Clinical trial NCT03439293
Conditions: Multiple Myeloma
Keywords: Drug Therapy Ixazomib Daratumumab Dexamethasone
Sponsor: Takeda
Start date: 2018-03-13; Completion date: 2023-06-26
Enrollment: 61 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to evaluate the percentage of participants with a response of very good partial response (VGPR) or better to IDd treatment.

Detailed description:
The regimen being tested in this study is the combination of ixazomib, daratumumab, and dexamethasone. This study will look at the efficacy and safety of IDd in people who have RRMM.

The study will enroll approximately 60 Participants. Participants will be assigned to the treatment group:

• Ixazomib 4.0 mg + Daratumumab 16.0 mg/kg + Dexamethasone 20 mg

All participants will be asked to take Ixazomib on Days 1, 8 and 15 of each 28-day cycle plus Daratumumab on Days 1, 8, 15 and 22 of each 28-day cycle for Cycles 1 and 2, on Days 1 and 15 of each 28-day cycle for Cycles 3 through 6 and on Day 1 of each 28-day cycle for Cycle 7 and beyond plus Dexamethasone orally on Days 1, 2, 8, 9, 15, 16, 22 and 23 of each 28-day cycle.

This multi-center trial will be conducted in the United States, Czech Republic, France, Poland, Greece and the Netherlands. The overall time to participate in this study is approximately 5 years. Participants will make multiple visits to the clinic, and every 12 weeks after PD until death or termination of the study by the sponsor.

Arms: arm 1: Ixazomib, 4 mg, capsules, orally, on Days 1, 8 and 15 of each 28-day cycle along with daratumumab, 16 mg/kg, intravenously (IV), on Days 1, 8, 15 and 22 of Cycles 1 and 2, on Days 1 and 15 (every 2 weeks) for Cycles 3 to 6 and on Day 1 (every 4 weeks) for Cycle 7 and beyond along with dexamethasone, 20 mg, tablets, orally on Days 1, 2, 8, 9, 15, 16, 22 and 23 of each 28-day cycle until progressive disease (PD), unacceptable toxicity, or withdrawal of consent, or up to 5 years.
Interventions: intervention 1: Ixazomib intervention 2: Daratumumab intervention 3: Dexamethasone
Intervention descriptions: intervention 1: Ixazomib capsule. intervention 2: Daratumumab IV infusion. intervention 3: Dexamethasone tablets.

Protocol documents:
Prot_000.pdf: 
Title: A Phase 2, Open-Label Study of Ixazomib+Daratumumab+Dexamethasone (IDd) in 
Relapsed and/or Refractory Multiple Myeloma (RRMM)
NCT Number: NCT03439293
Document Date: 30 March 2022
Certain information within this document has been redacted (ie, specific content is masked irreversibly 
from view with a black bar) to protect either personally identifiable (PPD) information or company 
confidential information (CCI). 


CONFIDENTIAL
PROTOCOL
A Phase 2, Open-Label Study of Ixazomib+Daratumumab+Dexamethasone (IDd) in Relapsed 
and/or Refractory Multiple Myeloma (RRMM)
Sponsor:
Takeda Development Center Americas, Inc
95 Hayden Avenue
Lexington, MA 02421, USA
Telephone: +1 (617) 679-7000
Study Number:
C16047
EudraCT Number:
Compound:
2017-003977-32
Ixazomib (NINLARO)
Date:
30 March 2022
Amendment Number: 07
Amendment History: 
Date
Amendment 
Number
Amendment Type (for Regional 
Europe Purposes Only)
Region
30 November 2017
Initial Protocol
Not applicable
Global
15 November 2018
01
Nonsubstantial
France
18 April 2019
02
Substantial
Global
18 April 2019
03
Substantial
France
28 September 2020
04
Substantial
Global
13 October 2020
05
Substantial
France
01 November 2021
06
Substantial (not implemented)
Global
30 March 2022
07
Substantial
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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Rationale for Amendment 07
This document describes the changes to the protocol incorporating Amendment 07. The primary 
reason for this amendment is to change the legal entity name of the sponsor to Takeda 
Development Center Americas, Inc. In addition, a new Schedule of Events has been added for use 
after the final analysis has been conducted, and the Management of Clinical Events section for 
ixazomib has been updated to reflect evolving data.
The global Protocol Amendment 06 (dated 01 November 2021) will not be implemented. Thus, 
the changes described below for the current Protocol Amendment 07 are relative to the most recent 
protocol version globally implemented, which was Protocol Amendment 04 (dated 
28 September 2020).
Minor grammatical, editorial, formatting, and administrative changes not affecting the conduct of 
the study are included for clarification and administrative purposes only. 
For specific descriptions of text changes and where the changes are located, see Appendix K.
Changes in Amendment 07
The purposes of this amendment are to:
1. Change the legal entity name of the sponsor.
2. Add a new Schedule of Events to Appendix A for use after the final analysis has been 
conducted.
3. Add language on local clinical laboratory evaluations for efficacy and safety after
implementation of Amendment 07.
4. Clarify language regarding procedures for reporting product complaints or medication errors.
5. Clarify language about study conduct regarding the coronavirus disease 2019 (COVID-19)
pandemic.
6. Update the Management of Clinical Events section for ixazomib to reflect evolving data, 
including the addition that ixazomib should be discontinued if Stevens-Johnson syndrome
(SJS) occurs.
7. Incorporate changes from France-specific Protocol Amendments 01 and 05.
8. Update the terms of the Posttrial Access program.
9. Clarify the daratumumab infusion time period.
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CONFIDENTIAL
1.0
ADMINISTRATIVE 
1.1
Contacts 
A separate contact information list will be provided to each site. The names and contact 
information for the medical monitor and responsible medical officer are in the Study Manual.
Serious adverse event and pregnancy reporting information is presented in Section 10.2 and 
Section 10.5, as is information on reporting product complaints. See the Study Manual for more 
information.
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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 Conference on Harmonisation E6 Good Clinical Practice: Consolidated 
Guideline.
!
All applicable laws and regulations, including, without limitation, data privacy laws, clinical 
trial disclosure laws, and regulations.
SIGNATURES
The signature of the responsible Takeda medical officer (and other signatories, as applicable) can 
be found on the signature page.
Electronic Signatures may be found on the last page of this document.
Date
Date
Date
Property of Takeda: Fo Non-Commerc l Use Only and Subject to the Applicable Terms of Use
dance
ance
wing:
wing:
olidated
idate
a privac
privac
other sig
ther si
thihis doc
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PPD
PPD
PPD


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CONFIDENTIAL
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 Conference on Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events defined in Section 10.0 of this 
protocol.

Terms outlined in the Clinical Study Site Agreement.

Responsibilities of the Investigator (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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TABLE OF CONTENTS 
1.0
ADMINISTRATIVE.......................................................................................................3
1.1
Contacts.....................................................................................................................3
1.2
Approval....................................................................................................................4
2.0
STUDY SUMMARY ....................................................................................................11
3.0
STUDY REFERENCE INFORMATION ......................................................................14
3.1
Study-Related Responsibilities.................................................................................14
3.2
Principal Investigator/Coordinating Investigator ......................................................14
3.3
List of Abbreviations ...............................................................................................15
3.4
Definition of Terms .................................................................................................17
3.5
Corporate Identification...........................................................................................17
4.0
INTRODUCTION.........................................................................................................18
4.1
Background .............................................................................................................18
4.2
Ixazomib..................................................................................................................18
4.2.1
Approval of Ixazomib+Lenalidomide and Dexamethasone for Patients 
Previously Treated for MM................................................................................19
4.2.2
Other Ixazomib Clinical Development ...............................................................19
4.3
Daratumumab ..........................................................................................................20
4.3.1
Approval of Daratumumab for Patients Previously Treated for MM...................20
4.4
Rationale for the Proposed Study.............................................................................21
4.4.1
Rationale for an IDd Regimen............................................................................21
4.4.2
Rationale for Dose and Schedule........................................................................23
4.4.3
Rationale for Correlative Science/Biomarker Assessments.................................23
4.4.4
Rationale for PK Assessments............................................................................24
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................24
5.1
Objectives................................................................................................................24
5.1.1
Primary Objective ..............................................................................................24
5.1.2
Secondary Objectives.........................................................................................24
5.1.3
Exploratory Objectives.......................................................................................25
5.2
Endpoints.................................................................................................................25
5.2.1
Primary Endpoints .............................................................................................25
5.2.2
Secondary Endpoints..........................................................................................25
5.2.3
Exploratory Endpoints .......................................................................................26
6.0
STUDY DESIGN..........................................................................................................26
6.1
Overview of Study Design.......................................................................................26
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6.1.1
Study Population................................................................................................27
6.2
Number of Patients ..................................................................................................27
6.3
Duration of Study ....................................................................................................27
6.3.1
Duration of an Individual Patient’s Study Participation ......................................27
6.3.2
End of Study/Study Completion Definition and Planned Reporting....................28
6.3.3
Timeframes for Primary and Secondary Endpoints to Support Disclosures.........28
6.3.4
Total Study Duration..........................................................................................28
6.3.5
Posttrial Access..................................................................................................29
7.0
STUDY POPULATION................................................................................................29
7.1
Inclusion Criteria .....................................................................................................29
7.2
Exclusion Criteria ....................................................................................................30
8.0
STUDY THERAPY ......................................................................................................32
8.1
Overview.................................................................................................................32
8.2
Study Treatment Administration ..............................................................................32
8.2.1
Order of Study Treatment Administration ..........................................................33
8.2.2
Daratumumab ....................................................................................................34
8.2.3
Ixazomib............................................................................................................36
8.2.4
Dexamethasone..................................................................................................36
8.3
Dose Modification Guidelines..................................................................................37
8.3.1
Criteria for Beginning or Delaying a Subsequent Treatment Cycle.....................37
8.3.2
Ixazomib Treatment Modification......................................................................38
8.3.3
Daratumumab Treatment Modification...............................................................39
8.3.4
Dexamethasone Treatment Modification............................................................41
8.4
Excluded Concomitant Medications and Procedures ................................................42
8.5
Permitted Concomitant Medications and Procedures................................................42
8.6
Precautions and Restrictions ....................................................................................43
8.7
Management of Clinical Events ...............................................................................43
8.7.1
Ixazomib............................................................................................................43
8.7.2
Daratumumab ....................................................................................................46
8.7.3
Dexamethasone..................................................................................................48
8.8
Blinding and Unblinding..........................................................................................48
8.9
Description of Investigational Agents ......................................................................48
8.9.1
Ixazomib............................................................................................................48
8.9.2
Daratumumab ....................................................................................................49
8.9.3
Dexamethasone..................................................................................................50
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8.10
Other Protocol-Specified Materials ..........................................................................50
9.0
STUDY CONDUCT......................................................................................................50
9.1
Study Personnel and Organizations..........................................................................50
9.2
Arrangements for Recruitment of Patients................................................................50
9.3
Treatment Group Assignments.................................................................................51
9.4
Study Procedures.....................................................................................................51
9.4.1
Assessments During the Treatment Period .........................................................51
9.4.2
Assessments During the Follow-Up Periods: PFS and OS..................................52
9.4.3
Clinical Laboratory Evaluations .........................................................................53
9.4.4
Disease Assessment ...........................................................................................55
9.4.5
Biomarker, Pharmacodynamic, and PK Samples ................................................56
9.4.6
QOL Assessments..............................................................................................58
9.5
PK Measurements....................................................................................................58
9.6
Completion of Study Treatment (for Individual Patients) .........................................59
9.7
Discontinuation of Treatment With Study Drug Treatment and Patient 
Replacement ............................................................................................................59
9.8
Withdrawal of Patients From Study .........................................................................60
9.9
Study Compliance....................................................................................................60
9.10
Study Closure ..........................................................................................................60
10.0
ADVERSE EVENTS ....................................................................................................61
10.1
Definitions...............................................................................................................61
10.1.1 Pretreatment Event Definition............................................................................61
10.1.2 AE Definition ....................................................................................................61
10.1.3 SAE Definition ..................................................................................................61
10.2
Procedures for Recording and Reporting AEs and SAEs..........................................62
10.3
Monitoring of AEs and Period of Observation .........................................................64
10.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events.........64
10.5
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose) ................................................................................................................65
10.6
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities...........65
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................65
12.0
DATA HANDLING AND RECORDKEEPING............................................................66
12.1
eCRFs......................................................................................................................66
12.2
Record Retention .....................................................................................................67
13.0
STATISTICAL METHODS..........................................................................................67
13.1
Statistical and Analytical Plans ................................................................................67
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13.1.1 Analysis Sets......................................................................................................67
13.1.2 Analysis of Demographics and Other Baseline Characteristics ...........................68
13.1.3 Efficacy Analyses ..............................................................................................68
13.1.4 PK Analysis .......................................................................................................69
13.1.5 MRD Analysis ...................................................................................................69
13.1.6 Analyses of Immune Dynamics in Blood and Bone Marrow ..............................69
13.1.7 Analysis of CR+VGPR Rate and PFS in High-Risk Cytogenetic Populations.....69
13.1.8 Analysis of Patient-Reported Outcomes .............................................................69
13.1.9 Safety Analysis ..................................................................................................70
13.2
Interim Analysis and Criteria for Early Termination ................................................71
13.3
Determination of Sample Size..................................................................................71
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................72
14.1
Study-Site Monitoring Visits ...................................................................................72
14.2
Protocol Deviations..................................................................................................72
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................73
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................73
15.1
IRB and/or IEC Approval ........................................................................................73
15.2
Subject Information, Informed Consent, and Subject Authorization .........................74
15.3
Subject Confidentiality ............................................................................................75
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................75
15.4.1 Publication.........................................................................................................75
15.4.2 Clinical Trial Registration..................................................................................76
15.4.3 Clinical Trial Results Disclosure ........................................................................76
15.5
Insurance and Compensation for Injury....................................................................77
16.0
REFERENCES..............................................................................................................78
LIST OF IN-TEXT TABLES 
Table 6.a
Primary and Secondary Endpoints for Disclosures .............................................28
Table 8.a
Infusion Rates for Daratumumab IV Administration ..........................................35
Table 8.b
Dose Reduction Steps for Ixazomib ...................................................................38
Table 8.c
Ixazomib and Daratumumab Dose Modification for Hematologic Toxicities......38
Table 8.d
Ixazomib Dose Modification for Nonhematologic Toxicities..............................39
Table 8.e
Daratumumab-Related Toxicity Management ....................................................40
Table 9.a
Clinical Chemistry and Hematology Tests..........................................................53
Table 9.b 
Primary Specimen Collection Table ...................................................................58
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LIST OF IN-TEXT FIGURES
Figure 6.a
Study Schema ....................................................................................................27
Figure 8.a
Study Treatment Administration ........................................................................33
LIST OF APPENDICES
Appendix A
Schedule of Events.............................................................................................83
Appendix B
Responsibilities of the Investigator.....................................................................89
Appendix C
Investigator Consent to Use of Personal Information..........................................91
Appendix D
Eastern Cooperative Oncology Group Scale for Performance Status ..................92
Appendix E 
IMWG Uniform Response Criteria for MM .......................................................93
Appendix F
EORTC QLQ-C30 (version 3) ...........................................................................94
Appendix G
EORTC QLQ-MY20..........................................................................................96
Appendix H
Acceptable Methods of Contraception................................................................98
Appendix I
Schedule of Events (28-Day Cycle) Previous to Amendment 02.........................99
Appendix J
COVID-19 Trial Communication Letter from Janssen-Cilag  International NV 107
Appendix K
Amendment 07 Detailed Summary of Changes ................................................109
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2.0
STUDY SUMMARY
Name of Sponsor(s):
Takeda Development Center Americas, Inc
Compound:
Ixazomib (NINLARO)
Title of Protocol: A Phase 2, Open-Label Study of Ixazomib+Daratumumab+Dexamethasone (IDd) in Relapsed 
and/or Refractory Multiple Myeloma (RRMM) 
Study Number: C16047
Phase: 2
Primary Objective:

To evaluate the proportion of patients with a response of very good partial response (VGPR) or better to IDd 
treatment.
Secondary Objectives:

To measure progression-free survival (PFS), time to progression (TTP), and overall survival (OS).

To measure overall response rate (ORR), time to response (TTR), and duration of response (DOR).

To collect plasma concentration-time data for ixazomib to contribute to population pharmacokinetic (PK) 
analyses. 

To evaluate the safety/tolerability of IDd administered in a 28-day cycle.
Subject Population: Adult patients (aged ≥18 years) who have documented evidence of progressive multiple 
myeloma (MM), as defined by International Myeloma Working Group (IMWG) criteria (see Appendix E) [1-3], on or 
after their last regimen. All patients must have received between 1 to 3 prior therapies for MM. 
Number of Subjects:
Estimated total: 60
Number of Sites: 
Estimated total: 25 sites globally
Study Treatment Dosing: 
For the purposes of this protocol, study treatment regimen is defined as the combination of ixazomib, daratumumab, 
and dexamethasone. All cycles are approximately 28 days with treatment given until PD or unacceptable toxicity. 
(Full details on study treatment administration are in Section 8.2.) See diagram below for details.

Ixazomib will be administered at 4 mg orally on Days 1, 8, and 15 of each 28-day cycle. In Cycle 1 ixazomib will 
be given after the daratumumab infusion; in subsequent cycles, if there have been no Grade 3 or higher 
infusion-related reactions (IRRs) in the previous cycle, ixazomib can be given prior to or at approximately the 
same time as the premedications (see Section 8.2.3).

Daratumumab will be administered intravenously (IV) at 16 mg/kg (note pre- and postinfusion medications of 
antipyretics and oral antihistamines listed in Section 8.2.2): Daratumumab will be given on the following 
schedule:
–
Cycles 1 and 2: Days 1, 8, 15, and 22 (every week; total of 8 doses).
–
Cycles 3 to 6: Days 1 and 15 (every 2 weeks; total of 8 doses).
–
Cycles 7 and beyond: Day 1 (every 4 weeks). 

Dexamethasone will be given as 20 mg on Day 1, 2, 8, 9, 15, 16, 22, and 23 in each 28-day cycle, to achieve the 
standard total of 40 mg per week (2 doses of 20 mg per week). This schedule allows for dexamethasone to be 
given the day of (before) and the day after the daratumumab infusion on daratumumab dosing days. 
Dexamethasone should be given IV before the first daratumumab dose; but can be given IV or orally thereafter. 
The dose of dexamethasone may be reduced in some patients (see details in Section 8.2.4). 
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Abbreviations: Dara,daratumumab; Dex, dexamethasone; PD, progressive disease. 
Duration of Treatment:
All patients will receive study therapy until they experience 
progressive disease (PD), have an unacceptable toxicity, or 
withdraw consent, or when the study has completed or until 
the sponsor terminates the study.
Period of Evaluation:
The study will be considered complete approximately 1 
year after 50% of patients have died or experienced 
PD. The estimated timeframe is approximately 4 years 
after the first patient in (FPI).
Main Inclusion Criteria: 

Adult patients (aged ≥18 years) who have been diagnosed with MM according to IMWG criteria 

All patients must have measurable disease by at least 1 of the following measurements:
–
Serum M-protein ≥1 g/dL (≥10 g/L).
–
Urine M-protein ≥200 mg/24 hours.

All patients must have documented evidence of PD on or after their last regimen as defined by IMWG criteria. All 
patients must have received between 1 to 3 prior therapies for MM.

All patients must have achieved a response (partial response [PR] or better) to at least 1 prior therapy.

All patients must have an Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2.

All patients must have adequate hematologic, hepatic, and renal function. 
*Full details in Section 7.0.
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Main Criteria for Exclusion:
Patients meeting any of the following exclusion criteria are not to be enrolled in the study:

Patients have undergone prior allogenic bone marrow transplantation.

Patients have received prior ixazomib at any time or daratumumab or other anti-CD38 therapies except as part of 
initial therapy if this was stopped to move on to stem cell transplant (SCT) and the patient did not progress on 
anti-CD38 treatment.

Patients are refractory to bortezomib or carfilzomib at the last exposure before this study (defined as patient 
having PD while receiving bortezomib or carfilzomib therapy or within 60 days after ending bortezomib therapy).

Patients planning to undergo a SCT prior to PD on this study (ie, these patients should not be enrolled in order to 
reduce disease burden prior to transplant).

Patients with Grade 2 or higher residual toxicities from prior therapy (including Grade 2 or higher peripheral 
neuropathy or any grade neuropathy with pain; excluding alopecia).

