enrolled in the first 
dose cohort. In the first dose cohort, patient enrollment will be staggered between the first and 
second patients by 7 days. The second and third patients can be dosed concurrently if the first 
patient in the cohort has gone through the Day 8 visit without clinically significant acute 
toxicities. Subsequent dose cohorts will not require staggering between patients.
Dose escalation will begin with the BIW schedule. TAK-981 dose escalation will be evaluated 
separately for each of the TAK-981 schedules.
Dose escalation decisions will be made by a Safety Monitoring Committee (SMC), composed of 
the principal investigators and sponsor. The SMC will regularly review safety data to ensure 
patients’ safety throughout the Phase 1b portion of the study. Dose escalation will follow an 
iBOIN design. Dose escalation decisions will take into consideration primarily the DLTs 
observed in Cycle 1 in the patients enrolled in each dose level/schedule according to the rules in 
Section 8.5 (DLT rules). Available safety information beyond Cycle 1, PK and 
pharmacodynamic information from previously dose patients will also be considered.
Evaluation of intermediate doses or doses up to the maximum dose of 160 mg (the maximum 
dose level permitted in TAK-981-1002 FIH study), alternative dosing schedules (dosing 
interval), and expansion of an existing dose level are all permissible following agreement by the 
SMC, if such measures are needed for patient safety or for a better understanding of the 
dose-related toxicity, efficacy, exposure, or pharmacodynamics of TAK-981. The dose 
escalation/de-escalation rules based on iBOIN design will be considered as a guidance for the 
next dose level, however, the final decision on the dose will be made by the SMC.
Selection of RP2D for TAK-981 in Combination With Mezagitamab
6.2.1.1
The selection of an RP2D which includes the dose level and schedule of TAK-981 in 
combination with mezagitamab will be made by the sponsor following evaluation of the 
available data from the Phase 1b – Part 1 portion of the trial which will include, but is not limited 
to safety data, preliminary PK data, preliminary pharmacodynamic data, preliminary 
translational data, PK/pharmacodynamic modeling and preliminary antitumor activity. The
RP2D may not be higher than the MTD as determined by iBOIN. Upon review of available 
Phase 1b data and agreement on the RP2D by the SMC, the Phase 1b Part 2 portion of the study 
of the combination of TAK-981 with daratumumab and hyaluronidase-fihj may begin.
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6.2.2
Phase 1b Part 2
In the second part of Phase 1b, the RP2D of TAK-981 in combination with daratumumab and 
hyaluronidase-fihj will be determined. 
Dose escalation of TAK-981 will be guided by iBOIN as described in Section 8.5. The starting 
dose for TAK-981 will be 1 dose-level below the RP2D defined for the combination with 
mezagitamab in Phase 1b Part 1 (RP2D-1). A minimum of 3 patients will be enrolled in the first 
cohort of this combination, and up to approximately 15 patients will be enrolled for the dose 
escalation. 
Selection of RP2D for TAK-981 in Combination With Daratumumab and 
6.2.2.1
Hyaluronidase-fihj
The selection of an RP2D of TAK-981 in combination with daratumumab and hyaluronidase-fihj 
will be made by the sponsor following evaluation of the available data from the Phase 1b – Part 2 
portion of the trial which will include, but is not limited to safety data, preliminary PK data, 
preliminary pharmacodynamic data, preliminary translational data, PK/pharmacodynamic 
modeling and preliminary antitumor activity. The RP2D may not be higher than the MTD as 
determined by iBOIN.
6.2.3
Selection of CD38 Antibody for Phase 2
The selection of the anti-CD38 antibody (mezagitamab or daratumumab and hyaluronidase-fihj) 
for combination with TAK-981 in Phase 2 will be made by the sponsor following evaluation of 
the available data from the Phase 1b – Part 1 portion of the trial which will include, but is not 
limited to safety data, selected RP2D, frequency of dose reduction/discontinuation observed for 
anti-CD38 antibody, preliminary pharmacodynamic data, preliminary translational data, 
PK/pharmacodynamic modeling and preliminary antitumor activity.
6.3
Phase 2 Study Design
The Phase 2 portion of the study will explore the efficacy and safety of TAK-981 in combination 
with an anti-CD38 antibody (mezagitamab or daratumumab and hyaluronidase-fihj) in patients 
with RRMM. Patients will be treated with the RP2D defined in Phase 1b for the respective 
antibody. Cycle duration is 28 days and treatment will be administered for up to 24 cycles or 
until disease progression or unacceptable toxicity, whichever occurs first. TAK-981, 
mezagitamab, and daratumumab and hyaluronidase-fihj administration details are in Section 8.0.
An adaptive 2-stage design for a single proportion will be used in Phase 2. For Stage I, each 
cohort will be analyzed when a prespecified number of patients (as defined in Section 13.0) have 
been enrolled and had the opportunity to complete 4 cycles of treatment. Enrollment may be 
paused until the Stage I analysis is completed. If the prespecified minimal response rate is not 
achieved in the first stage, enrollment will be closed. If the required response rate during Stage I 
or a good CBR is observed as mentioned above, then additional patients will be enrolled in the 
second stage of the corresponding cohort until a predetermined number of additional patients has 
been reached (as defined in Section 13.0). The final analysis of the primary endpoints will take 
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place when all ongoing patients have had the opportunity complete the 12-month disease 
assessment.
6.3.1
Early Stopping Rules
In the Phase 2 portion of the study, Grade 4 or higher drug-related AEs will be monitored 
starting from the first 11 response-evaluable patients and then every 4 response-evaluable 
patients up to the approximate maximum number of patients 36. 
Accrual to the study will be suspended if:

Grade 4 drug-related AEs meet the stopping bounds of the number of ≥4/11, ≥4/15, ≥5/19, 
≥6/23, ≥7/27, ≥7/31, ≥8/35, ≥8/36; or 

At any time if 1 or more patients present with fatal drug-related AEs.
After review and consideration by the SMC, a decision will be made as to whether accrual can be 
resumed.
The stopping bounds for Grade 4 drug-related AEs 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 16% with a prior beta distribution with parameters 0.4 and 1.6 for the 
binomially distributed toxicity rate [22]. 
6.4
Number of Patients
Overall this study will enroll up to approximately 81 patients in North America and/or globally. 
Approximately 15 patients will be enrolled in each dosing schedule in Phase 1b Part 1 and in 
Phase 1b Part 2. Up to approximately 36 patients will be enrolled in Phase 2. Approximately 
15 sites will participate in this study.
Patients who are withdrawn from treatment during Phase 1b Cycle 1 for reasons other than DLTs 
will be replaced.
6.5
Duration of Study
6.5.1
Duration of an Individual Patient’s Study Participation
Patients may receive the TAK-981 mAb combination for up to 24 cycles or until they experience 
PD or unacceptable toxicity, or until any other discontinuation criterion is met, whichever occurs 
first (see Section 9.7).
Patients will be followed for up to 30 days after their last dose of TAK-981, or until the start of a 
subsequent alternative anticancer therapy to permit the detection of any delayed 
treatment-related AEs (this is the EOT visit). For patients who discontinue study drug before PD, 
disease evaluations should continue to be performed as specified in the schedule of events 
(SOE). Patients who discontinue for PD will be followed for survival after documented PD for 
up to 12 months after the last patient discontinues or completes treatment, or until loss of 
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follow-up, consent withdrawal, death, study termination, or until ≥50% of patients in the cohort 
have died, whichever occurs first. (see details in Section 9.6 and the SOE Appendix A).
6.5.2
End of Study/Study Completion Definition and Planned Reporting
The analyses for the CSR will be conducted after all patients enrolled in the study have had the 
opportunity to complete 1 year of therapy. See Section 6.5.5 for patients still benefiting from 
treatment.
Patients who discontinue a mAb for reasons described in Section 9.5 may continue TAK-981 
treatment; however, once TAK-981 has been discontinued, patients cannot remain on the mAb as 
a single agent beyond the cycle during which TAK-981 was discontinued (ie, the patient can 
complete the planned mAb after TAK-981 was discontinued in the same cycle, but the mAb can 
not continue in subsequent cycles). In that case, patients will undergo the EOT visit.
6.5.3
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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Table 6.a
Primary and Secondary Endpoints for Disclosures
Endpoint
Definition
Maximum Time Frame
Primary (Phase 1b): 
Frequency and severity of TEAEs per 
dose level
Standard safety assessments a
Up to 24 months
Occurrence of DLTs in Cycle 1 per dose 
level
Standard safety assessments
Up to 24 months
Primary (Phase 2):
ORR defined by the investigator 
according to IMWG disease response 
criteria
ORR
Up to 24 months
Secondary:
Data permitting for dose escalation 
cohorts, PK parameters after the dose 
administration of TAK-981 on C1D1 : 
Cmax, tmax, AUCt, AUC∞, t1/2z, CL, Vss
Standard PK parameters to allow 
determination of PK profile
Up to 24 months
ADA negative, ADA transient or 
persistent positive, high or low ADA titer
ADA negative, ADA transient or 
persistent positive, high or low ADA titer
Up to 24 months
ORR
ORR
Up to 24 months
CBR
CBR
Up to 24 months
DOR
DOR
Up to 24 months
TTP
TTP
Up to 24 months
PFS
PFS
Up to 24 months
OS
OS
Up to 24 months
MRD
MRD
Up to 24 months
TAK-981-SUMO adduct formation, and 
SUMO pathway inhibition
TAK-981-SUMO adduct formation, and 
SUMO pathway inhibition in blood
Up to 24 months
Frequency and severity of TEAEs
Standard safety assessments a
Up to 24 months
AUCt: area under the plasma/blood/serum concentration-time curve from time 0 to time t; AUC∞: area under the 
plasma concentration-time curve from time 0 to infinity; C1D1: Cycle 1, Day 1; CBR: clinical benefit rate; CL: total 
clearance after intravenous administration; Cmax: maximum observed plasma concentration; CT: computed 
tomography; DLT: dose-limiting toxicity; DOR: duration of response; FDA: Food and Drug Administration; 
IMWG: International Myeloma Working Group; MRD: minimal residual disease; ORR: overall response rate; OS: 
overall survival; PFS: progression-free survival; PK: pharmacokinetic; SAE: serious adverse events; SUMO: small 
ubiquitin-like modifier; TEAE: treatment-emergent adverse event; t1/2z: terminal disposition phase half-life; TTP: 
time to progression; tmax: time of first occurrence of Cmax; Vss: volume of distribution at steady state after intravenous 
administration.
a Phase 1b and 2 safety for CT.gov will be disclosed in only 1 section of ClinicalTrials.gov results database. 
Reporting will follow the requirements of Section 801 of the Food and Drug Administration Amendments Act 
(FDAAA 801)
6.5.4
Total Study Duration
It is anticipated that this study will last for approximately 36 to 48 months.
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6.5.5
Posttrial Access
Patients who have met the primary (and secondary) endpoints of the study and, in the opinion of 
the investigator and confirmed by the sponsor, experienced a clinically important benefit from 
TAK-981 in combination with an assigned mAb may continue to receive TAK-981 or the 
combination in an extension phase of this study or will be given the opportunity to enroll in a 
separate open-label rollover study, if one is available, or have the possibility of using an 
individual patient investigational new drug to continue receiving both study drugs. Additionally, 
these patients should have no alternative therapeutic option and would be harmed without 
continued access.
Duration of Post-Study Access
6.5.5.1
Continued access to TAK-981 or the combination mAb for subjects may be terminated for those 
individuals who no longer benefit from TAK-981 or the combination (eg, they have completed 
the recommended course of therapy or their disease has resolved), that complete the protocol 
defined duration of treatment, for whom the benefit-risk no longer favors the individual, if 
TAK-981 ± mAb becomes available either commercially or via some other access mechanism, or 
when an alternative appropriate therapy becomes available. Post-study access may be terminated 
in a country or geographical region where marketing authorization has been rejected, the 
development of TAK-981 or mezagitamab has been suspended or stopped by the sponsor, or the 
TAK-981 or mezagitamab can no longer be supplied. Daratumumab and hyaluronidase-fihj 
(Darzalex Faspro) is a commercially available product and post-study access would continue to 
be via commercial sources.
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. Be willing and able to provide written informed consent for the study.
3. For patients with MM (for Phase 1b and Phase 2):
a.
A prior diagnosis of MM as defined by the IMWG criteria with documented disease 
progression (Appendix I [23,24]).
b. Has 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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c.
Has undergone stem cell transplant or is considered transplant ineligible, and

Patients with a history of autologous stem cell transplant are eligible if the transplant 
was > 100 days prior to study consent.
d. Has failed at least 3 prior lines of anti-myeloma treatments, including an anti-CD38 
antibody (eg, daratumumab, daratumumab and hyaluronidase-fihj, isatuximab) alone or 
in combination, and
e.
Is either refractory, or intolerant to at least 1 IMiD (ie, lenalidomide or pomalidomide 
[thalidomide excluded]), at least 1 proteasome inhibitor (ie, bortezomib, ixazomib or 
carfilzomib), and refractory to at least 1 anti-CD38 antibody and who have demonstrated 
disease progression with the last therapy. 

Refractory myeloma is defined as disease that is nonresponsive while on therapy or 
progresses within 60 days of last therapy. Nonresponsive disease is defined as either 
failure to achieve at least minimal response or development of PD while on therapy.

A line of therapy consists of ≥1 complete cycle of a single agent, a regimen consisting 
of a combination of several drugs, or a planned sequential therapy of various 
regimens (eg, 3-6 cycles of initial therapy with bortezomib-dexamethasone followed 
by a stem cell transplantation, consolidation, and maintenance is considered 1 line) 
[25]. 
4.
Have a performance status of 0-2 on the Eastern Cooperative Oncology Group (ECOG) 
Performance Scale.
5.
Have suitable venous access for safe drug administration and the study-required blood 
sampling, including PK and pharmacodynamic sampling.
6.
Have adequate organ function as specified below at screening:
a.
Platelet count ≥75, 000 mm3 (≥75 × 109/L); value of ≥50, 000 mm3 (≥50 × 109/L) 
may be acceptable for patients with ≥50% bone marrow burden following 
discussion with the sponsor (platelet transfusion will be allowed > 3 days before 
assessment)
b. Hemoglobin must be 8 g/dL. (RBC transfusion allowed ≥14 days before 
assessment).
c.
Absolute neutrophil count (ANC) ≥1000 mm3 (≥1.0 × 109/L); value of ≥750 mm3 
(≥0.75 × 109/L) may be acceptable for patients with ≥50% bone marrow burden 
following discussion with the sponsor
d. Estimated creatinine clearance using the Cockcroft-Gault formula ≥30 mL/minute 
for patients with serum creatinine concentrations above the upper limit of normal 
range (ULN).
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e.
AST (glutamic oxaloacetic transaminase [GOT]) and ALT (GPT) ≤3.0 × ULN; 
bilirubin ≤1.5 × ULN. Patients with Gilbert’s syndrome may have a bilirubin level 
>1.5 × ULN, per discussion between the investigator and the medical monitor.
7.
Have recovered to Grade 1 or baseline from all toxicity associated with previous therapy or 
have the toxicity established as sequela.
Note: except Neuropathy Grade ≤2, any grade alopecia, or bone marrow parameters [any of 
Grade 1 or 2 permitted if directly related to bone marrow involvement].
8.
Female patients who:

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 6 months after the last dose of drug in 
the combination. OR

Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, 
symptothermal, postovulation methods], withdrawal, spermicides only, and 
lactational amenorrhea are not acceptable methods of contraception. Female and 
male condoms should not be used together.)
9.
Male patients, even if surgically sterilized (ie, status postvasectomy), who:

Agree to practice effective barrier contraception during the entire study treatment 
period and through 6 months after the last dose of drug in the combination, OR

Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, 
symptothermal, postovulation methods], withdrawal, spermicides only, and 
lactational amenorrhea are not acceptable methods of contraception. Female and 
male condoms should not be used together.)
10.
Must be willing and able to comply with clinic visits and procedures outlined in the study 
protocol.
7.2
Exclusion Criteria
Patients meeting any of the following exclusion criteria are not to be enrolled in the study:
1. Received treatment with systemic anticancer treatments within 14 days before the first dose 
of study drug or any investigational products (IPs) within 5 half-lives of the first dose of 
study drug, whichever is appropriate to last therapy received. (eg, non-IP IMiD, proteasome 
inhibitor, anti-CD38 mAb could be considered to be eligible if there is at least 14 days after 
last dose before first dose of study drug).
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Note: Treatment with a single course of glucocorticoids (maximum dose of corticosteroids 
should not exceed the equivalent of 160 mg [for example, 40 mg/d for 4 days] of 
dexamethasone), hormonal therapy for prostate cancer or breast cancer (as adjuvant 
treatment), and treatment with bisphosphonates and receptor activator of nuclear factor 
kappa-Β ligand (RANKL) inhibitors are allowed. 
2. Current participation in another interventional study, including other clinical trials with 
investigational agents (including investigational vaccines or investigational medical device 
for disease under study) within 4 weeks of the first dose of TAK-981 and throughout the 
duration of this trial.
3. Prior radiation therapy within 14 days of the first dose of TAK-981.
Note: Prophylactic localized (“spot”) radiation for areas of pain is allowed.
4. Major surgery within 4 weeks before C1D1. Patients should be fully recovered from any 
surgically related complications.
Note: Kyphoplasty is not considered major surgery.
5. Plasmapheresis within 28 days of randomization.
6. Diagnosis of primary amyloidosis, Waldenström’s disease, monoclonal gammopathy of 
undetermined significance or smoldering multiple myeloma (SMM) per IMWG criteria or 
standard diagnostic criteria, plasma cell leukemia (according to the World Health 
Organization [WHO] criterion: ≥20% of cells in the peripheral blood with an absolute plasma 
cell count of more than 2 × 109/L), POEMS syndrome (polyneuropathy, organomegaly, 
endocrinopathy, monoclonal protein, and skin changes), myelodysplastic syndrome, or 
myeloproliferative syndrome. 
7. With disease where the only measurable parameter is plasmacytoma.
8. Second malignancy within the previous 3 years, except treated basal cell or localized 
squamous skin carcinomas, localized prostate cancer, cervical carcinoma in situ, resected 
colorectal adenomatous polyps, breast cancer in situ, or other malignancy for which the 
patient is not on active anticancer therapy.
9. Evidence of central nervous system involvement and/or meningeal involvement of MM 
exhibited during screening.
10. Known severe allergic or anaphylactic reactions to human recombinant proteins or excipients 
used in the TAK-981 formulation or the mAbs (such as daratumumab or daratumumab and 
hyaluronidase-fihj as per the prescribing information and for mezagitamab as outlined in the 
Mezagitamab IB).
11. History of treatment discontinuation due to treatment-related toxicity to the combination 
partner (daratumumab or daratumumab and hyaluronidase-fihj).
12. Prior treatment with more than 1 anti-CD38 antibody.
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13. Chronic obstructive pulmonary disease (COPD) with forced expiratory volume in 1 second 
(FEV1) <50% of predicted normal; or diagnosis of moderate or persistent asthma within the 
last 2 years, or currently uncontrolled asthma of any classification (controlled intermittent 
asthma or controlled mild persistent asthma is allowed); pulmonary fibrosis; or history of 
symptomatic bronchospasm. Note that FEV1 testing is required for patients with known or 
suspected COPD or asthma and patients must have a FEV1 ≥50% of predicted normal during 
screening.
14. Any concurrent or uncontrolled medical, comorbid, or psychiatric condition or disease that is 
likely to interfere with the study procedures or results, or that in the opinion of the 
investigator, would constitute a hazard for participating in this study.
15. History of HIV, hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.
16. Systemic infection requiring systemic antibiotic therapy or other serious infection within 
14 days before the first dose of TAK-981 or any agent in the combination. 
Note: Urinary tract infection is not considered a systemic infection.
17. History of autoimmune disease requiring systemic immunosuppressive therapy with daily 
doses of prednisone >10 mg/day or equivalent doses, or any other form of 
immunosuppressive therapy. Hormone therapy (eg, thyroxine, insulin, or physiologic 
corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered an 
excluded form of systemic treatment of an autoimmune disease.
18. Active or history of noninfectious pneumonitis that required steroids or a history of 
interstitial lung disease.
19. History of allogeneic tissue or solid organ transplant.
20. Receipt of any live vaccine (eg, varicella, pneumococcus) within 4 weeks of initiation of 
study treatment.
21. Receiving or requiring the continued use of medications that are known to be strong or 
moderate inhibitors and inducers of cytochrome P450 (CYP) 3A4/5 (Appendix F) or are 
strong P-glycoprotein (Pgp) inhibitors (Appendix G) at screening. To participate in this 
study, such patients should discontinue use of such agents for at least 2 weeks or 5 times the 
half-life (whichever is shorter) before receiving a dose of TAK-981.
22. Requires the use of drugs known to prolong the corrected QT interval (QTc) (during 
Phase 1b only) (Appendix I)
23. History of any of the following ≤6 months before first dose: congestive heart failure New 
York Heart Association Grade III or IV, unstable angina, myocardial infarction, unstable 
symptomatic ischemic heart disease, uncontrolled hypertension despite appropriate medical 
therapy, ongoing symptomatic cardiac arrhythmias >Grade 2, pulmonary embolism or 
symptomatic cerebrovascular events, or any other serious cardiac condition (eg, pericardial 
effusion or restrictive cardiomyopathy). Chronic atrial fibrillation on stable anticoagulant 
therapy is allowed. 
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24. Baseline prolongation of the QT interval with Fridericia’s correction method (QTcF) (eg, 
repeated demonstration of QTcF interval >480 ms, history of congenital long QT syndrome, 
or torsades de pointes). If a machine reading is above this value, the ECG should be reviewed 
by a qualified reader and confirmed on a subsequent ECG. 
25. Psychiatric illness/social circumstances that would limit compliance with study requirements 
and substantially increase the risk of AEs or has compromised ability to provide written 
informed consent.
26. Admission or evidence of illicit drug use, drug abuse, or alcohol abuse.
27. Female patients who are lactating and breastfeeding or have a positive serum pregnancy test 
during the screening period or a on Day 1 before first dose of TAK-981 study drug 
(Appendix A).
8.0
STUDY DRUG
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). All patients will receive TAK-981 
and specific mAb as specified in the SOE (Appendix A).
8.1
Investigational Medicinal Products
8.1.1
TAK-981 Study Drug Administration
In Phase 1b each 28-day treatment cycle will consist of TAK-981 administered IV in one of the 
following schedules: (Also see Table 8.a and Table 8.b below): 

BIW on Days 1, 4, 8, 11, and 15 during Cycles 1 and 2, then once every 2 weeks during 
Cycles 3 through 6, followed by once every 4 weeks dosing, OR