Patient has any concurrent medical condition or disease that is likely to interfere with study procedures, results, or 
assessment of safety or toxicity or that in the opinion of the investigator would constitute a hazard for 
participating in this study.
*Full details in Section 7.0.
Endpoints and Assessments: 
The primary endpoint is response of VGPR or better as assessed by the investigator. Additionally, efficacy will be 
assessed by PFS, TTP, ORR, TTR, DOR, and OS. Patients will be assessed for disease response by the investigator 
according to the IMWG criteria. 
Safety assessments will be evaluated through the incidence and severity of adverse events (AEs) and changes in 
clinical hematology and chemistry laboratory test results.
Statistical Considerations:
This phase 2 study is designed to evaluate the safety and efficacy of IDd. The total sample size will be approximately 
60 patients. 
Two interim analyses and a final analysis will be conducted. The primary endpoint and all response-related endpoints 
will be analyzed for the response-evaluable population; other endpoints and assessments (PFS, TTP, OS, safety) will 
be analyzed for the safety population. The definition of the response-evaluable population is patients who receive at 
least 1 dose of ixazomib, have measurable disease at baseline or screening, and have at least 1 postbaseline response 
assessment.
The first interim analysis will be conducted 6 months after the last patient is enrolled. The second interim analysis will 
be conducted after 50% of the PFS events have occurred. The final analysis will be conducted 1 year after 50% of the 
PFS events have occurred. No other formal statistical analyses are planned.
Sample Size Justification:
The sample size is calculated using binomial exact test for single proportion based on the rate of VGPR or better of the 
IDd treatment regimen. Statistical assumption was based on observed CR+VGPR rates in clinical studies with 
ixazomib [4], bortezomib [5], and daratumumab [6].
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3.0
STUDY REFERENCE INFORMATION
3.1
Study-Related Responsibilities 
The sponsor or designee will perform all study-related activities with the exception of those 
identified in the Clinical Study Supplier List or equivalent. The identified vendors in the template 
for specific study-related activities will perform these activities in full or in partnership with the 
sponsor.
3.2
Principal Investigator/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 as well as study participation. The Signatory Coordinating Investigator will be required to 
review and sign the clinical study report and by doing so agrees that it accurately describes the 
results of the study.
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3.3
List of Abbreviations 
AE
adverse event
ADCC
antibody-dependent cell mediated cytotoxicity
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
BMA
bone marrow aspirate
CDC
complement-dependent cytotoxicity
CFR
Code of Federal Regulations
COPD
chronic obstructive pulmonary disease
COVID-19
coronavirus disease 2019
CR
complete response
CRO
contract research organization
CT
computed tomography
DOR
duration of response
DSMB
Drug Safety Monitoring Board
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EMA
European Medicines Agency
EORTC QLQ-C30
European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire–
Core 30
EORTC QLQ-MY20
European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire–
Multiple Myeloma module
EOT
end of treatment
EU
European Union
FDA
Food and Drug Administration
FEV1
G-CSF
forced expiratory volume in 1 second
granulocyte colony-stimulating factor
FPI
first patient in
GCP
Good Clinical Practice
HR
hazard ratio
IB
investigator’s brochure
ICH
International Conference on Harmonisation
ICF
informed consent form
IDd
ixazomib+daratumumab+dexamethasone
IEC
independent ethics committee
IMiD
immunomodulatory drug
IMWG
International Myeloma Working Group
IRB
institutional review board
IRR
infusion-related reaction
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IV
intravenous(ly)
LenDex
lenalidomide+dexamethasone
mAb
monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
MM
multiple myeloma
MRD
minimal residual disease
MRI
magnetic resonance imaging
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NDMM
newly diagnosed multiple myeloma
NGF
next-generation flow cytometry 
NGS
next-generation sequencing
NSAIDs
nonsteroidal anti-inflammatory drugs
ORR
overall response rate
OS
overall survival
PD
progressive disease, progression of disease, disease progression
PET
positron emission tomography
PFS
progression-free survival
PI
proteasome inhibitor
PK
pharmacokinetic(s)
PR
partial response
PTA
posttrial access
QOL
quality of life
RBC
red blood cell
RRAL
relapsed and/or refractory systemic light-chain amyloidosis
RRMM
relapsed and/or refractory multiple myeloma
SAE
serious adverse event
SAP
statistical analysis plan
SCT
stem cell transplant
SJS
Stevens-Johnson syndrome
SPEP
serum protein electrophoresis
SUSARs
suspected unexpected serious adverse reactions
TEAEs
treatment-emergent adverse events
TEN
toxic epidermal necrolysis
TMA
thrombotic microangiopathy
TTP
time to progression
TTR
time to response
ULN
upper limit of normal range
UPEP
urine protein electrophoresis
US
United States
Vd
bortezomib+dexamethasone
VGPR
very good partial response
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WBC
white blood cell
WHO
World Health Organization
3.4
Definition of Terms
prior therapy
two or more cycles of therapy given as a treatment plan for MM (eg, a single-agent or 
combination therapy or a sequence of planned treatments, such as induction therapy 
followed by ASCT and then consolidation and/or maintenance therapy) [7]. Typically 
each prior therapy is separated by PD.
3.5
Corporate Identification 
TDC Europe
Takeda Development Centre Europe Ltd 
Takeda
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 genetically complex disease that is characterized by an abnormal 
clonal plasma cell infiltration that accumulates in the bone marrow [8]. Clinical complications 
include anemia, renal insufficiency, bone destruction, hypercalcemia, recurrent infections, 
cytopenias, bone pain/fractures and hyperviscosity syndrome [9]. Prognosis in myeloma is related 
to both patient factors and tumor variables at the time of diagnosis. Patient-related factors include 
age, performance status, and renal function; tumor factors include disease stage, as well as light 
chain and IgA disease [10-13]. 
Treatment of relapsed and/or refractory MM (RRMM) continues to present a therapeutic 
challenge. Although the prognosis for MM has improved over the past 2 decades because of the 
introduction of new and more effective therapies, it is still a fatal disease in nearly all cases. 
Despite the current therapeutic options, RRMM is characterized by frequent relapses; thus there is 
a need to sequence available therapy through multiple relapses. Such strategies involve 
consideration for the characteristics of prior therapy, including both depth and duration of 
response, tolerability of therapy, as well as combining different agents in an attempt to achieve 
long-term disease control [14]. As per the International Myeloma Working Group (IMWG) [3], 
different therapeutic approaches may be utilized according to the benefit/risk of each regimen and 
the patient’s age, disease status, and quality of life (QOL). 
Treatment of patients with MM continues to evolve. Proteasome inhibitors (PIs) form a backbone 
of current treatment strategies starting with the first-in-class PI, VELCADE (bortezomib) [15]. 
VELCADE is approved globally for patients with MM and is frequently used as a part of a 
patient’s initial therapy. Ixazomib was designed to build upon the attributes of VELCADE and 
improve the safety profile while also providing an option for oral administration. Ixazomib is now 
approved (under the brand name NINLARO®) in combination with lenalidomide+dexamethasone 
(LenDex) for the treatment of patients with MM who have received at least 1 prior therapy [16,17]. 
Monoclonal antibodies (mAbs) are a recent addition to MM therapies [18]. Daratumumab is an 
anti-CD38 mAb that has demonstrated substantial activity and good tolerability as monotherapy, 
as well as in combination with current standard treatments in RRMM. Daratumumab was the first 
anti-CD38 mAb approved (under the brand name DARZALEX®) for patients with RRMM 
[19,20]. Thus, this current study aims to examine the efficacy and safety of the 
ixazomib+daratumumab+dexamethasone (IDd) treatment regimen in a patient population 
comparable to that which was evaluated in pivotal trials with ixazomib and daratumumab.
4.2
Ixazomib
Ixazomib, an oral inhibitor of the 20S proteasome, is under development for the treatment of MM, 
plasma cell dyscrasias, amyloidosis, lymphoma, nonhematologic malignancies, and lupus 
nephritis. Inhibition of the 20S proteasome has been validated as a therapeutic target for the 
treatment of malignancies using VELCADE (bortezomib) for Injection, Takeda Development Center 
Americas, Inc’s first-in-class PI [21]. 
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Ixazomib (MLN2238) refers to the biologically active boronic acid form of the drug substance. 
The drug substance is administered as a stable citrate ester, designated as ixazomib citrate 
(MLN9708). Under physiological conditions, ixazomib citrate rapidly hydrolyzes to the 
biologically active boronic acid, ixazomib. Ixazomib is a peptide boronic acid that is structurally 
different from bortezomib. Detailed information regarding the nonclinical pharmacology and 
toxicology of ixazomib can be found in the ixazomib Investigator’s Brochure (IB) as well as in the 
NINLARO prescribing information.
4.2.1
Approval of Ixazomib+Lenalidomide and Dexamethasone for Patients Previously 
Treated for MM
Ixazomib was approved (under the brand name NINLARO) in combination with LenDex for the 
treatment of patients with MM who have received at least 1 prior therapy by the United States (US) 
Food and Drug Administration (FDA) in November 2015 [4,17]. Ixazomib is now approved in 
over 45 countries including Canada, the European Union (EU), and Japan with further applications 
for marketing authorization currently under review globally.
The efficacy of ixazomib+LenDex was evaluated in a global, randomized, double-blind, 
placebo-controlled, phase 3 study (C16010) in patients with RRMM who had received at least 
1 prior therapy [4]. The primary endpoint of progression-free survival (PFS) was met at the 
primary analysis, with a statistically significant and clinically meaningful PFS benefit for patients 
receiving ixazomib+LenDex versus placebo+LenDex (hazard ratio [HR]=0.742, p=0.012; median 
PFS 20.6 vs 14.7 months). The PFS benefit in the ixazomib regimen was supported by 
improvements versus the placebo regimen in other efficacy data, such as response rates, duration 
of response (DOR), and time to progression (TTP). After a median follow-up of approximately 23 
months, the median overall survival (OS) had not been reached in either regimen. The rates of 
serious adverse events (SAEs) and rates of on-study deaths were similar in the 2 regimens (47% 
with ixazomib, 49% with placebo; 4% and 6%, respectively); ≥Grade 3 adverse events (AEs) 
occurred in 74% and 69% of the patients, respectively, largely driven by increased 
thrombocytopenia in the ixazomib+LenDex regimen. The most common adverse reactions 
(≥20%) are diarrhea, constipation, thrombocytopenia, peripheral neuropathy, nausea, peripheral 
edema, vomiting, and back pain. Overall, the addition of ixazomib to LenDex did not add 
substantial toxicity [17].
The PFS benefit and safety profile seen in global Study C16010 was corroborated in the
China Continuation study, a double-blind, placebo-controlled study of similar design with the 
same inclusion criteria, stratification factors, and stringency of execution. As a regional expansion 
study, all patients were enrolled in China. In addition to the PFS benefit, an OS benefit in favor of 
the ixazomib+LenDex group was observed at the final analysis [22].
4.2.2
Other Ixazomib Clinical Development
Ixazomib has been tested as an intravenous (IV) and an oral formulation (during the early 
development of ixazomib); however, only the oral formulation is currently being developed for 
commercialization. The approved dosing schedule is a weekly dosing schedule, where ixazomib is 
given on Days 1, 8, and 15 of a 28-day cycle. Clinical development has focused on MM (newly 
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diagnosed MM [NDMM] and RRMM) and relapsed and/or refractory systemic light-chain 
amyloidosis (RRAL), with additional studies in the nononcology setting including but not limited 
to lupus nephritis and graft-versus-host disease. 
The safety profile indicates that ixazomib administration can lead to AEs that are generally 
manageable with appropriate monitoring for early recognition of adverse effects, dose 
modification, and supportive care. The most common treatment-emergent AEs (TEAEs) include 
nausea, vomiting, diarrhea, rash, and thrombocytopenia. Additionally, the AEs in the studies 
where ixazomib is given in combination with standard agents are consistent with the safety profile 
of the individual agents in the combination regimen (eg, myelosuppression is common in regimens 
containing melphalan, and rash is common in regimens containing lenalidomide). While some of 
these potential toxicities may be severe, they can be managed by clinical monitoring for early 
recognition of adverse effects and standard medical intervention (as found in the ixazomib IB). 
Across the program, ixazomib appears to show signs of antitumor activity as evidenced by at least 
50% reduction in disease burden in some patients, including patients that have been heavily 
pretreated as well as those with NDMM, and prolonging stabilization of the underlying disease in 
other patients across all ongoing studies. High quality responses, including achievement of 
minimal residual disease (MRD) negativity, has also been reported [23-25]. Although additional 
data are needed to establish the clinical benefit of this drug across additional indications, the 
emerging data support the continued development of ixazomib (see the ixazomib IB). Late-stage 
ixazomib development is ongoing in patients with NDMM, RRMM, and RRAL (Studies C16014 
[NCT01850524], C16019 [NCT02181413], C16021 [NCT02312258], C16029 [NCT03170882], 
and C16011 [NCT01659658]).
4.3
Daratumumab
Daratumumab is a human IgG1 anti-CD38 mAb that binds with high affinity to a unique epitope 
on CD38, a transmembrane glycoprotein. CD38 is highly and uniformly expressed on all MM 
cells. In binding to CD38, daratumumab inhibits the growth of CD38-expressing tumor cells by 
inducing apoptosis directly through Fc mediated cross-linking as well as by immune-mediated 
tumor cell lysis through complement-dependent cytotoxicity (CDC), antibody-dependent cell 
mediated cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis. For additional 
information regarding the pharmacokinetics (PK), pharmacodynamics, (pre)clinical experience, 
and safety profile of daratumumab, refer to the prescribing information [19,20]. 
4.3.1
Approval of Daratumumab for Patients Previously Treated for MM
Daratumumab received “breakthrough therapy” designation for RRMM by the US FDA in May 
2013 [26]. In November 2015, the FDA granted accelerated approval for daratumumab in 
monotherapy to treat patients with MM who have received at least 3 prior treatments including a PI 
and an immunomodulatory drug (IMiD) or who are double-refractory to a PI and an IMiD. In May 
2016 the European Medicines Agency (EMA) approved daratumumab monotherapy in Europe to 
treat patients with MM whose prior therapy included a PI and an IMiD and who have demonstrated 
PD on the last therapy. In 2017, both the FDA and the EMA approved daratumumab in 
combination with LenDex or bortezomib+dexamethasone (Vd) for the treatment of patients with 
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MM after at least 1 prior therapy. Daratumumab is also approved by the FDA in combination with 
pomalidomide and dexamethasone for the treatment of patients with MM who have received at 
least 2 prior therapies including lenalidomide and a PI. The approved dose and schedule when 
given in a 4-week treatment cycle is daratumumab 16 mg/kg IV every week for 8 doses, then every 
2 weeks for 8 doses, then every 4 weeks onwards [19,20]. 
In heavily pretreated patients with RRMM, single-agent daratumumab was associated with an 
overall response rate (ORR) of 31.1% based on the results of 2 open-label single-arm studies 
[20,27,28]. The efficacy of daratumumab in combination with standard MM regimens was 
evaluated in 2 global, randomized, phase 3 studies (POLLUX: LenDex±daratumumab and 
CASTOR: Vd±daratumumab) in patients with RRMM who had received at least 1 prior therapy. 
In both studies the primary endpoint was met. Of particular relevance to this study, the rate of PFS 
was significantly higher in the daratumumab group (daratumumab+Vd) than in the control group 
(Vd) as reported in the CASTOR study; the 12-month rate of PFS was 60.7% in the daratumumab 
group versus 26.9% in the control group. After a median follow-up period of approximately 
7 months, the median PFS was not reached in the daratumumab+Vd group compared with 
7.2 months in the Vd group (HR: 0.39; P<0.001) [15]. The most frequently reported adverse 
reactions (incidence ≥20%) in clinical trials were infusion reactions, neutropenia, 
thrombocytopenia, fatigue, nausea, diarrhea, constipation, vomiting, muscle spasms, arthralgia, 
back pain, pyrexia, chills, dizziness, insomnia, cough, dyspnea, peripheral edema, peripheral 
sensory neuropathy, and upper respiratory tract infection [20]. Daratumumab use is associated 
with special considerations, namely infusion-related reactions (IRRs) but also blood typing 
interference and interference with complete response (CR) assessment. With daratumumab, IRRs 
have been reported in about half of patients receiving daratumumab: 95% of these were seen at the 
first dose. Typically the IRRs involve the upper respiratory tract and include rhinitis, cough, 
wheeze, bronchospasm, laryngospasm, and chest pain. More rarely they include rash, fever, and 
nausea [20,29]. For IRRs of any grade/severity, the daratumumab infusion should be immediately 
interrupted and medical management instituted as needed. Management of infusion reactions may 
further require reduction in the rate of infusion. Permanently discontinue daratumumab therapy for 
life-threatening (Grade 4) reactions. For further guidance see the DARZALEX prescribing 
information [20] as well as Section 8.3.3 of this protocol. The clinical development of 
daratumumab is currently ongoing (ir.genmab.com/releasedetail.cfm?releaseid=1026834, 
GenMab company announcement, accessed 19 September 2017).
4.4
Rationale for the Proposed Study
4.4.1
Rationale for an IDd Regimen
Although the prognosis for MM has improved over the past 2 decades because of the introduction 
of new and more effective therapies, it is still a fatal disease in nearly all cases and new treatment 
options are needed.
Preclinical work has demonstrated that the antimyeloma activity of daratumumab can be 
potentiated by combination with a PI (eg, bortezomib) and IMiD (eg, lenalidomide), even in 
patients refractory to a PI and IMiD. PIs may enhance the therapeutic activity of daratumumab by 
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enhancing the susceptibility of myeloma cells to natural killer cell-mediated killing, a key 
mechanism of antibody-mediated lysis of MM cells [30-33]. 
Ixazomib and daratumumab have both been investigated in patients with RRMM, including the 
population to be enrolled in this study. Ixazomib is an oral PI approved (under the brand name 
NINLARO) for use in combination with LenDex in patients with MM who have received at least 1 
prior therapy [16,17]. Daratumumab is a human IgG1mAb against CD38. Daratumumab is 
approved (under the brand name DARZALEX) for patients with MM who have received at least 1 
prior therapy (in combination with either Vd or LenDex; US and EU), in addition to approvals in 
patients who have been more heavily pretreated [19,20].
The rationale to investigate the potential of the IDd regimen is multifactorial:

Bortezomib and lenalidomide have important antimyeloma activity in NDMM; however, not 
all patients respond. Even for patients who do respond, the natural course of MM is still 
characterized by multiple relapses which in many patients eventually are hampered by the 
development of drug resistance [34]. Therefore, there is an ongoing need to expand the active 
treatment options, prolong therapy with considerations to limiting toxicities, and improve 
patients’ QOL, as well as provide treatments for patients who have developed drug resistance. 

Despite the positive impact of bortezomib for the treatment of MM, its use in clinical practice 
is limited by significant side effects, constraining administration schedules, and the 
development of drug resistance [34]. Bortezomib has a high incidence of peripheral 
neuropathy and requires injectable administration (either IV or subcutaneous administration). 
The concern regarding peripheral neuropathy results in limited treatment duration (approved 
duration 8 cycles) and potential premature treatment termination. Ixazomib is the only 
approved oral PI and has a more benign side effect profile compared to other PIs, including 
bortezomib, allowing for prolonged treatment until progression. Therefore, it is possible that 
ixazomib in combination with daratumumab and dexamethasone could provide patients with a 
treatment option that is a safer and more convenient regimen, potentially resulting in longer 
treatment duration and tumor control.

Daratumumab has emerged as a very active and safe agent in MM, and therefore the IDd 
regimen could provide a PI combination that is lenalidomide sparing. This could be of 
particular relevance in patients treated with a lenalidomide-based combination regimen, 
namely since the recent approval of lenalidomide for NDMM and as maintenance therapy 
[35,36]. The increased exposure to lenalidomide in earlier lines of treatment necessitates 
options for PI-based therapy for patients who have relapsed while receiving, or who are 
refractory to, lenalidomide.

New approaches are needed for patients with RRMM. Combining agents of different classes 
that have nonoverlapping and synergistic mechanisms of action can be a successful strategy to 
improve clinical outcomes for patients with MM [30]. As noted, ixazomib and daratumumab 
have different and nonoverlapping mechanisms of action. Ixazomib, as with the first-in-class 
PI bortezomib, may enhance the therapeutic effect of daratumumab by sensitizing tumor cells 
for antibody-mediated lysis [33]. 
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!
Triplet regimens are recommended for patients with RRMM, given the regimens’ contribution 
to improvements in PFS [14,37,38]. The IDd regimen could offer patients an active triplet 
regimen with the extended treatment duration of PI therapy (ixazomib) that is non–
lenalidomide-containing, as many patients discontinue lenalidomide therapy and are refractory 
to lenalidomide-based regimens as frontline therapy. 
This phase 2 design will allow the assessment of efficacy and safety of the IDd regimen, given 
until progression, within the context of other available treatment options in RRMM. The primary 
endpoint will be the rate of very good partial response (VGPR) or better. Based on safety results 
from studies of both agents when given in combination regimens, it is expected that the safety 
profile will be consistent with that of the individual agents in the combination regimen (eg, IRR is 
common with daratumumab and rash is common with ixazomib) [16,17,19,20]. While some of the 
potential toxicities with either agent may be severe, they can be managed by clinical monitoring 
for early recognition of adverse effects and standard medical intervention. An internal interim 
safety review will be conducted early in the proposed trial given ixazomib and daratumumab have 
not been combined previously (see Section 13.2 for more details).
4.4.2
Rationale for Dose and Schedule
The dose and schedule for both ixazomib and daratumumab are the ones approved for patients with 
RRMM. Ixazomib will be given at 4 mg by mouth weekly on Days 1, 8, and 15 in a 28-day cycle. 
With a 28-day cycle (4-week treatment cycle), daratumumab will be given at a dose of 16 mg/kg 
IV every week for 8 doses, then every 2 weeks for 8 doses, then every 4 weeks onwards. 
Dexamethasone is part of the anti-MM background regimen, but in this combination consideration 
needs to be made for the management of daratumumab- induced IRR. Therefore, dexamethasone 
will be given weekly in split doses, ie, 20 mg the day before and after each daratumumab IV 
infusion. For patient consistency and aid in compliance, the same dexamethasone schedule (2 
sequential days) will be followed even on non-daratumumab infusion weeks [20].
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4.4.4
Rationale for PK Assessments
In order to characterize the PK of ixazomib in combination with daratumumab and 
dexamethasone, an adequate number of sparse PK samples will be collected in Cycles 1 to 5 of the 
study. The PK data collected in this study will contribute to population PK analyses for ixazomib 
and may also be used for exposure-response analyses. 
5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objective
!
To evaluate the proportion of patients with a response of VGPR or better to IDd treatment.
5.1.2
Secondary Objectives
The secondary objectives are:
!
To measure PFS, TTP, and OS.
!
To measure ORR, time to response (TTR), and DOR.
!
To collect plasma concentration-time data for ixazomib to contribute to population PK 
analyses. 
!
To evaluate the safety/tolerability of IDd administered in a 28-day cycle.
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5.1.3
Exploratory Objectives
5.2
Endpoints
5.2.1
Primary Endpoints
The primary endpoint is the rate of VGPR or better, as evaluated by the investigator according to 
IMWG criteria, in patients that are response-evaluable (see Appendix E) [1-3].
5.2.2
Secondary Endpoints
The secondary endpoints are:
!
PFS, defined as the time from the date of first dose of any study drug treatment to the date of 
first documentation of progressive disease (PD)-based IMWG criteria as evaluated by
investigator, or death due to any cause, whichever occurs first [1-3]. 
!
TTP, defined as the time from the date of first dose of any study drug treatment to the date of 
first documented evidence of PD.
!
OS, measured as the time from the date of first dose of any study drug treatment to the date of 
death.
!
ORR (defined as CR, VGPR, plus partial response [PR]; per IMWG criteria) during or after the 
study treatment, but before subsequent therapy or PD.
!
TTR, defined as the time from the date of first dose of any study drug treatment to the date of 
first documented PR or better.
!
DOR, measured as the time from the date of first documentation of PR or better to the date of 
first documented progression among those patients that responded.
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5.2.3
Exploratory Endpoints
6.0
STUDY DESIGN
6.1
Overview of Study Design
This is a prospective, open-label, multicenter, phase 2 study to evaluate the efficacy and safety of 
oral ixazomib in combination with daratumumab and dexamethasone in adult patients with MM 
who have received at least 1 prior therapy. It is expected that approximately 60 patients will be 
enrolled. The study design is illustrated in Figure 6.a.
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Figure 6.a
Study Schema
Abbreviations: Dara, daratumumab; Dex, dexamethasone.
(a) Patients must not have received prior daratumumab or other anti-CD38 therapies except as part of initial therapy if 
this was stopped to move on to SCT and the patient did not progress on anti-CD38 treatment.
(b) Note that treatment discontinuation applies only to discontinuation of the full study treatment regimen (ixazomib, 
daratumumab, and dexamethasone). For modifications of individual study drugs, see Section 8.3.
6.1.1
Study Population
The patient population will consist of adult patients who have been diagnosed with MM [1,2]. All 
patients must have documented evidence of PD, as defined by IMWG criteria (see Appendix E), 
on or after their last regimen [1-3]. All patients must have received between 1 to 3 prior therapies 
for MM. See Section 7.1 and Section 7.2 for eligibility criteria details.
6.2
Number of Patients
The expected enrollment is approximately 60 patients.
6.3
Duration of Study
6.3.1
Duration of an Individual Patient’s Study Participation
All patients will receive study therapy until they experience PD, have an unacceptable toxicity, 
withdraw consent, the study has completed, or until the sponsor terminates the study.
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6.3.2
End of Study/Study Completion Definition and Planned Reporting
The study will be completed approximately 1 year after 50% of patients have died or experienced 
PD. The estimated timeframe is approximately 4 years after first patient in (FPI). 
6.3.3
Timeframes for Primary and Secondary Endpoints to Support Disclosures
Refer to Table 6.a for disclosure information for all primary and secondary endpoints.
Table 6.a
Primary and Secondary Endpoints for Disclosures
Endpoint
Definition
Maximum Time 
Frame*
Primary: 
Rate of VGPR or better
Response of VGPR or better as evaluated by the investigator 
according to IMWG criteria [1-3].
Up to 3 years
Secondary: PFS
The time from first study drug treatment dose to the first 
occurrence of confirmed PD, as evaluated by an Investigator, 
according to IMWG criteria [49], or death from any cause, 
whichever occurs first.
Up to 5 years
Secondary: TTP
The time from first study drug treatment dose to first 
documentation of PD.
Up to 5 years
Secondary: OS
The time from first study drug treatment dose to death from 
any cause.
Up to 5 years
Secondary: ORR
PR, VGPR, or CR, as evaluated by the investigator according 
to IMWG criteria.
Up to 5 years
Secondary: TTR
The time from first study drug treatment dose to the first 
documentation of PR or better.
Up to 5 years
Secondary: DOR
The time from the first documentation of PR or better to first 
documentation of PD.
Up to 5 years
Abbreviations: DOR, duration of response; ORR, overall response rate; OS, overall survival; PFS, progression-free 
survival; TTP, time to progression; TTR, time to response.
*Some endpoints are event-driven and timing may shift.
6.3.4
Total Study Duration
It is anticipated that this study will last for approximately 4 years after FPI. However, the study 
duration is dependent on rate of accrual and of maturation of the different endpoints. 
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6.3.5
Posttrial Access
At the conclusion or termination of the study, participants still remaining on ixazomib and/or 
daratumumab will be given the opportunity to participate in the optional ixazomib (NINLARO) 
posttrial access (PTA) program in order to continue receiving ixazomib and/or daratumumab if, in 
the opinion of the investigator and confirmed by the sponsor, the patient continues to receive 
clinical benefit from ixazomib and/or daratumumab. This is a voluntary program. Alternatively, 
investigators have the option of transferring their patients to standard-of-care treatment or treating 
their patients outside of the PTA program. 
Duration of Posttrial Access
Participants in the PTA program will be offered ixazomib (NINLARO) until they no longer benefit 
from ixazomib, the benefit-risk no longer favors the individual, and/or ixazomib is commercially 
available for the indication under study in the participants’ market, and/or the sponsor deems the 
PTA program is no longer viable. The PTA program may also be terminated in a country or 
geographical region where the marketing authorization has been rejected, the development of 
ixazomib has been suspended or stopped by the sponsor, or where ixazomib can no longer be 
supplied.
7.0
STUDY POPULATION
7.1
Inclusion Criteria
Each patient must meet all of the following inclusion criteria to be enrolled in the study:

Adult patients (aged ≥18 years) who have been diagnosed with MM according to IMWG 
criteria [1-3].

All patients must have measurable disease by at least 1 of the following measurements:
–
Serum M-protein ≥1 g/dL (≥10 g/L).
–
Urine M-protein ≥200 mg/24 hours.

All patients must have documented evidence of PD on or after their last regimen as defined by 
IMWG criteria (see Appendix E) [1-3]. All patients must have received between 1 to 3 prior 
therapies for MM (a prior therapy is defined as 2 or more cycles of therapy given as a treatment 
plan for MM [eg, a single-agent or combination therapy or a sequence of planned treatments 
such as induction therapy followed by autologous SCT and then consolidation and/or 
maintenance therapy]). 

All patients must have achieved a response (PR or better) to at least 1 prior therapy.

All patients must have an Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2.

All patients must meet the following laboratory criteria:
–
Absolute neutrophil count (ANC) ≥1000/mm3. 
–
Platelet count ≥75,000/mm3.
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–
Total bilirubin ≤1.5 x the upper limit of the normal range (ULN) (except for Gilbert 
syndrome: direct bilirubin ≤2 x ULN).
–
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 x ULN.
–
Calculated creatinine clearance ≥50 mL/min.

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 use effective contraceptive measures during 
and for 90 days following treatment. Advise women using hormonal contraceptives to also 
use a barrier method of contraception (see Appendix H for details). For women of 
childbearing potential, a pregnancy test must be negative before the first dose of study 
treatment is administered.

Male patients, even if surgically sterilized (ie, status postvasectomy), who:
–
Agree to use effective contraceptive measures during and for 90 days following treatment 
(see Appendix H for details). 

Voluntary written consent must be given before performance of any study-related procedure 
not part of standard medical care, with the understanding that consent may be withdrawn by 
the patient at any time without prejudice to future medical care.

Patient is willing and able to adhere to the study visit schedule and other protocol 
requirements.
7.2
Exclusion Criteria
Patients meeting any of the following exclusion criteria are not to be enrolled in the study:

Patients have undergone prior allogenic bone marrow transplantation.

Patients have received prior ixazomib at any time or daratumumab or other anti-CD38 
therapies, except as part of initial therapy if this was stopped to move on to SCT and the patient 
did not progress on anti-CD38 treatment.

Patients are refractory to bortezomib or carfilzomib at the last exposure before this study 
(defined as patient having PD while receiving bortezomib or carfilzomib therapy or within 
60 days after ending bortezomib or carfilzomib therapy).

Patients planning to undergo SCT prior to PD on this study (ie, these patients should not be 
enrolled in order to reduce disease burden prior to transplant).

Patients receiving systemic treatment with strong CYP3A inducers (rifampin, rifapentine, 
rifabutin, carbamazepine, phenytoin, phenobarbital, St. John's wort) within 14 days before 
randomization. 
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
Patient has received autologous SCT within 12 weeks before the date of study treatment.

Patient has received an investigational drug (including investigational vaccines) within 
4 weeks before study treatment (except for investigational antimyeloma agents, which cannot 
be taken within 2 weeks prior or 5 PK half-lives of the treatment, whichever is longer, before 
the date of study treatment). The only exception is emergency use of a short course of 
corticosteroids (equivalent of dexamethasone 40 mg/day for a maximum 4 days) before 
treatment.

Patients with known chronic obstructive pulmonary disease (COPD) with a forced expiratory 
volume in 1 second (FEV1) <50% of predicted normal. Note: FEV1 testing is required for 
subjects suspected of having COPD and subjects must be excluded if FEV1 is <50% of 
predicted normal. 
–
Patients with Grade 2 or higher residual toxicities from prior therapy (including Grade 2 or 
higher peripheral neuropathy or any grade neuropathy with pain; excluding alopecia). This 
includes recovery from any major surgery. Note: Subjects with planned surgical 
procedures to be conducted under local anesthesia may participate. Kyphoplasty or 
vertebroplasty are not considered major surgery. 

Patients with known allergy to any of the study medications, their analogues, their excipients, 
mAbs or human proteins or known sensitivity to mammalian-derived products. 

Patient has uncontrolled clinically significant cardiac disease, including myocardial infarction 
within 6 months before date of study entry or unstable or uncontrolled angina, congestive heart 
failure, New York Heart Association (NYHA) Class III-IV, uncontrolled cardiac arrhythmia 
(Grade 2 or higher).

Patients with ongoing or active systemic infection requiring IV medical management; patients 
with known HIV-RNA positivity; patients with hepatitis B virus (HBV) surface antigen or core 
antibody positivity; and patients with known hepatitis C virus-RNA positivity. Patients who 
have positive hepatitis C antibody can be enrolled but must have hepatitis C virus-RNA 
negativity.
Note: Patients who are already enrolled at the time of Amendment 02 should have local HBV 
testing performed as soon as possible for HBV surface antigen, e antigen, core antibody, and 
DNA. If any of these tests is positive, consult a physician with expertise in managing HBV for 
guidance regarding stopping daratumumab, starting HBV antiviral therapy, and remaining on 
study [50,51]. See Sections 8.3.3.2, 8.7.2, 9.4.3.1, and Appendix A for more information. 

Patient has any concurrent medical condition or disease that is likely to interfere with study 
procedures, results, or assessment of safety or toxicity or that in the opinion of the investigator 
would constitute a hazard for participating in this study.

Patients diagnosed or treated for another malignancy within 2 years before randomization or 
previously diagnosed with another malignancy and have any evidence of residual disease. 
Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if 
they have undergone complete resection.
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
Patient is pregnant.
8.0
STUDY THERAPY
8.1
Overview
All protocol-specific criteria for administration of study therapy must be met and documented 
before drug administration. Study therapy will be administered only to eligible patients under the 
supervision of the investigator or identified subinvestigator(s). Daratumumab should be 
administered by a healthcare professional, with immediate access to emergency equipment and 
appropriate medical support to manage IRRs if they occur. Refer to DARZALEX prescribing 
information [20].
Patients should be monitored for toxicity as necessary and doses of the appropriate study therapy 
should be modified as needed to accommodate patient tolerance to treatment; this may include 
symptomatic treatment, dose holds, and adjustments of the dose (see Section 8.3).
Each AE should be attributed to a specific drug (ie, ixazomib, daratumumab, or dexamethasone), if 
possible, so that dose modifications can be made accordingly. Only 1 dose modification per cycle 
will be performed for a given agent when toxicity is suspected to be related primarily to that agent. 
Reduction, including discontinuation, of 1 agent and not the other is appropriate if the toxicity is 
suspected to be related primarily to that 1 agent. No dose increases of any agent are allowed. No 
daratumumab dose reductions are permitted (see Section 8.3.3 for permitted modifications).
The start of a cycle is defined as the start of either daratumumab or ixazomib. If both daratumumab 
and ixazomib are held, then this should be reported as a cycle delay. 
Every effort should be made to follow the planned dosing schedule; however, occasional changes 
are allowable for holidays, vacations, and other administrative reasons or for a longer window 
after discussion with the Takeda project clinician or designee. If the study cycle schedule is 
shifted, assessments must be shifted to ensure that collection of assessments is completed before 
dosing.
8.2
Study Treatment Administration
For the purposes of this protocol, study treatment regimen is defined as the combination of 
ixazomib, daratumumab, and dexamethasone. All cycles are approximately 28 days with treatment 
given until PD or unacceptable toxicity (see Figure 8.a).
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Figure 8.a
Study Treatment Administration
Abbreviations: Dara, daratumumab; Dex, dexamethasone; PD, progressive disease.
8.2.1
Order of Study Treatment Administration
In principle, when ixazomib and daratumumab are administered in the same week, they should be 
administered on the same day of the week to align the dexamethasone premedication, which is 
given before daratumumab, as noted below in Section 8.2.4. 

For Cycle 1: Due to the potential of IRR with daratumumab, during the first cycle of therapy it 
is preferable to give the daratumumab dose before the ixazomib dose to allow for accurate 
safety assessment and management of any IRRs. Given the long daratumumab infusion time 
during the first cycle, ixazomib should be taken later the same day after resolution of any IRR; 
however, if there was an IRR that required treatment or prolonged the daratumumab infusion, 
ixazomib should be given within 24 hours after the start of the daratumumab infusion. 

For Cycle 2 and beyond: If there have been no Grade 3 or higher IRRs in the previous cycle, 
ixazomib can be given prior to or at approximately the same time as the premedications. The 
daratumumab infusion should begin approximately 1 hour after the ixazomib administration. 
To support consistency for patients, the same dexamethasone schedule (split dose on 
2 sequential days) will be followed even on weeks without daratumumab infusion (see 
Figure 8.a).
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8.2.2
Daratumumab
Daratumumab will be administered as an IV infusion. Each patient’s dose will be calculated on the 
basis of the patient’s weight rounded to the nearest kilogram. The dose does not need to be 
recalculated for weight changes that are <10% from baseline. All infusions may be performed as 
outpatient visits.
Patients will receive pre- and postinfusion medications (see Section 8.2.2.1). All patients should 
have blood pressure monitored before and after all infusions. Additional vital sign monitoring may 
be done as medically needed. For complete details on daratumumab, refer to the most current local 
product prescribing information [20].
8.2.2.1
Concomitant Pre-infusion and Postinfusion Medications 
Pre-infusion Medication
Administer the following pre-infusion medications to reduce the risk of IRRs to all patients 1 to 3 
hours before every infusion of daratumumab:

Administer 20 mg dexamethasone before every daratumumab infusion (further described 
below in Section 8.2.4).
–
Note: Dexamethasone is given IV before the first daratumumab infusion and oral 
administration may be considered before subsequent infusions.

Antipyretics (oral acetaminophen 650 to 1000 mg).

Antihistamine (oral or IV diphenhydramine 25 to 50 mg or equivalent).

Montelukast 10 mg orally.
Postinfusion Medication

Administer 20 mg dexamethasone the day after every daratumumab infusion (further 
described below in Section 8.2.4).

In addition, for any patients with a history of COPD, consider prescribing postinfusion 
medications such as short- and long-acting bronchodilators and inhaled corticosteroids. After 
the first 4 infusions, if the patient experiences no major IRRs, these additional inhaled 
postinfusion medications may be discontinued [20]. In addition, these at-risk patients may be 
hospitalized for monitoring for up to 2 nights after an infusion. If these at-risk patients are 
hospitalized, then their FEV1 should be measured before discharge. If these patients are not 
hospitalized, then a follow-up telephone call should be made to monitor their condition within 
48 hours after all infusions. If no IRR has occurred, the follow-up telephone call 48 hours after 
the infusion is not required. If the patient did not experience a significant medical event but is 
hospitalized overnight only for observation, then the hospitalization should not be reported as 
an SAE. Investigators may prescribe bronchodilators, antihistamines, and corticosteroids that 
are deemed necessary to provide adequate supportive care in the event a bronchospasm occurs 
after patients are released from the hospital/clinic. If an at-risk subject experiences no major 
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IRRs, then these postinfusion medications may be waived after 4 doses at the investigator’s 
discretion. 
8.2.2.2
Daratumumab Schedule and Administration 
Daratumumab will be given on the following schedule (see Appendix A):

Cycles 1 and 2: Days 1, 8, 15, and 22 (every week; 8 doses in total).

Cycles 3 to 6: Days 1 and 15 (every 2 weeks; 8 doses in total).

Cycles 7 and beyond: Day 1 (every 4 weeks). 
Daratumumab infusion rates are given in Table 8.a. Incremental escalation of the infusion rate 
should only be considered in the absence of IRRs. 
Upon implementation of Amendment 04, to prioritize the safety of patients during the COVID-19 
pandemic, patients may have their infusion duration reduced to no less than 90 minutes if they did 
not have a history of an IRR at any time after the third dose (Table 8.a and Appendix J).
Table 8.a
Infusion Rates for Daratumumab IV Administration
Dilution 
Volume
Initial Rate 
(first hr)
Rate Increment (a)
Maximum Rate
First infusion
1000 mL
50 mL/hr
50 mL/hr every hr
200 mL/hr
Second infusion (b, c)
500 mL
50 mL/hr
50 mL/hr every hr
200 mL/hr
Subsequent infusions (d)
500 mL
100 mL/hr
50 mL/hr every hr
200 mL/hr
To prioritize the safety of 
patients during the 
COVID-19 pandemic, 
subsequent infusions may 
instead be administered to 
patients (if they do not have a
history of IRR at any time 
after their third dose) as noted 
here:
Daratumumab can be administered at an initial rate of 20% of the total dose over 30 
minutes, followed by the remaining 80% of the total dose over 60 minutes (no less 
than a 90-minute total infusion time). The accelerated infusion will be given in a total 
volume of 500 mL. This allows for a rate of 200 mL/hr for the first 30 minutes and a 
rate of 400 mL/hr for the final 60 minutes.
See Appendix J for the full memo from Janssen-Cilag International NV.
Source: DARZALEX prescribing information [20].
Abbreviations: COVID-19, coronavirus disease 2019; hr, hour; IV, intravenous; IRR, infusion-related reaction.
(a) Consider incremental escalation of the infusion rate only in the absence of infusion reactions.
(b) Use a dilution volume of 500 mL only if there were no Grade 1 (mild) or greater infusion reactions during the first 
3 hours of the first or second infusion. Otherwise, continue to use a dilution volume of 1000 mL and instructions for 
the first infusion.
(c) Alternative option for second dose is to use 1000 mL dilution volume but start at a faster rate and not decrease to 
500 mL dilution volume until dose 3. 
(d) Use a modified initial rate for subsequent infusions (ie, third infusion onwards) only if there were no Grade 1 
(mild) or greater infusion reactions during a final infusion rate of ≥100 mL/hr in the first 2 infusions. Otherwise, 
continue to use instructions for the second infusion.
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Missed (Held) Daratumumab Doses
Every effort should be made to keep patients on the planned dosing schedule. However, doses 
given within 3 days of the scheduled dose are permitted, as long as the interval between doses is at 
least 5 days. If daratumumab administration does not commence within the prespecified window 
of the scheduled administration date, for toxicity or other reasons, then the dose will be considered 
a missed (held) dose. Administration may resume at the next planned dosing date. A missed (held) 
dose will not be made up. If a planned dose of daratumumab is missed (held), bring the situation to 
the attention of the Takeda project clinician or designee at the earliest possible time. 
Patients missing ≥3 consecutive planned doses of daratumumab for reasons other than toxicity 
should be withdrawn from daratumumab treatment, unless, upon consultation with the sponsor and 
the review of safety and efficacy, continuation is agreed upon. Any dose hold of more than 28 days 
due to toxicity will result in permanent discontinuation of daratumumab. Ixazomib dosing may 
continue if the toxicity was attributable to daratumumab.
See Section 8.3 dose modification and Section 8.7 management of clinical events for more 
information. 
8.2.3
Ixazomib
Ixazomib will be given as an oral dose weekly (Days 1, 8, and 15) for 3 weeks, followed by 1 week 
without ixazomib in a 28-day cycle (Appendix A). Refer to the Study Manual for additional 
instructions regarding study therapy administration.
Patients should be instructed to swallow ixazomib capsules whole with water and not to break, 
chew, or open the capsules. Ixazomib should be taken on an empty stomach, at least 1 hour before 
or at least 2 hours after food. The capsule should be swallowed with water. A total of 
approximately 240 mL (8 ounces) of water should be taken with the capsules. Missed doses can be 
taken as soon as the patient remembers as long as the next scheduled dose is 72 hours or more 
away. A double dose should not be taken to make up for a missed dose. If the patient vomits after 
taking a dose, the patient should not repeat the dose but should resume dosing at the time of the 
next scheduled dose.
8.2.4
Dexamethasone
Dexamethasone is usually given as 1 dose; however, in this study, it will be given in split doses as 
follows, as it is being used for both its antimyeloma activity and as prophylaxis for 
daratumumab-induced IRRs: 

Dexamethasone will be given as 20 mg on Days 1, 2, 8, 9, 15, 16, 22, and 23 in each 28-day 
cycle, to achieve the standard total of 40 mg per week (2 doses of 20 mg per week). 

Dexamethasone should be given IV before the first daratumumab dose but can be given IV or 
orally thereafter. The subsequent doses (ie, day after daratumumab infusion) can be given 
orally. 
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
For patient consistency and compliance, the same dexamethasone schedule (2 sequential days) 
will be followed even on weeks without daratumumab infusion (see Figure 8.a).

The dose of dexamethasone can be reduced to 20 mg once weekly for patients who are older 
than 75 years, have poorly controlled diabetes, or had prior intolerance to or AE from 
corticosteroid therapy (see Section 8.3.4). On daratumumab dosing days, the dose of 
dexamethasone must be given prior to daratumumab infusion (see Section 8.3.4).
Dexamethasone should be administered considering patient tolerability. Ideally it would be taken 
at approximately the same time each dosing day. If a dose of dexamethasone is missed, the dose 
should be taken as soon as the patient remembers it. If enough time has elapsed that it is almost
time for the next dose (within 6 hours), the missed dose should be skipped and the next dose taken 
according to the regular dosing schedule. A double dose should not be taken to make up for a 
missed dose. If the patient vomits after taking a dose, the patient should not repeat the dose but 
should resume dosing at the time of the next scheduled dose. Note the use of dexamethasone as a 
pre- and postinfusion medication for daratumumab.
8.3
Dose Modification Guidelines
8.3.1
Criteria for Beginning or Delaying a Subsequent Treatment Cycle
The criteria for toxicity recovery before the patient can begin the next cycle of treatment are as 
follows:

ANC ≥1000/mm3.

Platelet count ≥75,000/mm3 without platelet transfusion support.