QW on Days 1, 8, 15, 22 during Cycles 1 and 2, then once every 2 weeks during Cycles 3 
through 6, followed by once every 4 weeks dosing thereafter until PD.
In Phase 2, a schedule for TAK-981 will be selected for continued evaluation based on data from 
Phase 1b.
The initial Phase 1b starting dose of TAK-981 will be 60 mg. Dose escalation will begin with the 
BIW schedule.
TAK-981 will be administered as a 60 ±10 minute IV infusion. If infusion reactions are 
observed, the length of the infusion can be extended up to 2 hours for all patients without 
requiring a protocol amendment.
For C1D1 only (Phase 1b and Phase 2), the mAb will be administered first (before the TAK-981 
infusion). Starting at C1D8 onwards, TAK-981 will be administered before the mAb. On days in 
which both agents are given on the same visit day at least 1 hour should elapse between the 
completion of the first drug and the administration of the second drug. [Refer to Section 8.1.2
and Section 8.2.1 for more details.]
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TAK-981 administration should occur in an area with resuscitating equipment and medications 
such as antihistamines, acetaminophen, corticosteroids, epinephrine, and bronchodilators readily 
available. Patient’s vital signs (such as blood pressure, heart rate, and temperature) must be 
monitored before, during, at the end of administration of TAK-981, and again before discharging 
the patient or at any time if the patient complains of symptoms. If an AE is observed, extended 
monitoring of vital signs can be added as medically indicated. Treatment must be stopped if the 
patient experience symptoms compatible with an infusion reaction of Grade 2 or greater. During 
C1, vital signs need to be monitored as above and up to 4 hours after the end of the infusion (for 
C1D1 up to 6 hours after the end of infusion). From C2 onwards, vital signs will be monitored 
immediately before the start of infusion and after the end of infusion and the patient can be 
discharged from the site per investigator discretion. The management of infusion reactions and 
CRS is detailed in Sections 8.11.1 and Section 8.11.2, respectively.
Note: Fever is a common TEAE associated with the TAK-981 infusion. Consider prescribing
postinfusion antipyretic medications for up to 24 hours after the end of the TAK-981 infusion as 
a preventative measure. For any patient that has an infusion related fever, consider premedication 
with an antipyretic medication as prophylaxis. Investigator may consider reducing, even 
discontinuing, predose and postdose antipyretics if the patient experiences no major 
infusion-related fever. The clinical site is responsible for sourcing any pre- and post-medications 
outlined in the protocol.
Dose administration should be performed on schedule; however, a dose delay of up to 4 days 
may occur because of such things as inclement weather, holidays, vacations, or administrative 
reasons. A dose delay of up to 7 days is allowed to accommodate for COVID-19 vaccine 
administration after discussion with the sponsor (see Section 8.9). At least 72 hours should lapse 
between consecutive doses of TAK-981. If the TAK-981 dose is delayed for the reasons above, 
the mAb would also be delayed. The reason for the delay will be documented in electronic data 
capture (EDC). 
As with other potentially toxic compounds, caution should be exercised in handling this drug. 
The use of gloves is recommended. Following topical exposure, events could include redness or 
blistering. Given the possibility of extravasation, it is advisable to closely monitor the infusion 
site for possible infiltration during drug administration. Administration through a central port is 
always preferred versus a peripheral line.
TAK-981 Formulation
8.1.1.1
TAK-981 will be provided as a Solution for Infusion containing 10 mg/mL TAK-981 drug 
substance (refer to the pharmacy manual). The sponsor will provide TAK-981.
8.1.2
Mezagitamab (TAK-079)
After patients have received premedication, treatment with (Section 8.1.2.1) mezagitamab doses 
will be administered with syringes as SC injections up to a maximum volume of approximately 
2 mL per injection (ie, 200 mg/2 mL) (refer to the pharmacy manual). The injection sites need to 
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be rotated, using the abdomen, thighs, arms, and upper buttock area. Time and anatomical site 
should be recorded for each SC injection.
Mezagitamab will be given by SC injection at a fixed dose of 600 mg in combination with 
TAK-981 (assigned dose and schedule; Section 8.1). During Phase 1b, 2 dosing schedules for 
TAK-981 will be evaluated: one utilizing a BIW schedule and the other a weekly schedule. The 
schedule for mezagitamab will be the same (Table 8.a and Table 8.b). Enrollment to the dose 
cohort will be sequential for the first cohort in each schedule and will begin with the BIW 
schedule. The pharmacodynamic, PK, safety, and efficacy data from these schedules will inform 
the dose and schedule to be used in Phase 2. Alternative schedules to that in Table 8.a or 
Table 8.b may be explored if recommended by the SMC.
Table 8.a
Administration Schedule of TAK-981 and Mezagitamab (BIW TAK-981 
Schedule)
Cycle
28-Day Cycles C1 and C2
28-Day Cycles C3 
Through C6
28-Day Cycles C7 
Through PD
Day of Cycle
D1
D4
D8
D11
D15
D22
D1
D8
D15
D22
D1
D8
D15
D22
Premedication
X
X
X
X
X
X
X
TAK-981a
X
X
X
X
X
X
X
X
Mezagitamab
X
X
X
X
X
X
X
BIW: twice weekly; C: cycle; C1D1: Cycle 1, Day 1; D: day; PD: progressive disease.
a On C1D1, only the monoclonal antibody will be administered before TAK-981 administration.
Table 8.b
Administration Schedule of TAK-981 and Mezagitamab (QW TAK-981 
Schedule)
Cycle
28-Day Cycles C1 and C2
28-Day Cycles C3 Through 
C6
28-Day Cycles C7 Through 
PD
Day of Cycle
D1
D8
D15
D22
D1
D8
D15
D22
D1
D8
D15
D22
Premedication
X
X
X
X
X
X
X
TAK-981 a
X
X
X
X
X
X
X
Mezagitamab
X
X
X
X
X
X
X
C: cycle; C1D1: Cycle 1, Day 1; D: day; PD: progressive disease; QW: once weekly.
a On C1D1, only the monoclonal antibody will be administered before TAK-981 administration.
For C1D1 only, mezagitamab will be administered first (before TAK-981 infusion). Starting at 
C1D8 onwards, TAK-981 will be administered before the anti-CD38 mAb. On days on which 
both agents are given on the same visit day, at least 1 hour should elapse between the completion 
of the first drug and the administration of the second drug.
As an anti-CD38 mAb, systemic administration reactions are possible with mezagitamab; 
however, unlike daratumumab or daratumumab and hyaluronidase-fihj, none have been reported 
with the SC route of administration in patients with RRMM or newly diagnosed multiple 
myeloma (NDMM) to date (See mezagitamab current IB). Based on this, the rationale for dosing 
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mezagitamab before TAK-981 on C1D1 is to keep consistency with the TAK-981/ daratumumab
and hyaluronidase-fihj combination and not for safety reasons. 
Premedications
8.1.2.1
Before each injection, patients will receive the following premedication approximately 1 to 
3 hours before the mezagitamab injection 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. May 
consider reducing the dose of dexamethasone to approximately 12 mg orally following the 
second dose before subsequent injections if no major systemic administration-related 
reactions reported. If the patient does not experience a major systemic administration-related 
reaction the physician may use their clinical judgement in discontinuing the administration of 
corticosteroids. 

Antipyretics: oral acetaminophen (650 to 1000 mg).

Antihistamine: oral or IV diphenhydramine (25 to 50 mg, or equivalent).
Note: For any patient with a history of COPD, consider premedication with montelukast 10 mg 
(or equivalent leukotriene inhibitor). Also consider prescribing postinfusion medications, such as 
short- and long-acting bronchodilators and inhaled corticosteroids. After the first 4 injections, if 
the patient experiences no major infusion reaction, these additional inhaled postinfusion 
medications may be discontinued.
The clinical site is responsible for sourcing any pre- and post-medications outlined in the 
protocol. Investigator may consider reducing, even discontinuing, predose and postdose 
medications, including corticosteroids after the first 3 mezagitamab injections, if the patient 
experiences no major systemic administration reaction. Additionally, dose reductions of pre-
medications, specifically, dexamethasone, may be done at the physician’s discretion based on 
reported dexamethasone-induced AEs.
Postmedication
8.1.2.2
Patients may receive low-dose methylprednisolone ≤20 mg (or an approximate equivalent such 
as dexamethasone ≤ 4 mg) for the prevention of delayed systemic administration reactions as 
clinically indicated after an injection. 
Investigators may consider postinjection site care: such as corticosteroid cream topically to 
injection site(s) and apply ice locally for approximately 10 to 15 minutes. If used, report the 
corticosteroid cream as a concomitant medication.
Mezagitamab Formulation
8.1.2.3
Mezagitamab will be provided in vials of 100 mg/mL mezagitamab drug substance (refer to the 
pharmacy manual). The sponsor will provide mezagitamab.
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8.2
Standard of Care Agents
8.2.1
Daratumumab and Hyaluronidase-fihj
The combination of TAK-981 and daratumumab and hyaluronidase-fihj will be evaluated. In 
Phase 1b Part 2, a safety lead-in of the combination of daratumumab and hyaluronidase-fihj with 
the dose and schedule of TAK-981 defined in Phase 1b Part 1 to confirm the RP2D of TAK-981 
in combination with daratumumab and hyaluronidase-fihj. Daratumumab and hyaluronidase-fihj 
will be given at the recommended dose of 1800 mg subcutaneous injection according to the 
Darzalex Faspro US Prescribing Information (USPI). The dose will be administered SC as per 
the prescribing information [15]. The pharmacodynamic, PK, safety, and efficacy data from 
Phase 1b will inform the dose and schedule of TAK-981 to be used in Phase 2. Further 
information on the dose of TAK-981 is discussed in Section 8.1.1.
Table 8.c
Administration Schedule TAK-981 and Daratumumab
Cycle
28-Day Cycles C1 and C2
28-Day Cycles C3 
Through C6
28-Day Cycles C7 
Through PD
Day of Cycle
D1
D8
D15
D22
D1
D8
D15
D22
D1
D8
D15
D22
Premedication
X
X
X
X
X
X
X
TAK-981 a
The final schedule for TAK-981 in Phase 2 will be determined by the results from Phase 1b 
Part 1.
Daratumumab and 
hyaluronidase- fihj
X
X
X
X
X
X
X
C: cycle; C1D1: Cycle 1, Day 1; D: day; PD: progressive disease. 
a On C1D1, only the monoclonal antibody will be administered before TAK-981 administration.
For C1D1 only, daratumumab and hyaluronidase-fihj will be administered first (before TAK-981 
infusion). At least 4 hours should elapse between the completion of the administration of the 
daratumumab and hyaluronidase-fihj and the initiation of the TAK-981 infusion. Admission to 
the hospital or a clinical unit may be necessary for drug administration and research sample 
collection.
The rationale for dosing daratumumab and hyaluronidase-fihj before TAK-981 on C1D1 is that 
most of the infusion reactions due to daratumumab have been reported primarily during the first 
infusion with median time to onset of onset of 3.7 hours (range 9 minutes to 3.5 days). Of the 
systemic IRR reported, 87% occurred on the day of daratumumab and hyaluronidase-fihj 
administration [15]. The proportion of patients experiencing acute IRRs decreases with 
subsequent courses of daratumumab [15]. Although most daratumumab and 
hyaluronidase-fihj-related reactions are mild to moderate in severity, there is a theoretical risk 
that when combined with TAK-981 any such reactions could be more severe. Therefore, 
daratumumab and hyaluronidase-fihj is administered after premedication and before TAK-981 
infusion on C1D1. Subsequent daratumumab and hyaluronidase-fihj injections are administered 
after TAK-981 infusion to facilitate PK/pharmacodynamic sampling.
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
Starting at C1D8 onwards, TAK-981 will be administered before daratumumab and 
hyaluronidase-fihj. On days on which both agents are given on the same visit day at least 
1 hour should elapse between the completion of TAK-981 infusion and the administration of 
daratumumab and hyaluronidase-fihj.

For IRRs of any grade/severity, immediately interrupt the daratumumab and hyaluronidase-
fihj infusion and manage symptoms. Management of IRRs may further require treatment 
discontinuation of daratumumab and hyaluronidase-fihj. Permanently discontinue the 
infusion in case of anaphylactic reactions or life-threatening IRRs and institute appropriate 
emergency care. Follow dose administration recommendations in the daratumumab and 
hyaluronidase-fihj prescribing information [15].
Vital Signs
8.2.1.1
Vital signs (blood pressure, heart rate, and temperature) should be checked before the start of the 
infusion, at the end of the infusion, as medically appropriate during the infusion based on patient 
symptomatology, and before discharge.
Premedications
8.2.1.2
Before each injection, patients will receive the following premedication approximately 1 to 
3 hours before the daratumumab and hyaluronidase-fihj on each dosing day [15]:

Methylprednisolone 100 mg (or approximate equivalent such as dexamethasone 20 mg) IV 
for the initial injection. Consider reducing the dose of methylprednisolone to 60 mg (or 
approximate equivalent such as dexamethasone 12 mg) orally or IV following the second 
dose of daratumumab and hyaluronidase-fihj before subsequent injections. If the patient does 
not experience a major systemic administration-related reaction after the physician may use 
their judgement in discontinuing the administration of corticosteroids. 

Antipyretics: oral acetaminophen (650 to 1000 mg).

Antihistamine: oral or IV diphenhydramine (25 to 50 mg, or equivalent).
Note: For any patient with a history of COPD, consider prescribing short and long-acting 
bronchodilators and inhaled corticosteroids. Following the first 4 doses of daratumumab and 
hyaluronidase-fihj, consider discontinuing these additional post-medications, if the patient does 
not experience a major systemic administration-related reaction [15].
Postmedication
8.2.1.3
Administer methylprednisolone 20 mg (or an equivalent dose of an intermediate- or long-acting 
corticosteroid such as dexamethasone 4 mg) orally for 2 days starting the day after the 
administration of daratumumab and hyaluronidase-fihj [15].
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Prophylaxis for Herpes Zoster Reactivation
8.2.1.4
Initiate antiviral prophylaxis to prevent herpes zoster reactivation within 1 week after starting 
daratumumab and hyaluronidase-fihj and continue for 3 months following the EOT [15]. 
The clinical site is responsible for sourcing daratumumab and hyaluronidase-fihj and any 
premedications and postmedications outlined in the protocol. 
8.3
Definitions of DLT
Toxicity will be evaluated according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE), Version 5.0 [26]; except CRS which will be graded 
according to ASTCT Consensus Grading for CRS [27]. 
Patients will be monitored through all cycles of therapy for treatment-related toxicities. DLTs 
will be evaluated at the end of Cycle 1. Primarily, only toxicities that occur during Cycle 1 will 
be used for the purposes of defining DLT for future cohort expansion or dose modification 
decisions. If noncompliance with protocol defined requirements (eg, antiviral prophylaxis) 
results in toxicities of ≥ Grade 3, these toxicities should not qualify as DLTs. Use of platelet 
transfusions or growth factors to manage AEs that may represent DLTs, but are not yet clearly a 
DLT, should be discussed with the sponsor. TEAEs that are clearly due to extraneous causes will 
not be defined as DLTs. 
A DLT will be defined as any of the following events that are considered by the investigator to 
be at least possibly related TAK-981: 
1. Any Grade 5 AE.
2. Hematologic toxicity, clearly unrelated to the underlying disease are defined as follows:
a.
Nonfebrile Grade 4 neutropenia (ANC <0.5 × 109/L; ANC 500 cells/mm3) lasting more 
than 7 consecutive days. 
b. Febrile neutropenia: Grade ≥3 neutropenia (ANC <1 × 109/L; ANC 1000 cells/mm3) 
with fever and/or infection, where fever is defined as a body temperature 38.5C.
c.
Grade 4 thrombocytopenia.
d. Grade 3 thrombocytopenia with clinically significant bleeding where clinically 
significant bleeding requires a RBC transfusion.
e.
Grade 4 anemia, unexplained by the underlying disease.
3. Nonhematologic toxicity of Grade 3 or higher clearly unrelated to the underlying disease, 
with the exception of: 
a.
Grade 3 arthralgia/myalgia that responds to nonsteroidal anti-inflammatory drugs within 
7 days. 
b. Grade 3 endocrine disorders, including adrenal insufficiency, hypophysitis,
hypothyroidism, hyperthyroidism, hypopituitarism, and type 1 diabetes mellitus, that are 
managed with or without therapy and the patient is asymptomatic.
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c.
Grade ≥3 IRR that resolves within 6 hours with appropriate clinical management. Note: 
C1D1 IRRs due to the mAb will not be considered a DLT if the IRR occurred before 
TAK-981 administration and the patient did not receive TAK-981; the patient will not be 
considered DLT-evaluable and will be replaced.
d. Grade ≥3 CRS that resolves to Grade ≤1 48 hours without end-organ damage; graded 
according to ASTCT Consensus Grading for CRS [27].
e.
Asymptomatic laboratory changes (other than renal and hepatic laboratory values) 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.
f.
Grade 3 elevation in ALT, AST, and/or alkaline phosphatase that resolves to Grade ≤2 or 
baseline with supportive care within 7 days and is not associated with other clinically 
relevant consequences.
g. Grade 3 nausea and/or emesis that can be controlled to <Grade 3 in ≤3 days with the use 
of optimal antiemetics (defined as an antiemetic regimen that employs both a serotonin 
receptor subtype 3 (5-HT3) antagonist and a corticosteroid given in standard doses and 
according to standard schedules).
h. Grade 3 diarrhea that can be controlled to <Grade 3 in ≤3 days with appropriate 
treatment.
i.
Grade 3 rash lasting ≤72 hours after treatment that includes topical steroid treatment, oral 
antihistamines, and pulse oral steroids (if necessary).
4. Grade 2 nonhematologic toxicities that are considered by the investigator to be related to 
study drug (TAK-981) and dose-limiting (dose reduction or discontinuation). 
5. Delay in the initiation of Cycle 2 by more than 14 days due to a lack of adequate recovery of 
treatment-related hematological or nonhematologic toxicities. 
6. Missed >1 planned doses of TAK-981 or ≥1 planned dose of mAb in Cycle 1 due to 
treatment-related AEs. 
8.4
Definition of DLT-Evaluable Patients
Patients assigned to a particular dose cohort in Phase 1b are considered evaluable for assessment 
of a DLT if either of the following criteria are met during the DLT assessment period of 28 days 
following the first dose of treatment (Cycle1):

The patient experienced a DLT at any time after initiation of the first infusion of TAK-981.
OR

The patient completed all Cycle 1 doses of mAb and at least 75% of planned TAK-981 
doses. 
For the Phase 1b part of the study, patients who withdraw before completing the 4-week DLT 
assessment period for reasons other than a DLT, or who do not fulfill either of the criteria above, 
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will not be evaluable for assessment of DLT for dose review decisions and will be replaced in 
the cohort.
8.5
Dose Escalation Rules
In the Phase 1b portion of the study, only TAK-981 will be escalated/de-escalated. Each 
individual mAb is administered at its established dose. The first part of the Phase 1b will 
determine the dose and schedule of TAK-981 in combination with a fixed dose and schedule of 
mezagitamab for expansion. The second part of the Phase 1b will determine the dose of 
TAK-981 for the combination with daratumumab and hyaluronidase-fihj. 
In the Phase 1b Part 1, the starting dose level of TAK-981 will be 60 mg which is 1 dose level 
below the monotherapy dose that has cleared the DLT period in the ongoing FIH single agent 
study (Study TAK-981-1002). The following dose levels of TAK-981 will be potentially 
considered: 60 , 90, and 120 mg, (Table 8.d). TAK-981 cannot be escalated above the MTD 
defined in the FIH study. Evaluation of lower or intermediate dose levels and alternative 
schedules are permissible following discussions between the sponsor and the investigators, if 
such measures are needed for patient safety or for a better understanding of toxicity, exposure, or 
pharmacodynamics of TAK-981. 
Dose escalation will follow an iBOIN design [28]. Each schedule will be evaluated separately. 
Approximately 3 patients will be enrolled in the first cohort. The decision to escalate or 
de-escalate the dose of TAK-981 will be based the predetermined DLT rate threshold for dose 
escalation/de-escalation boundaries as defined by the iBOIN .model and on the cumulative DLT 
rate. The target DLT rate for this study is 0.3. The dose escalation and de-escalation rules for 
TAK-981 are as follows (Figure 8.a).
1. If the observed DLT rate at the current dose is <  , escalate the dose to the next higher 
dose level;
2. If the observed DLT rate at the current dose is >  , de-escalate the dose to the next lower 
dose level;
3. Otherwise, stay at the current dose. 
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Figure 8.a
Phase 1b Dose Escalation Schema
DLT: dose-limiting toxicity; MTD: maximum tolerated dose.
It is estimated that up to approximately 15 DLT-evaluable patients will be enrolled to evaluate 
dose escalation for each dosing schedule of TAK-981. For each cohort of patients enrolled at a 
given dose level, the observed DLT rate will be calculated for that dose level. If the observed 
DLT rate at the current dose is < , the next cohort of patients will be treated at the next higher 
dose level; if it is > , the next cohort of patients will be treated at the next lower dose level. 
The values for  and  vary with dose level and the number of patients treated on a dose. The 
boundary guiding the number of patients treated at the current dose is displayed in Appendix H
in which the operating characteristics of the iBOIN design based on 1000 simulations of each 
scenario are presented.
Alternative dosing schedules for TAK-981 will be explored. The dose escalation for different 
TAK-981 schedules will be evaluated separately. 
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Once the RP2D is defined for the combination with mezagitamab, the TAK-981 dose and 
schedule will be determined using the same methodology as described above. The starting dose 
and schedule of TAK-981 for the combination with daratumumab and hyaluronidase-fihj will be 
1 dose level below the RP2D of TAK-981 defined in combination with mezagitamab (RP2D-1). 
The dose of TAK-981 will not be escalated beyond the RP2D determined for the combination 
with mezagitamab. 
Approximately 3 patients will be enrolled in the combination. The decision to escalate or 
de-escalate the dose of TAK-981 will be based on the cumulative DLT rate at the current dose 
level and the predetermined DLT rate threshold for dose escalation/de-escalation boundaries as 
defined by the iBOIN design in which the prior information on the dose-toxicity relationship 
from the Phase 1b Part 1 for the dose escalation of combination with mezagitamab. 
It is estimated that up to approximately 15 DLT-evaluable patients will be enrolled to evaluate 
the dose of TAK-981 in combinations with daratumumab and hyaluronidase-fihj using similar 
approach for dose escalation of TAK-981 in combination with mezagitamab.
Dose escalation and cohort expansion decisions will be determined by the SMC. The SMC will 
review the Cycle 1 safety of all treated patients and will take into consideration the pattern of 
AEs beyond the DLT window across all patients enrolled and make decisions regarding dose 
escalation. In addition, the available PK and pharmacodynamic information will also be 
evaluated to support the dose escalation. 
The planned dose levels for the Phase 1b portion of TAK-981 are shown in Table 8.d.
Table 8.d
Planned Dose Levels
Dose Level
Dose (Unit) a
-2
25 mg
-1
40 mg
1
60 mg
2
90 mg
3
120 mg
a Dose levels indicate the maximum dose escalation per step. Intermediate dose levels 
can be used based on clinical observations and on data from other TAK-981 studies. 
8.6
Intrapatient Dose Escalation
Patients who have tolerated treatment at the initially assigned dose may have their doses of 
TAK-981 increased to the RP2D once it has been determined. After discussion with the sponsor, 
at the investigators’ discretion, patients may be switched to the RP2D in a stepwise process, 
including intermediate dose levels identified at the investigator’s discretion.
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8.7
Dose Modification Guidelines for Phase 1b Dose Escalation and Phase 2 Expansion 
Cohorts
Toxicities should be attributed, whenever possible, to a specific drug (TAK-981, mezagitamab, 
or daratumumab and hyaluronidase-fihj, as applicable based on the assigned regimen) so that 
dose modification can be made rationally. Reduction of a single agent and not others is 
appropriate if toxicity is considered to be related primary to one of the agents. If multiple 
toxicities are attributed to an individual agent dose adjustments should be made according to the 
guidelines for the most severe toxicity. Dose modification are based on the nature and severity of 
AEs and causality determination by investigators. Further clarification can be obtained in 
consultation with the sponsor clinician (or designee). See details for managing specific AEs in 
Section 8.11.
8.7.1
Criteria for Beginning or Delaying a Subsequent Treatment Cycle
A treatment cycle in this study is 28 days. 
For a new cycle of treatment to begin, the patient must meet the following criteria:

ANC ≥1.0 × 109/L.

Platelet count ≥75.0 × 109/L.
Before starting a new treatment cycle, TAK-981/mAb-related AEs or laboratory abnormalities 
must have returned to Grade ≤1 or baseline (unless otherwise specified) or to a level considered 
acceptable by the physician if the toxicity is a nonhematologic one. If the patient fails to meet the 
criteria cited above for retreatment, initiation of the next cycle of treatment should be delayed for 
1 week. When the agents are held based on the listed criteria, clinical and laboratory 
reevaluations should be repeated at least weekly or more frequently, depending on the nature of 
the toxicity observed. At the end of that week, the patient should be re-evaluated to determine 
whether the criteria for retreatment have been met. Should the start of the next cycle need to be 
delayed for more than 2 weeks because of incomplete recovery from treatment-related toxicity, 
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. Note: delay in the initiation of 
Cycle 2 by more than 14 days due to a lack of adequate recovery of treatment-related 
hematological or nonhematologic toxicities represents a DLT.
If the dose of TAK-981 causes a delay in the initiation of a cycle, all drugs in the combination 
are also delayed. Further, if a dose is delayed (interrupted), then the dates of all subsequent doses 
and assessments must be adjusted accordingly. Specific issues related to this approach can be 
discussed with the Takeda project clinician/designee.
8.7.2
Criteria for Dose Interruption or Dose Reduction During a Cycle
Toxicities should be attributed, whenever possible, to a specific drug (TAK-981, mezagitamab, 
or daratumumab and hyaluronidase-fihj as applicable based on the assigned regimen) so that 
dose interruption or reduction can be made rationally. Reduction of a single agent and not others 
is appropriate if toxicity is considered to be related primary to 1 of the agents. All toxicities that 
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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-981, a mAb, or the 
combination may continue study treatment with the same dose, may have the treatment held, or 
may be permanently discontinued from the study. Patients who have study drugs held because of 
treatment-related or possibly related AEs should resume study drug treatment according to the 
dose modification guidelines below.
8.7.3
Dose Modification and Discontinuation Criteria for TAK-981
Dose Modification Criteria for TAK-981
8.7.3.1
Dosing of TAK-981 should be interrupted during a treatment cycle or reduced according to the 
dose modification recommendations listed in Table 8.e for nonhematologic toxicity and Table 8.f
for hematologic toxicities. When the dose of TAK-981 is withheld based on the listed criteria,
clinical and laboratory reevaluation should be repeated at QW or more frequently, depending on
the nature of the toxicity observed until the toxicity resolves to the Grade specified in Table 8.e
and Table 8.f. If indicated, TAK-981 dose should be reduced by at least 1 dose level.
In the BIW schedule, if TAK-981 alone or in combination with the mAb cannot be administered 
within a cycle in a 48-hour window, because of an AE, the dose will be missed, and the patient 
will be scheduled for the next administration per SOE. In the QW schedule a window of 72-
hours is permitted. In these cases, the subsequent dose will be administered as planned. 
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, or there were other circumstances contributing to the 
AE that are unlikely to recur, the dose may be re-escalated to the original dose level. Up to 2 
dose level reductions of TAK-981 due to AEs are permitted. If more than 2 dose level reductions 
of TAK-981 are needed to manage TAK-981 related AEs, treatment with TAK-981 should be 
discontinued.
In the Phase 1b portion of the study, dose reductions of TAK-981 are not permitted in Cycle 1 
unless the patient experiences a DLT attributed to TAK-981. DLTs are defined in Section 8.3. 
Patients experiencing a DLT in Cycle 1 may continue in the study upon resolution of the 
toxicity; however, a dose reduction by at least 1 dose level of TAK-981 should be considered 
based on the toxicity and discussion between investigator and sponsor.
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Table 8.e
General Dose Modification Recommendations for TAK-981 
Nonhematologic Drug-Related AEs
Criteria
Action
Grade 1 AEs 
No dose reductions or interruptions.
Grade 2 AEs
Treat according to local practice.
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 and then restarted at the 
same dose or, depending on the toxicity, at the previous safe dose level
Grade 3 and Grade 4
non-life-threatening AEs
Hold TAK-981 until resolution to Grade ≤1 or baseline, and then resume 
treatment at the next lower dose level.
Grade 4 life-threatening AEs
Permanently withdraw the patient from the study.
AEs of all grades
If treatment has been held for >14 consecutive days without resolution of the 
toxicity (to baseline or Grade ≤1 or if considered a sequela), consider 
permanently discontinuing study treatment unless there is clinical benefit for the 
patient as assessed by the investigator and with sponsor’s approval. Treatment 
should be resumed at a reduced dose level after resolution of AEs to Grade ≤1 or 
baseline.
AE: adverse event.
For specific instructions in case of CRS, refer to Table 8.i.
Table 8.f
Dose Adjustments for Hematologic Toxicities
Criteria
Action
Neutropenia (ANC)
Grade 1 (ANC < LLN- 1.5 × 109 cells/L)
Continue TAK-981 at the same dose level.
Grade 2 (ANC 1.0- <1.5 × 109 cells/L)
Continue TAK-981 at the same dose level.
Grade 3 (ANC 0.5- <1 × 109 cells/L) without fever
Withhold dose until resolved to Grade ≤2 or baseline, 
then: If resolved in ≤7 days, resume treatment at the 
same dose level. If resolved in >7 days, resume 
treatment at the previous safe lower dose level (ie, 
reduce by 1 dose level).
Grade 4 (ANC <0.5 × 109 cells/L) without fever
Withhold dose until resolved to Grade ≤2 or baseline, 
then if resolved in ≤7 days, resume treatment at the 
same dose level. If recovered in >7 days, second Grade 
4 neutropenia event, ANC >0.1 × 109/L, or 
concomitant occurrence of mucositis or
thrombocytopenia, resume treatment at the previous 
safe dose level.
Febrile neutropenia (ANC <1.0 × 109 cells/L, with a 
single temperature of >38.3°C or sustained temperature 
of ≥38°C for more than 1 hour)
Withhold dose until fever/infection have recovered and 
ANC Grade ≤2 or baseline, then resume treatment at 
the previous safe lower dose level (ie, reduce by 1 dose 
level).
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Table 8.f
Dose Adjustments for Hematologic Toxicities
Criteria
Action
Thrombocytopenia (PLT)
Grade 1 (PLT < LLN- 75.0 × 109 cells/L)
Continue TAK-981 at the same dose level.
Grade 2 (PLT <75.0 - 50.0 × 109 cells/L)
Continue TAK-981 at the same dose level.
Grade 3 (PLT <50.0 - 25.0 × 109 cells/L) without
bleeding
Withhold dose until resolved to Grade ≤1 or baseline, 
then:
If resolved in ≤7 days, resume treatment at the same 
dose level. If resolved in >7 days, resume treatment at 
the previous safe lower dose level (ie, reduce by 1 dose 
level).
Grade 4 (PLT <25.0 × 109 cells/L) without bleeding
Withhold dose until resolved to Grade ≤1 or baseline, 
then if resolved in ≤7 days, resume treatment at the 
same dose level, if resolved in >7 days, then resume 
treatment at the previous safe lower dose level.
PLT <10.0 × 109 cells/L, thrombocytopenia Grade ≥3
associated clinically significant bleeding, second event 
of Grade 4 thrombocytopenia >7 days
Consider permanently withdrawing the patient from the 
study, except when the investigator determines that the 
patient is obtaining clinical benefit and has discussed 
this with the sponsor, then resume treatment at the 
previous safe lower dose level (ie, reduce by 1 dose 
level).
ANC: absolute neutrophil count; C; cycle; LLN: lower limit of normal; PLT: platelets. 
Discontinuation Criteria for TAK-981
8.7.3.2
In dose escalation, TAK-981 should be discontinued in patients experiencing an AE in Cycle 1 
meeting criteria for a DLT for which the investigator considers that retreatment of the patient 
could be dangerous. For Grade 4, life-threatening nonhematologic TEAEs, permanently 
withdraw the patient from the study.
If more than 2 dose reductions are required, or if the next cycle of TAK-981 is delayed for 
>14 days because of TAK-981–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 is determined, the EOT visit should be 
completed within 30 (+7) days of the last administration of TAK-981 and before the start of 
subsequent anticancer therapy.
8.7.4
Dose Modification and Discontinuation Criteria for Mezagitamab
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 
mezagitamab may continue study treatment with the same dose, may have mezagitamab 
treatment held, or may be permanently discontinued from the study, depending on the nature and 
severity of the AE and whether it is the first occurrence, or it is recurrent. TEAEs that are not 
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attributed by the investigator to the mezagitamab 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 mezagitamab.
Table 8.g provides general dose modification recommendations. 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 mAbs as a means to reduce dose intensity [14,29,30].
Table 8.g
Dose Modification Recommendations for Mezagitamab Toxicities
Criteria
Action
Grade 1 AEs
No dose interruptions
Grade 2 AEs

Treat according to local practice. The decision whether to hold treatment or to 
continue it at the same dose is made 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 (see Section 8.11 for AEs of short 
duration and/or those that respond to medical management).

Grade ≥3 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 non-hematologic toxicity 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 mezagitamab administration does not commence within the prespecified 
window (see Appendix A) of the scheduled administration date, then the dose 
will be considered a missed dose (see Table 8.h). Administration may resume at 
the next planned dosing date upon recovery as described previously.
AE: adverse event.
If an initial dose interruption does not provide sufficient relief, the dose of mezagitamab should 
be considered for permanent discontinuation.
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Table 8.h
Mezagitamab-Related Toxicity Management
Dose Frequency
Dose Missed
Dose Resumption
Weekly
>3 days
Skip dose, move to next planned weekly dose.
Every 2 weeks
>7 days
Skip dose, move to next planned every 2 week dose.
Every 4 weeks
>21 days
Skip dose, move to next planned every 4 week dose.
A mezagitamab 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. Patients missing ≥3 consecutive planned doses of mezagitamab 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 mezagitamab to be administered every 4 weeks may be delayed (interrupted) up to 
4 weeks (see Table 8.h). 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 mezagitamab 
that requires a dose delay (interruption) of more than 28 days should result in permanent 
discontinuation of mezagitamab, unless both the investigator and the sponsor study clinician 
believe the patient is deriving clinical benefit. 
8.7.5
Dose Modification and Discontinuation Criteria for Daratumumab and 
Hyaluronidase-fihj
All toxicities that occur during the study will be actively managed following medical standard of 
care unless otherwise specified in the protocol. Toxicities attributed to daratumumab and 
hyaluronidase-fihj, as applicable, should be managed according to the relevant guidelines in the 
respective product information. Toxicity is managed using dose interruptions, including missed 
doses, as is standard with administration of mAbs as a means to reduce dose intensity [15].
8.7.6
COVID-19
If a patient is diagnosed with COVID-19 infection while on study, study treatment must be 
withheld until resolution of the infection. A patient may restart study treatment if the following 
criteria are met; otherwise the patient must discontinue treatment:

The infection must have resolved without ongoing clinical sequalae.

There must be 2 sequential negative SARS-CoV-2 tests 12 hours apart. 

The patient must be asymptomatic and the investigator believes, with agreement of the 
sponsor, that the patient would benefit from resuming study treatment.
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8.8
Excluded Concomitant Medications and Procedures
The following medications and procedures are prohibited during the study:
1. Radiation therapy for the disease under study. (Note that, in general, the requirement for 
local radiation therapy indicates PD; “spot” radiation for areas of pain is permitted after 
agreement with the sponsor study clinician/designee and after PD is ruled out).
2. Any antineoplastic treatment with activity against the disease under study, other than that 
described in this study.
3. Any investigational agent other than TAK-981 or mezagitamab, including agents that are 
commercially available for indications other than the disease under study that are under 
investigation for the treatment of the disease under study.
4. Concomitant corticosteroid administration of >10 mg of prednisone or equivalent unless 
given as treatment or prophylaxis for IRRs, as premedication for administration of certain 
blood products (80 mg methylprednisolone is accepted) or short courses for TEAE 
management eg, exacerbations of respiratory tract disorders or for acute control of emerging 
tumor pain.
5. In Phase 1b, initiation of prophylactic use of myeloid growth factors (eg, G-CSF, granulocyte 
macrophage-colony stimulating factor) are not allowed in the first cycle before confirmation 
of DLT but may be administered to manage patients who experience Grade 4 and/or febrile 
neutropenia if clinically indicated in accordance with American Society of Clinical Oncology 
guidelines and/or institutional practices. Use of growth factors before confirmation of DLT 
will result in the event being defined as a DLT. 
6. In Phase 1b, platelet transfusion in the first cycle before confirmation of DLT, given to 
manage patients who experience Grade 4 thrombocytopenia if clinically indicated, will result 
in the event being defined as a DLT.
7. Initiation of new erythropoietin therapy is not allowed during the first cycle. (Note Permitted 
Medication below regarding patients already on chronic erythropoietin).
8.8.1
Excluded Concomitant Medications and Procedures for TAK-981
The following medications and procedures are prohibited during the study:
1.
Strong and moderate CYP3A4/5 inhibitors and inducers (see list in Appendix E). During the 
study, should patients require the use of medications that are known to be strong and 
moderate inhibitors/inducers of CYP3A4/5, they should temporarily discontinue the use of 
TAK-981. Patients in dose escalation or cancer treatment expansions can resume treatment 
with TAK-981 approximately 2 weeks or 5 times the half-life (whichever is shorter) after 
discontinuing the use of these strong and moderate inhibitors and inducers of CYP3A4/5.
2.
Strong inhibitors of Pgp (see list in Appendix G).
3.
Drugs known to prolong QTc interval (see list in Appendix I).
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4.
For patients enrolled in Phase 1b, any vaccination during Cycle 1 is not permitted as this 
may confound the evaluation of safety and the determination of DLTs.
8.8.2
Excluded Concomitant Medications and Procedures for Monoclonal Antibodies
For important drug interactions involving daratumumab, refer to the prescribing information 
[14,15].
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, prescription 
and over-the-counter medications including influenza vaccines, received as of the first study 
drug administration until 30 days after the final dose or before initiation of new anticancer 
therapy (whichever comes first) will be recorded in the designated electronic case report form 
(eCRF). Initiation of a CoV-2 vaccination and/or COVID-19 treatment should be discussed with 
the sponsor/designee. Patients must be instructed not to take any medications, including over-
the-counter medications and herbal supplements, without first consulting with the investigator.
The following medications and procedures are permitted while the patient is receiving TAK-981 
or any of the mAbs:
1. Concomitant treatment with bisphosphonates or RANKL inhibitors will be allowed for 
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 [31]. If 
bisphosphonate therapy was not started before the study commenced, it should be initiated as 
soon as clinically indicated.
2. Unless there is a clinical contraindication, prophylactic herpes zoster antiviral prophylaxis 
therapy is required for all patients while receiving daratumumab and hyaluronidase-fihj as 
per relevant product information or standard of care/local practice [15]. For patients 
receiving other mAbs, prophylaxis can be started at investigator’s discretion. 
3. Agents involved in this study may cause fetal harm when administered to a pregnant woman. 
Please follow relevant product information instructions for daratumumab and hyaluronidase-
fihj, as well instructions in Section 8.10.
4. Concomitant corticosteroid administration given as treatment or prophylaxis for IRRs, as 
premedication for administration of certain blood products or short courses for exacerbations 
of respiratory tract disorders or for acute control of emerging tumor pain. Doses of > 10 mg 
of prednisone or equivalent should be used with caution given its antimyeloma effect.
5. Myeloid growth factors (eg, G-CSF, granulocyte macrophage-colony stimulating factor). 
Their use should follow the product label, published guidelines, and institutional practice 
[32]. (Note: Excluded medication list for use during Cycle 1 of Phase 1b).
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6. Patients currently on chronic erythropoietin support for anemia may continue to receive 
erythropoietin.
7. Transfusions with RBCs and platelets as clinically indicated; however, use during Phase 1b 
Cycle 1 may represent a DLT.
8. Localized radiation for pain management for osteolytic lesions.
9. Topical or inhaled steroids and short-acting β2 adrenergic receptor agonists (eg, for the 
treatment of asthma) are permitted.
10. Nonresorbable corticosteroids (eg, budesonide).
11. Plasmapheresis.
12. Narrow therapeutic range Pgp substrates such as digoxin or dabigatran may be used with 
caution, and patients required use of these drugs will be closely monitored.
13. Trimethoprim-sulfamethoxazole prophylaxis for pneumocystis is permitted at the physician’s 
discretion 
14. Supportive measures consistent with optimal patient care to prevent and actively manage 
AEs or comorbidity may be given throughout the study treatment period. Treatment of AEs 
with prohibited concomitant medications (except anticancer treatments) is allowed per the 
investigator’s judgment. In this situation, treatment with TAK-981 must be interrupted. 
Treatment with TAK-981 may be resumed, if the patients meets criteria for resuming 
treatment with TAK-981, once treatment with the prohibited medication is stopped and a 
washout period (7 days or 5 half-lives whichever is shorter) is completed. This situation 
requires discussion between the investigator and the medical monitor.
15. COVID-19 vaccination is generally allowed for patients enrolled in the study with the 
exception of live attenuated vaccines which must be completed at least 4 weeks prior to 
treatment initiation. COVID-19 vaccination should follow local guidances and regulations. 
Ideally, patients will have completed vaccination prior to treatment initiation. For patients 
enrolled in Phase 1b, vaccination during Cycle 1 is not permitted as this may confound the 
evaluation of safety and the determination of DLTs. Vaccination should be avoided within 
±3 days of TAK-981 administration and should be administered after the last dose of 
TAK-981 of a given cycle; study treatment may be delayed for up to 7 days to accommodate 
a vaccine dose administration after discussion with the sponsor. Vaccination should be 
captured as a concomitant medication.
8.10
Precautions and Restrictions
It is not known what effects TAK-981 or the mAbs have 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 (see also 
Appendix E for acceptable methods of contraception).
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Female patients must meet 1 of the following:

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 6 months after the last dose of drug in 
the combination, OR

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of 
the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, 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 1 of the 
following:

Agree to practice effective barrier contraception during the entire study treatment period and 
through 6 months after the last dose of drug in the combination, OR

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of 
the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.)
Before starting treatment, male patients should be advised to seek counseling on sperm 
storage, and female patients should be advised to seek counseling on egg storage. 
8.11
Management of Clinical Events 
Therapies that are required to manage AEs and control cancer symptoms are allowed based on 
standard clinical practice, unless specifically excluded. Supportive care agents, such as 
erythropoietin, granulocyte-colony stimulating factor, blood products (RBC and platelet 
transfusions), and pain medications are permitted as needed per American Society of 
Hematology/American Society of Clinical Oncology guidelines or local institutional practice. If 
dose alterations are necessary as a result of the events detailed below, refer to Section 8.6.
In the sections below guidance for the management of some expected AEs based on observations 
in nonclinical toxicology or other AEs that have not been substantiated in these experiments but 
that could be expected because of the MOA of TAK-981 and mezagitamab, and warnings and 
precautions in the daratumumab and hyaluronidase-fihj product label [15]. This guidance is not 
expected to replace investigator judgment in the management of AEs.
8.11.1
IRRs
In all cases, patients should be treated in a location with resuscitation equipment and where 
medications such as antihistamines, acetaminophen, corticosteroids, epinephrine, and 
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bronchodilators are readily available. Patients’ vital signs must be monitored before, during, and 
at the end of administration of TAK-981 as well as before and after the daratumumab and 
hyaluronidase-fihj injections as per the assigned cohort. Treatment must be stopped immediately 
if the patient experiences symptoms compatible with an IRRs.
Depending on the severity of the potential IRRs observed, the TAK-981 infusion rate may be 
decreased by 50% or discontinued. The relevant mAb administration may also need to be 
interrupted (daratumumab and hyaluronidase-fihj and possibly mezagitamab) as per the 
prescribing information [15]. The patient should be promptly treated for signs and symptoms 
with antihistamines and corticosteroids at the investigator’s discretion. Concomitant medications 
administered as treatment for IRRs will be recorded in the eCRF. 
TAK-981
8.11.1.1
Although TAK-981 is not a biological, its immune activating properties may produce AEs in the 
category of IRRs. If they were to occur, it might manifest with fever, chills, rigors, headache, 
rash, pruritus, arthralgias, hypotension or hypertension, bronchospasm, or other symptoms. 
Treatment and monitoring of patients until symptoms resolve should be consistent with 
institutional standards and guidelines as appropriate. The patient should be closely monitored 
until recovery of symptoms. The patient will be permanently discontinued from the trial in case 
of a Grade 4 life-threatening reaction. All Grade 3 or 4 infusion reactions should be reported 
within 24 hours to the medical monitor and communicated as an serious adverse event (SAE) if 
criteria are met. Concomitant medications administered for infusion reaction treatment should be 
collected in the eCRF. If a patient presents signs and symptoms compatible with infusion 
reaction, and at investigator discretion, premedication can be instituted for the rest of the 
treatment.
Monoclonal Antibodies
8.11.1.2
IRRs have been reported with the selected mAbs at different rates and different severities. 