All nonhematologic toxicity considered to be related to treatment with study therapy must have 
resolved to ≤Grade 1, to the patient’s baseline values, or to a severity level considered stable 
and tolerable by the investigator/patient (eg, Grade 2 chronic kidney disease due to underlying 
MM).
If the patient does not meet the above-cited criteria for retreatment, initiation of the next cycle of 
IDd should be delayed for 1 week. After 1 week, the patient should be re-evaluated to determine 
whether the criteria for retreatment have been met. If the patient continues not to meet the 
previously cited criteria, delay IDd and continue to re-evaluate. Should the start of the next cycle 
need to be delayed >2 weeks because of incomplete recovery from treatment-related toxicity, 
consult with the Takeda project clinician or designee. Each AE should be attributed to a specific 
drug (ie, ixazomib, daratumumab, or dexamethasone), if possible, so that dose modifications can 
be made accordingly. In cases where the residual toxicity after >2 weeks can clearly be attributed 
to 1 of the drugs (eg, only to ixazomib or only to daratumumab), continuation of therapy with the 
other drugs within the study treatment regimen rather than permanent discontinuation of all study 
treatment can be considered.
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8.3.2
Ixazomib Treatment Modification
Patients experiencing AEs attributed to ixazomib may continue in the study but may have doses of 
ixazomib modified (delayed, held, or reduced by at least 1 dose level [dose reduction levels as per 
Table 8.b]). When a dose reduction of ixazomib is required because of toxicity, no dose 
re-escalation will be permitted. Treatment reductions because of ixazomib-related AEs are 
outlined for hematologic and nonhematologic toxicities in Table 8.c and Table 8.d. 
Table 8.b
Dose Reduction Steps for Ixazomib
Current Dose
First Dose Reduction
Second Dose Reduction
Third Dose Reduction
4 mg
3 mg
2.3 mg
Discontinue ixazomib
Table 8.c
Ixazomib and Daratumumab Dose Modification for Hematologic Toxicities
Hematologic Toxicities
Recommended Actions
Thrombocytopenia (Platelet Count)
Platelet count less than 25,000/mm3 without clinically 
significant bleeding, need for transfusion, or results in 2 
weeks or less delay in start of the next cycle of therapy.
Clinically significant bleeding is determined by 
investigator medical judgement.
Hold ixazomib and daratumumab until platelet count 
resolved to ≥75,000/mm3. Note platelet count must 
recover to at least 75,000/mm3 without platelet 
transfusion support to start a new cycle of therapy as per 
Section 8.3.1.

Following recovery, resume both ixazomib and 
daratumumab at the most recent dose. 
Platelet count less than 25,000/mm3 with clinically 
significant bleeding, need for transfusion, or results in 
more than a 2-week delay in start of next cycle.
Clinically significant bleeding is determined by 
investigator medical judgement.
Hold ixazomib and daratumumab until platelet count 
resolved to ≥75,000/mm3. Note platelet count must be to 
at least 75,000/mm3 without platelet transfusion support 
to start a new cycle of therapy as per Section 8.3.1.

Following recovery, resume ixazomib at the next 
lower dose and resume daratumumab.
Neutropenia (ANC)
ANC less than 500/mm3without febrile neutropenia, 
infection, or results in 2 weeks or less delay in start of the 
next cycle of therapy.
Withhold ixazomib and daratumumab until ANC 
resolved to at least 1000/mm3. Consider adding 
granulocyte colony-stimulating factor (G-CSF) as per 
clinical guidelines. 

Following recovery, resume ixazomib and 
daratumumab at the most recent dose 
ANC less than 500/mm3 with febrile neutropenia, 
infection, or results in more than a 2 week delay in start of 
next cycle.
Withhold ixazomib and daratumumab until ANC 
resolved to at least 1000/mm3. Symptomatic management 
per clinical practice. Consider adding G-CSF as per 
clinical guidelines. 

Following recovery, resume ixazomib at the next 
lower dose and resume daratumumab. 
ANC, absolute neutrophil count; G-CSF, granulocyte colony stimulating factor.
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Table 8.d
Ixazomib Dose Modification for Nonhematologic Toxicities
Nonhematologic Toxicities
Recommended Actions
Rash 
Grade 2 or 3 
Withhold ixazomib until rash recovers to Grade 1 or 
lower. Supportive care and prophylaxis are recommended 
(see Section 8.7).

Following recovery, resume ixazomib at the next 
lower dose. 
Note: if Stevens-Johnson syndrome occurs, ixazomib 
should be discontinued
Grade 4
Discontinue ixazomib.
Peripheral Neuropathy 
Grade 1 Peripheral Neuropathy with Pain or Grade 2 
Peripheral Neuropathy 
Withhold ixazomib until peripheral neuropathy recovers 
to Grade 1 or lower without pain or patient's baseline. 

Following recovery, resume ixazomib at the most 
recent dose. 
Grade 2 Peripheral Neuropathy with Pain or Grade 3 
Peripheral Neuropathy 
Withhold ixazomib. Toxicities should, at the physician’s 
discretion, generally recover to patient’s baseline 
condition or Grade 1 or lower prior to resuming 
ixazomib. 

Following recovery, resume ixazomib at the next 
lower dose. 
Grade 4 Peripheral Neuropathy
Discontinue ixazomib.
Other Nonhematologic Toxicities 
Other Grade 3 or 4 Nonhematologic Toxicities 
Withhold ixazomib. Toxicities should, at the physician’s 
discretion, generally recover to patient’s baseline 
condition or Grade 1 or lower prior to resuming 
ixazomib. 

If attributable to ixazomib, resume ixazomib at the 
next lower dose following recovery. 
8.3.3
Daratumumab Treatment Modification
Increasing the frequency of daratumumab dosing is not permitted at any point. Also no 
daratumumab dose reductions are permitted.
8.3.3.1
Infusion Rates and Management of IRRs 
Administer daratumumab infusion IV at the infusion rate described above in Table 8.a. Consider 
incremental escalation of the infusion rate only in the absence of infusion reactions.
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For infusion reactions of any grade/severity, immediately interrupt the daratumumab infusion and 
manage symptoms. Management of IRRs may further require reduction in the rate of infusion, or 
treatment discontinuation, of daratumumab as outlined below:

Grade 1 or 2 (mild to moderate): Once reaction symptoms resolve, resume the infusion at no 
more than half the rate at which the reaction occurred. If the patient does not experience any 
further reaction symptoms, infusion rate escalation may resume at increments and intervals as 
clinically appropriate, up to the maximum rate of 200 mL/hour (Table 8.a).

Grade 3 (severe): Once reaction symptoms resolve, consider restarting the infusion at no more 
than half the rate at which the reaction occurred. If the patient does not experience additional 
symptoms, resume infusion rate escalation at increments and intervals as outlined in Table 8.a. 
Repeat the procedure above in the event of recurrence of Grade 3 symptoms. Permanently 
discontinue daratumumab upon the third occurrence of a Grade 3 or higher IRR.

Grade 4 (life threatening): Permanently discontinue daratumumab treatment.
No daratumumab dose reductions are permitted. If any of the following criteria are met and the 
event is ascribed to daratumumab, the daratumumab infusion must be held to allow for recovery 
from toxicity:

Hematologic toxicities are overlapping toxicities with ixazomib and daratumumab, thus also 
note Table 8.c above for dose modification considerations.

Grade 3 or higher nonhematologic toxicities with the following exceptions:
–
Grade 3 nausea or Grade 3 vomiting that responds to antiemetic treatment.
–
Grade 3 diarrhea that responds to antidiarrheal treatment.
–
Grade 3 fatigue or asthenia that lasts for <7 days after the last administration of 
daratumumab.
Daratumumab treatment should be resumed when the toxicity has resolved to ≤Grade 2 (see 
Section 8.3.1 and Table 8.c). If daratumumab administration does not commence within the 
prespecified window of the scheduled administration date, then the dose will be considered a 
missed (held) dose (see Section 8.2.2.2). Administration may resume at the next planned dosing 
date (see Table 8.e). A missed (held) dose will not be made up.
Table 8.e
Daratumumab-Related Toxicity Management
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A daratumumab dose held for more than 3 days after the per-protocol administration date for any 
reason other than toxicities suspected to be related to daratumumab should be brought to the 
attention of the sponsor at the earliest possible time. Patients missing ≥3 consecutive planned 
doses of daratumumab for reasons other than toxicity should be withdrawn from treatment, unless, 
upon consultation with the sponsor and the review of safety and efficacy, continuation is agreed 
upon.
Any dose hold of more than 28 days due to toxicity will result in permanent discontinuation of 
daratumumab. Ixazomib dosing may continue if the toxicity was attributable to daratumumab.
8.3.3.2
Management of HBV Reactivation
Patients who are already enrolled at the time of Amendment 02 should undergo local HBV testing 
as soon as possible for HBV surface antigen, e antigen, core antibody, and DNA. If any of these 
tests is positive, consult a physician with expertise in managing HBV for guidance regarding 
stopping daratumumab, starting HBV antiviral therapy, and remaining on study. These patients 
should be monitored every cycle during, and for at least 6 month after the end of, daratumumab 
treatment for clinical and laboratory signs of HBV reactivation (ie, positive HBV surface antigen, 
positive HBV e antigen, or positive HBV DNA) [50,51]. If this monitoring reveals HBV 
reactivation, further treatment, including stopping daratumumab if relevant, should be discussed 
with a physician with expertise in managing HBV. The sponsor’s study clinician (or designee) 
should be consulted about the continued administration of the other study drugs (ixazomib and 
dexamethasone).
See Section 9.4.3.1 and Appendix A for more information.
8.3.4
Dexamethasone Treatment Modification 
Patients experiencing AEs attributed to dexamethasone may have doses of dexamethasone 
modified. When a dose reduction of dexamethasone is required because of toxicity, no dose 
re-escalation will be permitted. All dexamethasone treatment modifications are according to the 
local prescribing information. 
After Cycle 6, the dose of dexamethasone may be reduced to a minimum of 20 mg/week at the 
investigator’s discretion (see Section 8.2.4). The 20 mg dose of dexamethasone given before the 
infusion (whether given IV or orally) on the day of daratumumab dosing must not be decreased. 
When dexamethasone is reduced to 20 mg/week and is given as pre-infusion medication, patients 
may receive low-dose methylprednisolone (≤20 mg) orally (or equivalent in accordance with local 
standards) for the prevention of delayed IRRs as clinically indicated. If the patient isn’t tolerating 
dexamethasone at 20 mg/week, alternative low-dose corticosteroids may be considered in 
accordance with local standards and in consultation with the Takeda project clinician or designee.
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8.4
Excluded Concomitant Medications and Procedures
The following medications and procedures are prohibited during the study.
Systemic treatment with any of the following drug-metabolizing enzyme inducers should be 
avoided unless there is no appropriate alternative medication for the patient’s use. (Rationale: If 
there were to be a drug-drug interaction with an inducer, ixazomib exposure would be decreased.)

Strong cytochrome P-450 3A inducers: rifampin, rifapentine, rifabutin, carbamazepine, 
phenytoin, phenobarbital, and St John’s wort.
Refer to the local prescribing information for drug-drug interaction information for daratumumab 
[19,20].
The following procedures are prohibited during the treatment period of the study:

Any antineoplastic treatment with activity against MM, other than study therapy.

Radiation therapy (note that, in general, the requirement for local radiation therapy indicates 
PD; “spot” radiation for areas of pain is permitted).
8.5
Permitted Concomitant Medications and Procedures
All necessary supportive care consistent with optimal patient care will be available to patients, as 
necessary. All blood products and concomitant medications received from the signing of the 
informed consent form (ICF) until 30 days after the final dose of study therapy will be recorded in 
the electronic case report forms (eCRFs).
The following medication is mandatory during the study:

Unless there is a clinical contraindication, prophylactic varicella-zoster virus antiviral therapy 
is required for all patients while receiving study treatment. Examples of acceptable antiviral 
therapy include acyclovir (eg, 400 mg given orally, 3 times a day), famciclovir (eg, 125 mg 
given orally, twice a day), or valacyclovir (eg, 500 mg given orally, twice a day) or standard of 
care/local practice. 
The following medications and procedures are permitted during the study:

Myeloid growth factors (eg, G-CSF) are permitted. Use should follow the local prescribing 
information, published guidelines, and/or institutional practice; however, alternative usage 
may be reviewed with the Takeda project clinician or designee.

Patients should be transfused with red cells and platelets as clinically indicated except to meet 
study inclusion criteria or within 3 days of the start of the next cycle as a means to meet platelet 
thresholds to start the next cycle.

Patients with previously identified lytic destruction of bone or with osteopenia can receive 
treatment with bisphosphonates or denosumab, if available for patients with MM, according to 
the American Society of Clinical Oncology Clinical Practice Guidelines or institutional 
practice in accordance with the local prescribing information, unless specifically 
contraindicated. 
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
Patients with evidence of HBV exposure or reactivation may receive HBV therapy as clinically 
indicated by a physician with expertise in managing HBV [50,51]. 