Daratumumab and hyaluronidase-fihj: systemic hypersensitivity reactions have been 
reported in approximately 11% of patients (37% of patients who received the IV formulation 
of daratumumab) overall [14,15]. Reactions primarily occur with the first injection with a 
median time to onset of 3.7 hours (range 9 minutes to 3.5 days). Nearly all reactions (87%) 
occurred on the day of daratumumab and hyaluronidase-fihj administration. Delayed 
systemic administration related reactions have also been reported. Severe reactions included 
hypoxia, dyspnea, and hypertension. Other signs and symptoms may include respiratory 
symptoms, such as bronchospasm, nasal congestion, cough, throat irritation, allergic rhinitis, 
and wheezing as well as anaphylactic reactions, pyrexia, chest pain, pruritis, chills, vomiting, 
nausea, and hypotension. Premedication is required (see Section 8.2.1). Monitor patients for 
systemic IRRs, especially during and following the first and second injections. For 
anaphylactic or life-threatening reactions, immediately and permanently discontinue 
daratumumab and hyaluronidase-fihj and treat as medically appropriate [15]. Consider 
administering corticosteroids and other medications after the administration of daratumumab 
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and hyaluronidase-fihj depending on medical judgement to minimize the risk of delayed 
systemic IRRs.

Mezagitamab: Based on the MOA of mezagitamab and qualitative similarities to that of 
daratumumab, systemic administration-related reactions and CRS are possible. 
(Mezagitamab IB) Generally, symptoms of hypersensitivity range from mild skin rash to 
more severe reactions, including the following: wheezing, hypotension, poor perfusion, and 
respiratory arrest. Nonanaphylactic clinical hypersensitivity can occur within the first hour, 
but delayed responses have also been reported in the literature with other biologic agents 
[33]. It is noteworthy however, that as of the current IB, no IRRs have been documented with 
mezagitamab in patients in the RRMM, NDMM, or SLE studies (each population receives 
preinjection medications of an antipyretic and an antihistamine, while patients with RRMM 
and NDMM also receive low-dose dexamethasone). Refer to the Mezagitamab IB for 
additional information and see Section 8.1.2.1 for premedications.
8.11.2
CRS
CRS should be diagnosed and managed following institutional guidelines and graded following 
ASTCT Consensus Grading for CRS [27]. CRS may occur after the first infusion of the drug 
because of 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 is a 
disorder that may also be characterized by tachypnea, headache, tachycardia, hypotension, chills, 
fatigue, nausea and/or vomiting, rash, urticaria, and/or hypoxia caused by the release of 
cytokines [34,35]. CRS should be diagnosed and managed following institutional guidelines. 
Investigators should try to differentiate CRS syndrome from other IRRs. Patients who develop 
severe CRS should have dosing interrupted immediately and should receive aggressive 
symptomatic treatment.
Recommendations for management of CRS are shown in Section 8.11.2 and can be implemented 
at the investigator’s discretion.
TAK-981
8.11.2.1
Acute and transient mild increased body temperature and reactive increased heart rate without 
changes in blood pressure with onset between 6 and 24 hours postinfusion were observed in 
nonclinical studies. These acute toxicology findings shortly after the infusion and the MOA of 
stimulation of IFN-I signaling raise the possibility of IRRs/CRS even with a negative cytokine 
release assay. Mild to moderate CRS have been reported in clinical studies with TAK-981. Refer 
to the TAK-981 IB for additional information. 
Mezagitamab
8.11.2.2
CRS represents an important IRR associated with the use of mAbs. Nonclinical studies suggest 
that mezagitamab is unlikely to cause cytokine release due to cell activation; however, 
mezagitamab is a cell-depleting antibody so it could cause cytokine release due to cell lysis. 
Infusion-related reactions including hypersensitivity reactions and CRS have been reported with 
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other biologic agents, therefore, similar AEs may be seen with mezagitamab. The limited clinical 
data in healthy subjects given mezagitamab is insufficient to fully characterize infusion reactions 
(hypersensitivity reactions, CRS) associated with mezagitamab administration. However, as 
noted with IRR as per the mezagitamab IB, no CRS has been formally diagnosed in the RRMM, 
NDMM, or SLE studies. Refer to the Mezagitamab IB for additional information. 
CRS Management
8.11.2.3
Patients should be monitored during and after infusion as defined in the protocol and should be 
considered clinically stable by the investigator or designee before discharge.
In all cases, patients should be treated in a location with resuscitation equipment and where 
medications such as antihistamines, acetaminophen, corticosteroids, epinephrine, and 
bronchodilators are readily available. Patients’ vital signs must be monitored before, during, and 
at the end of administration of TAK-981 and after last drug in the combination. Treatment must 
be stopped immediately if the patient experiences symptoms compatible with an IRR or CRS.
Depending on the severity of the potential IRRs observed, the TAK-981 infusion rate may be 
decreased by 50% or discontinued. The relevant mAb administration may also need to be 
interrupted (daratumumab and hyaluronidase-fihj and possibly mezagitamab). The patient 
promptly treated for signs and symptoms with antihistamines and corticosteroids at the 
investigator’s discretion. Concomitant medications administered as treatment for IRRs will be 
recorded in the eCRF. 
Table 8.i
CRS Management Recommendations and TAK-981 Dose Modifications
ASTCT Consensus Grade
CRS Management Recommendations and TAK-981 Dose 
Modifications
Grade 1: 
Fever a (≥38°C)

Monitor fluid status.

Supportive care: antipyretics, analgesics.
TAK-981 dosing

Continue TAK-981 at the same dose level.
Grade 2:
Fever a (≥38°C) with hypotension not 
requiring vasopressors; and/or b requiring low-
flow c nasal cannula
As per Grade 1 and:

Closely monitor all organ functions, including cardiac 
function.

IV fluid bolus.

Supportive care.
TAK-981 dosing

Withhold all agents in the combination until recovers to Grade 
≤1.

Once recovered, restart TAK-981 at the same dose level; 
restart the monoclonal antibody at the same dose
A maximum of 2 consecutive TAK-981 doses can be skipped; 
otherwise TAK-981 must be permanently discontinued.
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Table 8.i
CRS Management Recommendations and TAK-981 Dose Modifications
ASTCT Consensus Grade
CRS Management Recommendations and TAK-981 Dose 
Modifications
Grade 3:
Fever a (≥38°C) with hypotension requiring a 
vasopressor with or without vasopressin; 
and/or b requiring high-flow c nasal cannula, 
facemask, nonrebreather mask, or Venturi 
mask
As Grade 2 and:

Closely monitor all organ functions, including cardiac 
function.

Tocilizumab (8 mg/kg IV; maximum dose 800 mg) can be 
repeated after 6 hours.

If refractory to tocilizumab, dexamethasone 10 mg IV every 6 
hours; if refractory, increase to 20 mg every 6 hours or 
equivalent methyl prednisone.

Vasopressors as needed.

Supplemental oxygen as needed for hypoxia (including high-
flow O2 and CPAP).

Transfer to ICU.
TAK-981 dosing

Withhold all agents in the combination until recovers to Grade 
≤1. Restart the monoclonal antibody at the same dose.

If recovered within 2 weeks, reduce TAK-981 by 1 dose level.
A maximum of 2 consecutive TAK-981 doses can be skipped; 
otherwise TAK-981 must be permanently discontinued.
Grade 4:
Fever a (≥38°C) with hypotension requiring 
multiple vasopressors (excluding 
vasopressin); and/or b requiring positive 
pressure (eg, CPAP, BiPAP, intubation)
As per Grade 3 and:

Substitute dexamethasone with methyl prednisone 1 g IV per 
day.

Mechanical ventilation.
TAK-981 dosing

Permanently discontinue TAK-981. Per Section 6.5.2, once 
TAK-981 is permanently discontinued, the monoclonal 
antibody is also discontinued.
ASTCT: American Society for Transplantation and Cellular Therapy; BiPAP: bilevel positive airway pressure; C: 
cycle; CPAP: continuous positive airway pressure; CRS: cytokine release syndrome; ICU: intensive care unit; IV: 
intravenous; O2: supplemental oxygen.
ASTCT consensus grade adapted from Lee et. al. 2019 [27]; CRS management recommendations are adapted from 
Neelapu et al, 2018 [36] and should be implemented at the investigator’s discretion.
a Fever is defined as temperature ≥ 38°C not attributable to any other cause. In patients who have CRS then receive 
antipyretic or anticytokine therapy such as tocilizumab or steroids, fever is no longer required to grade subsequent 
CRS severity. In this case, CRS grading is driven by hypotension and/or hypoxia.
b CRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other cause. For 
example, a patient with temperature of 39.5°C, hypotension requiring 1 vasopressor, and hypoxia requiring low-flow 
nasal cannula is classified as grade 3 CRS.
c Low-flow nasal cannula is defined as oxygen delivered at ≤6 L/minute. High-flow nasal cannula is defined as 
oxygen delivered at >6 L/minute.
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8.11.3
Anemia, Thrombocytopenia, and Neutropenia
Hematologic toxicity is an overlapping toxicity between TAK-981 and the selected mAbs, 
though the severity of hematologic toxicity may vary between the mAbs ([14], Mezagitamab IB). 
Treatment decisions will be based on patient platelet counts; eg low platelet counts (Grade 4) 
should cause scheduled treatment to be postponed or to be permanently discontinued if reco very 
is delayed. Platelet transfusion, evaluation of coagulation parameters, and the Coombs test 
parameters (namely for patients receiving anti-CD38 mAbs) on the basis of signs and symptoms 
per investigator discretion are recommended. Please refer to Table 8.f, Table 8.g, and the 
relevant product labels for dose delay and reduction recommendations for hematologic toxicities 
as relevant to the assigned regimen. Complete blood counts should be monitored periodically 
during treatment. 
TAK-981 should be held if a significant treatment-emergent cytopenia or bleeding is suspected 
to be related to, or can be worsened by, study treatment. Consider holding the relevant mAb to 
allow for cytopenia recovery. 

Precautionary measures should be taken to prevent bleeding and overwhelming infections. 
Blood transfusions (RBCs or platelet) and hematopoietic or thrombopoietic stimulating 
factors may be used to treat cytopenia/thrombocytopenia at the discretion of the investigator 
per standard clinical practice. 

Use of myeloid growth factor (eg, granulocyte-colony stimulating factor) support to treat 
Grade ≥3 neutropenia and/or febrile neutropenia is recommended per regional guidelines or 
local institutional practice; prophylaxis is permitted per regional guidelines or local 
institutional practice. 
8.11.4
Infusion Site Care
TAK-981
8.11.4.1
Skin lesions, which may include inflammation or necrosis, represent a potential risk of 
TAK-981. In rats there were microscopic injection site (vascular/perivascular) lesions. Local 
institutional guidelines must be applied to stress proper administration and prevention of 
accidental extravasation of TAK-981. Usage of IV port is highly recommended. IV line should 
be flushed at the end of the infusion accordingly to local procedures. Monitoring at the beginning 
and during infusion must be ensured. If extravasation occurs, the infusion must be discontinued 
immediately, and institutional guidelines applied. Treatment and monitoring of patients until 
symptoms resolve should be consistent with institutional standards and guidelines as appropriate. 
Patients should be instructed to report any discomfort, pain, or swelling at the infusion site.
Mezagitamab
8.11.4.2
Rotate injection sites for successive injections. Never inject either mAb into areas where the skin 
is red, bruised, tender, hard or areas where there are scars. Pause or slow down delivery rate if 
the patient experiences pain; change sites as necessary. Prophylactic postinjection site care is 
allowed such as corticosteroid cream topically to injection site(s) and apply ice locally for 
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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). If necessary 
management may include discontinuation of the mAb. 
With mezagitamab, injection site reactions have been very limited (0.22%), only mild, transient, 
and primarily erythema or tenderness with palpitation. Refer to the Mezagitamab IB for 
additional information.
Daratumumab and Hyaluronidase-fihj
8.11.4.3
Injection -site reactions have occurred in 8% of patients, including Grade 2 reactions in 0.6%. 
The most frequent injection site reaction was injection site erythema. Onset of local reactions 
occurred a median of 7 minutes (range 0-4.7 days) after starting administration of daratumumab 
and hyaluronidase-fihj. Monitor for local reactions and consider symptomatic management [15].
8.11.5
Nausea and Vomiting
Phase 1b part of the study will not initially employ prophylactic antiemetics before the first dose 
of the study drug during dose escalation. However, a patient who develops nausea or vomiting 
will be actively managed by employing optimal antiemetic treatment based on local standard 
practice. Additionally, antiemetics may be used prophylactically as clinically indicated following 
the occurrence of a first event of study drug-related or possibly related nausea and/or vomiting. 
An optimal antiemetic regimen is defined as one that employs both a 5-hydroxytryptamine 3 
serotonin receptor antagonist and a short course of corticosteroid given in standard doses and 
according to standard schedules. If these are inadequate, an NK-1 antagonist may be added.
8.11.6
Diarrhea
This study will not initially employ prophylactic antidiarrheals; however, there is no prohibition 
against their use in the management of a patient who develops diarrhea. Patients will be 
instructed to take antidiarrheal medication(s) at the physician’s discretion until they are diarrhea-
free for at least 12 hours. Fluid intake should be maintained to avoid dehydration.
8.11.7
Interference with Serologic Testing
Anti-CD38 mAbs, such as daratumumab, daratumumab and hyaluronidase-fihj, and isatuximab, 
have been reported to bind to CD38 on RBC and result in a positive indirect coombs test, which 
may persist for up to 6 months [14,15,37]. The determination of a patient’s ABO and Rh blood 
type are not impacted, but the RBC binding may mask detection of antibodies to minor antigens 
in the patient’s serum [14,15,37,38]. It is possible mezagitamab 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 study treatment. This information 
may be available historically depending on previous exposure to a mAb. 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 [38].
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8.13.3
Non-investigational Monoclonal Antibody
Daratumumab and Hyaluronidase-fihj
8.13.3.1
Daratumumab and hyaluronidase-fihj will be procured by the site from commercial sources. 
Additional details are provided in the package insert [15]. 
Daratumumab and hyaluronidase-fihj vials should be stored at temperatures in accordance with 
the instructions provided in the manufacturer’s product label.
8.14
Investigational Drug Assignment and Dispensing Procedures: TAK-981 and 
Mezagitamab
Patients will be assigned using an integrated voice response system/interactive web response 
system (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 (MED ID) numbers 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.
8.15
Other Protocol-Specified Materials
TAK-981 and mezagitamab will be supplied by the sponsor. No other drugs or ancillary 
materials are supplied by sponsor for use in this trial.
9.0
STUDY CONDUCT
This trial 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, and other vendors such as the 
interactive response technology (IRT) provider and the contract research organization (CRO),
may be found in the study manual. A full list of investigators is available in the sponsor’s 
investigator database.
For 24-hour contact information, please refer to the study manual or equivalent.
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 institutional review board (IRB)/
independent ethics committee (IEC). 
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9.3
Treatment Group Assignments
The study uses a non-randomized, uncontrolled, parallel arm design. All patients will receive 
open-label treatment with TAK-981, daratumumab and hyaluronidase-fihj, or mezagitamab as 
indicated in the respectively assigned treatment cohort and Phase of the study. Patients will be 
assigned to a treatment regimen in a nonrandomized manner based upon the investigator’s 
judgment and the recruitment status of the available cohort as communicated by the sponsor. 
Once a treatment cohort has been fully enrolled, further enrollment will be stopped to that 
combination unless a decision has been made to expand the cohort for a better understanding of 
efficacy, safety, PK, or pharmacodynamics.
After written informed consent has been obtained and preliminary eligibility has been 
established, the study site will submit documentation supporting eligibility to the sponsor and 
obtain the sponsor’s approval to enroll the patient. Once the sponsor reviews and approves the 
patient for enrollment, the patient cohort and treatment group will be assigned via IRT.
9.4
Study Procedures
Tests and procedures should be performed on schedule, but unless otherwise specified, 
occasional changes are allowable (up to 4 days) for inclement weather, holidays, vacations, and 
other administrative reasons or a longer window after discussion with the sponsor project 
clinician or designee. If the study schedule is shifted, assessments must be shifted to ensure that 
collection of assessments is completed before dosing.
Patients will be evaluated at scheduled visits over the following study periods: screening, 
treatment, EOT visit, and follow-up (PFS and OS), and end of study. Evaluations during the 
screening period are to be conducted within 28 days before administration of the first dose of the 
study drug. Procedures conducted during the screening period that are performed within 3 days 
of C1D1 may also be used as the predose evaluation and do not need to be repeated, unless 
otherwise specified.
Unless otherwise noted, evaluations during the treatment period must occur before drug 
administration on scheduled visits. Tests and procedures should be performed on schedule for all 
visits. The timing of PK and pharmacodynamics assessment is specified in the SOE 
(Appendix A). Laboratory assessments and procedures may occur up to 3 days before the 
scheduled day due to extenuating circumstances (ie, inclement weather, holidays, vacations, or 
other administrative reasons). The timing of the EOT visit should occur before any subsequent 
therapy is given or up to 30 days after the last dose of study drug, whichever occurs first.
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.
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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. The 
history will emphasize the background and progress of the patient’s malignancy and include a 
description of prior therapies for it and the best response achieved by each one. For example, 
patients with MM this would include the initial diagnosis date, stage of MM using the Revised 
International Staging System (ISS) system [39] and Salmon-Durie staging. Confirm that the 
medical status does not include active chronic HBV, HCV, or HIV infection. In addition, the 
history should include a review of all current medications; concomitant medications will be 
recorded as specified in Section 9.4.8. Severe acute respiratory syndrome cornoavirus 2 (SARS-
CoV2)  positive testing, COVID-19 infection, and COVID vaccination as appropriate prior to 
ICF should be captured as part of medical history.
.
9.4.4
Physical Examination
A physical examination will be completed per standard of care at the screening visit. Symptom-
directed assessments will be conducted at the times specified in the SOE (see Appendix A) as per 
standard clinical practice. Any changes in the symptom-directed assessments that are 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 10.0.
9.4.5
Patient Height and Weight
Height will be measured during the screening visit only. Weight will be measured on as indicated 
in the SOE and any time appropriate based on symptom directed assessments (Appendix A).
9.4.6
Vital Signs
Vital sign measurements, including systolic and diastolic blood pressure, heart rate, and 
temperature, will be assessed as specified in the SOE (Appendix A). Additional details on drug 
administration days can be found in Section 8.1.1 for TAK-981 and Section 8.2 for daratumumab 
and hyaluronidase-fihj. 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 10.0.
9.4.7
Pregnancy Test
A serum or urine pregnancy test will be obtained for women of childbearing potential at 
screening and as specified in the SOE (Appendix A). The screening results must be available and 
negative before enrollment. For women of childbearing potential, if menstrual period is delayed 
during the study, absence of pregnancy must be confirmed by serum pregnancy test.
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9.4.8
Concomitant Medications and Procedures
Medications used by the patient and therapeutic procedures completed by the patient will be 
recorded in the eCRF from the time of informed consent through the EOT visit or the start of 
subsequent antineoplastic therapy, whichever occurs first. See Section 8.7.6 for a list of 
medications and therapies that are prohibited during the study.
9.4.9
Adverse Events
Monitoring of AE, serious and nonserious, will be conducted throughout the study as specified in 
the SOE (Appendix A). Refer to Section 10.0 for details regarding definitions, documentation, 
and reporting of AEs and SAEs.
9.4.10
Enrollment
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. Enrollment is defined 
as the time of initiation of the first dose of study drug. Procedures for completing enrollment 
information are described in the study manual.
9.4.11
12-Lead ECG
A 12-lead standard safety ECG will be performed as specified in the SOE (Appendix A). A 
qualified person will interpret the ECGs locally. Additional ECGs may be obtained as clinically 
indicated at the discretion of the investigator.
9.4.12
Clinical Laboratory Evaluations
Clinical laboratory evaluations will be performed locally. Handling and shipment of clinical 
laboratory samples will be outlined in the study manual. Clinical laboratory evaluations will be 
performed as outlined below:
Clinical Chemistry, Hematology, Coagulation, and Urinalysis 
9.4.12.1
Blood samples for analysis of the clinical chemistry and hematology parameters shown in 
Table 9.a and urine samples for analysis of the parameters shown in Table 9.b will be obtained as 
specified in the SOE (Appendix A). These labs will be performed locally.
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Table 9.a
Clinical Chemistry, Hematology, and Coagulation Tests
Hematology
Serum Chemistry
Coagulation
Hematocrit
Hemoglobin
Leukocytes with 
differential a
Neutrophils (ANC)
Platelet (count)
CD4/CD8 count and 
ratio
Albumin
Alkaline phosphatase (ALP)
Alanine aminotransferase 
(ALT)
Aspartate aminotransferase 
(AST)
Bilirubin (total)
Blood urea nitrogen (BUN)
Calcium
Carbon dioxide (CO2) or 
Bicarbonate (HCO3)
Creatinine
Chloride
Glucose
Lactate dehydrogenase (LDH)
Magnesium
Phosphate
Potassium
Sodium
Standard C-reactive protein
Urate
Activated partial 
thromboplastin time 
(aPTT)
Prothrombin time (PT)
Coombs test (direct and 
indirect)
Fibrinogen
ANC: absolute neutrophil count; EDC: electronic data capture. 
a neutrophils captured as ANC in EDC.
Table 9.b
Clinical Urinalysis Tests and Creatinine Clearance
Urinalysis
Bilirubin
Glucose
Ketones
Leukocytes
Nitrite
Occult blood
pH
Protein
Specific gravity
Turbidity and color
Urobilinogen
Microscopic analysis of urine sediment should be performed if significant 
abnormalities are detected in proteins, leukocytes, or blood.
Creatinine clearance is to be estimated, 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. 
Other formulas, such as estimated glomerular filtration rate (eGFR) or Modification of Diet in 
Renal Disease (MDRD) glomerular filtration rate (GFR) may be used after discussion with 
Takeda clinician/ designee if that is the standard formula used in the institution/ clinical center. 
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Any changes in clinical laboratory parameters that are 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 10.0.
Immunosafety Markers
9.4.12.2
Blood samples for the analysis of autoimmune endocrinopathies as shown in Table 9.c will be 
obtained as specified in the SOE (Appendix A). They will be performed locally only. Any 
changes in immunosafety markers that are 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 10.0.
Table 9.c
Immunosafety Determinations in Serum
Serum Chemistry
Thyroid-stimulating hormone (TSH)
Free Thyroxine (FT4)
Adrenocorticotropic hormone (ACTH)
Blood Type Assessment
9.4.12.3
As discussed in Section 8.11.7, it is recommended that baseline type and serological screening be 
established before starting study treatment. This information may be available historically 
depending on previous exposure to a mAb. 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.
9.4.13
Myeloma Disease Assessment
Patients with MM will be assessed for disease response according to the IMWG criteria [23,24]. 
All procedures and tests should be done as outlined in the SOE (Appendix A). After 24 cycles on 
treatment, the patient may be monitored according to standard clinical practice per the treating 
physician.
Table 9.d
Myeloma Disease Assessments
Serum/Urine
Bone Marrow/Imaging
SPEP
Bone marrow biopsy and/or aspirate a
UPEP
Immunofixation (serum and urine)
Imaging (skeletal survey, CT, PET/CT, MRI)
Quantification immunoglobulin levels
Serum FLC
Interference testing
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CT: computed tomography, FLC: free light chains; BMA: bone marrow aspirate; MRI: magnetic resonance imaging; 
PET: positron emission tomography; SPEP: serum protein electrophoresis; UPEP: urine protein electrophoresis
a Clinically indicated BMA drawn prior to consent is acceptable for the baseline assessment provided that it is 
collected within 8 weeks of screening if acceptable results are available for morphology and clinical staging (Note 
details in Section 9.4.13.4). BMA will be needed during screening however for research samples.
For more details See Sections 9.4.13
2-Microglobulin and Albumin 
9.4.13.1
A blood sample will be collected during screening for measurement of serum 2-microglobulin 
and albumin for determination of disease stage according to the ISS; these results will be 
analyzed locally and recorded on the eCRF.
M-Protein Assessment
9.4.13.2
In addition to M-protein component assessment at screening and during treatment, a prior result 
most recent to the screening sample will also be obtained and entered in the EDC system in order 
to understand the kinetics of the disease progression. 
For M-protein component quantification, samples will be obtained from all patients for SPEP, 
24-hour urine collection for UPEP, serum FLC, serum and urine immunofixation testing, and 
total immunoglobulin levels will be obtained. 
Exception: If the patient has measurable M-protein restricted to the urine, M-protein component 
quantification can be determined by UPEP only. Patients measurable by SPEP only will have 
24-hour urine collected at screening and EOT and to document PR, very good partial response 
(VGPR), complete response (CR), or PD. 
9.4.13.2.1
Immunofixation and Immunoglobulin Levels
Immunofixation will also be done to confirm CR.
Blood samples for IgG, IgA, and IgM will be obtained at screening and throughout the study at 
the time points specified in the SOE (Appendix A). Quantitative IgD and IgE will be done at 
screening only; unless it has already been documented that the patient has another type of MM 
and does not have IgD or IgE MM. For the rare patient with documented IgD or IgE MM, the 
quantitative test for that antibody will be followed at the same time points as IgG and IgA.
M-protein labs will be performed locally. 
Serum and 24-hour urine samples will be collected as per the SOE (Appendix A).
Interference Testing
9.4.13.3
IgG mAbs as being given in this study can interfere with assays used to monitor endogenous 
M-protein. The SPEP and serum immunofixation can be positive due to mAb. This interference 
can impact the determination of CR and of disease progression in some patients with IgG 
myeloma protein. 
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Study drug must be permanently discontinued for patients meeting any of the following criteria:

Pregnancy.

Withdrawal by subject.

AE that leads to TAK-981 discontinuation.

Treatment completion.
Treatment with study drug may also be discontinued for any of the following reasons:

AE/ SAE.

Protocol deviation.

PD.

Symptomatic deterioration.

Unsatisfactory therapeutic response.

Initiation of hematopoietic stem cell transplant.

Study terminated by sponsor.

Withdrawal by subject.

Lost to follow-up.

Other.
Once study drug has been discontinued, all study procedures outlined for the EOT visit will be 
completed as specified in the SOE (Appendix A). The primary reason for study drug 
discontinuation will be recorded on the eCRF.
In the case of study closure (whether completion of the study or early study termination by the 
sponsor), eligible patients may have continued access to TAK-981 and/or mezagitamab 
(according to treatment cohort) as described in Section 6.5.5. 
Note that some patients may discontinue study therapy for reasons other than PD before 
completing the full treatment course; these patients will remain in the study for PFS follow-up 
assessments as outlined in the SOE (Appendix A) until PD occurs. Unless the patient withdraws 
consent to follow-up, PFS and/or OS follow-up assessments will continue to be conducted as 
outlined in the SOE (Appendix A) and Section 9.10. Public records may be consulted as 
permitted per local regulations.
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.
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
Withdrawal consent by subject.

Completed study.

Death. 

Other.
The consequence of a patient withdrawing consent from further treatment and/or follow-up is 
that no new information will be collected from the withdrawn patient and added to the 
existing data or any database. It is important to be clear what the patient is withdrawing 
consent from: treatment, follow-up or both. However, every effort will be made to follow all 
patients for safety. Data collected during patient consent, however, must be included in the 
database. 
Patients who are withdrawn from treatment during Phase 1b Cycle 1 for reasons other than 
DLT will be replaced.
9.9
Study Compliance
Study drug will be administered or dispensed 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 discontinue study treatment for reasons other than disease progression will continue 
PFS follow-up every 4 (±1) weeks from the EOT until the occurrence of PD, death, the start of 
subsequent anticancer therapy, other discontinuation criterion is met, study termination, or until 
50% of patients have PD, whichever occurs first. (Section 9.7). Patients in follow-up will 
continue with disease assessment as described in Section 9.4.13. Follow-up visits for patients 
who discontinue study treatment for reasons other than disease progression (PFS follow-up) 
should be conducted at the site when possible.
Patients who stop treatment due to PD will be followed every 12 (±1) weeks after documented 
PD for OS until death, loss to follow-up, consent withdrawal, study termination, for up to 
12 months after the last patient discontinues or completes treatment, or until 50% of patients 
have died, 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.
Subsequent follow-up for PFS and OS respectively, will be calculated from last contact.
See Appendix A for appropriate assessments during follow-up.
NOTE: Related SAEs must be reported to the Global Pharmacovigilance department or designee. 
This includes deaths that the investigator considers related to study drug that occur during 
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posttreatment follow-up. Refer to Section 10.0 for details regarding definitions, documentation, 
and reporting of SAEs.
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, 
on the basis of appropriate medical judgment, it may jeopardize the patient, require medical 
or surgical intervention to prevent one of the outcomes listed above, or involves suspected 
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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 
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 5.0 [26], except CRS which will be graded according to ASTCT 
Consensus Grading for CRS [27]. 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 is 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 less than 
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 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 a single comprehensive event.
Regardless of causality, SAEs must be reported (see Section 10.3 for the period of observation) 
by the investigator to the Takeda Global Pharmacovigilance department or designee within 
24 hours of becoming aware of the event. This will be done by transmitting an EDC SAE report. 
If transmission of an EDC SAE report is not feasible, then a facsimile of the completed Takeda 
paper-based SAE form will be sent. A sample of the paper-based SAE form and processing 
directions are in the study manual. Information in the SAE report or form must be consistent 
with the data provided on the eCRF.
If information not available at the time of the first report becomes available at a later date, then 
the investigator will transmit a follow-up EDC SAE report (or a paper-based SAE form if an 
EDC SAE report is not feasible) or provide other documentation immediately within 24 hours of 
receipt. Copies of any relevant data from the hospital notes (eg, ECGs, laboratory tests, discharge 
summary, postmortem results) should be sent to the addressee, if requested.
All SAEs should be followed up until resolution or permanent outcome of the event. The 
timelines and procedure for follow-up reports are the same as those for the initial report.
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Planned hospital admissions or surgical procedures for an illness or disease that existed before 
the patient was enrolled in the trial 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. 
Severity (toxicity grade) for each AE, including any lab abnormality, will be determined using 
the NCI CTCAE, Version 5.0, [26], except CRS, which will be graded according to ASTCT 
Consensus Grading for CRS [27]. 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 second-
line alternative therapy, or 6 months after PD has occurred whichever comes first.

SAEs will be reported to the Takeda Global Pharmacovigilance department or designee from 
the signing of informed consent 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 due to 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 sending a completed pregnancy form to the 
Takeda Global Pharmacovigilance department or designee. 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 sending a completed pregnancy 
form to the Takeda Global Pharmacovigilance department or designee. 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 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 email address provided below.
Product
Call Center
Email
TAK-981 and Mezagitamab
Takeda
ctmcomplaint@takeda.com 
Product complaints and medication errors in and of themselves are not AEs. If a product 
complaint or a medication error results in an SAE, the SAE should be reported. 
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 and 
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 expedited reports 
within 7 days for fatal and life-threatening events and within 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. 
11.0
STUDY-SPECIFIC COMMITTEES
11.1
SMC
During the study, an SMC composed of the principal investigators, and sponsor clinician will 
regularly review safety data to ensure patients’ safety throughout the study and make decisions 
on Phase 1b dose escalation and on Phase 2 expansion as defined for the SMC within this 
protocol. 
In accordance with Takeda standard operating procedures and considering applicable regulations 
and guidance, each clinical trial is evaluated to determine if an Independent Data Monitoring 
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Committee (IDMC) should be convened. An IDMC is not indicated at this time for this study 
given Takeda’s standards and processes, which include continuous review and evaluation of 
safety data reported from all participating sites through the conduct of the study, which are 
appropriate for the ongoing monitoring of patient safety and data integrity. However, taking into 
consideration the evolving benefit/risk profile of the combinations being evaluated, the decision 
to convene an IDMC could be taken any time during the conduct of Study TAK-981-1503.
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, medical history, and concurrent conditions will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the WHO 
Drug Dictionary.
12.1
eCRFs 
Completed eCRFs are required for each subject 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 designee) 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 the 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, either onsite or remotely in extenuating circumstances, by study monitors. The sponsor (or 
designee) will be permitted to review the subject’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 
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participating subjects, medical records, temporary media such as thermal-sensitive paper, source 
worksheets, all original signed and dated ICFs, subject authorization forms regarding the use of 
personal health information (if separate from the ICFs), electronic copies of eCRFs including the 
audit trail, and detailed records of drug disposition to enable evaluations or audits from 
regulatory authorities and the sponsor (or designees). Any source documentation printed on 
degradable thermal-sensitive paper should be photocopied by the site and filed with the original 
in the subject’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 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 for record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of 
any such documents.
13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
A statistical analysis plan (SAP) will be prepared and finalized before database lock. This 
document will provide further details regarding the definition of analysis variables and analysis 
methodology to address all study objectives.
13.1.1
Analysis Sets
The analysis sets will include the following:
Safety analysis set: Patients who have received at least 1 dose, even if incomplete, of any study 
drug will be used for all safety analyses and for some efficacy analyses.
PK analysis set: Patients with sufficient dosing and TAK-981 PK data to reliably estimate 1 or 
more TAK-981 PK parameters for PK analyses.
Immunogenicity Set: Patients who receive at least 1 dose of anti-CD38 monoclonal antibodies 
and have an ADA status assessment at baseline, and at least 1 post-baseline sample.
DLT-evaluable analysis set: The DLT-evaluable analysis set will include patients who receive 
at least 75% of planned TAK-981 doses, all mAb doses, and have completed Cycle 1 procedures, 
or experience a DLT in Cycle 1 in the Phase 1b portion of the study. The DLT-evaluable 
population will be used to determine the RP2D/MTD. 
Response-evaluable analysis set:. The response-evaluable analysis set is a subset of the safety 
analysis set including patients with measurable disease at baseline and at least 1 posttreatment 
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Phase 2:
The primary endpoint for Phase 2 portion is ORR for each regimen based on investigator’s 
assessment based on standard disease response criteria.
ORR is defined as the proportion of patients who achieve PR or better (determined by the 
investigator) during the study based on IMWG criteria.
The primary efficacy analysis will be based on the response-evaluable population.
Estimates of the ORR will be presented with 2-sided 95% exact binomial confidence intervals.
Secondary Efficacy Analysis
13.1.3.2
Phase 1b:
Secondary efficacy endpoints in Phase 1b portion include ORR and CBR.
ORR is defined as the proportion of patients who achieve PR or better (determined by the 
investigator) during the study based on IMWG criteria.
CBR for each regimen based on investigator’s disease assessment (response of at least stable 
disease for at least 3 months or better) based on IMWG criteria.
These efficacy analyses will be based on the response-evaluable population.
Estimates of the ORR and CBR will be presented with 2-sided 95% exact binomial confidence 
intervals.
Phase 2:
Secondary efficacy endpoints in Phase 1b portion include DOR, time to response, TTP, TTNT, 
1-year PFS, and OS.
DOR is the time from the date of first documentation of a PR or better to the date of first 
documentation of PD for responders (PR or better). Responders without documentation of PD 
will be censored at the date of last response assessment that is stable disease or better.
Time to Response is the time from the date of the first dose to the date of the first 
documentation of objective response as defined by standard disease criteria.
TTNT is defined as the time from the date of first dose randomization to the date of the first 
dose initiation of the next line of antineoplastic therapy, for any reason. Patients who have not 
started the second-line therapy will be censored at date of last known to be alive subsequent anti-
cancer therapy.
TTP is defined as the time from the date of the first dose to the date of the first documentation of 
PD as defined by standard disease criteria.
PFS is defined as the time from the date of the first dose administration to the date of first 
documentation of PD or death due to any cause, whichever occurs first. PD will be determined 
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by IMWG criteria. Patients without documentation of PD will be censored at the date of the last 
response assessment.
OS is defined as the time from the date of randomization to the date of death. Patients without 
documentation of death at the time of analysis will be censored at the date last known to be alive.
TTNT, TTP, PFS, and OS will be analyzed descriptively using Kaplan-Meier (KM) method for 
safety analysis set. DOR will be analyzed using KM method for response-evaluable analysis set. 
Time to response will be summarized descriptively for response-evaluable analysis set.
Selected efficacy endpoints may be analyzed using mITT population. Further details on the 
efficacy endpoint analyses will be discussed in the SAP.
13.1.4
PK Analysis
PK of TAK-981
13.1.4.1
The PK of TAK-981 will be characterized in this study.
PK parameters for TAK-981 will be estimated using noncompartmental methods with Phoenix 
WinNonlin software for patients in the dose escalation phase. The PK parameters will be 
estimated from the concentration-time profiles for the PK population. The following 
PK parameters will be estimated, as permitted by data, for samples collected during C1D1:

Cmax (maximum observed plasma concentration).

tmax (time of first occurrence of maximum observed concentration).

AUC∞ (area under the plasma concentration-time curve from time 0 to infinity).

AUCt (area under the plasma/blood/serum concentration-time curve from time 0 to time t).

t1/2z (terminal disposition phase half-life).

Total clearance (CL).

Vss.
PK parameters will be summarized using descriptive statistics. Individual TAK-981 
concentration-time data and individual PK parameters will be presented in listings and tabulated 
using summary statistics by dose cohort. Individual and mean concentration-time profiles will be 
plotted by dose cohort. The above parameters will not be estimated for the sparse PK samples 
collected during the Phase 2 portion of study.
The serial and sparse PK data collected in this study are intended to contribute to future 
population PK analyses of TAK-981. These population PK analyses may include data collected 
in other TAK-981 clinical studies. The analysis plan for the population PK analysis will be 
separately defined, and the results of these analyses will be reported separately.
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study may be pooled with similar data from other clinical studies for population analysis 
purposes. The results of such PK-pharmacodynamic and population PK-pharmacodynamic 
analyses and quantitative systems pharmacology modeling may not be presented in the CSR for 
this study but will be presented in a separate report.
MRD Analysis
13.1.6.2
MRD negativity is defined as the absence of MRD and MRD positivity is defined as the presence 
of MRD. For patients with suspected CR or VGPR, MRD assessment will be conducted on BMA 
collected at screening and at time of suspected CR and VGPR. The BMA collected at screening 
will be used to identify the patient’s MM clones at baseline. The presence and abundance of 
these specific tumor clone(s) will be evaluated in the BMA sample collected in patients who 
achieve a VGPR or suspected CR to determine the presence or absence of residual disease. 
The number and percentage of patients with MRD negative status as determined by NGS will be 
summarized.
In addition, MRD negative rate over time, defined as percentage of participants who have 
achieved MRD negative status at 1 year, will be also summarized.
Further details on the MRD analyses will be discussed in the SAP.
13.1.7
Immunogenicity Analysis
Immunogenicity will be summarized using the Immunogenicity set. Descriptive statistics will be 
used to summarize subjects in the following categories: ADA negative, transiently and 
persistently ADA positive, low or high ADA titer.
The relationship between immunogenicity status (ADA and ADA titer) and PK (mezagitamab 
and daratumumab ) and safety may be explored. Further details will be provided in the SAP.
13.1.8
Safety Analysis
Safety will be evaluated by the frequency of AEs, severity and types of AEs, and by changes 
from baseline in patients’ vital signs, weight, and clinical laboratory results using the safety 
analysis set.
Exposure to study drug and reasons for discontinuation will be tabulated.
TEAEs that occur after administration of the first dose of study drug and through 30 days after 
the last dose of study drug will be tabulated.
AEs will be tabulated according to the MedDRA and will include the following categories:

TEAEs.

Drug-related TEAEs.

Grade 3 or higher TEAEs.