Supportive measures consistent with optimal patient care may be given throughout the study.
8.6
Precautions and Restrictions
Fluid deficit should be promptly corrected before initiation of, and during treatment with, 
ixazomib.
Nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided with impaired renal function 
given reported NSAID-induced renal failure in patients with decreased renal function.
Caution should be used when administering contrast materials for imaging in patients with 
impaired renal function, as per standard practice.
It is not known what effects ixazomib and daratumumab 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 group and male patients should use effective 
methods of contraception through defined periods during and after study treatment as specified 
below.
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 use effective contraceptive measures during and 
for 90 days following treatment. Dexamethasone is known to be a weak to moderate inducer of 
CYP3A4 as well as other enzymes and transporters. Because ixazomib is administered with 
dexamethasone, the risk for reduced efficacy of contraceptives needs to be considered. Advise 
female patients using hormonal contraceptives to also use a barrier method of contraception 
(see Appendix H for details).
Male patients, even if surgically sterilized (ie, status postvasectomy), agree to use effective 
contraceptive measures during and for 90 days following treatment (see Appendix H for details).
8.7
Management of Clinical Events
8.7.1
Ixazomib
Symptomatic measures for ixazomib-related AEs are detailed below. Refer to Section 8.3 for 
information on dose modifications. 
Prophylaxis Against Risk of Reactivation of Herpes Infection
Patients may be at an increased risk of infection including reactivation of herpes zoster and herpes 
simplex viruses. Unless there is a clinical contraindication, prophylactic antiviral therapy is 
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required for every patient while receiving study treatment (see Section 8.5 for examples of 
acceptable antiviral therapy).
Nausea or Vomiting
Prophylaxis with standard antiemetics, including serotonin 5-hydroxytryptamine 3 receptor 
antagonists, is recommended for emesis. Any fluid deficit occurring during treatment should be 
promptly corrected.
Diarrhea
Diarrhea should be managed according to clinical practice, including the administration of 
antidiarrheals once infectious causes are excluded. Fluid intake should be maintained to avoid 
dehydration. Any fluid deficit occurring during treatment should be promptly corrected.
Erythematous Rash With or Without Pruritus
Rash may range from limited erythematous areas, macular or small papular bumps that may or 
may not be pruritic over a few areas of the body, to a more generalized eruption that is 
predominantly on the trunk or extremities. Rash has been most commonly characterized as 
maculopapular or macular. To date, when it does occur, rash is most commonly reported within the 
first 3 cycles of therapy. The rash is often transient and self-limiting and is typically Grade 1 or 2 in 
severity. If rash occurs, consideration should be given to alternate causes of the rash such as 
concomitant medications, infections, etc; these other causative agents should be discontinued and 
alterative agents considered if medically necessary.
Symptomatic measures such as antihistamines or corticosteroids (oral or topical) have been 
successfully used to manage rash and have been used prophylactically in subsequent cycles. The 
use of a topical, IV, or oral steroid is permitted. 
Management of a Grade 3 rash may require IV antihistamines or corticosteroids. Administration of 
ixazomib should be modified per protocol and reinitiated at a reduced level from where rash was 
noted (see Table 8.d). In line with clinical practice, dermatology consult and biopsy of Grade 3 or 
higher rash or any SAE involving rash is recommended. Prophylactic measures should also be 
considered if a patient has previously developed a rash (eg, using a thick, alcohol-free emollient 
cream on dry areas of the body or oral or topical antihistamines).
The rare risks of Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), drug reaction with 
eosinophilia and systemic symptoms (DRESS syndrome), and pemphigus vulgaris have been 
reported in oncology studies when ixazomib (or placebo) was given with concomitant medications 
that are known to cause rash (eg, Bactrim, lenalidomide, aspirin), and/or in the setting of 
confounding TEAEs. These severe, potentially life-threatening or deadly conditions may involve 
rash with skin peeling and mouth sores and should be clinically managed according to standard 
medical practice. Punch biopsies for histopathological analysis are encouraged at the discretion of 
the investigator. Study medications should be discontinued in the event of severe, potentially 
life-threatening rash. If Stevens-Johnson syndrome (SJS) occurs, discontinue ixazomib. 
Additional information regarding these reactions can be found in the IB.
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Thrombocytopenia
Blood counts should be monitored regularly as outlined in the protocol, with additional testing 
obtained according to standard clinical practice. Thrombocytopenia may be severe but has been 
manageable with platelet transfusions according to standard clinical practice. Ixazomib 
administration should be modified according to dose modification recommendations in the 
protocol when thrombocytopenia occurs (see Table 8.c). Therapy can be reinitiated at a reduced 
level upon recovery of platelet counts. Thrombotic microangiopathy (TMA), including thrombotic 
thrombocytopenia purpura and hemolytic uremic syndrome (HUS), are rare, serious blood 
disorders that cause low levels of platelets and red blood cells and result in blood clots in small 
blood vessels. Symptoms may include fatigue, fever, bruising, nose bleeds, and decreased 
urination. These disorders, including fatal cases, have been reported in patients receiving 
ixazomib. If TMA is suspected, consider withdrawal of the suspected causative agent and manage 
it according to standard medical practice.
Neutropenia
Blood counts should be monitored regularly with additional testing, as appropriate, according to 
standard clinical practice. Neutropenia may be severe but has been manageable. Growth factor 
support is not required but may be considered according to standard clinical practice. Ixazomib 
administration should be modified according to dose modification recommendations when 
neutropenia occurs (see Table 8.c). Febrile neutropenia should be managed as per local guidelines. 
Therapy can be reinitiated at a reduced level upon recovery of ANC.
Fluid Deficit
Dehydration should be avoided because ixazomib may cause vomiting, diarrhea, and dehydration. 
Acute renal failure has been reported in patients treated with ixazomib, commonly in the setting of 
the previously noted gastrointestinal toxicities and dehydration. Fluid deficit should be promptly 
corrected before administration of ixazomib and as needed during treatment to avoid dehydration.
Hypotension
Symptomatic hypotension and orthostatic hypotension with or without syncope have been 
reported with ixazomib. Blood pressure should be closely monitored as per standard of care while 
the patient is on study treatment, and fluid deficit should be corrected as needed, especially in the 
setting of concomitant symptoms such as nausea, vomiting, diarrhea, or decreased appetite. 
Patients taking medications or diuretics to manage their blood pressure (for either hypotension or 
hypertension) should be managed according to standard clinical practice, including considerations 
for dose adjustments of their concomitant medications during the course of the trial. Fluid deficit 
should be corrected before administration of ixazomib and as needed during treatment to avoid 
dehydration.
Posterior Reversible Encephalopathy Syndrome
Posterior reversible encephalopathy syndrome has been reported with ixazomib. This condition is 
usually transient and reversible. It is characterized by headache, seizures, and visual loss, and 
abrupt increase in blood pressure. Diagnosis may be confirmed by magnetic resonance imaging 
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(MRI) or computed tomography (CT). If the syndrome is diagnosed or suspected, 
symptom-directed treatment should be maintained until the condition is reversed by control of 
hypertension or other instigating factors. Ixazomib therapy should be discontinued.
Transverse Myelitis
Transverse myelitis has been reported with ixazomib. It is not known whether ixazomib causes 
transverse myelitis; however, because transverse myelitis has happened in patients receiving 
ixazomib, the possibility that ixazomib may have contributed to the transverse myelitis cannot be 
excluded. Transverse myelitis should be managed according to standard medical practice.
Overdose
Overdose has been reported in patients taking ixazomib, and the symptoms of overdose are 
generally consistent with the known risks of ixazomib. Reports of accidental overdose have been 
associated with SAEs, such as severe nausea, aspiration pneumonia, multiple organ failure, and 
death.
Health care providers should instruct patients and caregivers that only 1 dose of ixazomib should 
be taken at a time, and only at the prescribed interval (1 capsule, once a week, on Days 1, 8, and 15 
of a 28-day cycle). The importance of carefully following all dosage instructions should be 
discussed with patients starting treatment.
There is no known specific antidote for ixazomib overdose. If an overdose occurs, consider 
admitting the patient to the hospital for IV hydration, monitoring for adverse drug reactions, 
monitoring of vital signs, and appropriate supportive care. Gastric lavage and administration of 
charcoal may be considered if instituted within 1 hour of ingestion of an ixazomib overdose.
8.7.2
Daratumumab
See the daratumumab local prescribing information for more information.
Infusion-Related Reactions
Daratumumab can cause serious IRRs, including anaphylaxis. Approximately half of all patients 
experienced an IRR, most during the first infusion. Monitor patients throughout the infusion and 
the postinfusion period. Severe reactions have occurred, including bronchospasm, hypoxia, 
dyspnea, and hypertension, laryngeal edema and pulmonary edema. Signs and symptoms may 
include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, 
vomiting, and nausea. Fatal outcomes have been reported. Less common symptoms were 
wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, and hypotension (refer to 
Section 8.2.2 for additional risk minimization strategies).
Thrombocytopenia and Neutropenia
Daratumumab may increase thrombocytopenia and neutropenia induced by background therapy 
[20]. Monitor complete blood cell counts periodically during treatment according to 
manufacturer’s prescribing information for background therapies. Daratumumab dose delay may 
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be required to allow recovery of platelets, as specified in Table 8.c. No dose reduction of 
daratumumab is recommended. Consider supportive care with transfusions (see Section 8.5).
Monitor patients with neutropenia for signs of infection. Daratumumab dose delay may be 
required to allow recovery of neutrophils, as specified in Table 8.c. No dose reduction of 
daratumumab is recommended. Consider supportive care with growth factors (see Section 8.5).
Interference With Serological Testing
Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive Indirect 
Antiglobulin Test (Indirect Coombs Test). Daratumumab-mediated positive indirect antiglobulin 
test may persist for up to 6 months after the last daratumumab infusion. Daratumumab bound to 
RBCs masks detection of antibodies to minor antigens in the patient’s serum [20,52]. The 
determination of a patient’s ABO and Rh blood type are not impacted [20]. Notify blood 
transfusion centers of this interference with serological testing and inform blood banks that a 
patient has received daratumumab. Type and screen patients prior to starting daratumumab or 
follow applicable local institutional guidelines.
If an emergency transfusion is required, non-cross-matched ABO/RhD-compatible RBCs can be 
given per local blood bank practices.
Overdose 
The dose of daratumumab at which severe toxicity occurs is not known. In the event of an 
overdose, monitor patients for any signs or symptoms of adverse effects and provide appropriate 
supportive treatment. See the daratumumab local prescribing information for more 
information [20].
Reactivation of HBV
Daratumumab can be associated with potential HBV reactivation. Patients found to have positive 
HBV serology (ie, positive HBV surface antigen or positive HBV core antibody) during screening 
are excluded. 
Patients who are already enrolled at the time of Amendment 02 should be tested locally as soon as 
possible for HBV surface antigen, e antigen, core antibody, and DNA. If any of these tests is 
positive, consult a physician with expertise in managing HBV for guidance regarding stopping 
daratumumab, starting HBV antiviral therapy, and remaining on study. These patients should be 
monitored every cycle during, and for at least 6 months after the end of, daratumumab treatment 
for clinical and laboratory signs of HBV reactivation (ie, positive HBV surface antigen, positive 
HBV e antigen, or positive HBV DNA) [50,51]. If this monitoring reveals HBV reactivation, 
further treatment, including stopping daratumumab if relevant, should be discussed with a 
physician with expertise in managing HBV. The sponsor’s study clinician (or designee) should be 
consulted about the continued administration of the other study drugs (ixazomib and 
dexamethasone).
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8.7.3
Dexamethasone
See the dexamethasone local prescribing information for management of any 
dexamethasone-related clinical events. 
8.8
Blinding and Unblinding
This is an open-label study; thus there is no blinding or unblinding. 
8.9
Description of Investigational Agents
8.9.1
Ixazomib
8.9.1.1
Preparation, Reconstitution, and Dispensation
Ixazomib is dispensed in blister packaging in a child-resistant carton. For the 2.3, 3.0, and 4.0 mg 
capsule strengths, there are 3 capsules in each wallet/carton.
Ixazomib is an anticancer drug, and as with other potentially toxic compounds, caution should be 
exercised during handling. See the Pharmacy Manual for more information.
8.9.1.2
Packaging and Labeling
Ixazomib will be provided by Takeda. The ixazomib local prescribing information will fulfill all 
requirements specified by governing regulations.
8.9.1.3
Storage, Handling, and Accountability
On receipt at the investigative site, ixazomib should remain in the blister packaging and carton 
provided until use or dispensation. For storage conditions, refer to the Pharmacy Manual or 
equivalent. All excursions from the temperature storage guidelines should immediately be brought 
to the sponsor’s attention for assessment and authorization for continued use. Ensure that the drug 
is used before the retest expiry date provided by Takeda. Expiry extensions will be communicated 
accordingly with updated documentation to support the extended shelf life. If circumstances due to 
the COVID-19 pandemic prevent a patient from attending the study site, sites may use alternative 
strategies to deliver ixazomib to patients (eg, via courier or site staff), per local standard practice 
and regulations and with prior approval from the investigator and the sponsor’s project 
clinician/designee.
Ixazomib dispensed to the patient for take-home dosing should remain in the blister packaging and 
carton and stored as directed until the point of use. Patients taking ixazomib should be given only 1 
cycle of medication at a time; more than 1 cycle of medication may be dispensed (except in 
France; patients in France must not be dispensed more than 1 cycle of medication at a time) on a 
case-by-case basis for holidays, travel, or other circumstances upon discussion with the 
investigator and sponsor’s project clinician/designee. The investigator and/or health care provider 
must review the proper dosing instructions with the patient to avoid the potential for incorrect 
self-administration or overdose of medication. Patients should be instructed to store the 
medication as indicated in the Pharmacy Manual or equivalent. Patients should be instructed to 
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return their empty or partially used cartons to the investigative site at their next visit, rather than 
discarding them, as permitted by site policy. Reconciliation will occur accordingly when the 
patient returns at his/her next visit for take-home medication. If circumstances due to the 
COVID-19 pandemic prevent a patient from attending the study site, drug packs and dosing diaries 
should be returned at the next available on-site clinic visit. Any excursions in temperature should 
be reported and dealt with on a case-by-case basis. 
Ixazomib is an anticancer drug and, as with other potentially toxic compounds, caution should be 
exercised during handling. Patients should be instructed not to chew, break, or open capsules. In 
case of contact with broken capsules, raising dust should be avoided during the cleanup operation. 
The product may be harmful by inhalation, ingestion, or skin absorption. Gloves and protective 
clothing should be worn during cleanup and during return of broken capsules and powder to 
minimize skin contact. The area should be ventilated and the site washed with soap and water after 
material pick up is complete. The material should be disposed of as hazardous medical waste in 
compliance with federal, state, and local regulations. 
In case of contact with the powder (eg, from a broken capsule), skin should be washed 
immediately with soap and copious amounts of water for at least 15 minutes. In case of contact 
with the eyes, copious amounts of water should be used to flush the eyes for at least 15 minutes. 
Medical personnel should be notified.
Patients are to be instructed on proper storage, accountability, and administration of ixazomib, 
including that study drug treatment is to be taken as intact capsules.
Refer to the Pharmacy Manual for this study for additional instructions.
8.9.2
Daratumumab
8.9.2.1
Preparation, Reconstitution, and Dispensation
Daratumumab is dispensed as a colorless to pale yellow preservative-free solution for IV infusion 
in single-dose vials as described in the local prescribing information [19,20].
Daratumumab is an anticancer drug, and as with other potentially toxic compounds, caution should 
be exercised during handling.
8.9.2.2
Packaging and Labeling
Daratumumab will be supplied from the manufacturer.
8.9.2.3
Storage, Handling, and Accountability
Daratumumab should be stored according to the instructions provided in the manufacturer’s 
package insert.
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8.9.3
Dexamethasone
8.9.3.1
Preparation, Reconstitution, and Dispensation
Dexamethasone is dispensed as a solution for IV administration or tablet for oral administration, as 
described in the local prescribing information [53].
8.9.3.2
Packaging and Labeling
Dexamethasone is to be dispensed from local site supplies, where possible. Dexamethasone may 
be supplied by the site from commercial sources or from the sponsor, depending on regional 
availability. Additional details are provided in the prescribing information.
8.9.3.3
Storage, Handling, and Accountability
Dexamethasone should be stored according to the manufacturer’s prescribing information. 
8.10
Other Protocol-Specified Materials
No other drugs or ancillary material are supplied for use in this study.
9.0
STUDY CONDUCT
This trial 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 Conference on 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.
9.1
Study Personnel and Organizations
The contact information for the project clinician for this study, the central laboratory, any 
additional clinical laboratories, the coordinating investigator, and any other vendors 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. Advertisements should be reviewed 
by the institutional review board (IRB)/independent ethics committee (IEC) and Takeda (or 
designee). In France, investigators participating in the study approached patients who were 
potentially eligible for the study to explain the study and provide further information. Patients 
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were provided with a copy of the ICF and had as much time as needed for reflection and questions 
before signing; this was expected to be between 1 and 2 weeks.
9.3
Treatment Group Assignments
This is a single-arm, open-label study. After written informed consent has been obtained, the 
patient will be enrolled in the study. Patient eligibility will be confirmed by a Takeda project 
clinician or designee before the study. Procedures for completion of the enrollment information 
are described in the Study Manual.
9.4
Study Procedures
Refer to the updated Schedule of Events (Appendix A) for timing of assessments (the previous 
Schedule of Events is now moved to Appendix I for reference only). Additional details are 
provided as necessary in the sections that follow. After the final analysis is conducted, the sponsor 
will notify the investigators and sites when the new Schedule of Events in Appendix A, will go 
into effect. 
In acknowledgement of hospital, local, state, or national government restrictions, or other 
site-related factors caused by the COVID-19 pandemic that may prevent investigators from 
conducting the study according to the Schedule of Events at the clinical study site, investigators 
may continue patients in the study despite departure from the Schedule of Events. Investigators are 
expected to evaluate the impact to the safety of the study participants and site personnel for 
patients to continue. In evaluating such requests, the investigator/study site staff will give the 
highest priority to the safety and welfare of the patients. Patients must be willing and able to 
continue taking study medication and remain compliant with the protocol. For patients who are 
impacted by these unavoidable circumstances, any procedures not conducted per the study 
protocol will be documented in the eCRF. 
Alternative methods for administering study procedures/assessments may be considered when it is 
not possible for the patient to come to the study site due to the COVID-19 pandemic. Alternative 
methods should be considered for performing the assessments by other means than the patient 
presenting to the clinic (eg, remote assessment, having lab assessment performed at a facility 
closer to the patient’s home, etc). If an in-clinic visit is not possible, the permitted alternatives are 
as follows (see Appendix A). These assessments/procedures may be waived: symptom-directed 
physical examination, ECOG performance status, vital signs, weight, whole blood, and serum 
sample for antibody titers. These assessments/procedures may be deferred until the next in-clinic 
visit: soft-tissue plasmacytoma, SPEP, UPEP, serum free light-chain assay, immunofixation, 
quantification of immunoglobulins, BMA, and biopsy. These assessments/procedures may be 
performed locally if possible and, if not, may be deferred until the next in-clinic visit: HBV testing 
and hematology and chemistry laboratory tests. 
9.4.1
Assessments During the Treatment Period
Patients will have study assessments performed at regular intervals while they are participating in 
the study (see Appendix A for details). Patients will receive study therapy until documented, 
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confirmed PD (on the basis of the IMWG criteria [Appendix E]), intolerable toxicities, withdrawal 
of consent, or sponsor termination of study, whichever comes first. 
At every cycle during the treatment period, the investigator will assess disease response and 
progression, per IMWG criteria, for the purpose of treatment decisions. ECOG performance score 
and AEs will be assessed, and laboratory values and vital signs will be obtained to evaluate the 
safety and tolerability of the study therapy. Toxicity will be evaluated according to National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 4.03, 
effective date 14 June 2010. Clinical, laboratory, response, 
 data will be collected. 
Unscheduled visits may occur between treatment cycles as required. For example, symptomatic 
pain progression should result in an interim unscheduled visit, as would ongoing Grade 3 or worse 
AEs. 
Patients will attend an end of treatment (EOT) visit up to 30 days (+1 week) after receiving their 
last dose of study therapy. 
Note: Related SAEs occurring during follow-up periods after the EOT visit must be reported to the 
Takeda Global Pharmacovigilance department or designee. This includes deaths that the 
investigator considers related to study therapy that occur during post-treatment follow-up. In 
addition, new primary malignancies that occur during follow-up periods, irrespective of causality 
to study therapy, must be reported to the Takeda Global Pharmacovigilance department or 
designee. Refer to Section 10.3 for details regarding definitions, documentation, and reporting of 
SAEs.
9.4.2
Assessments During the Follow-Up Periods: PFS and OS
After a patient completes the EOT visit or a patient discontinues study therapy before confirmed 
PD, he/she will enter a follow-up period. 
Patients who have stopped treatment for any reason other than PD will first enter the PFS 
follow-up period. During this period, follow-up will occur every 4 weeks until the occurrence of 
PD. 
After PD occurs during the PFS follow-up period, or if a patient has PD while on study therapy
during the treatment period, the patient will enter into the OS follow-up period, in which patients 
will be followed every 12 weeks until death or termination of the study by the sponsor. During the 
OS follow-up period, assessments do not require a clinic visit. Data may be collected by methods 
that include, but are not limited to, telephone, email, mail, social security indexes, and other public 
records as permitted by local regulations. Both the patient and the current treating physician will 
be contacted by the site study team during the OS follow-up period to provide information about 
all MM treatments (best response, date of progression, drug regimen, start/stop date).
 
.
Information about any new primary malignancies will be collected during the study, including 
during both follow-up periods.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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9.4.3
Clinical Laboratory Evaluations 
If the screening laboratory tests were performed more than 14 days before the first dose (Cycle 1 
Day 1), the chemistry/hematology tests and serum free light chain, UPEP, SPEP, and pregnancy 
tests will be repeated before dosing. The test closest to the first dose will be considered baseline. In 
contrast, collection of whole blood for immune profiling and immune cell function assays, whole 
blood for T-cell clonality, serum for antibody titers, and BMA need not be repeated. 
Hematology and chemistry laboratory samples will be collected centrally and may be collected up 
to 3 days before dosing, as specified in the Schedule of Events (Appendix A). Local laboratory 
evaluations may be done more frequently at the investigator’s discretion (ie, for acute management 
of TEAEs and dosing decisions). 
Upon implementation of Amendment 07, centralized clinical laboratory evaluations of efficacy 
and safety are no longer required, and thus either central or local laboratory evaluations may be 
used, depending on the site’s decision (Appendix A). Abnormal hematology and chemistry 
laboratory data should be entered into the eCRF only if required to document or support a TEAE. 
For dosing decisions and all other safety assessments for the patient, local hematology and 
chemistry laboratory results should be used and do not need to be entered into the eCRF. Local 
laboratory evaluations may be done more frequently at the investigator’s discretion (ie, for acute 
management of TEAEs), per the investigator’s judgement of standard of care.
9.4.3.1
Clinical Chemistry and Hematology
Blood samples for analysis of the clinical chemistry and hematologic parameters shown in 
Table 9.a will be obtained and recorded in the eCRFs as specified in the Schedule of Events 
(Appendix A). 
Table 9.a
Clinical Chemistry and Hematology Tests
Hematology
Serum Chemistry
Hemoglobin
Leukocytes with complete 
differential [total and percent 
neutrophils (ANC), lymphocytes, 
monocytes, eosinophils and 
basophils] 
Platelet (count)
Albumin
Alkaline phosphatase (ALP)
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST)
2-microglobulin
Bilirubin (a)
Blood urea nitrogen
Calcium
Chloride
Creatinine
Lactate dehydrogenase
Magnesium
Potassium
Sodium
(a) Direct bilirubin if patient has known Gilbert's syndrome.
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Serology Antibody Titers
Measles
Varicella-zoster virus
Tetanus
In addition, HBV testing should be performed, on the basis of a newly identified safety risk of 
potential HBV reactivation with daratumumab (also see Sections 8.3.3.2 and 8.7.2 and 
Appendix A) [50,51]. 

Patients who are already enrolled at the time of Amendment 02 should undergo local HBV 
testing as soon as possible for HBV surface antigen, e antigen, core antibody, and DNA. If any 
of these tests is positive, consult a physician with expertise in managing HBV for guidance 
regarding stopping daratumumab, starting HBV antiviral therapy, and remaining on study. 
These patients should be monitored every cycle during, and for at least 6 months after the end 
of, daratumumab treatment for clinical and laboratory signs of HBV reactivation (ie, positive 
HBV surface antigen, positive HBV e antigen, or positive HBV DNA) [50,51]. If this 
monitoring reveals HBV reactivation, further treatment, including stopping daratumumab, 
should be discussed with a physician with expertise in managing HBV. The sponsor’s study 
clinician (or designee) should be consulted about the continued administration of the other 
study drugs (ixazomib and dexamethasone).

Patients being considered for study enrollment should be tested during screening for HBV 
serology: test patients locally for HBV surface antigen and HBV core antibody; if either of 
these tests is positive, then exclude the patient from the study. 
If creatinine clearance is to be estimated, the Cockcroft-Gault formula will be employed as 
follows:
Estimated creatinine clearance
= ([140 – Age] × Weight [kg]) / (72 × serum creatinine [mg/dL])
For female patients, the result of the formula above should be multiplied by 0.85. 
9.4.3.2
Clinical Laboratory Evaluations for Disease Assessments
A blood sample will be collected during screening for measurement of serum 2-microglobulin 
and albumin for determination of disease stage according to the International Staging System; 
these results will be sent to the central laboratory for evaluation and recorded on the eCRF.
Clinical laboratory evaluations for disease assessments, SPEP, 24-hour UPEP, serum free 
light-chain, immunofixation, and total immunoglobulin levels must be sent to the central 
laboratory for evaluation.
Immunofixation will also be done to confirm CR. As daratumumab is a monoclonal IgG kappa 
antibody, the SPEP and IFE can be positive due to daratumumab. Therefore, an automated MM 
reflex at Covance will trigger interference testing whenever the SPEP values reach ≤0.2 g/dL for 2 
consecutive disease evaluations. Currently, if the interference test results come back POSITIVE, 
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then the assay is considered positive for endogenous protein, and thus there is still disease present. 
If the interference test results come back NEGATIVE, then the assay is considered negative for 
endogenous protein, and thus the remaining protein is likely daratumumab. This is communicated 
back to the sites, and the sites can proceed to perform a confirmatory BMA evaluation for possible 
CR if not already performed earlier.
Blood samples for IgM, IgG, and IgA will be obtained at screening and throughout the study at the 
time points specified in the Schedule of Events (Appendix A). Quantitative IgD and IgE will be 
done at screening only. 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.
BMA or biopsy disease assessment is to be performed at a local laboratory to assess disease status 
at screening. BMA will be repeated if the patient is considered possibly to have resolution of 
serum and urine M-protein consistent with CR or to investigate suspected PD. A clinically 
indicated BMA or biopsy drawn before consent is acceptable for the baseline assessment provided 
that it is collected within 42 days before the first dose. 
9.4.3.3
Pregnancy Test
A serum pregnancy test will be performed for women of childbearing potential at screening and 
within 3 days prior to the first dose of study drug treatment. The results from these tests must be 
available and negative before the first dose of study drug treatment is administered. If Cycle 1 Day 
1 serum pregnancy results will not be available before dosing, a urine pregnancy test may be 
performed.
Pregnancy tests will be performed at Day 1 of every cycle during the study if requested by an
IEC/IRB or if required by local regulations.
9.4.4
Disease Assessment
Disease will be assessed using IMWG criteria (see Appendix E) based on central laboratory results 
along with local BMA and imaging results. After the final analysis, disease will be assessed on the 
basis of local laboratory results.
9.4.4.1
Radiographic Assessment of Disease
Skeletal survey or CT scan (according to institutional practice) will be performed at screening to 
document lytic bone and/or extramedullary disease. Patients with documented soft tissue 
extramedullary disease must have radiographic disease assessments (CT, CT/positron emission 
tomography [PET], or CT/MRI) performed as outlined in Appendix A, until PD. The same 
imaging technique should be used throughout the study to allow for consistent disease assessment. 
Additional imaging assessments can be done at the discretion of the investigator (ie, for suspected 
increased or new bone lesions). 
9.4.4.2
Bone Marrow
BMA will be obtained at screening for (1) clinical staging performed by the local laboratory
(unless a biopsy is used for this purpose instead; see Section 9.4.4.2); 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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 The BMA first, second, and third pulls should correspond to the purposes listed 
above. 
Patients suspected of achieving a CR should have a BMA obtained to document CR per IMWG 
criteria. Determination of percentage plasma cells will be done by local laboratory.
Suspected CR is defined independently of the immunofixation result; BMA is to be performed 
when the M-protein measurement in SPEP (for heavy-chain patients) or UPEP (for light-chain 
patients) becomes below detection limits/nonquantifiable. 
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PPD


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Table 9.b
Primary Specimen Collection Table
Specimen Name in Schedule 
of Procedures
Primary 
Specimen
Primary 
Specimen 
Derivative 1
Primary 
Specimen 
Derivative 2
Description of 
Intended Use
Sample 
Collection
Plasma sample for ixazomib 
PK
Plasma
N/A
N/A
PK 
Measurements
Mandatory
Abbreviation: 
 N/A, not applicable; PK, pharmacokinetics.
9.5
PK Measurements
Plasma concentrations of ixazomib (the complete hydrolysis product of ixazomib citrate) will be 
measured using a validated liquid chromatography tandem-mass spectrometry assay. Details 
regarding the preparation, handling, and shipping of the PK samples are provided in the Study
Manual. Blood samples (3 mL) for the determination of plasma concentrations of ixazomib will be 
collected during Cycles 1 through 5 as indicated in Appendix I.
Propert
9.5
9.5
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N/A
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PPD
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Upon implementation of Amendment 04, PK sample collection will be considered complete and 
no additional PK samples will be collected.
9.6
Completion of Study Treatment (for Individual Patients)
Patients will be considered to have completed the study when they have died or have had PD or 
when the sponsor terminates the study. 
9.7
Discontinuation of Treatment With Study Drug Treatment and Patient 
Replacement
Study therapy must be permanently discontinued for patients meeting any of the following criteria: 

Withdrawal by subject. 

Pregnancy.
Treatment with study therapy may also be discontinued for any of the following reasons:

AE.

PD.

Unsatisfactory therapeutic response.

Initiation of hematopoietic stem cell transplant.

Protocol deviation.

Study terminated by sponsor.

Lost to follow-up.

Physician decision.

Other.
Once study therapy has been discontinued, all study procedures outlined for the EOT visit will be 
completed as specified in the Schedule of Events (Appendix A). The primary reason for study 
therapy discontinuation will be recorded on the eCRF. 
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 Schedule of Events (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 Schedule of Events (Appendix A). Public records may be consulted as 
permitted per local regulations.
Patients remaining on study therapy at the time of study closure (whether completion of the study 
or any other reason) will be provided continued access to study therapy by the sponsor, either 
through commercial drug supply (where available and reimbursable) or through continued 
treatment in another extension or rollover study (see Section 6.3.5).
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9.8
Withdrawal of Patients From Study
A patient will be withdrawn from the study for any of the following reasons:

Death.

Study terminated by sponsor.

Withdrawal by subject.

Lost to follow-up. 

Other.
The consequence of a patient withdrawing consent from further treatment and follow-up is that no 
new information will be collected from the withdrawn patient and added to the existing data or any 
database. However, every effort will be made to follow all patients for safety. Data collected 
during patient consent, however, must be included in the database.
9.9
Study Compliance
Study drug treatment 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 treatment receipt and dispensing.
9.10
Study Closure
The study will be considered complete approximately 4 years after enrollment of the first patient, 
at the time of follow-up of approximately 1 additional year after 50% of patients have died or 
progressed. Patients remaining on ixazomib after study closure (whether completion of the study 
or any other reason) will be provided continued access to ixazomib by the sponsor (see 
Section 9.7).
Within 90 days of the end of the study, the sponsor will notify the competent authorities and the 
IECs in all member states where the study is being carried out that the study has ended.
Within 1 year after the end of the study, a summary of the clinical study results will be submitted to 
the competent authorities and IECs in all member states involved in the study.
Study participation by individual sites or the entire study may be prematurely terminated if, in the 
opinion of the investigator or Takeda, there is sufficient reasonable cause. Written notification 
documenting the reason for study termination will be provided to the investigator or Takeda by the 
terminating party.
Circumstances that may warrant termination include, but are not limited to:

Determination of unexpected, significant, or unacceptable risk to patients.

Failure to enter patients at an acceptable rate.

Insufficient adherence to protocol requirements.
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
Insufficient, incomplete, and/or unevaluable data.

Determination of efficacy based on an interim analysis.

Plans to modify, suspend, or discontinue the development of the study drug treatment.
Should the study be closed prematurely, the site will no longer be able to access the electronic data 
capture (EDC) application, will not have a right to use the EDC application, and will cease using 
the password or access materials once its participation in the study has concluded. In the event that 
any access devices for the EDC application have been provided, these will be returned to Takeda 
once the site’s participation in the study has concluded.
Within 15 days after premature closure, Takeda must notify the competent authorities and IECs of 
any member state where the study is being conducted, providing the reasons for study closure. 
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
An 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 treatment.
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).
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
Requires inpatient hospitalization or prolongation of an existing hospitalization (see 
clarification in the paragraph in Section 10.2 on planned hospitalizations).

Results in persistent or significant disability or incapacity. (Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions).

Is a congenital anomaly/birth defect.

Is a medically important event. This refers to an AE that may not result in death, be 
immediately life threatening, or require hospitalization, but may be considered serious when, 
based on appropriate medical judgment, may jeopardize the patient, require medical or 
surgical intervention to prevent 1 of the outcomes listed above, or involves suspected 
transmission via a medicinal product of an infectious agent. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse; any organism, virus, or infectious particle 
(eg, prion protein transmitting transmissible spongiform encephalopathy), pathogenic or 
nonpathogenic, is considered an infectious agent.
In this study, intensity for each AE, including any lab abnormality, will be determined using the 
NCI CTCAE, Version 4.03, effective date 14 June 2010 [54]. 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 (WBC) count of 
1000/mm3 to less than 2000 is considered Grade 3 (severe) but may not be considered serious. 
Seriousness (not intensity) serves as a guide for defining regulatory reporting obligations.
10.2
Procedures for Recording and Reporting AEs and SAEs 
All AEs spontaneously reported by the patient and/or in response to an open question from study 
personnel or revealed by observation, physical examination, or other diagnostic procedures will be 
recorded on the appropriate page of the eCRF (see Section 10.3 for the period of observation). Any 
clinically relevant deterioration in laboratory assessments or other clinical finding is considered an 
AE. When possible, signs and symptoms indicating a common underlying pathology should be
noted as 1 comprehensive event.
Regardless of causality, SAEs 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 
after becoming aware of the event. This should 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 should be sent. A sample of the paper-based SAE form and reporting 
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instructions are in the Study Manual. Information in the SAE report or form must be consistent 
with the data provided on the eCRF.
SAE Follow-Up
If information not available at the time of the first report becomes available at a later date, then the 
investigator should transmit a completed 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.
The paper SAE forms should be submitted via fax (see fax numbers below) within 24 hours of 
awareness. In case of fax, site personnel need to confirm successful transmission of all pages and 
include an email address on the fax cover sheet so that an acknowledgment of receipt can be 
returned via email within 1 business day. Email submission of paper SAE forms with a PDF 
attachment should only be used in the case where fax is not possible within 24 hours of receiving 
the event. In case of email, site personnel need to confirm successful transmission by awaiting an 
acknowledgment of the receipt via email within 1 business day. If SAEs are reported via fax or by 
email, the EDC application must be updated as soon as possible with the appropriate information.
SAE Reporting Contact Information
US and Canada
Cognizant
Toll-Free Fax #: 1-800-963-6290
Email: takedaoncocases@cognizant.com
All Other Countries Except Japan
Cognizant
Fax #: 1-202-315-3560
Email: takedaoncocases@cognizant.com
Planned hospital admissions or surgical procedures for an illness or disease that existed before 
study drug treatment was given are not to be considered AEs unless the condition deteriorated in 
an unexpected manner during the trial (eg, surgery was performed earlier or later than planned).
For both serious and nonserious AEs, the investigator must determine both the severity (toxicity 
grade) of the event and the relationship of the event to study drug treatment administration. 
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Severity (toxicity grade) for each AE, including any lab abnormality, will be determined using the 
NCI CTCAE, Version 4.03, effective date 14 June 2010 [17]. The criteria are provided in the 
Study Manual.
Relationship of the event to study drug treatment 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 treatment?”
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 therapy 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 
therapy 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 return to baseline or are clearly determined to be due to a patient’s stable or 
chronic condition or intercurrent illness(es). In addition, all cases of new primary malignancy 
must be immediately reported to the Takeda Department of Pharmacovigilance or designee, 
irrespective of causality to the study treatment regimen, from the time of first dose of the study 
treatment regimen through death (including the follow-up periods) or until termination of the 
study by the sponsor, whichever comes first. 

For the purposes of this study, HBV reactivation will be considered a medically significant 
event and should be reported as an SAE in the eCRF.
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 treatment. The 
sponsor must also be contacted immediately by transmitting 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 transmitting 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 to 
ctmcomplaint@takeda.com.
Product complaints or medication errors in and of themselves are not AEs. If a product complaint 
or medication error results in an SAE, an SAE Form should be completed and sent to Cognizant 
(refer to Section 10.2).
A medication error is a preventable event that involves an identifiable patient and that leads to 
inappropriate medication use, which may result in patient harm. Whereas overdoses and 
underdoses constitute medication errors, doses missed inadvertently by a patient do not. 
Individuals who identify a potential medication error (including overdose) situation should 
immediately report this to Cognizant (refer to Section 10.2).
10.6
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, including the EMA 
investigators and IRBs or IECs, as applicable, in accordance with national regulations in the 
countries where the study is conducted. Relative to the first awareness of the event by/or further 
provision to the sponsor or sponsor’s designee, SUSARs will be submitted to the regulatory 
authorities as an expedited report within 7 days for fatal and life-threatening events and 15 days for 
other serious events, unless otherwise required by national regulations. The sponsor will also 
prepare an expedited report for other safety issues where these might materially alter the current 
benefit-risk assessment of an investigational medicinal product or that would be sufficient to 
consider changes in the investigational medicinal product’s administration or in the overall 
conduct of the trial. The investigational site also will forward a copy of all expedited reports to his 
or her IRB or IEC in accordance with national regulations. 
11.0
STUDY-SPECIFIC COMMITTEES
In accordance with Takeda standard operating procedures, each clinical trial is evaluated to 
determine whether a Drug Safety Monitoring Board (DSMB) should be convened. Applicable 
regulation and guidance (including the guidance set forth by the FDA as described in the Guidance 
for Clinical Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring 
Committees [www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126578.pdf]) are 
used to evaluate each trial in terms of potential confounding factors that complicate evaluation of 
the study safety and/or efficacy data, and potential risks of the study design or treatment to study 
participants. 
A DSMB is not indicated at this time for this study given that 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, are appropriate for the ongoing monitoring of patient safety and 
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data integrity. However, the decision to convene a DSMB could be made at any time during the 
conduct of Study C16047 (see below and Section 13.2 for a description of an internal interim 
safety review).
Though a formal DSMB will not be formed, a steering committee is planned that may include but 
is not limited to, a subset of study investigators, trial clinician, and a sponsor senior clinical and 
pharmacovigilance representative. This committee will examine the internal safety interim review 
described in Section 13.1.9. This review will be prepared by the sponsor and provided to this 
committee for review and possible study conduct recommendations.
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, PTEs, medical history, and concurrent conditions will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the 
World Health Organization (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, contract research 
organization (CRO) partners, and regulatory authorities. Investigative sites must complete eCRFs 
in English.
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site.
Any change of, modification of, or addition to the data on the eCRFs should be made by the 
investigator or appropriate site personnel. Corrections to eCRFs are recorded in an audit trail that 
captures the old information, the new information, identification of the person making the 
correction, the date the correction was made, and the reason for change.
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the principal investigator must retain 
full responsibility for the accuracy and authenticity of all data entered on the eCRFs.
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The sponsor or its designee will be permitted to review the 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.
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12.2
Record Retention 
The following procedure is applied for all countries involved in this study. The investigator agrees 
to keep the records stipulated in Section 12.1 and those documents that include (but are not limited 
to) the study-specific documents, the identification log of all participating 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 copy of eCRFs, including the audit trail, and detailed records of 
drug disposition to enable evaluations or audits from regulatory authorities, the sponsor, or its 
designees. Any source documentation printed on degradable thermal sensitive paper should be 
photocopied by the site and filed with the original in the 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 on 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
This phase 2 study is designed to evaluate the safety and efficacy of IDd. Approximately 
60 patients will be enrolled. The primary endpoint is the rate of confirmed VGPR or better 
(CR+VGPR) as defined by IMWG criteria and evaluated by the investigator. An interim safety 
review will be conducted after the first 15 patients have been enrolled and have had the chance to 
have been treated for 4 cycles. The first interim analysis, of the CR+VGPR rate, will be conducted 
6 months after the last patient is enrolled. The second interim analysis will be conducted after 50% 
of the PFS events (ie, death or PD) have occurred. The final analysis will be conducted 1 year after 
50% of the PFS events have occurred. 
A statistical analysis plan (SAP) will be prepared and finalized before database lock for the first 
interim analysis. Deviations from the statistical analyses outlined in this protocol will be indicated 
in the SAP; any further modifications will be noted in the final clinical study report.
13.1.1
Analysis Sets
The populations used for analysis will include the following:

Safety population: Patients who receive at least 1 dose of any study treatment regimen. 
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
Response-evaluable population: Patients who receive at least 1 dose of ixazomib, have 
measurable disease during the screening period, and have at least 1 postbaseline disease 
assessment. 
13.1.2
Analysis of Demographics and Other Baseline Characteristics
The demographic and baseline characteristics will be summarized in a descriptive fashion. Data to 
be evaluated will include age, sex, race or ethnic group, baseline disease characteristics, and other 
parameters, as appropriate.
13.1.3
Efficacy Analyses
13.1.3.1
Primary Efficacy
The primary endpoint is the rate of VGPR or better. The first interim analysis, which is the primary 
efficacy analysis, will be based on the response-evaluable population. Estimates of the rate of 
VGPR or better will be presented with 2-sided 95% exact binomial confidence intervals. This 
analysis will occur 6 months after the last patient is enrolled.
13.1.3.2
Secondary Efficacy
The secondary efficacy parameters include PFS, TTP, OS, ORR, TTR, and DOR. The second 
interim analysis, which is the secondary efficacy analysis, will be conducted after 50% of the PFS 
events have occurred.
PFS is defined as the time from the date of first dose of study treatment to the date of first 
documented PD or death, whichever occurs first. Patients without PD or death will be censored at 
the date of last response assessment that is stable disease or better. 
TTP is defined as the time from the date of first dose of study treatment to the date of first 
documentation of PD. Patients without PD will be censored at the date of last response assessment 
that is stable disease or better. 
OS is defined as the time from the date of first dose of study treatment to the date of death. Patients 
without death will be censored at the date last known to be alive. 
ORR is defined as the pooled rate of PR, VGPR, and CR, as evaluated by the investigator
according to IMWG criteria.
TTR is defined as the time from the date of first dose of study treatment to the date of the first 
documentation of a confirmed response.
DOR is defined as the time from the date of first documentation of a confirmed response to the date 
of first documented PD.
PFS, TTP, and OS will be analyzed for the safety population. TTR and DOR, measured in the 
population of patients with a confirmed response, will be analyzed for the response-evaluable 
population. These data will be analyzed using standard survival analysis techniques based on 
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Kaplan-Meier estimates and will be summarized by 25th, 50th (median), and 75th percentiles with 
associated 2-sided 95% confidence intervals, as well as percentage of censored observations.
The response rates will be analyzed for the response-evaluable population. The response rates will 
be analyzed similarly to the primary endpoint. 
13.1.4
PK Analysis 
PK data collected in this study will contribute to future population PK analyses of ixazomib. These 
analyses may include data from other ixazomib clinical studies. The plan for the population PK 
analysis will be defined separately and the results will be reported separately. The PK data 
collected in this study may also contribute to exposure-response (safety/efficacy) analyses. The 
results of any exposure-response analyses will be reported separately.
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time. This will be repeated for all subscales of the EORTC QLQ-C30 and QLQ-MY20 with 
specific interest on the global QOL summary score, physical functioning, fatigue, 
nausea/vomiting, pain, dyspnea, appetite loss, and constipation/diarrhea. The change in score from 
baseline will also be presented using cumulative distribution function figures. The number and 
percentage of patients with an improvement in score from baseline based on minimally important 
differences will be summarized over time. The scores will also be analyzed using repeated 
measures linear mixed models.
13.1.9
Safety Analysis
Safety data will be included in data listings and tabulations. Data that are potentially spurious or 
erroneous will be examined according to standard data management operating procedures.
Safety will be evaluated by the incidence of AEs, severity and type of AEs, and changes from 
baseline in the patient’s vital signs, weight, and clinical laboratory results in the safety population. 
Exposure to study therapy and reasons for discontinuation will be tabulated.
TEAEs that occur after administration of the first dose of study therapy and through 30 days after 
the last dose of study therapy will be tabulated. 
AEs will be tabulated according to MedDRA and will include the following categories: 

TEAEs.

Drug-related TEAEs.

Grade 3 TEAEs.

Grade 4 or higher TEAEs.

Grade 3 drug-related TEAEs.

Grade 4 or higher drug-related TEAEs.

The most commonly reported TEAEs (ie, those reported by ≥10% of all patients).

All SAEs.

New primary malignancies. 

Any AE resulting in dose modification or discontinuation of any study therapy.

Any other AE that in the opinion of the investigator is a clinically significant event. 
Descriptive statistics for the actual values of clinical laboratory parameters (and/or change from 
baseline in clinical laboratory parameters) will be presented for all scheduled measurements over 
time. Mean laboratory values over time will be plotted for key laboratory parameters. 
Shift tables for laboratory parameters will be generated for changes in NCI CTCAE grade from 
baseline to the worst postbaseline value. Graphical displays of key safety parameters, such as 
scatter plots of baseline versus worst postbaseline values, may be used to understand the ixazomib 
safety profile.
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Descriptive statistics for the actual values (and/or the changes from baseline) of vital signs and 
weight will be tabulated by scheduled time point. ECOG performance scores will be summarized 
using a shift table.
Incidence rate will be calculated for the safety population based on the new primary malignancy 
assessment:

Incidence proportions, defined as the percentage of the subjects reporting any new primary 
malignancy in the safety population with available information, along with 95% confidence 
intervals, will be calculated. 
Analyses of new primary malignancies may be performed separately for hematologic and 
nonhematologic malignancies.
All concomitant medications collected from the first dose of study therapy throughout the study 
period will be classified to preferred terms according to the WHO Drug Dictionary.
An interim safety review will be conducted after the first 15 patients have been enrolled and have 
had the chance to have been treated for 4 cycles. A descriptive evaluation of the available data 
from these patients will include toxicity characterization (Grade 3 or 4 AEs, SAEs, all grades of 
peripheral neuropathy, and treatment discontinuation) and study drug treatment exposure. The 
study will continue during this safety review, which will be conducted by a steering committee 
(see Section 11.0) and reviewed with at least a subset of study investigators.
Additional safety analyses may be performed to more clearly enumerate rates of toxicities and to 
further define the safety profile of ixazomib in combination with daratumumab and 
dexamethasone.
13.2
Interim Analysis and Criteria for Early Termination
Two interim analyses will be conducted: the first, 6 months after the last patient is enrolled in the 
study; the second, after 50% of PFS events have occurred. 
13.3
Determination of Sample Size
Statistical assumption was based on observed CR+VGPR rates in clinical studies with ixazomib 
[4], bortezomib [5], and daratumumab [6].
The sample size is calculated using the binomial exact test for single proportion based on the rate 
of VGPR or better of the IDd treatment regimen. With 54 response-evaluable patients, there will 
be 95% power to test a null hypothesis of a rate of VGPR or better of 30% and an alternative 
hypothesis of a rate of VGPR or better of 55% at 2-sided significance level of α=0.05. Therefore, 
assuming 10% of patients are not response-evaluable, the total enrollment will be approximately 
60 patients.
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14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and institution guarantee access to source documents by the sponsor or its 
designee (CRO) and by the IRB or IEC.
All aspects of the study and its documentation will be subject to review by the sponsor or designee 
(as long as blinding is not jeopardized), including but not limited to the IB, 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.
In the event a monitor cannot visit the site in a timely manner due to the COVID-19 pandemic, 
alternative monitoring approaches such as remote source data verification or telephone contact 
may be used to ensure data quality and integrity and maintain patient safety. Alternative 
monitoring approaches should be used only where allowed by the local health authority and 
permitted by the IRB/IEC, if required. For France, alternative monitoring approaches should be 
used only if approved as a contingency measure by ANSM (French Agency for Medicines and 
Health Products Safety) and permitted by the IEC, if required.
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 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 will be 
reported to regulatory authorities as a serious breach of GCP and the protocol.
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 IEC, 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 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 will be 
reported to regulatory authorities as a serious breach of GCP and the protocol.
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14.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the FDA, the United Kingdom Medicines and Healthcare 
products Regulatory Agency, the Pharmaceuticals and Medical Devices Agency of Japan). If the 
study site is contacted for an inspection by a regulatory body, the sponsor should be notified 
immediately. The investigator and institution guarantee access for quality assurance auditors to all 
study documents as described in Section 14.1.
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 due to privacy and conflict of interest concerns should instead provide a Federal Wide 
Assurance Number or comparable number assigned by the Department of Health and Human 
Services.
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the IB, a copy of the ICF, and, if 
applicable, subject recruitment materials and/or advertisements and other documents required by 
all applicable laws and regulations, must be submitted to a central or local IRB or IEC for 
approval. The IRB’s or IEC’s written approval of the protocol and 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 exact protocol title, number, and version date; identify 
versions of other documents (eg, ICF) reviewed; and state the approval date. If required by either 
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 
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site regulatory documentation and, when applicable, the sponsor has received permission from 
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 
approvals and relevant documentation for these items must be provided to the sponsor or its 
designee.
Subject incentives should not exert undue influence for participation. Payments to 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, as well as 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 prior to 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. In the event 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 or not to participate in the study. If the 
subject, or the subject’s legally acceptable representative, determines 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 prior to the 
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subject entering into the study. The subject or the subject’s legally acceptable representative 
should be instructed to sign using their legal names, not nicknames, using blue or black ballpoint 
ink. The investigator must also sign and date the ICF and subject authorization (if applicable) at 
the time of consent and prior to subject entering into the study; however, the sponsor may allow a 
designee of the investigator to sign to the extent permitted by applicable law.
Once signed, the original ICF, subject authorization form (if applicable), and subject information 
sheet (if applicable) will be stored in the investigator’s site file. The investigator must document 
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 only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited 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, FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the 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 
personally identifiable information removed (ie, 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 
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law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
this section and the Clinical Study Site Agreement. In the event of any discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail.
15.4.2
Clinical Trial Registration
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum register 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov or other 
publicly accessible websites on or before start of study, as defined in Takeda Policy/Standard. 
Takeda contact information, along with investigator’s city, state (for 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 to find a clinical trial by helping them locate trial sites closest 
to their homes by providing the investigator name, address, and phone number via email/phone or 
other methods callers requesting trial information. Once 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.gov and 
www.clinicaltrialsregister.eu, as well as on other publicly accessible websites (including the 
Takeda corporate site) and registries, as required by Takeda Policy/Standard, applicable laws 
and/or regulations. 
Data Sharing
The sponsor is committed to responsible sharing of clinical data with the goal of advancing 
medical science and improving patient care. Qualified independent researchers will be permitted 
to use data collected from patients during the study to conduct additional scientific research, which 
may be unrelated to the study drug treatment or the patient’s disease. The data provided to external 
researchers will not include information that identifies patients personally.
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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 
compensation and treatment for injury. If the investigator has questions regarding this policy, he or 
she should contact the sponsor or sponsor’s designee.
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16.0
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26. Laubach JP, Tai YT, Richardson PG, Anderson KC. Daratumumab granted breakthrough drug 
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28. Lonial S, Weiss BM, Usmani SZ, Singhal S, Chari A, Bahlis NJ, et al. Daratumumab 
monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, 
randomised, phase 2 trial. Lancet 2016;387(10027):1551-60.
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therapeutic human CD38 antibody daratumumab improves the anti-myeloma effect of newly 
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32. Kong S-Y, Li X-F, Nahar S, Song W, de Weers M, Parren P, et al. Daratumumab directly 
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34. Bonnet A, Moreau P. Safety of ixazomib for the treatment of multiple myeloma. Expert Opin 
Drug Saf 2017;16(8):973-80.
35. REVLIMID (lenalidomide) [prescribing information]. Summit, NJ: Celgene Corporation, 
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36. Revlimid 2.5 mg hard capsules (lenalidomide) [Summary of Product Characteristics]. United 
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Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and 
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40. Foroni L, Coyle LA, Papaioannou M, Yaxley JC, Sinclair MF, Chim JS, et al. Molecular 
detection of minimal residual disease in adult and childhood acute lymphoblastic leukaemia 
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flow cytometric remission is the most relevant prognostic factor for multiple myeloma patients 
who undergo autologous stem cell transplantation. Blood 2008;112(10):4017-23.
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46. Martinez-Sanchez P, Montejano L, Sarasquete ME, Garcia-Sanz R, Fernandez-Redondo E, 
Ayala R, et al. Evaluation of minimal residual disease in multiple myeloma patients by 
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47. Paiva B, Martinez-Lopez J, Vidriales MB, Mateos MV, Montalban MA, Fernandez-Redondo 
E, et al. Comparison of immunofixation, serum free light chain, and immunophenotyping for 
response evaluation and prognostication in multiple myeloma. Journal of Clinical Oncology 
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48. Krejcik J, Casneuf T, Nijhof IS, Verbist B, Bald J, Plesner T, et al. Daratumumab depletes 
CD38+ immune regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in 
multiple myeloma. Blood 2016;128(3):384-94.
49. Rajkumar SV, Dimopoulos MA, Palumbo A, Blade J, Merlini G, Mateos MV, et al. 
International Myeloma Working Group updated criteria for the diagnosis of multiple 
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52. Chapuy CI, Nicholson RT, Aguad MD, Chapuy B, Laubach JP, Richardson PG, et al. 
Resolving the daratumumab interference with blood compatibility testing. Transfusion 
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Appendix A
Schedule of Events
A-1 
Schedule of Events (28-Day Cycle) for Use Until Final Analysis
Study Procedure
Treatment Period (a)
EOT
Follow-Up
Cycle X and Beyond, Day 1 of Each 28-Day Cycle
Up to 30 Days 
After Last Dose
PFS
Q4 Wk Until PD
OS
Q12 Wk After PD
Window, ± 2 days
Window, +1 wk
Window, ±1 wk
Informed Consent (Reconsent)
X (b)
Complete Physical Examination
X
Symptom-Directed Physical Examination 
(c)
X
HBV Testing (c)
X (d)
X (d)
X (d)
X (c, e)
ECOG Performance Status (c)
X
X
Vital Signs (c, f)
X
X
Weight in kg (c)
X
X
EORTC QLQ-C30 (g) 
X (h)
X (h)
X (h)
X (h)
EORTC QLQ-MY20 (g)
X (h)
X (h)
X (h)
X (h)
Soft-tissue plasmacytoma (c, i)
X (i)
X (i)
Investigator’s assessment of disease 
response/status
X
X
X
X
AE reporting (j)
New onset recorded from signing of ICF through 30 days after last dose of study therapy
SAEs collected from signing of ICF through 30 days after last dose of study therapy 
(see Section 10.3)
Monitoring of concomitant 
medications/procedures
Recorded from signing of ICF through 30 days after last dose of study therapy
New primary malignancy
Assessment continuous from start of study drug administration until death or termination of study by the sponsor (see Section 10.3)
Survival
X
Subsequent therapy
X (k)
Study Therapy Administration
Dexamethasone (l)
Days 1, 2, 8, 9, 15, 16, 22, and 23 in each cycle
Daratumumab (m)
IV infusion Q4 wk (from Cycle 7) until PD
Ixazomib (m)
Days 1, 8, and 15 of each cycle
Samples/Laboratory Assessments 
Hematology laboratory tests (c, n)
X
X
Chemistry laboratory tests (c, n)
X
X
Urinalysis
X
Property o
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da: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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OT
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to 30
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After L
A
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Study Procedure
Treatment Period (a)
EOT
Follow-Up
Cycle X and Beyond, Day 1 of Each 28-Day Cycle
Up to 30 Days 
After Last Dose
PFS
Q4 Wk Until PD
OS
Q12 Wk After PD
Window, ± 2 days
Window, +1 wk
Window, ±1 wk
Whole blood for immune profiling and 
immune cell function assays (c, o)
X
X
Whole blood for T-cell clonality (c, p)
X
X
Serum sample for antibody titers (c, q)
X
X
M-protein measurements (SPEP) (c)
X
X
X
M-protein measurements (UPEP [24-hr 
urine collection]) (c)
X
X
X
Serum free light-chain assay (c)
X
X
X
Immunofixation - serum and urine (c, r)
X
X
X
Quantification of immunoglobulins (c, s)
X
X
X
BMA or biopsy for disease assessment (c)
X (u, v)
X (u)
X (u)
Abbreviations: AE: adverse event; BMA, bone marrow aspirate; COVID-19, coronavirus disease 2019; CR, complete response; CT, computed tomography; ECOG, Eastern Cooperative 
Oncology Group; eCRF, electronic case report form; EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire; EORTC QLQ-MY20, 
European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire–Multiple Myeloma Module; EOT, end of treatment; GCP, Good Clinical Practice; HBV, hepatitis 
B virus; hr, hour; ICF: informed consent form; IMWG: International Myeloma Working Group; IRB, institutional review board; IRR, infusion-related reaction; IV, intravenous; MRI, magnetic 
resonance imaging; 
; OS, overall survival; PD, progressive disease; PET, positron emission tomography; PFS, progression-free survival; Q, every; wk, week; 
SPEP, serum protein electrophoresis; TEAE, treatment-emergent adverse event; UPEP, urine protein electrophoresis; WBC, white blood cell.
(a) Tests and procedures should be performed on schedule, but, unless otherwise specified, occasional changes are allowable within a 2-day window for holidays, vacations, and other 
administrative reasons. If a visit or procedure cannot be performed within the window, then the Takeda project clinician or designee should be consulted. If the study schedule is shifted, 
assessments should be shifted to be aligned with the new schedule. 
(b) Before dosing on Day 1 of the next full treatment cycle upon implementation of Amendment 04, patients remaining on study treatment will need to be reconsented. Reconsenting should be 
done in person. Remote reconsenting is permitted as long as the process adheres to site, IRB/IEC, and GCP standards and local regulations.
(c) Alternative methods for administering study procedures/assessments may be considered when it is not possible for the patient to come to the study site due to the COVID-19 pandemic. 
Alternative methods should be considered for performing the assessments by other means than the patient presenting to the clinic (eg, remote assessment, having lab assessment performed at a 
facility closer to the patient’s home, etc). If an in-clinic visit is not possible, the permitted alternatives are as follows. These assessments/procedures may be waived: symptom-directed physical 
examination, ECOG performance status, vital signs, weight, whole blood, and serum sample for antibody titers. These assessments/procedures may be deferred until the next in-clinic visit: 
soft-tissue plasmacytoma, SPEP, UPEP, serum free light-chain assay, immunofixation, quantification of immunoglobulins, BMA, and biopsy. These assessments/procedures may be performed 
locally if possible and, if not, may be deferred until the next in-clinic visit: HBV testing and hematology and chemistry laboratory tests.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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e
b
Dose
ose
ab
ab
ab
ab
w, +1 wk
+1 wk
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eloma Wo
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vival;
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PD
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unless 
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schedul
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PPD