Grade 3 or higher drug-related TEAEs.
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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, either onsite or remote 
in extenuating circumstances, 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, subject medical records, informed consent documentation, 
documentation of subject 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 subjects. 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 subject’s source documents. In the event 
of a significant deviation, the site should notify the sponsor or its designee (and IRB or EC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the subject, or confound interpretation of the primary 
study assessment.
The sponsor will assess any protocol deviation; if it is likely to affect to a significant degree the 
safety and rights of a subject or the reliability and robustness of the data generated, it may be 
reported to regulatory authorities as a serious breach of GCP and 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 US[FDA], the United Kingdom [UK] Medicines 
and Healthcare products Regulatory Agency [MHRA], the Pharmaceuticals and Medical Devices 
Agency of Japan [PMDA]). If the study site is contacted for an inspection by a regulatory body, 
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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.
15.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
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 B. 
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 state and 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 because of privacy and conflict of interest concerns should instead 
provide a Federalwide Assurance number or comparable number assigned by the US 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, subject recruitment materials and 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 subject 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 its exact protocol title, number, and version date; identify 
versions of other documents (eg, ICF) reviewed; and state the approval date. If required by 
country or regional regulations or procedures, approval from the competent regulatory authority 
will be obtained before commencement of the study or implementation of a substantial 
amendment. The sponsor will ship drug/notify site once the sponsor has confirmed the adequacy 
of site regulatory documentation and, when applicable, the sponsor has received permission from 
the competent authority to begin the trial. Until the site receives drug/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 subjects, 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 
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approvals and relevant documentation for these items must be provided to the sponsor (or 
designee).
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor.
15.2
Subject Information, Informed Consent, and Subject 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, subject authorization form (if applicable), and subject 
information sheet (if applicable) describe the planned and permitted uses, transfers, and 
disclosures of the subject’s personal and personal health information for purposes of conducting 
the study. The ICF and the subject information sheet (if applicable) further explain the nature of 
the study, its objectives, and potential risks and benefits, and the date informed consent is 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 subject authorization form. The ICF, subject authorization form (if 
applicable), and subject information sheet (if applicable) must be approved by both the IRB or 
IEC and the sponsor before use.
The ICF, subject authorization form (if applicable), and subject information sheet (if applicable) 
must be written in a language fully comprehensible to the prospective subject. It is the 
responsibility of the investigator to explain the detailed elements of the ICF, subject 
authorization form (if applicable), and subject information sheet (if applicable) to the subject. 
Information should be given in both oral and written form whenever possible and in the manner 
deemed appropriate by the IRB or IEC. If the subject is not capable of rendering adequate 
written informed consent, then the subject’s legally acceptable representative may provide such 
consent for the subject in accordance with applicable laws and regulations.
The subject, or the subject’s legally acceptable representative, must be given ample opportunity 
to (1) inquire about details of the study and (2) decide whether to participate in the study. If the 
subject, or the subject’s legally acceptable representative, determines that he or she will 
participate in the study, then the ICF and subject authorization form (if applicable) must be 
signed and dated by the subject, or the subject’s legally acceptable representative, at the time of 
consent and before the subject enters into the study. The subject or the subject’s legally 
acceptable representative should be instructed to sign using their legal names, not nicknames, 
using a ballpoint pen with either blue or black ink. The investigator must also sign and date the 
ICF and subject authorization (if applicable) at the time of consent and before the subject enters 
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, subject authorization form (if applicable), and subject information 
sheet (if applicable) will be stored in the investigator’s site file. The investigator must document 
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the date the subject signs the informed consent in the subject’s medical record. Copies of the 
signed ICF, the signed subject authorization form (if applicable), and subject information sheet 
(if applicable) shall be given to the subject.
All revised ICFs must be reviewed and signed by relevant subjects or the relevant subject’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 subject’s medical record, and the 
subject should receive a copy of the revised ICF.
15.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will be linked to the 
sponsor’s clinical study database or documentation only via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or 
date of birth, and subject initials may be used to verify the subject and accuracy of the subject’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, US FDA, UK MHRA, Japan PMDA), the sponsor-designated 
auditors, and the appropriate IRBs and IECs to review the subject’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 subject’s 
study participation, and autopsy reports. Access to a subject’s original medical records requires 
the specific authorization of the subject as part of the informed consent process (see 
Section 15.2).
Copies of any subject source documents that are provided to the sponsor must have certain 
identifying personal information removed, eg, subject name, address, and other identifier fields 
not collected on the subject’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 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 
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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.
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 by Takeda policy/standards. 
Takeda contact information, along with investigator’s city, state (for Americas 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 in finding 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 preferred by callers requesting trial information. Once subjects 
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 subject 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.govand other publicly accessible 
websites (including the Takeda corporate site) and registries, as required by Takeda 
policy/standards, 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 subject in the study must be insured in accordance with the regulations applicable to the 
site where the subject 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 
subjects. Refer to the clinical study site agreement regarding the sponsor’s policy on subject 
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compensation and treatment for injury. If the investigator has questions regarding this policy, he 
or she should contact the sponsor or sponsor’s designee.
16.0
REFERENCES
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Zhang L, Tai YT, Ho MZG, Qiu L, Anderson KC. Interferon-alpha-based 
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Decque A, Joffre O, Magalhaes JG, Cossec JC, Blecher-Gonen R, Lapaquette P, et al. 
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Diamond MS, Kinder M, Matsushita H, Mashayekhi M, Dunn GP, Archambault JM, et 
al. Type I interferon is selectively required by dendritic cells for immune rejection of 
tumors. J Exp Med 2011;208(10):1989-2003.
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Fuertes MB, Kacha AK, Kline J, Woo SR, Kranz DM, Murphy KM, et al. Host type I 
IFN signals are required for antitumor CD8+ T cell responses through CD8{alpha}+ 
dendritic cells. J Exp Med 2011;208(10):2005-16.
14.
DARZALEX (daratumumab) [prescribing information]. USPI. Horsham, PA: Janssen 
Biotech, Inc., November, 2015.
15.
DARZALEX FASPRO (daratumumab and hyaluronidase-fihj) [Package Insert]. 
Horsham, PA: Janssen Biotech, Inc., May 2020.
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16.
Fedyk E, Idamakanti N, Chen J, Estevam J, Hernandez V, Wagoner M, et al. The Binding 
of CD38 Therapeutics to Red Blood Cells and Platelets Subverts Depletion of Target 
Cells. Blood (ASH Annual Meeting Abstracts) 2019;134(Suppl 1):3136. Suppl 1.
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Krishnan A, Patel K, Hari P, Jagannath S, Niesvizky R, Silbermann R, et al. Preliminary 
Results from a Phase 1b Study of TAK-079, an Investigational Anti-CD38 Monoclonal 
Antibody (mAb) in Patients with Relapsed/ Refractory Multiple Myeloma (RRMM). 
Blood 2019;134(Supplement_1). 140.
18.
Krishnan A, Patel K, Hari P, Jagannath S, Niesvizky R, Silbermann R, et al. A Phase 1b 
study of TAK-079, an investigational anti-CD38 monoclonal antibody in patients with 
relapsed/refractory multiple myeloma: preliminary results. J Clin Oncol 2020;38(Suppl 
15):8539. Suppl 15.
19.
Siegel DS. Relapsed/Refractory multiple myeloma: defining refractory disease and 
identifying strategies to overcome resistance. Semin Hematol 2012;49 Suppl 1:S3-15.
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Shah N, Aiello J, Avigan DE, Berdeja JG, Borrello IM, Chari A, et al. The Society for 
Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of 
multiple myeloma. J Immunother Cancer 2020;8(2).
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Bauvois B, Durant L, Laboureau J, Barthelemy E, Rouillard D, Boulla G, et al. 
Upregulation of CD38 gene expression in leukemic B cells by interferon types I and II. 
Journal of Interferon & Cytokine Research 1999;19(9):1059-66.
22.
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-
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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.
24.
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.
25.
Rajkumar SV, Richardson P, San Miguel JF. Guidelines for determination of the number 
of prior lines of therapy in multiple myeloma. Blood 2015;126(7):921-2.
26.
Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. U.S. 
Department of Health and Human Services, National Institutes of Health, National 
Cancer Institute. November 2017.
27.
Lee DW, Santomasso BD, Locke FL, Ghobadi A, Turtle CJ, Brudno JN, et al. ASTCT 
Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated 
with Immune Effector Cells. Biol Blood Marrow Transplant 2019;25(4):625-38.
28.
Yuan Y, Hess KR, Hilsenbeck SG, Gilbert MR. Bayesian optimal interval design: A 
simple and well-performing design for phase i oncology trials. Clin Cancer Res 
2016;22(17):4291-301.
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RITUXAN (rituximab) [prescribing information]. San Francisco, CA: Genentech, Inc.,
2013.
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Appendix A
SOEs
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Table A-1
SOEs (28-Day Cycle)
Study Procedures
Screening
Treatment Period a
EOT
Follow-up
28-Day Cycles
PFS
OS
Cycle
Cycles 1 and 2
Cycles 3 to 6
Cycle 7 and Beyond
Up to 30 
Days After 
Last Dose
Every 4 
Weeks 
Until PD
Every 12 
Weeks 
After PD
Days
-28 to -1
1
2 b
8
15
22
1
8
15
22
1
8
15
22
Window
±2 Days
+1 Week
±1 Week
±1 Week
Informed consentc
X
Eligibility criteriad
X
Demographics
X
Complete medical history 
X
BMA for baseline 
morphology/ clinical staging
Xe
Complete physical exam 
X
X
Symptom-directed physical 
exam
X
X
X
ECOG performance status 
X
X
X
X
X
Height 
X
Weight
X
X
Vital signsg
X
X
X
X
X
X
X
X
X
Blood type assessment 
X
12-lead ECGh
X
Xh
Xh
Xh
Xh
Xh
-
Safety Laboratory Assessments
Window
X
±2 Days
+1 Week
±1 Week
±1 Week
Pregnancy testi
X
X
X
X
X
Hematologyj
X
X
X
X
X
X
X
X
X
Clinical chemistryj
X
X
X
X
X
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Coagulationj
X
X
X
X
Direct/indirect coombsj
X
X
X
X
X
Urinalysisj
X
X
X
X
Immunosafety markersk
X
X
X
X
Disease Assessment Tests
M-protein measurements 
(SPEP/UPEP)l 
X
X
X
X
X
X
X
X
Albumin and β2-
microglobulin
X
Serum free light chain assayl
X
X
X
X
X
X
X
X
Immunofixation - serum and 
urinel,m
X
X
X
X
X
X
X
Quantification of 
immunoglobulinsn
X
X
X
X
X
X
BMA (disease assessment)f
At suspected CR and VGPR to document CR/stringent CR [sCR].
See Section  9.4.13.4 for more detail
X optional 
at relapse
BMA sample for MRD 
Xe
At suspected CR and VGPR. If negative, at 6 and 12 months later. Should be 
repeated if MRD positive at a clinically relevant timepoint. If now negative 
at subsequent testing, BMA should also be repeated to support sustained 
MRD status as noted above.
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t 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), until start of second-line alternative therapy, or 6 months after PD has occurred, whichever comes first.
u Patients will be followed every 12 weeks until death, loss to follow-up, consent withdrawal, or study termination. Assessments can be made over the phone and 
do not require a clinic visit. Data may be collected by methods that include but are not limited to telephone, e-mail, mail, and social security indexes.
v For subsequent therapy, type of therapy, start and end date, best response, and date of progression should be recorded in the eCRF if available.
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Table A-2
Weekly Dosing Schedules
Window
± 2 days
Weekly TAK-981 Dosing With Mezagitamab Regimen
Cycle
28-day Cycles C1 and 2
28-day Cycles C3 through 6
28-day Cycles C7 through PD
Day of cycle
D1
D8
D15
D22
D1
D8
D15
D22
D1
D8
D15
D22
Premedication a
X
X
X
X
X
X
X
TAK-981 b
X
X
X
X
X
X
X
Mezagitamab b, c
X
X
X
X
X
X
X
Weekly TAK-981 Dosing With Daratumumab and Hyaluronidase-fihj Regimen
Premedication a
X
X
X
X
X
X
X
TAK-981 b
X
X
X
X
X
X
X
Daratumumab and 
hyaluronidase-fihj b
X
X
X
X
X
X
X
C: cycle; C1D1, Cycle 1, Day 1; C1D8: Cycle 1, Day 8; D: day; PD: progressive disease.
a Premedication of dexamethasone, oral antipyretics and oral antihistamine will be administered. See Section 8.1.2 and Section 8.2.1 for more premedication/ 
postmedication details.
b For C1D1 only, the monoclonal antibody will be administered first (before the TAK-981 infusion). Starting at C1D8 onwards, TAK-981 will be administered 
before the monoclonal antibody. See Section 8.1. for more details about the order of drug administration.
c For mezagitamab: time and anatomical site should be recorded for each injection.
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Table A-3
BIW Dosing Schedules
Window
± 2 days
BIW TAK-981 Dosing With Monoclonal Antibody 
Cycle
28-day Cycles C1 and C2
28-day Cycles C3 through 6
28-day Cycles C7 through PD
Day of cycle
D1
D4
D8
D11
D15
D18
D22
D1
D8
D15
D22
D1
D8
D15
D22
Premedication a
X
X
X
X
X
X
X
TAK-981 b
X
X
X
X
X
X
X
X
Monoclonal 
antibody b, c

Mezagitamab D1, 8, 15, 22 Cycle 1 and 2, then Day 1 and 15 Cycles 3 through 6, followed by once every 4 weeks Cycle 7 through PD

Daratumumab and hyaluronidase-fihj D1, 8, 15, 22 Cycle 1 and 2, then Day 1 and 15 Cycles 3 through 6, followed by once every 4 
weeks Cycle 7 through PD
C: cycle; C1D1: Cycle 1 Day 1; C1D8: Cycle 1, Day 8; D: day; PD: progressive disease. 
a Premedication of dexamethasone, oral antipyretics and oral antihistamine will be administered. See Section 8.1.2 and Section 8.2.1 for more premedication/ 
postmedication details.
b For C1D1 only, the monoclonal antibody will be administered first (before the TAK-981 infusion). Starting at C1D8 onwards, TAK-981 will be administered 
before the monoclonal antibody. See Section 8.1. for more details about the order of drug administration.
c For mezagitamab: time and anatomical site should be recorded for each injection.
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Table A-4
TAK-981 Plasma PK Sampling: Phase 1b and Phase 2
Cycle 1
Cycle 2
Day 1
Day 8
Day 15
Day 1
Day 15
PK (Plasma)
PK (Plasma)
PK (Plasma)
PK (Plasma)
PK (Plasma)
Phase 1b
Pre-TAK-981 dose (within 1h before the start of 
infusion)
X
X
X
X
X
End of TAK-981 infusion (±10 min)
X
X
X
X
X
2 h after end of TAK-981 infusion (±30 min)
X
4 h after end of TAK-981 infusion (±30 min)
X
24 h after end of TAK-981 infusion (±60 min)
X
Total time points/samples
5
2
2
2
2
Phase 2
Pre-TAK-981 dose (within 1 h before the start 
of infusion)
X
X
X
X
End of TAK-981 infusion (±10 min)
X
X
X
X
1-4 h after end of TAK-981 infusion (±30 min)
X
Total time points/samples
3
0
2
2
2
h: hour; PK: pharmacokinetic(s).
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Appendix B
Responsibilities of the Investigator
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 who will assist in the protocol.
3. If the investigator/institution retains the services of any individual or party to perform 
trial-related duties and functions, the investigator/institution should ensure that this 
individual or party is qualified to perform those trial-related duties and functions and should 
implement procedures to ensure the integrity of the trial-related duties and functions 
performed and any data generated.
4. Ensure that study-related procedures, including study-specific (nonroutine/nonstandard 
panel) screening assessments, are NOT performed on potential subjects before the receipt of 
written approval from relevant governing bodies/authorities.
5. Ensure that all colleagues and employees assisting in the conduct of the study are informed 
of these obligations.
6. 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.
7. 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 subjects. 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.
8. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH and local 
regulations, are met.
9. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each ICF should contain a subject authorization section 
that describes the uses and disclosures of a subject’s personal information (including personal 
health information) that will take place in connection with the study. If an ICF does not 
include such a subject authorization, then the investigator must obtain a separate subject 
authorization form from each subject or the subject’s legally acceptable representative.
10. 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 
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contact and receive written approval from the sponsor before disposing of any such 
documents.
11. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
12. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor.
13. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.
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Appendix C
Investigator Consent to Use of Personal Information 
Takeda will collect and retain personal information of the investigator, including his or her name, 
address, and other identifying personal information. In addition, the investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
UK, US, 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.
The 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 the 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.
The 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 the 
investigator’s own country.
The 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 D
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, 1982 [43].
ECOG: Eastern Cooperative Oncology Group. 
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Appendix E
Methods of Contraception Considered to be Effective
A. Acceptable Methods Considered Highly Effective
Birth control methods that can achieve a failure rate of less than 1% per year when used 
consistently and correctly are considered as highly effective. Such methods include:

Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation a:
–
Oral.
–
Intravaginal.
–
Transdermal.

Progestogen-only hormonal contraception associated with inhibition of ovulation a:
–
Oral.
–
Injectable.
–
Implantable b.

Intrauterine device (IUD) b.

Intrauterine hormone-releasing system (IUS) b.

Bilateral tubal occlusion b.

Vasectomised partner b, c.

Sexual abstinence d.
B. Methods That Are Considered Less Highly Effective
Acceptable birth control methods that result in a failure rate of more than 1% per year include:

Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mode of action.

Male or female condom with or without spermicide e.

Cap, diaphragm or sponge with spermicide e.
Source: European Heads of Medicines Agencies (HMA) Clinical Trial Facilitation Group (CTFG); see 
hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf.
a Hormonal contraception may be susceptible to interaction with the investigational medicinal product, which may 
reduce the efficacy of the contraception method.
b Contraception methods that in the context of this guidance are considered to have low user dependency.
c Vasectomised partner is a highly effective birth control method provided that partner is the sole sexual partner of 
the woman of childbearing potential participant of the study and that the vasectomized partner has received medical 
assessment of the surgical success.
d In the context of this guidance sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred 
and usual lifestyle of the subject.
e A combination of male condom with either cap, diaphragm or sponge with spermicide (double-barrier methods) 
are also considered acceptable, but not highly effective, birth control methods.
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Appendix F
Drugs that Interact With the CYP3A Family of Cytochromes P450
Drugs listed below that are strong or moderate inducers or inhibitors of the CYP3A family of 
CYPs are prohibited as concomitant medications with TAK-981. This list is not intended to be 
exhaustive, and a similar restriction will apply to other agents that are known to strongly 
modulate CYP3A activity. Appropriate medical judgment is required. Please contact the 
sponsor’s medical monitor with any queries.
Drugs Inducing or Inhibiting CYP3A Metabolism That are Prohibited Concomitant 
Medications With TAK-981
Strong CYP3A Inducers a
Strong CYP3A Inhibitors b
apalutamide
carbamazepine
enzalutamide
mitotane
phenytoin
rifampin
St John’s Wort
boceprevir
clarithromycin
cobicistat
danoprevir and ritonavir
elvitegravir and ritonavir
grapefruit juice
idelalisib
indinavir and ritonavir
itraconazole
ketoconazole
lopinavir and ritonavir
nefazodone
paritaprevir and ritonavir and (ombitasvir and/or dasabuvir)
posaconazole
ritonavir
saquinavir and ritonavir
telaprevir
telithromycin
tipranavir and ritonavir
troleandomycin
voriconazole
Moderate CYP3A Inducers a
Moderate CYP3A Inhibitors b
bosentan
efavirenz
etravirine
phenobarbital
primidone
aprepitant
ciprofloxacin
conivaptan
crizotinib
cyclosporine
diltiazem
dronedarone
erythromycin
fluconazole
fluvoxamine
imatinib
tofisopam
verapamil
CYP: cytochrome P450.
a fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-
inducers#table3-3 (accessed 05 August 2021).
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b fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-
inducers#table3-2 (accessed 05 August 2021).
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Appendix G
Examples of Clinical Inhibitors of Pgp
Drugs listed below that are inhibitors of Pgp are prohibited as concomitant medications with 
TAK-981. 
Transporter
Gene
Inhibitor
Pgp
ABCB1
amiodarone
carvedilol
clarithromycin
dronedarone 
itraconazole
lapatinib
lopinavir and ritonavir
propafenone
quinidine
ranolazine
ritonavir
saquinavir and ritonavir
telaprevir
tipranavir and ritonavir
verapamil
Source: fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-
inhibitors-and-inducers#table5-2 (accessed 05 August 2021).
Pgp: P-glycoprotein.
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Appendix H
iBOIN Design
In Phase 1b Part 1, It is estimated that up to approximately 15 DLT-evaluable patients will be 
enrolled to evaluate dose escalation for 1 dosing schedule of TAK-981 with 3 dose levels.
Dose escalation will follow an iBOIN design{Lee, 2019 #14382}. Each schedule will be 
evaluated separately. Approximately 3 patients will be enrolled in the first cohort. The decision 
to escalate or de-escalate the dose of TAK-981 will be based on the cumulative DLT rate at the 
current dose level and the predetermined DLT rate threshold for dose escalation/de-escalation 
boundaries as defined by the iBOIN model. The target DLT rate for this study is 0.3. According 
to the single agent Study TAK-981-1002, the prior DLT rate for the 3 doses are (0.25, 0.26, 0.5) 
and the prior effective sample size are (2, 2, 0). The total number of patients at each dose level 
could be up to approximately 9. The dose escalation and de-escalation rules for TAK-981 are as 
follows.
1. If the observed DLT rate at the current dose is <  , escalate the dose to the next higher 
dose level;
2. If the observed DLT rate at the current dose is >  , de-escalate the dose to the next 
lower dose level;
3. Otherwise, stay at the current dose.
The values for  and  vary with dose level and the number of patients treated on a dose. 
Table H-1 provides an equivalent decision boundaries, which will be used in the trial for dose 
escalation and de-escalation.
Table H-1
Dose Escalation/De-escalation Rule for the iBOIN Design
1
2
3
4
5
6
7
8
9
Dose level 1
Escalate if # of DLT ≤
0
0
0
1
1
1
1
1
2
Deescalate if # of DLT ≥
1
1
2
2
2
3
3
3
4
Eliminate if # of DLT ≥a
NA
NA
3
3
4
4
5
5
5
Dose level 2
Escalate if # of DLT ≤
0
0
0
1
1
1
1
1
2
Deescalate if # of DLT ≥
1
1
2
2
2
3
3
3
4
Eliminate if # of DLT ≥
NA
NA
3
3
4
4
5
5
5
Dose level 3
Escalate if # of DLT ≤
0
0
0
0
1
1
1
1
2
Deescalate if # of DLT ≥
1
1
2
2
2
3
3
3
4
Eliminate if # of DLT ≥
NA
NA
3
3
4
4
5
5
5
DLT: dose-limiting toxicity; iBOIN: Bayesian Optimal Internal Design With Informative Prior; NA: not applicable. 
a Eliminate the current and higher doses from the trial to prevent treating any future patients at these doses when 
they are overly toxic.
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The operating characteristics of the iBOIN design based on 1000 simulations of each scenario 
are presented in the following table: 
Table H-2
Operating Characteristics of the iBOIN Design
1
2
3
Number of Patients
% Early Stopping
Scenario 1
True DLT Rate
0.3
0.5
0.67
Selection %
65.8
19.2
1
14
% Patients Treated
67
30.1
2.9
11.8
Scenario 2
True DLT Rate
0.13
0.3
0.48
Selection %
23.5
55.5
20.5
0.5
% Patients Treated
39.7
42.3
18
14.3
Scenario 3
True DLT Rate
0.05
0.13
0.3
Selection %
1.6
27.8
70.6
0
% Patients Treated
24.9
34.3
40.8
14.9
Scenario 4
True DLT Rate
0.05
0.1
0.2
Selection %
1.7
12.8
85.5
0
% Patients Treated
24.2
29.7
46.1
14.9
DLT: dose-limiting toxicity; iBOIN: Bayesian Optimal Internal Design with Informative Prior. 
“% Early Stopping” refers to early stopping due to excessive DLT.
The operating characteristics show that the proposed iBOIN design selects the true MTD, if any, 
with high probability and allocates more patients to the dose levels with the DLT rate closest to 
the target of 0.3. For example, in scenario 1, the first dose is the true MTD, and the iBOIN 
design yields the high selection percentage of 65.8% with 7.9 patients allocated to this dose 
level.
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Appendix I
Examples of QTc Interval Prolonging Agents (During Phase 1b only)
The use of the following drugs known to prolong QTc interval are prohibited during Phase 1. In 
Phase 2, patients taking such medications need not to discontinue if their baseline QTcF 
<480 msec.
Drug Class
Examples of Drugs That Increase Risk of Torsade de Pointes, Name 
(Brand Name)
Antiarrhythmic
amiodarone (Cordarone, Pacerone)
bepridil (Vascor)
disopyramide (Norpace)
dofetilide (Tikosyn)
flecainide (Tambocor)
ibutilide (Corvert)
procainamide (Pronestyl, Procan)
quinidine (Cardioquin, Quinaglute)
sotalol (Betapace)
Antibiotic
azithromycin (Zithromax)
clarithromycin (Biaxin)
erythromycin (Erythrocin, EES)
moxifloxacin (Avelox)
pentamidine (NebuPent, Pentam)
sparfloxacin (Zagam)
Anticancer
arsenic trioxide (Trisenox)
vandetanib (Caprelsaa)
Antidepressant
citalopram (Celexa)
Antiemetic
domperidone (Motilium)
droperidol (Inapsine)
Antihistamine
astemizole (Hismanal)
terfenadine (Seldane)
Antilipemic/
Hypercholesterolemia
probucol (Lorelco)
Antimalarial
chloroquine (Aralen)
halofantrine (Halfan)
Antipsychotic
chlorpromazine (Thorazine)
haloperidol (Haldol)
mesoridazine (Serentil)
pimozide (Orap)
thioridazine (Mellaril)
GI stimulant/Heartburn
cisapride (Propulsid)
Opiate agonist
levomethadyl (Orlaam)
methadone (Dolophine, Methadose)
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Appendix J
IMWG criteria
IMWG = International Myeloma Working Group
Source: Rajkumar et al, 2011 [23], Palumbo et al 2014 [24]
All response categories (CR, sCR, VGPR, PR, and PD) require 2 consecutive assessments made at any time before 
the institution of new therapy. VGPR and CR 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. For PD, serum M-component 
increases of more than or equal to 1 g/dL are sufficient to define relapse if starting M-component is ≥ 5 g/dL. 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 
plasmacytomas, or hypercalcemia, and the “lowest response value” does not need to be a confirmed value. 
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Appendix K
 
 
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Appendix N
Protocol History
Date
Amendment Number
Region
30 August 2021
Amendment 2
Global
22 December 2020 
Amendment 1
Global
03 November 2020
Initial protocol
Global
Rationale for Amendment 1 
This section describes the changes to the protocol incorporating Amendment 1. 
The primary reason for this amendment was to address the changes requested by United States 
(US) Food and Drug Administration (FDA) during Investigational New Drug (IND) application 
review. 
Minor grammatical, editorial, formatting, and administrative changes not affecting the conduct of 
the study are included for clarification and administrative purpose only.
Protocol Amendment 1
Summary of Changes Since Last Version of the Approved Protocol
Sections Affected by Change
Description of Each Change and Rationale
Location
Description
Rationale
Section 6.3 Phase 2 Study Design
Section 13.2 Interim Analysis and 
Criteria for Early Termination
Added subsection for early stopping 
rules.
Changes made in response to FDA’s 
request for addition of study 
stopping rules.
Section 2.0 STUDY SUMMARY
Section 7.1 Inclusion Criteria
Modified inclusion criterion 3 to 
remove population of 2 or more 
lines of prior therapy.
Changes made in response to FDA’s 
request to amend the inclusion 
criteria to limit the patient 
population to patients who have 
been treated with 3 or more lines of 
therapy.
Section 2.0 STUDY SUMMARY
Section 7.2 Exclusion Criteria 
Modified exclusion criterion 2 to 
clarify that patients participating in 
investigational vaccines or 
investigational medical device “for 
disease under study” will be 
excluded.
Change made for providing clarity 
on exclusion criterion.
Section 2.0 STUDY SUMMARY
Section 7.2 Exclusion Criteria 
Section 8.8.1 Excluded Concomitant 
Medications and Procedures for 
TAK-981
Appendix I Examples of QTc 
Interval Prolonging Agents (During 
Phase 1 only)
Addition of exclusion criterion to 
exclude patients who require the use 
of drugs known to prolong the 
corrected QT (QTc) interval (during 
Phase 1 only). Addition of new 
appendix listing drugs known to 
prolong QTc interval.
Changes made in response to FDA’s 
request to restrict concomitant use of 
drugs known to prolong the QT/QTc 
interval.
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Protocol Amendment 1
Summary of Changes Since Last Version of the Approved Protocol
Sections Affected by Change
Description of Each Change and Rationale
Location
Description
Rationale
Section 8.3 Definitions of DLT
Modified list of events that may be 
considered dose-limiting toxicities 
(DLTs).
Changes made in response to FDA’s 
request for modifications of DLT 
definition.
Section 8.1.1 TAK-981 Study Drug 
Administration
Section 8.2.1.1 Vital Signs
Incorporated additional vital sign 
monitoring. 
Changes made in response to FDA’s 
request.
Section 2.0 STUDY SUMMARY
Section 8.5 Dose Escalation Rules
Provided more clarity on TAK-981 
dose escalation with respect to 
recommended Phase 2 dose.
Changes made in response to FDA’s 
request.
Section 8.9 Permitted Concomitant 
Medications and Procedures
Added language to discuss with 
sponsor/designee prior to initiation 
of a CoV2 vaccination and/or 
COVID-19 treatment.
Addition of language made to have 
more clarity on process to follow for 
initiation of a CoV2 vaccination 
and/or COVID-19 treatment.
Section 9.4.14.1 Primary Specimen 
Collection (Table 9.e)
Section 9.4.17 Immunogenicity and 
Sparse PK Sample Collection
Appendix A Schedule of Events, 
Table 5
Added collection of blood samples 
for sparse pharmacokinetics (PK).
Changes made in response to FDA’s 
request to collect sparse PK samples 
to characterize the PK of 
mezagitamab in the proposed 
combination regimen.
Appendix A Schedule of Events, 
Table 1
Addition of 12-lead 
electrocardiograms (ECGs) to 
monitor QT interval, at pre-TAK-
981 dosing, and end of TAK-981 
infusion on Days 1 and 8 of Cycles 1 
and 2 during Phase 1b.
Changes made in response to FDA’s 
request to monitor ECGs at the 
expected maximum plasma 
concentration of TAK-981.
Section 8.10 Precautions and 
Restrictions
Clarified that if the last dose 
received is mezagitamab, 
contraception is required through 
6 months.
Addition made to provide more 
clarity on contraception duration.
Appendix H iBOIN Design
Modified the appendix for clarity.
Modification made in response to 
FDA’s feedback.
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SAP_001.pdf: 
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Statistical Analysis Plan v2.0
17 April 2023
CONFIDENTIAL
Amendment History:
Date
Version Number
Amendment Type
17 April 2023
Version 2.0
Substantial
13 January 2020
Initial SAP
Not applicable
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Statistical Analysis Plan v2.0
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1.1
Approval Signatures
Study Title:
A Phase 1b/2 Open-Label, Multicenter Study to Evaluate the Safety and 
Efficacy of TAK 981 in Combination With Monoclonal Antibodies in Adult 
Patients With Relapsed and/or Refractory Multiple Myeloma 
Approvals:
 PhD
 Oncology Statistics
Date
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Statistical Analysis Plan v2.0
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CONFIDENTIAL
2.0
TABLE OF CONTENTS 
1.0
TITLE PAGE ..................................................................................................................1
1.1
Approval Signatures ..................................................................................................3
2.0
TABLE OF CONTENTS.................................................................................................4
List of In-Text Tables............................................................................................................6
List of In-Text Figures...........................................................................................................6
3.0
LIST OF ABBREVIATIONS..........................................................................................7
4.0
OBJECTIVES .................................................................................................................9
4.1
Primary Objectives ....................................................................................................9
4.2
Secondary Objectives.................................................................................................9
4.3
Exploratory Objectives ............................................................................................10
4.4
Study Design ...........................................................................................................10
4.4.1
Phase 1b Study Design.......................................................................................11
4.4.1.1 Phase 1b Part 1 .................................................................................................12
4.4.1.2 Phase 1b Part 2 .................................................................................................13
4.4.1.3 Selection of CD38 Antibody for Phase 2.............................................................13
4.4.2
Phase 2 Study Design.........................................................................................13
4.4.2.1 Early Stopping Rules..........................................................................................14
5.0
ANALYSIS ENDPOINTS.............................................................................................14
5.1
Primary Endpoints ...................................................................................................14
5.2
Secondary Endpoints ...............................................................................................15
5.3
Exploratory Endpoints .............................................................................................15
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................16
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................18
7.1
General Principles....................................................................................................18
7.1.1
Definition of Study Visit Windows ....................................................................18
7.1.2
Conventions for Missing/Partial Dates in Screening Visit...................................18
7.1.3
Conventions for Missing Adverse Event Dates...................................................19
7.1.4
Conventions for Missing Prior Medications/Therapy and Concomitant 
Medication/Therapy Dates .................................................................................20
7.1.5
Conventions for Missing Subsequent Medication/Therapy Dates .......................20
7.2
Analysis Sets ...........................................................................................................21
7.3
Disposition of Subjects ............................................................................................22
7.4
Study Drug Exposure and Compliance.....................................................................22
7.5
Efficacy Analysis.....................................................................................................23
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LIST OF IN-TEXT TABLES
Table 6.a
...............................................................................17
Table 7.a
Clinical Chemistry and Hematology Tests to be summarized .............................34
Table 7.b
.........................................................36
Table 7.c
.................37
LIST OF IN-TEXT FIGURES
Figure 4.a
Study Schema ....................................................................................................11
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3.0
LIST OF ABBREVIATIONS
Abbreviation
Term
AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical
AUC∞
area under the plasma/blood/serum concentration-time curve from time 0 to infinity
AUCt
area under the plasma concentration versus time curve from time 0 to time t
BIW
twice weekly
BMA
bone marrow aspirate
CBR
clinical benefit rate
CL
total clearance after intravenous administration
Cmax
maximum observed concentration
CR
complete response 
DCR
disease control rate
DL
dose level
DLT
dose-limiting toxicity
DOR
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EOT
end-of-treatment
GGT
gamma glutamyl transferase
iBOIN
Bayesian Optimal Interval Design with Informative Prior
iCR
immunophenotypic complete response
IFN
interferon
IMWG
International Myeloma Working Group
IRR
infusion-related reaction
IV
intravenous
KM
Kaplan-Meier
LDH
lactate dehydrogenase
LYRIC
lymphoma response to immunomodulatory therapy criteria
MAD
maximally administered dose
mCR
molecular complete response
MedDRA
Medical Dictionary for Regulatory Activities
MID
minimally important difference
MM
multiple myeloma
mITT
modified intent-to-treat
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Abbreviation
Term
MR
minimal response
MRD
minimal residual disease
MTD
maximum tolerated dose
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
ORR
overall response rate
OS
overall survival
PAD
pharmacologically active dose
PD
progressive disease (disease progression)
PFS
progression-free survival
PK
pharmacokinetic(s)
PR
partial response 
QTc
corrected QT interval
QW
weekly
RBC
red blood cell
RP2D
recommended phase 2 dose
RRMM
relapsed and/or refractory multiple myeloma
sCR
stringent complete response
SD
stable disease
STD
standard deviation
SMC
Safety Monitoring Committee
SUMO
small ubiquitin-like modifier
t1/2z
terminal disposition phase half-life
tmax
first time to reach maximum (peak) plasma concentration
TEAE
treatment-emergent adverse events
TLS
tumor lysis syndrome
TTNT
time to next treatment
TTP
time to progression
WHO
World Health Organization
VGPR
very good partial response
Vss
volume of distribution at steady state after intravenous administration
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4.0
OBJECTIVES
The study will be conducted in 2 phases:

Phase 1b dose escalation of TAK-981 guided by Bayesian Optimal Interval Design with 
Informative Prior (iBOIN) in combination with fixed doses of mezagitamab or daratumumab 
and hyaluronidase-fihj, respectively in patients with relapsed and/or refractory multiple 
myeloma (RRMM).

Phase 2 study of TAK-981-based monoclonal antibody combinations with multiple treatment 
arms in patients with RRMM.
The study objectives will be separated based on the phase of the study.
4.1
Primary Objectives
The primary objectives are:
Phase 1b:

To determine the safety and tolerability of TAK-981 in combination with mAbs in patients 
with RRMM.

To determine the recommended Phase 2 dose (RP2D).
Phase 2:

To evaluate the efficacy of TAK-981 in combination with monoclonal antibodies in patients 
with RRMM.
4.2
Secondary Objectives
The secondary objectives are:

To characterize the PK profile of TAK-981 in combination with anti-CD38 mAb.

To assess immunogenicity of anti-CD38 monoclonal antibodies (mezagitamab and 
daratumumab) to help interpreting PK profile, efficacy and safety of TAK-981 in 
combination with monoclonal antibodies.
Phase 1b:

To evaluate preliminary efficacy of the TAK-981-monoclonal antibody combination 
according to standard International Myeloma Working Group (IMWG) criteria.

To assess target engagement of TAK-981 (TAK-981- small ubiquitin-like modifier [SUMO] 
adduct formation) and SUMOylation pathway inhibition in blood.
Phase 2:

To further characterize efficacy of TAK-981 in combination with anti-CD38 mAb in RRMM 

To evaluate the safety and tolerability of TAK-981 in combination with anti-CD38 mAb.
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Figure 4.a
Study Schema
Patient participation will include a screening phase, a treatment phase, and a follow-up phase 
(see Section 9.0 of the protocol). The screening phase will be up to approximately 28 days before 
Cycle 1, Day 1 (C1D1). The treatment phase will extend from C1D1 until patients experience 
disease progression or unacceptable toxicity, or until any other discontinuation criterion is met 
(Refer Section 9.7 of the protocol). The follow-up phase of the study begins once a patient 
discontinues study treatment and completes the end-of-treatment (EOT) visit; study follow-up 
continues until the study ends or the patient completes OS follow-up (Refer Section 9.10 of the 
protocol).
4.4.1
Phase 1b Study Design
The Phase 1b part of the study will enroll patients with RRMM with the purpose of defining the 
RP2D and schedule of TAK-981 in combination with mezagitamab or daratumumab and 
hyaluronidase-fihj, respectively. The first part of the Phase 1b will determine the dose and 
schedule of TAK-981 in combination with a fixed dose and schedule of mezagitamab. The 
second part of the Phase 1b will determine the dose of TAK-981 for the combination with 
daratumumab and hyaluronidase-fihj. The RP2D and recommended schedule with be used in the 
Phase 2 expansion. 
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4.4.1.1
Phase 1b Part 1
Dose escalation of TAK-981 will be guided by iBOIN (see Section 8.5 and Appendix H of the 
protocol for details). Up to approximately 15 patients will be enrolled to each of the TAK-981 
schedules until either maximum tolerated dose (MTD) or a pharmacologically active dose (PAD) 
is identified: 

Arm A: TAK-981 given IV twice weekly (BIW) on Days 1, 4, 8, 11, and 15 in Cycles 1 and 
2 followed by every 2 weeks in Cycles 3 through 6, then monthly. TAK-981 will be given in 
combination with mezagitamab. 

Arm B: TAK-981 given IV weekly (QW) on Days 1, 8, 15, and 22 in Cycles 1 and 2 
followed by every 2 weeks in Cycles 3 through 6, then monthly. TAK-981 will be given in 
combination with mezagitamab.
The starting dose for TAK-981 will be 60 mg; the rationale for the initial TAK-981 dose is 
provided in Section 4.4 of the protocol. The dose of mezagitamab is the established RP2D at 
600 mg. 
Once enrolled into the study, patients will be assigned to a treatment arm in a nonrandomized, 
sequential manner based upon the recruitment status of the TAK-981 arm schedule, as 
communicated by the sponsor/ designee. A minimum of 3 patients will be enrolled in the first 
dose cohort. In the first dose cohort, patient enrollment will be staggered between the first and 
second patients by 7 days. The second and third patients can be dosed concurrently if the first 
patient in the cohort has gone through the Day 8 visit without clinically significant acute 
toxicities. Subsequent dose cohorts will not require staggering between patients. 
Dose escalation will begin with the BIW schedule and will be followed by the QW schedule at 
the same starting dose level. TAK-981 dose escalation will be evaluated separately for each of 
the TAK-981 schedules.
Dose escalation decisions will be made by a Safety Monitoring Committee (SMC), composed of 
the principal investigators and sponsor. The SMC will regularly review safety data to ensure 
patients’ safety throughout the Phase 1b portion of the study. Dose escalation will follow an 
iBOIN design. Dose escalation decisions will take into consideration primarily the DLTs 
observed in Cycle 1 in the patients enrolled in each dose level/schedule according to the rules in 
Section 8.5 of the protocol (DLT rules). Available safety information beyond Cycle 1, PK and 
pharmacodynamic information from previously dose patients will also be considered.
Evaluation of intermediate doses or doses up to that evaluated and found safe in the TAK-981 
monotherapy study TAK-981-1002, alternative dosing schedules (dosing interval), and 
expansion of an existing dose level are all permissible following agreement by the SMC, if such 
measures are needed for patient safety or for a better understanding of the dose-related toxicity, 
efficacy, exposure, or pharmacodynamics of TAK-981. The dose escalation/de-escalation rules 
based on iBOIN design will be considered as a guidance for the next dose level, however, the 
final decision on the dose will be made by the SMC.
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4.4.1.1.1
Selection of RP2D for TAK-981 in Combination With Mezagitamab
The selection of an RP2D which includes the dose level and schedule of TAK-981 in 
combination with mezagitamab will be made by the sponsor following evaluation of the 
available data from the Phase 1b – Part 1 portion of the trial which will include, but is not limited 
to safety data, preliminary PK data, preliminary pharmacodynamic data, preliminary 
translational data, PK/pharmacodynamic modeling and preliminary antitumor activity. The 
RP2D may not be higher than either the MTD as determined by iBOIN. Upon review of 
available phase 1 data and agreement on the RP2D by the SMC, the Phase 1b Part 2 portion of 
the study of the combination of TAK-981 with daratumumab and hyaluronidase-fihj may begin. 
4.4.1.2
Phase 1b Part 2
In the second part of Phase 1b, the RP2D of TAK-981 in combination with daratumumab and 
hyaluronidase-fihj will be determined. 
Dose escalation of TAK-981 will be guided by iBOIN as described in Section 8.5 of the 
protocol. The starting dose for TAK-981 will be one dose-level below the RP2D defined for the 
combination with mezagitamab in Phase 1b Part 1 (RP2D-1). The dose of daratumumab is the 
approved dose of 1800 mg. A minimum of 3 patients will be enrolled in the first cohort of this 
combination, and up to approximately 15 patients will be enrolled for the dose escalation. The 
SMC will regularly review safety data and make decisions for dose escalation.
4.4.1.2.1
Selection of RP2D for TAK-981 in Combination With Daratumumab and 
Hyaluronidase-fihj
The selection of an RP2D of TAK-981 in combination with daratumumab and hyaluronidase-fihj
will be made by the sponsor following evaluation of the available data from the Phase 1b – Part 2 
portion of the trial which will include, but is not limited to safety data, preliminary PK data, 
preliminary pharmacodynamic data, preliminary translational data, PK/pharmacodynamic 
modeling and preliminary antitumor activity. The RP2D may not be higher than the MTD as 
determined by iBOIN. 
4.4.1.3
Selection of CD38 Antibody for Phase 2
The selection of the anti-CD38 antibody (mezagitamab or daratumumab and hyaluronidase-fihj) 
for combination with TAK-981 in Phase 2 will be made by the sponsor following evaluation of 
the available data from the Phase 1b – Part 1 and 2 portions of the trial which will include, but is 
not limited to safety data, selected RP2D, frequency of dose reduction/discontinuation observed 
for anti-CD38 antibody, preliminary pharmacodynamic data, preliminary translational data, 
PK/pharmacodynamic modeling and preliminary antitumor activity.
4.4.2
Phase 2 Study Design
The Phase 2 portion of the study will explore the efficacy and safety of TAK-981 in combination 
with an anti-CD38 antibody (mezagitamab or daratumumab and hyaluronidase-fihj) in patients 
with RRMM. Patients will be treated with the RP2D and recommended schedule of TAK-981 
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with fixed doses of the anti-CD-38 mAb, mezagitamab or daratumumab and hyaluronidase-fihj. 
(TAK-981, mezagitamab, and daratumumab and hyaluronidase-fihj administration details are in 
Section 8 of the protocol). 
An adaptive 2-stage design for a single proportion will be used in Phase 2. For Stage I, each 
cohort will be analyzed when a prespecified number of patients (as defined in Section 6.0) have 
been enrolled and had the opportunity to complete 4 cycles of treatment. Enrollment may be 
paused until the Stage I analysis is completed. If the prespecified minimal response rate is not 
achieved in the first stage, enrollment will be closed. If the required response rate during Stage I 
or a good CBR is observed as mentioned above, then additional patients will be enrolled in the 
second stage of the corresponding cohort until a predetermined number of additional patients has 
been reached (as defined in Section 6.0). The final analysis of the primary endpoints will take 
place when all ongoing patients have had the opportunity complete the 12-month disease 
assessment.
4.4.2.1
Early Stopping Rules
In the Phase 2 portion of the study, Grade 4 or higher drug-related AEs will be monitored 
starting from the first 11 response-evaluable patients and then every 4 response-evaluable 
patients up to the approximate maximum number of patients 36.
Accrual to the study will be suspended if:

Grade 4 drug-related AEs meet the stopping bounds of the number of ≥4/11, ≥4/15, ≥5/19, 
≥6/23, ≥7/27, ≥7/31, ≥8/35, ≥8/36; or 

At any time if 1 or more patients present with fatal drug-related AEs.
After review and consideration by the SMC, a decision will be made as to whether accrual can be 
resumed.
The stopping bounds for Grade 4 drug-related AEs 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 16% with a prior beta distribution with parameters 0.4 and 1.6 for the 
binomially distributed toxicity rate.
5.0
ANALYSIS ENDPOINTS
5.1
Primary Endpoints
The primary endpoints are:

Phase 1b:
–
Frequency and severity of TEAEs for all dose groups.
–
Occurrence of DLT in Cycle 1.
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7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
General Principles 
In general, summary tabulations will display the number of observations, mean, standard 
deviation (STD), median, minimum, and maximum for continuous variables, and the number and 
percent (of non-missing values) per category for categorical data. 
All available efficacy and safety data will be included in data listings and tabulations as needed. 
Data that are potentially spurious or erroneous will be examined under the auspices of standard 
data management operating procedures.
Baseline values are defined as the last observed value before the first dose of study medication. 
Means and medians will be presented to 1 more decimal place than the recorded data. The STDs 
will be presented to 2 more decimal places than the recorded data. 95% Confidence intervals 
about a parameter estimate will be presented using the same number of decimal places as the 
parameter estimate.
In general, the summary tables for efficacy endpoints will be provided by dose cohort, overall for 
Phase 1b-Part 1 and Phase 1b-Part 2, and by expansion cohort (and overall if more than 1 
expansion cohort) for Phase 2; the summary tables for non-efficacy endpoints (disposition, 
baseline and demographics, medical history, medication history, exposure, patient reported 
outcomes, safety analysis) will be provided by dose cohort, overall for Phase 1b-Part 1 and 
Phase 1b-Part 2, and by expansion cohort (and overall if more than 1 expansion cohort) for 
Phase 2, and overall for both phases combined unless specified otherwise. 
Screen failure subjects will be grouped and listed at the end.
All statistical analyses will be conducted using SAS® Version 9.4, or higher.
7.1.1
Definition of Study Visit Windows
All data will be categorized based on the scheduled visit at which it was collected unless 
otherwise specified. These visit designators are predefined values that appear as part of the visit 
tab in the eCRF.
7.1.2
Conventions for Missing/Partial Dates in Screening Visit
The following rules apply to dates recorded during the screening visits. 

If only the day-component is missing, the first day of the month will be used if the year and 
the month are the same as those for the first dose of study drug. Otherwise, the fifteenth will 
be used. 

If only the year is present, and it is the same as the year of the first dose of study drug, the 
fifteenth of January will be used unless it is later than the first dose, in which case the date of 
the first of January will be used, unless other data indicate that the date is earlier.
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
If only the year is present, and it is not the same as the year of the first dose of study drug, the 
fifteenth of June will be used, unless other data indicate that the date is earlier.
7.1.3
Conventions for Missing Adverse Event Dates
Adverse events with start dates that are completely or partially missing will be analyzed as 
follows:

If month and year are known but day is missing.
–
If month and year are the same as month and year of first dose date, then impute to first 
dose date.
–
If month and year are different than month and year of first dose date, then impute to first 
date of the month.

If year is known but day and month are missing.
–
If year is same as year of 1st dose date, then 1st dose date will be used instead.
–
If year is different than year of 1st dose date, then 1st of January of the year will be 
imputed. 

If all is missing, then it is imputed with 1st dose date.
Imputing missing AE start date is mandatory. After the imputation, all imputed dates are checked 
against the start dates to ensure the stop date does not occur before start date 
Adverse events with stop dates that are completely or partially missing will be analyzed 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,
–
If YYYY < year of last dose, then 31st of December will be imputed.
–
If YYYY = year of last dose, then 31st of December will be imputed.
–
If YYYY > year of last dose, then 1st of January will be imputed.