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(d) Patients who are already enrolled at the time of Amendment 02 should undergo local testing as soon as possible, on the basis of a newly identified safety risk of potential HBV reactivation 
with daratumumab. The HBV testing should consist of tests for HBV surface antigen, e antigen, core antibody, and DNA. If any of these tests is positive, consult a physician with expertise in 
managing HBV for guidance regarding stopping daratumumab, starting HBV antiviral therapy, and remaining on study. These patients should be monitored every cycle during, and for at least 
6 months after the end of, daratumumab treatment for clinical and laboratory signs of HBV reactivation (ie, positive HBV surface antigen, positive HBV e antigen, or positive HBV DNA) 
[50,51]. If this monitoring reveals HBV reactivation, further treatment, including stopping daratumumab if relevant, should be discussed with a physician with expertise in managing HBV. The 
sponsor’s study clinician (or designee) should be consulted about the continued administration of the other study drugs (ixazomib and dexamethasone).
(e) Patients undergoing monitoring for HBV reactivation must visit the clinic for testing during the OS follow-up period. 
(f) Measurement of blood pressure and heart rate is to be performed during the treatment period; temperature and respiratory rate are collected only as clinically indicated. Blood pressure must 
be checked before and after each daratumumab infusion. 
(g) Patient-reported outcomes should be completed before any other study procedures are performed or study therapy is administered. 
(h) Patient-reported outcome questionnaires are to be provided to patients at every other cycle starting at Cycle 2. If the patient discontinues treatment for a reason unrelated to PD, then EORTC 
QLQ-C30 and QLQ-MY20 completion should continue every 8 weeks until PD. After progression, EORTC QLQ-C30 and QLQ-MY20 should be completed at first 2 OS follow-up visits. 
Patient-reported outcome questionnaires are preferred to be completed by patients in the clinic, but if needed during the COVID-19 pandemic, the EORTC QLQ-C30 and QLQ-MY20 may be 
completed at the patient’s home using mailed paper versions of the questionnaires; if self-reporting by a patient is not possible at the clinic or at home, the questionnaires may be completed over 
the telephone.
(i) Imaging to assess extramedullary disease will be done at screening (within 8 weeks before enrollment) for all patients by means of CT, MRI, or PET/CT. In patients for whom extramedullary 
disease is found at screening, additional assessments should be done, using the same modality, at Cycle 2 Day 1 and every other cycle thereafter during the treatment period (ie, Cycle 4 Day 1, 
Cycle 6 Day 1), and every 8 weeks during PFS follow-up until the patient has PD. Imaging should be done at EOT if it supports PD, unless progression has already been shown on imaging 
acceptable to the investigator; otherwise it may be done at the physician’s discretion. 
(j) 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. 
(k) For subsequent therapy, type of therapy, start and end date, best response, and date of progression should be recorded in the eCRF if available.
(l) Dexamethasone is usually given as 1 dose; however in this study it will be given in split doses as follows: dexamethasone will be given as 20 mg on Day 1, 2, 8, 9, 15, 16, 22, and 23 in each 
28-day cycle, to achieve the standard total of 40 mg per week (2 doses of 20 mg per week). During weeks when the patient receives an infusion of daratumumab, the first dexamethasone dose 
will be given before the daratumumab infusion, with the second dexamethasone dose given the day after. Dexamethasone should be given IV before the first daratumumab dose; but can be given 
IV or orally thereafter. The dose of dexamethasone can be reduced to 20 mg once weekly for patients who are older than 75 years, have poorly controlled diabetes, or had prior intolerance to or 
AE from corticosteroid therapy. See Section 8.2.4 for more details on dexamethasone administration. 
(m) Pre-infusion medication of oral antipyretics and oral antihistamine will be administered. If ixazomib and daratumumab are to be administered in the same week, they should be administered 
on the same day of the week. With the potential of IRRs with daratumumab, during the first cycle of therapy it is preferable to give the daratumumab dose before the ixazomib dose to allow for 
the correct safety assessment and management of any IRR. If no Grade 3 or higher IRR occurred during the previous cycle, starting with Cycle 2 and with subsequent cycles on daratumumab 
infusion days, ixazomib may be administered prior to or at approximately the same time as the premedications. The daratumumab infusion should then begin approximately 1 hour after the 
ixazomib administration. See Section 8.2.2 for more details on daratumumab administration and Section 8.2.3 for more details on ixazomib administration.
(n) Hematology and chemistry laboratory samples will be collected centrally and may be collected up to 3 days before Day 1 dosing and within 24 hours before Days 8 and 15 dosing, where 
required. Local laboratory evaluations may be done more frequently at the investigator’s discretion (ie, for acute management of TEAEs) and may be used for dosing decisions. A differential 
WBC count with absolute lymphocyte count is requested approximately 3 months after EOT, if feasible. 
(o) Whole blood measurements are to be taken for immune profiling to measure changes in immune cell subsets, T-cell clonality, titers of noninvolved immunoglobulins, etc. Samples to be 
taken at study entry (predose) and then blood collected every cycle for the first 6 cycles and then every 3 cycles thereafter until PD; a sample is also requested at relapse if feasible. 
(p) Whole blood measurements are to be taken for analysis of immune cell function. Samples to be taken on Day 1 of each cycle up to Cycle 6 and then every 3 cycles thereafter until 
progression; a sample is also requested at relapse if feasible. 
(q) Samples for antibody titers to be taken on Day 1 of each cycle up to Cycle 6 and then every 3 cycles thereafter until progression.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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CONFIDENTIAL
(r) Immunofixation is to be done to confirm CR (undetectable M-protein by protein electrophoresis in both serum and urine will lead the central laboratory to perform immunofixation testing in
both serum and urine). 
(s) Blood samples for IgM, IgG, and IgA will be obtained at screening and throughout the study at the time points specified. 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 for IgG and IgA. 
Property of Takeda: For Non-Commercial Use Only and Subj
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A-2
Schedule of Events After Final Analysis
Study Procedure
Treatment Period (a)
EOT
Cycle X and Beyond, Day 1 of Each 
28-Day Cycle
Up to 30 Days After Last Dose
Window, ± 2 days
Window, +1 wk
Informed consent (reconsent)
X (b)
Physical examination (c)
X
HBV testing (d)
X (e)
X (e)
Vital signs (d, f)
X
X
Weight in kg (d)
X
X
Investigator’s assessment of disease 
response/status
X
X
AE reporting (g)
New onset recorded from signing of ICF through 30 days after last dose of study therapy
SAEs collected from signing of ICF through 30 days after last dose of study therapy 
(see Section 10.3)
Monitoring of concomitant 
medications/procedures
Recorded from signing of ICF through 30 days after last dose of study therapy
New primary malignancy
Assessment continuous from start of study drug administration until death or termination of 
study by the sponsor (see Section 10.3)
Study Therapy Administration
Dexamethasone (h)
Days 1, 2, 8, 9, 15, 16, 22, and 23 in each 
cycle
Daratumumab (i)
IV infusion Q4 wk (from Cycle 7) until PD
Ixazomib (i)
Days 1, 8, and 15 of each cycle
Samples/Laboratory Assessments
Hematology laboratory tests (d, j)
X
X
Chemistry laboratory tests (d, j)
X
X
Pregnancy test (k)
X 
Abbreviations: AE, adverse event; COVID-19, coronavirus disease 2019; EOT, end of treatment; GCP, Good Clinical Practice; HBV, 
hepatitis B virus; ICF, informed consent form; IEC, independent ethics committee; IRB, institutional review board; IRR, infusion-related 
reaction; IV, intravenous; OS: overall survival; PD, progressive disease; Q, every; wk, week; SAE: serious adverse event; TEAE, 
treatment-emergent adverse event; WBC, white blood cell; wk: week.
Note: After the final analysis is conducted, the sponsor will notify the investigators and sites when this new Schedule of Events will go into 
effect. At this time, an end of study form should be completed for any patient in OS follow up.
(a) Tests and procedures should be performed on schedule, but, unless otherwise specified, occasional changes are allowable within a 2-day 
window for holidays, vacations, and other administrative reasons. If a visit or procedure cannot be performed within the window, then the 
Takeda project clinician or designee should be consulted. If the study schedule is shifted, assessments should be shifted to be aligned with 
the new schedule. 
(b) Reconsenting should be done in person. Remote reconsenting is permitted as long as the process adheres to site, IRB/IEC, and GCP 
standards and local regulations.
(c) Assessment will be performed at the discretion of the investigator.
(d) Alternative methods for administering study procedures/assessments may be considered when it is not possible for the patient to come 
to the study site due to the COVID-19 pandemic. Alternative methods should be considered for performing the assessments by other means 
than the patient presenting to the clinic (eg, remote assessment, having laboratory assessment performed at a facility closer to the patient’s 
home). If an in-clinic visit is not possible, the permitted alternatives are as follows. These assessments/procedures may be waived: physical
examination, vital signs, and weight. These assessments/procedures may be performed locally if possible and, if not, may be deferred until 
the next in-clinic visit: HBV testing and hematology and chemistry laboratory tests.
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(e) Patients who are already enrolled at the time of Amendment 02 should undergo local testing as soon as possible, on the basis of a newly 
identified safety risk of potential HBV reactivation with daratumumab. The HBV testing should consist of tests for HBV surface antigen, e 
antigen, core antibody, and DNA. If any of these tests is positive, consult a physician with expertise in managing HBV for guidance 
regarding stopping daratumumab, starting HBV antiviral therapy, and remaining on study. These patients should be monitored every cycle 
during, and for at least 6 months after the end of, daratumumab treatment for clinical and laboratory signs of HBV reactivation (ie, positive 
HBV surface antigen, positive HBV e antigen, or positive HBV DNA) [50,51]. If this monitoring reveals HBV reactivation, further 
treatment, including stopping daratumumab if relevant, should be discussed with a physician with expertise in managing HBV. The 
sponsor’s study clinician (or designee) should be consulted about the continued administration of the other study drugs (ixazomib and 
dexamethasone).
(f) Measurement of blood pressure and heart rate is to be performed during the treatment period; temperature and respiratory rate are 
collected only as clinically indicated. Blood pressure must be checked before and after each daratumumab infusion. 
(g) Patients should be assessed and treated per standard of care. All AEs/SAEs will be recorded in the eCRF according to the criteria 
outlined in Section 10.0. Patient safety outside the protocol assessments should be monitored during the time between on-site visits at the 
investigator's discretion, per standard of care. At minimum, there will be a phone call with an investigator within the specified-visit window 
timeframe, which will include an assessment of AEs/SAEs.
(h) Dexamethasone is usually given as 1 dose; however in this study it will be given in split doses as follows: dexamethasone will be given 
as 20 mg on Day 1, 2, 8, 9, 15, 16, 22, and 23 in each 28-day cycle, to achieve the standard total of 40 mg per week (2 doses of 20 mg per 
week). During weeks when the patient receives an infusion of daratumumab, the first dexamethasone dose will be given before the 
daratumumab infusion, with the second dexamethasone dose given the day after. Dexamethasone should be given IV before the first 
daratumumab dose; but can be given IV or orally thereafter. The dose of dexamethasone can be reduced to 20 mg once weekly for patients 
who are older than 75 years, have poorly controlled diabetes, or had prior intolerance to or AE from corticosteroid therapy. See Section 
8.2.4 for more details on dexamethasone administration. 
(i) Pre-infusion medication of oral antipyretics and oral antihistamine will be administered. If ixazomib and daratumumab are to be 
administered in the same week, they should be administered on the same day of the week. With the potential of IRRs with daratumumab, 
during the first cycle of therapy it is preferable to give the daratumumab dose before the ixazomib dose to allow for the correct safety 
assessment and management of any IRR. If no Grade 3 or higher IRR occurred during the previous cycle, starting with Cycle 2 and with 
subsequent cycles on daratumumab infusion days, ixazomib may be administered prior to or at approximately the same time as the 
premedications. The daratumumab infusion should then begin approximately 1 hour after the ixazomib administration. See Section 8.2.2
for more details on daratumumab administration and Section 8.2.3 for more details on ixazomib administration.
(j) Patients should be assessed and treated according to standard of care using either central or local laboratory evaluations, depending on 
the site's decision. Abnormal hematology and chemistry data are to be collected and recorded in the eCRF only to the extent that they are 
needed to document or support an AE. Laboratory assessments to inform dosing decisions and routinely monitor patients do not need to be 
recorded in the eCRF. 
(k) Pregnancy tests will be performed at Day 1 of every cycle during the study upon request by IECs/IRBs or if required by local 
regulations.
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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 Code of Federal Regulations (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. This responsibility lies on 
the appropriate individual, designated by the site in Japan.
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 investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, 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.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study medication.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s own 
country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.
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Appendix D
Eastern Cooperative Oncology Group 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, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response criteria 
of the Eastern Cooperative Oncology Group. American Journal of Clinical Oncology 1982;5(6):649-55.
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Appendix E
IMWG Uniform Response Criteria for MM 
Source: Palumbo 2014 [3]
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Appendix F
EORTC QLQ-C30 (version 3)
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Appendix G
EORTC QLQ-MY20
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Appendix H
Acceptable Methods of Contraception
Female patients: Unless the patient cannot have children because of surgery or other medical
reasons (had an effective tubal ligation, had the ovaries or the uterus removed, or is 
postmenopausal), the patient must use 2 effective methods of birth control from the time of signing
the ICF, for the entire study drug treatment period (including interruptions in treatment) and for 90
days after completing study drug treatment. It is strongly recommended that at least 1 of these 2
methods be highly effective (see examples below):
Highly Effective Methods
Other Effective Methods (Barrier)
Intra-Uterine Devices (IUD)
Latex or nonlatex condom with or without a 
spermicidal agent
Hormonal (birth control pills/oral contraceptives, 
injectable contraceptives, contraceptive patches, or 
contraceptive implants)
Diaphragm with spermicide; cervical cap with a 
spermicide; sponge with a spermicide
If 1 of the highly effective methods cannot be used, using 2 effective methods at the same time is recommended.
The patient must use birth control methods as directed above, unless the patient completely avoids
having heterosexual intercourse.
Male patients: We do not know if using ixazomib will affect sperm. Therefore, due to potential
risk, the patient should not get a partner pregnant during the study drug treatment period (including 
interruptions in treatment). Even if the patient is surgically sterilized (ie, had a vasectomy) the 
patient must agree to use an appropriate method of barrier contraception (latex or nonlatex condom 
with or without a spermicidal agent) during the entire study drug treatment period and for 90 days
after completing study drug treatment. Or, the patient should completely avoid having heterosexual
intercourse.
Highly Effective Methods
Other Effective Methods (Barrier)
Vasectomy
Latex or nonlatex condom with or without a spermicidal
agent
Diaphragm with spermicide; cervical cap with 
spermicide; sponge with spermicide
If 1 of the highly effective methods cannot be used, using 2 effective methods at the same time is recommended.
All patients (male or female): If the patient or a partner becomes pregnant during this study, the 
patient must tell the study doctor immediately. The doctor will advise the patient of the possible 
risks to the unborn child and discuss options for managing the pregnancy with the patient. For 
female patients who become pregnant while on this study, the study drug will be stopped
immediately and the pregnancy will be followed until conclusion.
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Appendix I
Schedule of Events (28-Day Cycle) Previous to Amendment 02
Study Procedures
Screening
Treatment Period (a)
EOT
Follow-Up
28-Day Cycles
PFS
OS
Cycle
Cycle 1
Cycles 2-3
Cycle 4 Onward
Up to 
30 Days 
After 
Last 
Dose
Every 4 
Weeks 
Until PD
Every 
12 
Weeks 
After 
PD
Days
-28 to 
-1
1
8
15
22
1
8
15
22
1
8
15
22
Window
± 2 days
+1 wk
±1 wk
±1 wk
Informed Consent
X
Inclusion/Exclusion Criteria 
(b) 
X
Demographics
X
Complete Medical History 
X
Complete Physical Exam 
X
X
Symptom-Directed Physical 
Exam
X
X
X
X
HBV Testing
X (c)
X (d)
X (d)
X (d)
X (d)
X (d)
X (e)
ECOG Performance Status 
X
X
X
X
X
Vital Signs (f) 
X
X
X
X
X
Height (cm) 
X
Weight (kg)
X
X
X
X
X
Forced expiratory testing for 
patients with known or 
suspected COPD 
X
Footnotes are on last table page.
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Schedule of Events (28-Day Cycle) Previous to Amendment 02 (continued)
Study Procedures
Screening
Treatment Period (a)
EOT
Follow-Up
28-Day Cycles
PFS
OS
Cycle
Cycle 1
Cycles 2-3
Cycle 4 Onward
Up to 
30 
Days 
After 
Last 
Dose
Every 
4 
Weeks 
Until 
PD
Every 
12 
Week
s 
After 
PD
Days
-28 to 
-1
1
8
15
22
1
8
15
22
1
8
15
22
Window
± 2 days
+1 wk
±1 wk
±1 wk
Blood type assessment prior 
to first dose of 
daratumumab only
X
EORTC QLQ-C30 (g)
X
X
X (h)
X (h)
X (h)
X (h)
X (h)
EORTC QLQ-MY20 (g)
X
X
X (h) 
X (h)
X (h)
X (h)
X (h)
Imaging Disease 
Assessments
Bone (i)
X
Soft-tissue 
plasmacytoma (j)
X (j)
X (j)
X (j)
X (j)
Investigator’s assessment of 
disease response/status 
X
X
X
X
X
X
AE reporting (k)
New onset recorded from the signing of ICF through 30 days after last dose of study therapy. 
SAEs collected from the signing of ICF through 30 days after last dose of study therapy (see Section 10.3).
Monitoring of concomitant 
medications/procedures
Recorded from the signing of ICF through 30 days after last dose of study therapy.
New Primary Malignancy
Assessment continuous from the start of study drug administration until death or termination of the study by the sponsor (see Section 10.3).
Survival
X
Subsequent therapy
X (l)
Footnotes are on last table page.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Protocol Incorporating Amendment No. 07
30 March 2022
CONFIDENTIAL
Schedule of Events (28-Day Cycle) Previous to Amendment 02 (continued)
Study Procedures
Screening
Treatment Period (a)
EOT
Follow-Up
28-Day Cycles
PFS
OS
Cycle
Cycle 1
Cycles 2-3
Cycle 4 Onward
Up to 
30 
Days 
After 
Last 
Dose
Every 
4 
Weeks 
Until 
PD
Every 
12 
Weeks 
After 
PD
Days
-28 to 
-1
1
8
15
22
1
8
15
22
1
8
15
22
Window
± 2 days
+1 wk
±1 wk
±1 wk
Study Therapy Administration
Dexamethasone (m)
Days 1, 2, 8, 9, 15, 16, 22, and 23 in each cycle.
Daratumumab (n)
IV infusion weekly in Weeks 1 through 8 (corresponding to Cycles 1 and 2; total of 8 doses)
Every 2 weeks in Weeks 9 through 24 (corresponding to Cycles 3 through 6; total of 8 doses),
and every 4 weeks (from Cycle 7) thereafter until PD. 
Ixazomib (n)
Days 1, 8, and 15 of each cycle
Footnotes are on last table page.
Property of Takeda: For Non-Commercial U
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Ixazomib (NINLARO)
Study No. C16047
Page 102 of 118
Protocol Incorporating Amendment No. 07
30 March 2022
CONFIDENTIAL
Schedule of Events (28-Day Cycle) Previous to Amendment 02 (continued)
Study Procedures
Screening
Treatment Period (a)
EOT
Follow-Up
28-Day Cycles
PFS
OS
Cycle
Cycle 1
Cycles 2-3
Cycle 4 Onward
Up to 
30 
Days 
After 
Last 
Dose
Every 
4 
Weeks 
Until 
PD
Every 
12 
Weeks 
After 
PD
Days
-28 to 
-1
1
8
15
22
1
8
15
22
1
8
15
22
Window
± 2 days
+1 wk
±1 wk
±1 wk
Samples/Laboratory Assessments 
Pregnancy test (o)
X
X
Hematology laboratory tests (p)
X
X
X
X
X
X
X
X
Chemistry laboratory tests (p)
X
X
X
X
X
Urinalysis
X
X
Archival Tumor Sample (q)
X
Whole blood for immune 
profiling and immune cell 
function assays (r)
X
X
X
X
X
Whole blood for T-cell clonality 
(s)
X
X
X
X
X
Serum sample for antibody titers 
(t)
X
X
X
X
X
Footnotes are on last table page.
Te
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pli
App
ct t
22
22
ec
S
c
ys
Su
and 
d
an
y
On
e O
e
Us
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cia
me
m
Com
on
on
on
on
m