If all are missing, then impute date to 31st of December, in the year of last dose. 
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 the imputed stop date occurs prior to start date, then 
keep the imputed date same as the start date. If subject dies, then use death date for AE stop date.
After the imputation, all imputed dates are checked against the start dates to ensure the stop date 
does not occur before start date. If the imputed stop date occurs prior to start date, then keep the 
imputed date the same as the start date. 
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7.1.4
Conventions for Missing Prior Medications/Therapy and Concomitant 
Medication/Therapy Dates
Concomitant medications/therapies with start dates that are completely or partially missing will 
be analyzed as follows:

If month and year are known, but day is missing, then impute day to first of the month

If year is known, but day and month are missing, then 1st of January of the year will be 
imputed

If all is missing, then impute date to Date of Birth (DOB) 
–
If DOB is not available but age is available, then estimate DOB by using screening date 
and age (DOB = screening date – age[years]*365.25) 
Concomitant therapies with stop dates that are completely or partially missing will be analyzed 
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, 
–
If YYYY < year of last dose, then 31st of December will be imputed 
–
If YYYY = year of last dose, then 31st of December will be imputed 
–
If YYYY > year of last dose, then 1st of January will be imputed 

If all is missing, then impute date to 31st of December in the year of last dose.
Imputing missing concomitant therapies is optional. However, if it is to be done, the rules are 
outlined above. If subject dies, then use death date for concomitant therapies stop date. After the 
imputation, all imputed dates are checked against the start dates to ensure stop date does not 
occur before start date. If the imputed stop date occurs prior to start date, then keep the imputed 
date same as the start date.
7.1.5
Conventions for Missing Subsequent Medication/Therapy Dates
Subsequent therapies with start dates that are completely or partially missing will be analyzed as 
follows:

When month and year are present and the day of the month is missing, 
–
If the onset month and year are the same as the month and year of last dose with study 
drug, the day of last dose + 1 will be imputed.
–
If the onset month and year are not the same as the month and year of last dose with 
study drug, the first day of the month is imputed. 
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Prescribed dose is determined by the dose level to which a patient is scheduled to receive and 
will take into consideration of planned dose reduction or escalation during the study. 
Relative dose intensity will also be displayed as <50%, 50% - < 80%, 80% - <100%, = 100%, 
and >100%.
The extent of exposure will be summarized by dose cohort, overall for Phase 1b-Part 1 and 
Phase 1b-Part 2, by expansion cohort (and overall if more than 1 expansion cohort) for Phase 2, 
and overall for both phases combined.
Dosing data will also be presented in a by-patient listing.
Action on Study Drug:
Action on study drug could include dose increased (TAK-981 only), dose reduced, dose delayed, 
drug infusion interrupted (TAK-981 only), drug withdrawn, dose interrupted. 
Action on study drug will be summarized by Cycles 1- 6, Cycle 7- 12, Cycles 13-18, Cycle ≥19 
and total, for each dose cohort, overall for Phase 1b-Part 1 and Phase 1b-Part 2, for expansion 
cohort (and overall if more than 1 expansion cohort) for Phase 2, and overall for both phases 
combined.
7.5
Efficacy Analysis
7.5.1
Primary Efficacy Endpoint(s)
Phase 1b:
Efficacy is not the primary objective for this study in the Phase 1b portion. The efficacy analysis 
will mainly focus on the Phase 2 portion of this study.
In the Phase 1b portion of this study, efficacy parameters such as ORR and CBR will be 
summarized as appropriate. Disease response will be categorized and presented in listings.
Phase 2:
The primary endpoint for Phase 2 portion is ORR for each regimen based on investigator’s 
assessment based on IMWG response criteria.
Overall Response Rate (ORR)
The ORR is defined as the proportion of patients who achieved a confirmed PR or better during 
the study per investigator assessment as defined by IMWG Response Criteria. Response 
evaluations after the start of alternative anti-multiple-myeloma therapy will not be taken into 
account in the calculation of ORR.
The primary efficacy analysis will be provided based on the response-evaluable analysis set by 
expansion cohort (and overall if more than 1 expansion cohort) for Phase 2.
The ORR will be summarized by frequencies and percentages and estimates of the ORR will be 
presented with 2-sided 95% exact binomial confidence intervals.
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The primary efficacy analysis of ORR will also be provided for mITT population and modified 
response-evaluable population.
7.5.2
Secondary Efficacy Endpoint(s)
Secondary efficacy endpoints include are described below for Phase 1b and Phase 2. 
Response evaluations after the start of alternative anti-multiple-myeloma therapy will not be 
taken into account in the calculation of efficacy endpoints.
No formal statistical tests will be performed for these secondary endpoints. 
Phase 1b:
Secondary efficacy endpoints in Phase 1b portion include ORR, CBR, DOR, TTP, TTNT, PFS 
based on based on IMWG criteria and OS.
Phase 2:
Secondary efficacy endpoints in Phase 2 portion include CBR, DOR, time to response, TTP, 
TTNT, PFS, and OS.
Overall Response Rate (ORR)
Similar to analysis of ORR for phase 2 in Section 7.5.1, analysis of ORR will be provided based 
on the response-evaluable analysis set by dose cohort, overall for Phase 1b-Part 1 and Phase 1b-
-Part 2.
Clinical Benefit Rate (CBR)
The CBR includes patients with a response of at least stable disease for at least 3 months or 
better (strigent complete response [sCR], immunophenotypic complete response [iCR], 
molecular complete response [mCR], complete response [CR], very good partial response 
[VGPR], partial response [PR], minimal response [MR] or stable disease [SD]) during the study 
per investigator assessment as defined by IMWG Uniform Response Criteria. The CBR will be 
summarized by frequencies and percentages based on response-evaluable analysis set by dose
cohort, overall for Phase 1b-Part 1 and Phase 1b-Part 2, and by expansion cohort (and overall if 
more than 1 expansion cohort) for Phase 2. Estimates of the CBR will be presented with 2-sided 
95% exact binomial confidence intervals.
The CBR will also be summarized for mITT population and modified response-evaluable
population.
Duration of Response (DOR)
The DOR will be calculated for those patients with a confirmed PR or better in the response-
evaluable analysis set. The DOR is defined as the number of days from the first documentation 
of a confirmed response until progressive disease or until the last adequate response assessment 
if there is no progressive disease (censored). If the patient dies from causes other than 
progression, the patient will be censored.
DOR (months) = (date of progression or censor – date of confirmed response + 1)/30.4375.
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The analysis of DOR will be provided by dose cohort, overall for Phase 1b-Part 1 and 
Phase 1b-Part 2, and by expansion cohort (and overall if more than 1 expansion cohort) for 
Phase 2 based on those patients with a confirmed PR or better in the response-evaluable analysis 
set. The Kaplan-Meier method will be used to estimate the distribution of DOR. The 25th, 50th 
(median), and 75th percentiles, and the corresponding 2-sided 95% confidence intervals (CIs) 
based on Brookmeyer and Crowley method will be presented. The number of patients with 
events and the number of patients censored will be summarized.
The DOR analysis will be repeated for patients with a confirmed PR or better in the mITT 
population and modified response-evaluable population.
Progression Free Survival (PFS) 
PFS is defined as the time from the date of first dose to the date of PD per IMWG criteria, or the 
date of death due to any cause, whichever occurs first. 
Patients without documentation of PD will be censored at the date of the last response 
assessment. Patients who received any subsequent anticancer therapy without a prior reported 
progression will be censored at the last response assessment prior to or on the date of initiation of 
the subsequent anticancer therapy. Patients with no post baseline response assessment will be 
censored on day 1 unless they have a death event.
PFS (months) = (earliest date of progression or death or censor – date of first dose + 1)/30.4375.
The analysis of PFS will be based on safety analysis set by dose cohort, overall for Phase 1b-
Part 1 and Phase 1b-Part 2, and by expansion cohort (and overall if more than 1 expansion 
cohort) for Phase 2. The Kaplan-Meier method will be used to estimate the distribution of PFS. 
Kaplan-Meier survival curves, the 25th, 50th (median), and 75th percentiles, along with 
associated 2-sided 95% confidence intervals (CIs) based on Brookmeyer and Crowley method, 
and Kaplan-Meier PFS probability estimates with 95% CIs at 3, 6 and 12 months (or later time 
points if data permits) will be presented. The number of patients with events along with the type 
of events (death or progressive disease) and the number of patients censored will be summarized.
The analysis of PFS will be repeated for the mITT population and modified response-evaluable
population.
Time to Response (TTR)
Time to response is defined as the time in weeks from first dose to the date of first 
documentation of confirmed objective response (PR or better). Patients with no confirmed PR or 
better will be censored on the last date of adequate response assessment. Patients with no post 
baseline response assessment will be censored on day 1.
TTR (months)= (date of confirmed response or censor – date of first dose + 1)/30.4375).
The analysis of TTR will be based on response-evaluable analysis set. The Kaplan-Meier method 
will be used to estimate the distribution of TTR by dose cohort, overall for Phase 1b-Part 1 and 
Phase 1b-Part 2, and by expansion cohort (and overall if more than 1 expansion cohort) for 
Phase 2. Kaplan-Meier curves, the 25th, 50th (median), and 75th percentiles, along with 
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associated 2-sided 95% confidence intervals (CIs) based on Brookmeyer and Crowley, and 
Kaplan-Meier estimates with 95% CIs at 3 and 6 months (or later time points if data permits) 
will be presented. The number of patients with events and the number of patients censored will 
be summarized.
The analysis of TTR will be repeated for the mITT population and modified response-evaluable
population.
Time to Next Treatment (TTNT)
TTNT is defined as the time from the date of first dose to the date of the first dose initiation of 
the next line of antineoplastic therapy, for any reason. Patients who have not started the 
second-line therapy will be censored at date of last known to be alive subsequent anti-cancer 
therapy.
The analysis of TTNT will be based on safety analysis set by dose cohort, overall for 
Phase 1b-Part 1 and Phase 1b-Part 2, and by expansion cohort (and overall if more than 
1 expansion cohort) for Phase 2. The Kaplan-Meier method will be used to estimate the 
distribution of TTNT. The 25th, 50th (median), and 75th percentiles, and the corresponding 
2-sided 95% confidence intervals (CIs) based on Brookmeyer and Crowley method will be 
presented. The number of patients with events and the number of patients censored will be 
summarized.
The analysis of TTNT will be repeated for the mITT population and modified response-
evaluable population.
Time to Progression (TTP)
TTP is defined as the time from the date of the first dose to the date of the first documentation of 
PD as defined by standard disease criteria. Patients without documentation of PD at the time of 
analysis will be censored at the date of last response assessment. Patients who die during 
treatment without PD will also be censored at the date of last response assessment. Patients who 
received any subsequent anticancer therapy without a prior reported progression will be censored 
at the last response assessment prior to or on the date of initiation of the subsequent anticancer 
therapy.
The analysis of TTP will be based on the safety analysis set by dose cohort, overall for 
Phase 1b-Part 1 and Phase 1b-Part 2, and by expansion cohort (and overall if more than 
1 expansion cohort) for Phase 2. The Kaplan-Meier method will be used to estimate the 
distribution of TTP. The 25th, 50th (median), and 75th percentiles, and the corresponding 
2-sided 95% confidence intervals (CIs) based on Brookmeyer and Crowley method will be 
presented. The number of patients with events and the number of patients censored will be 
summarized.
The analysis of TTP will be repeated for the mITT population and modified response-evaluable
population.
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Overall Survival (OS)
OS is defined as the time from the date of the first dose to the date of death. Patients without 
documentation of death at the time of analysis will be censored at the date last known to be alive.
The analysis of OS will be based on safety analysis set by dose cohort, overall for 
Phase 1b-Part 1 and Phase 1b-Part 2, and by expansion cohort (and overall if more than 
1 expansion cohort) for Phase 2. The Kaplan-Meier method will be used to estimate the 
distribution of OS. Kaplan-Meier survival curves, the 25th, 50th (median), and 75th percentiles, 
along with associated 2-sided 95% confidence intervals (CIs) based on Brookmeyer and Crowley 
method, and Kaplan-Meier PFS probability estimates with 95% CIs at 3 and 6 months (or later 
time points if data permits) will be presented. The number of patients with events and the 
number of patients censored will be summarized.
The analysis of OS will be repeated for the mITT population.
7.5.3
Additional Efficacy Endpoint(s)
Best Overall Response
Best overall response is defined as the best response recorded after the first dose of study drug 
until subsequent anti-multiple-myeloma therapy.
Best Overall Response (unconfirmed): This will be the best response reported by the 
investigator; ordered from best to worst: sCR, iCR, mCR, CR, VGPR, PR, MR, SD, PD. The 
best response can also be Not Evaluable (NE) or No assessment performed if this is the only 
investigator assessment of response available for the patient.
Best Overall Response (confirmed): This will be the best response reported by the investigator; 
ordered from best to worst: sCR, Complete Response, VGPR, Partial Response, Minimal 
Response, Stable Disease, Progressive Disease, NE. 
Confirmed Response: All response categories (sCR, iCR, mCR, CR, VGPR, PR, MR, SD, PD) 
require 2 consecutive assessments made at any time before the initiation of alternative 
anti-multiple-myeloma therapy. There is no requirement on the time between the two visits. 
Consecutive visits are needed for response confirmation, except if there is one or two NE/ND 
assessments in between. 
For categories other than PD, the consecutive assessment usually means next cycle (a few days 
apart might not be appropriate). Either one or two consecutive occurrences of “ND” or “NE” 
between responses can be skipped when confirming a response such as:
PR -> NE -> PR: PR is considered to be confirmed in this case.
CR -> ND -> CR: CR is considered to be confirmed in this case.
VGPR => NE -> PR: PR is considered confirmed in this case
If the subject only has one assessment, the confirmed response should be “NE”.
Confirmation of SD: 
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Like all other response categories (CR, sCR, iCR, mCR, VGPR, PR, and PD), SD needs two 
consecutive assessments (with no evidence of PD) to confirm. For the following case, the best 
confirmed response is PD if there is an alternative therapy after PD. SD is not confirmed as only 
one SD is recorded.
BL(baseline) SD PD
Alternatively, for example, SD-> PR (or SD -> NE -> PR) would be considered as confirmed 
SD.
Confirmation of PD:
In practice, sometimes it is difficult to have two consecutive PDs entered in clinical database to 
confirm PD.
1. If only one PD is recorded as the last available assessment on study or the last available 
assessment on study prior to the alternative therapy, it can be counted as a confirmed PD. It will
be considered as an event for DOR, TTP, PFS analyses.
BL SD PD Alternative therapy/End – It is a confirmed PD
2. If only one PD value is recorded in the middle as below, it will not be counted as a confirmed
PD. It will not be considered as an event for DOR, TTP, PFS analyses.
BL SD PD SD SD Alternative therapy/End – It is a confirmed 
SD, not confirmed PD.
Best overall response will be summarized by frequencies and percentages based on response-
evaluable analysis set by dose cohort, overall for Phase 1b-Part 1 and Phase 1b-Part 2, and by 
expansion cohort (and overall if more than 1 expansion cohort) for Phase 2.
The summary will also be repeated for mITT population and modified response-evaluable
population.
Best M-Protein Response
The best m-protein response is defined as the percent change from baseline to the best (lowest) 
value post-baseline. For subjects with measurable serum m-protein at baseline, the best m-
protein response is based on serum m-protein. For subjects with non-measurable serum m-
protein at baseline, but measurable urine m-protein at baseline, the best m-protein response is 
based on the urine m-protein. A waterfall plot of the best m-protein response will be generated. 
The plot will have the following information:
1. Response.
2. Dose cohort.
3. Urine M-protein/Serum M-protein.
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7.6
Pharmacokinetic/Pharmacodynamic Analysis
7.6.1
Pharmacokinetic (PK) Analysis 
The PK of TAK-981 will be characterized in this study. For mezagitamab and daratumumab, 
onlyPK concentration from sparse sampling will be summarized.
PK parameters for TAK-981 will be estimated using noncompartmental methods with Phoenix 
WinNonlin software for patients in the dose escalation phase. The PK parameters will be 
estimated from the concentration-time profiles for the PK population. The following PK 
parameters will be estimated, as permitted by data, for samples collected during C1D1 and 
C1D15:

Cmax (maximum observed plasma concentration).

tmax (time of first occurrence of maximum observed concentration).

AUC∞(area under the plasma concentration-time curve from time 0 to infinity).

AUCt (area under the plasma/blood/serum concentration-time curve from time 0 to time t).

t1/2z (terminal disposition phase half-life).

Total clearance (CL).

Vss.
PK parameters will be summarized using descriptive statistics. Individual TAK-981 
concentration-time data and individual PK parameters will be presented in listings and tabulated 
using summary statistics by dose cohort. Individual mezagitamab and daratumumab 
concentration-time data will be presented in listings and tabulated using summary statistics by 
dose cohort as well. Individual and mean concentration-time profiles will be plotted by dose 
cohort. The above parameters will not be estimated for the sparse PK samples collected during 
the Phase 2 portion of study.
The serial and sparse PK data collected in this study are intended to contribute to future 
population PK analyses of TAK-981. These population PK analyses may include data collected 
in other TAK-981 clinical studies. The analysis plan for the population PK analysis will be 
separately defined, and the results of these analyses will be reported separately.
7.6.2
Pharmacodynamic Analysis
The analysis of blood and bone marrow biomarker profiles for each dose and timepoint tested 
will be tabulated. When possible, the dynamic range for each biomarker and fold change will be 
determined to better understand TAK-981 biological activity range and duration of 
pharmacodynamic effect, and to help determine the PAD/RP2D for the TAK-981 in each 
antibody combination. In addition, candidate response biomarkers will be evaluated.
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that occur after administration of the first dose of any study drug and through 30 days after the 
last dose of any study drug. 
Adverse events will be tabulated according to MedDRA by system organ class, high level term
and preferred term and will include the following categories: 

Treatment-emergent AEs.

Drug-related treatment-emergent AEs.

Grade 3 or higher treatment-emergent AEs.

Grade 3 or higher drug-related treatment-emergent AEs.

The most commonly reported treatment-emergent AEs (ie, those events reported by ≥10% of 
all patients).

Serious AEs (SAEs) (related and regardless of relationship).

Treatment-emergent AEs leading to study drug modification (includes reduction, delay, 
interruptions).

Treatment-emergent AEs leading to 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.
Treatment-emergent AEs will also be summarized by the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. Patients with the same AE 
more than once will have the maximum intensity of that event counted within each body system,
once within each high level term, and once within each preferred term. 
The most commonly reported treatment-emergent AEs (ie, those events reported by ≥10% of any 
treatment arm) will be tabulated by preferred term. Patients with the same AE more than once 
will have that event counted only once within each preferred term.
An overall summary treatment-emergent AE table will include numbers and percentages of 
patients who had any treatment-emergent AE, drug-related treatment-emergent AE, grade 3 or 
higher treatment-emergent AE, grade 3 or higher drug-related treatment-emergent AE, serious 
AE (SAE), drug-related SAE, treatment-emergent AE resulting in discontinuation of study drug, 
and on-study deaths. 
In general, TEAEs will be summarized by dose cohort, overall for Phase 1b-Part 1 and 
Phase 1b-Part 2, by expansion cohort (and overall if more than 1 expansion cohort) for Phase 2, 
and overall for both phases combined.
By-patient listing of grade 3 or higher treatment-emergent AE will also be provided, where the 
cycle day information for the AE onset and end dates will be included in the listing.
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7.8.2.2
Serious Adverse Events
The number and percentage of subjects experiencing at least 1 treatment emergent SAEs 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-subject listing of the SAEs will be presented (the subject listing will contain all 
SAEs regardless of treatment emergent AE status).
7.8.2.3
Deaths
A by-subject listing of the deaths will be presented. All deaths occurring on-study and during 
follow-up will be displayed (regardless of treatment-emergent AE status).
On-study death is defined as the death that occurs between the first dose of any study drug and 
within 30 days of the last dose of any study drug.
7.8.2.4
Adverse Events Resulting in Discontinuation of Study Drug
A by-patient listing of treatment-emergent AEs resulting in discontinuation of study drug will be 
presented. All AEs resulting in discontinuation of study drug occurring on-study and during 
follow-up will be displayed (regardless of treatment-emergent AE status). 
7.8.3
Clinical Laboratory Evaluations
For the purposes of summarization in both the tables and listings, all laboratory values will be 
converted to standardized units. If a lab value is reported using a non-numeric qualifier (eg, less 
than (<) a certain value, or greater than (>) a certain value), the given numeric value will be used 
in the summary statistics, ignoring the non-numeric qualifier.
Laboratory test results from the local laboratories will be used as there are no central laboratory 
test results available for this study.
If a patient has repeated laboratory values for a given time point, the value from the last 
evaluation will be used.
The actual values of laboratory test results and percent change from baseline will be summarized 
according to the scheduled sample collection time point dose cohort, overall for Phase 1b-Part 1 
and Phase 1b-Part 2, by expansion cohort (and overall if more than 1 expansion cohort) for Phase
2, and overall for both phases combined. Laboratory data will also be presented in listings.
Unscheduled laboratory test results will be listed and included in laboratory shift tables.
Shift tables will be constructed for laboratory parameters to tabulate changes in toxicity from 
baseline to post baseline worst on study CTCAE grade based on NCI CTCAE v5.0, if available.
Grading may also be based on NCI CTCAE v4.03 if grading based on NCI CTCAE v5.0 cannot 
be programmatically derived. Parameters to be tabulated for shift tables are included in
Table 7.a. In addition, shift table will also be constructed for immunosafety markers to tabulate 
changes in baseline categories (below normal range, within normal range, above normal range) 
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to post baseline worst on study categories (below normal range, within normal range, above 
normal range).
Table 7.a
Clinical Chemistry and Hematology Tests to be summarized 
Hematology
Serum Chemistry
Coagulation
Hematocrit
Hemoglobin
Leukocytes 
Lymphocytes
Neutrophils (ANC)
Platelet (count)
CD4/CD8 count and 
ratio
Alkaline phosphatase (ALP)
Alanine aminotransferase 
(ALT)
Aspartate aminotransferase 
(AST)
Bilirubin (total)
Calcium
Creatinine
Glucose
Lactate dehydrogenase (LDH)
Potassium
Sodium
Standard C-reactive protein
None
ANC: absolute neutrophil count; EDC: electronic data capture. 
a neutrophils captured as ANC in EDC.
By-patient listings to be presented include all parameters for hematology, clinical chemistry,
coagulation (Protocol Table 9.a), urinalysis(Protocol Table 9.b), immunosafety markers
(Protocol Table 9.c).
Mean laboratory values over time will be plotted for key lab parameters, including hemoglobin, 
leukocytes, lymphocytes, neutrophils, platelet count, alkaline phosphatase, alanine 
aminotransferase, aspartate aminotransferase, bilirubin, creatinine, and standard C-reactive 
protein. The analysis for other lab parameters may be performed as needed.
7.8.4
Vital Signs
The actual values of vital sign parameters (blood pressure and heart rate) and weight will be 
summarized over time by dose cohort, overall for Phase 1b-Part 1 and Phase 1b-Part 2, by 
expansion cohort (and overall if more than 1 expansion cohort) for Phase 2, and overall for both 
phases combined. Change of vital signs from baseline values will also be summarized over time. 
Vital sign values will also be presented in a by-patient listing.
7.8.5
12-Lead ECGs
Descriptive statistics for the actual values and changes from values at baseline in 
Electrocardiograms (ECGs) will be provided by time point.
QTc interval will be calculated using Bazett’s correction and Fridericia’s correction, if necessary.
The formulas are:
QTc (Bazett) = QT / (RR0.5)
QTc (Fridericia) = QT / (RR0.33)
where RR = 60 / heart rate (bpm)
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