Ixazomib (NINLARO)
Study No. C16047
Page 103 of 118
Protocol Incorporating Amendment No. 07
30 March 2022
CONFIDENTIAL
Schedule of Events (28-Day Cycle) Previous to Amendment 02 (continued)
Study Procedures
Screening
Treatment Period (a)
EOT
Follow-Up
28-Day Cycles
PFS
OS
Cycle
Cycle 1
Cycles 2-3
Cycle 4 Onward
Up to 
30 
Days 
After 
Last 
Dose
Every 
4 
Weeks 
Until 
PD
Every 
12 
Weeks 
After 
PD
Days
-28 to 
-1
1
8
15
22
1
8
15
22
1
8
15
22
Window
± 2 days
+1 wk
±1 wk
±1 wk
Samples/Laboratory Assessments 
M-protein measurements 
(SPEP) 
X
X (u)
X
X
X
X
M-protein measurements
(UPEP [24-hr urine
collection]) 
X
X (u)
X
X
X
X
Albumin and 
β2-microglobulin
X
Serum free light-chain
assay
X
X (u)
X
X
X
X
Immunofixation - serum 
and urine (v)
X
X (u)
X
X
X
X
Quantification of 
immunoglobulins (w)
X
X
X
X
X
X
BMA or biopsy for disease 
X 
(x,y,z)
X (aa)
X 
(aa,bb)
X (aa)
X (aa)
Abbreviations: EOT, end of treatment; HBV, hepatitis B virus; hr, hour; OS, overall survival; PFS, progression-free survival; wk, week. 
(a) Tests and procedures should be performed on schedule, but, unless otherwise specified, occasional changes are allowable within a 2-day window for holidays, vacations, and other 
administrative reasons. If a visit or procedure cannot be performed within the window, then the Takeda project clinician or designee should be consulted. If the study schedule is shifted, 
assessments should be shifted to be aligned with the new schedule. 
Property of T
da: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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PPD


Ixazomib (NINLARO)
Study No. C16047
Page 104 of 118
Protocol Incorporating Amendment No. 07
30 March 2022
CONFIDENTIAL
(b) Confirmation of patient eligibility by a Takeda project clinician or designee is required before enrollment. Cycle 1 Day 1 should be no later than 7 days after the date of enrollment call in
interactive response technology.
(c) HBV testing should be performed during screening, on the basis of a newly identified safety risk of potential HBV reactivation with daratumumab. The HBV testing should occur as follows: 
test patients locally for HBV surface antigen and HBV core antibody; if either of these tests is positive, then exclude the patient from the study.
(d) Patients who are already enrolled at the time of Amendment 02 should undergo local testing as soon as possible, on the basis of a newly identified safety risk of potential HBV reactivation 
with daratumumab. The HBV testing should consist of tests for HBV surface antigen, e antigen, core antibody, and DNA. If any of these tests is positive, consult a physician with expertise in 
managing HBV for guidance regarding stopping daratumumab, starting HBV antiviral therapy, and remaining on study. These patients should be monitored every cycle during, and for at least 
6 months after the end of, daratumumab treatment for clinical and laboratory signs of HBV reactivation (ie, positive HBV surface antigen, positive HBV e antigen, or positive HBV DNA) 
[50,51]. If this monitoring reveals HBV reactivation, further treatment, including stopping daratumumab if relevant, should be discussed with a physician with expertise in managing HBV. The 
sponsor’s study clinician (or designee) should be consulted about the continued administration of the other study drugs (ixazomib and dexamethasone).
(e) Patients undergoing monitoring for HBV reactivation must visit the clinic for testing during the OS follow-up period.
(f) Measurement of blood pressure and heart rate is to be performed during the treatment period; temperature and respiratory rate are collected only as clinically indicated. Blood pressure must 
be checked before and after each daratumumab infusion. 
(g) Patient-reported outcomes should be completed before any other study procedures are performed or study therapy is administered. 
(h) Patient-reported outcome questionnaires are to be provided to patients at every other cycle starting at Cycle 2. If the patient discontinues treatment for a reason unrelated to PD, then 
QLQ-C30 and MY20 should continue every 8 weeks until PD. After progression, QLQ-C30 and MY20 should be completed at first 2 OS follow-up visits; during OS follow-up only the 
questionnaires may be completed over the telephone if the patient does not attend clinic in person. 
(i) Imaging to assess status of bone disease will be done at screening (within 8 weeks before enrollment) for all patients by means of skeletal survey, CT, MRI, or PET/CT. Additional 
assessments for bone disease can be done at the discretion of the investigator (ie, for suspected increased or new bone lesions or PD) and should be done by the same modality. 
(j) Imaging to assess extramedullary disease will be done at screening (within 8 weeks before enrollment) for all patients by means of CT, MRI, or PET/CT. In patients for whom extramedullary 
disease is found at screening, additional assessments should be done, using the same modality, at Cycle 2 Day 1 and every other cycle thereafter during the treatment period (ie, Cycle 4 Day 1, 
Cycle 6 Day 1), and every 8 weeks during PFS follow-up until the patient has PD. Imaging should be done at EOT if it supports PD, unless progression has already been shown on imaging 
acceptable to the investigator; otherwise it may be done at the physician’s discretion. 
(k) 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. 
(l) For subsequent therapy, type of therapy, start and end date, best response, and date of progression should be recorded in the eCRF if available.
(m) Dexamethasone is usually given as 1 dose; however in this study it will be given in split doses as follows: dexamethasone will be given as 20 mg on Day 1, 2, 8, 9, 15, 16, 22, and 23 in each 
28-day cycle, to achieve the standard total of 40 mg per week (2 doses of 20 mg per week). During weeks when the patient receives an infusion of daratumumab, the first dexamethasone dose 
will be given before the daratumumab infusion, with the second dexamethasone dose given the day after. Dexamethasone should be given IV before the first daratumumab dose; but can be given 
IV or orally thereafter. The dose of dexamethasone can be reduced to 20 mg once weekly for patients who are older than 75 years, have poorly controlled diabetes, or had prior intolerance to or 
AE from corticosteroid therapy. See Section 8.2.4 for more details on dexamethasone administration. 
(n) Pre-infusion medication of oral antipyretics and oral antihistamine will be administered. If ixazomib and daratumumab are to be administered in the same week, they should be administered 
on the same day of the week. With the potential of IRRs with daratumumab, during the first cycle of therapy it is preferable to give the daratumumab dose before the ixazomib dose to allow for 
the correct safety assessment and management of any IRR. If no Grade 3 or higher IRR occurred during the previous cycle, starting with Cycle 2 and with subsequent cycles on daratumumab 
infusion days, ixazomib may be administered prior to or at approximately the same time as the premedications. The daratumumab infusion should then begin approximately 1 hour after the 
ixazomib administration. See Section 8.2.2 for more details on daratumumab administration and Section 8.2.3 for more details on ixazomib administration.
(o) For women of childbearing potential, 2 pregnancy tests (with 1 or both being a serum test) must be performed and results must be available and negative before dosing. The Cycle 1 Day 1 
pregnancy test may be collected up to 3 days prior. Pregnancy tests will be performed at Day 1 of every cycle during the study upon request by IECs/IRBs or if required by local regulations.
(p) Hematology and chemistry laboratory samples will be collected centrally and may be collected up to 3 days before Day 1 dosing and within 24 hours before Days 8 and 15 dosing, where 
required. Local laboratory evaluations may be done more frequently at the investigator’s discretion (ie, for acute management of TEAEs) and may be used for dosing decisions. A differential 
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Ixazomib (NINLARO)
Study No. C16047
Page 105 of 118
Protocol Incorporating Amendment No. 07
30 March 2022
CONFIDENTIAL
WBC count with absolute lymphocyte count is requested approximately 3 months after EOT, if feasible. 
(q) The material should consist of (in order of preference) unstained slides; BMA as a formalin-fixed, paraffin-embedded block; or stained slides. Bone marrow biopsy samples will not be 
accepted. This is a mandatory sample if available. 
(r) Whole blood measurements are to be taken for immune profiling to measure changes in immune cell subsets, T-cell clonality, titers of noninvolved immunoglobulins, etc. Samples to be 
taken at study entry (predose) and then blood collected every cycle for the first 6 cycles and then every 3 cycles thereafter until PD; a sample is also requested at relapse if feasible. 
(s) Whole blood measurements are to be taken for analysis of immune cell function. Samples to be taken on Day 1 of each cycle up to Cycle 6 and then every 3 cycles thereafter until progression; 
a sample is also requested at relapse if feasible. 
(t) Samples for antibody titers to be taken on Day 1 of each cycle up to Cycle 6 and then every 3 cycles thereafter until progression.
(u) Clinical laboratory evaluations for disease assessments (SPEP, UPEP, serum free light-chain, immunofixation, and immunoglobulin) must be sent to the central laboratory for evaluation 
until the secondary endpoint of PFS has been evaluated in this study. At that time, all central efficacy and investigator assessments for protocol purposes will be stopped and not recorded in the 
eCRF. 
(v) Immunofixation is to be done to confirm CR (undetectable M-protein by protein electrophoresis in both serum and urine will lead the central laboratory to perform immunofixation testing in 
both serum and urine). 
(w) Blood samples for IgM, IgG, and IgA will be obtained at screening and throughout the study at the time points specified. 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 for IgG and IgA. 
(x) Bone marrow biopsy or, if BMA used instead of biopsy, first pull of BMA to be used to assess disease status at screening. Assessment to be performed at a local laboratory. A clinically 
indicated BMA or biopsy drawn prior to consent is acceptable for the baseline assessment provided that it is collected within 42 days before the first dose.
t.
(
 Day 1 (± 1 week) for evaluation of immune profiling. If a patients is suspected to be in CR or has PD at this time, then the sequence of BMA 
pulls should be as described for those timepoints.
Property of Takeda: For Non-Co
r al U
ly and Subject to the Applicable Terms of Use
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ides. Bone
es. Bo
of noninv
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PPD


Ixazomib (NINLARO)
Study No. C16047
Page 106 of 118
Protocol Incorporating Amendment No. 07
30 March 2022
CONFIDENTIAL
Appendix I 
Previous Table A - PK Sampling Schedule (completed as of Amendment 04)
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Day 8
Day 15
Day 22
Day 1
Day 15
Day 1
Day 15
Day 1
Day 1
Predose (a)
X
X
X
X
X
X
X
X
X
(a) If a PK sample is collected on an ixazomib dosing day, the predose PK sample can be collected at any time before 
administration of ixazomib. If a PK sample is collected on a non-ixazomib dosing day, the PK sample can be collected 
at any time during the study visit. 
Note: If a predose PK sample is collected from the patient and the patient does not receive a dose of ixazomib on that 
protocol visit day, a second predose sample does not need to be collected on the subsequent visit where the dose is 
administered. All future visits should be performed per the protocol.
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Ixazomib (NINLARO)
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CONFIDENTIAL
Appendix J
COVID-19 Trial Communication Letter from Janssen-Cilag 
International NV
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Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


Ixazomib (NINLARO)
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Protocol Incorporating Amendment No. 07
30 March 2022
CONFIDENTIAL
Appendix K
Amendment 07 Detailed Summary of Changes 
The primary sections of the protocol affected by the changes in Amendment 07 are indicated. The 
corresponding text has been revised throughout the protocol.
Change 1: Change the legal entity name of the sponsor.
The change occurs on the Cover Page, in the Sponsor row:
Initial 
wording:
Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda 
Pharmaceutical Company Limited
40 Landsdowne Street
Cambridge, MA 02139, USA
Telephone: +1 (617) 679-7000
Please note: Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda Pharmaceutical 
Company Limited, may be referred to in this protocol as “Millennium,” “Sponsor,” or “Takeda”.
Amended or 
new wording:
Takeda Development Center Americas, IncMillennium Pharmaceuticals, Inc, a 
wholly owned subsidiary of Takeda Pharmaceutical Company Limited
40 Landsdowne Street95 Hayden Avenue
CambridgeLexington, MA 02139421, USA
Telephone: +1 (617) 679-7000
Please note: Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda Pharmaceutical 
Company Limited, may be referred to in this protocol as “Millennium,” “Sponsor,” or “Takeda”.
Rationale for Change: To reflect the new legal entity name for the sponsor of Takeda Development 
Center Americas rather than Millennium.
The following sections also contain this change:

Section 2.0 STUDY SUMMARY.

Section 3.5 Corporate Identification.

Section 4.2 Ixazomib.
Change 2: Add a new Schedule of Events to Appendix A for future use, after the final analysis has 
been conducted.
The primary change occurs in to Appendix A Schedule of Events:
Description of 
change:

Added new Schedule of Events
The following sections also contain this change:

Section 9.4 Study Procedures.

Section 9.4.4 Disease Assessment.

Appendix I Schedule of Events (28-Day Cycle) Previous to Amendment 02.
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Protocol Incorporating Amendment No. 07
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CONFIDENTIAL
Change 3: Add language on local clinical laboratory evaluations for efficacy and safety after 
implementation of Amendment 07.
The primary change occurs in to Section 9.4.3:
Initial 
wording:
If the screening laboratory tests were performed more than 14 days before the first 
dose (Cycle 1 Day 1), the chemistry/hematology tests and serum free light chain, 
UPEP, SPEP, and pregnancy tests will be repeated before dosing. The test closest to 
the first dose will be considered baseline. In contrast, collection of whole blood for 
immune profiling and immune cell function assays, whole blood for T-cell clonality, 
serum for antibody titers, and BMA need not be repeated. 
Hematology and chemistry laboratory samples will be collected centrally and may 
be collected up to 3 days before dosing, as specified in the Schedule of Events 
(Appendix A). Local laboratory evaluations may be done more frequently at the 
investigator’s discretion (ie, for acute management of TEAEs and dosing decisions). 
Amended or 
new wording:
If the screening laboratory tests were performed more than 14 days before the first 
dose (Cycle 1 Day 1), the chemistry/hematology tests and serum free light chain, 
UPEP, SPEP, and pregnancy tests will be repeated before dosing. The test closest to 
the first dose will be considered baseline. In contrast, collection of whole blood for 
immune profiling and immune cell function assays, whole blood for T-cell clonality, 
serum for antibody titers, and BMA need not be repeated. 
Hematology and chemistry laboratory samples will be collected centrally and may 
be collected up to 3 days before dosing, as specified in the Schedule of Events 
(Appendix A). Local laboratory evaluations may be done more frequently at the 
investigator’s discretion (ie, for acute management of TEAEs and dosing decisions). 
Upon implementation of Amendment 07, centralized clinical laboratory 
evaluations of efficacy and safety are no longer required, and thus either 
central or local laboratory evaluations may be used, depending on the site’s 
decision. Abnormal hematology and chemistry laboratory data should be 
entered into the eCRF only if required to document or support a TEAE. For 
dosing decisions and all other safety assessments for the patient, local 
hematology and chemistry laboratory results should be used and do not need to 
be entered into the eCRF. Local laboratory evaluations may be done more 
frequently at the investigator’s discretion (ie, for acute management of 
TEAEs), per the investigator’s judgement of standard of care.
The following sections also contain this change:

Section 9.4 Study Procedures.

Section 9.4.3.1 Clinical Chemistry and Hematology.

Appendix A, Table A-2, footnote j and g
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CONFIDENTIAL
Change 4: Clarify language regarding procedures for reporting product complaints or medication 
errors.
The change occurs in Section 10.5 Procedures for Reporting Product Complaints or Medication Errors 
(Including Overdose):
Initial 
wording:
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 e-mail addresses provided below.
A medication error is a preventable event that involves an identifiable patient and 
that leads to inappropriate medication use, which may result in patient harm. 
Whereas overdoses and underdoses constitute medication errors, doses missed 
inadvertently by a patient do not. Individuals who identify a potential medication 
error (including overdose) situation should immediately report this via the phone 
numbers or e-mail addresses provided below.
Product
Call Center
Phone Number
E-mail
Fax
NINLARO 
(ixazomib)
Dohmen Life 
Science 
Services 
(DLSS)
1-844-617-6468
(1-844-N1-POINT)
GlobalOncologyMedi
nfo@takeda.com
1-800-881-6092
Product complaints or medication errors in and of themselves are not AEs. If a 
product complaint or medication error results in an SAE, the SAE should be 
reported.
Amended or 
new wording:
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 e-mail addresses provided belowto
ctmcomplaint@takeda.com.
Product complaints or medication errors in and of themselves are not AEs. If a 
product complaint or medication error results in an SAE, an SAE Form should 
be completed and sent to Cognizant (refer to Section 10.2).
A medication error is a preventable event that involves an identifiable patient and 
that leads to inappropriate medication use, which may result in patient harm. 
Whereas overdoses and underdoses constitute medication errors, doses missed 
inadvertently by a patient do not. Individuals who identify a potential medication 
error (including overdose) situation should immediately report this via the phone 
numbers or e-mail addresses provided below to Cognizant (refer to Section 10.2).
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CONFIDENTIAL
Product
Call Center
Phone Number
E-mail
Fax
NINLARO 
(ixazomib)
Dohmen Life 
Science 
Services 
(DLSS)
1-844-617-6468
(1-844-N1-POINT)
GlobalOncologyMedin
fo@takeda.com
1-800-881-6092
Product complaints or medication errors in and of themselves are not AEs. If a 
product complaint or medication error results in an SAE, the SAE should be 
reported.
Rationale for Change: To clarify proper reporting procedures for product complaints and medication 
errors.
Change 5: Clarify language about study conduct regarding the coronavirus disease 2019 (COVID-19)
pandemic.
The change occurs in Section 8.9.1.3 Storage, Handling, and Accountability:
Initial 
wording:
On receipt at the investigative site, ixazomib should remain in the blister packaging 
and carton provided until use or dispensation. For storage conditions, refer to the 
Pharmacy Manual or equivalent. All excursions from the temperature storage 
guidelines should immediately be brought to the sponsor’s attention for assessment 
and authorization for continued use. Ensure that the drug is used before the retest 
expiry date provided by Takeda. Expiry extensions will be communicated 
accordingly with updated documentation to support the extended shelf life. In case 
of extenuating circumstances that prevent a patient from attending the study site (eg, 
the COVID-19 pandemic), sites may use alternative strategies to deliver ixazomib to 
patients (eg, via courier or site staff), per local standard practice and regulations and 
with prior approval from the investigator and the sponsor’s project 
clinician/designee.
Amended or 
new wording:
On receipt at the investigative site, ixazomib should remain in the blister packaging 
and carton provided until use or dispensation. For storage conditions, refer to the 
Pharmacy Manual or equivalent. All excursions from the temperature storage 
guidelines should immediately be brought to the sponsor’s attention for assessment 
and authorization for continued use. Ensure that the drug is used before the retest 
expiry date provided by Takeda. Expiry extensions will be communicated 
accordingly with updated documentation to support the extended shelf life. In case 
of extenuating If circumstances due to the COVID-19 pandemicthat prevent a 
patient from attending the study site (eg, the COVID-19 pandemic), sites may use 
alternative strategies to deliver ixazomib to patients (eg, via courier or site staff), per 
local standard practice and regulations and with prior approval from the investigator 
and the sponsor’s project clinician/designee.
Rationale for Change: Clarified that alternative strategies can occur only for circumstances related to 
the COVID-19 pandemic.
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The following sections also contain this change:

Section 9.4 Study Procedures.

Appendix A Schedule of Events.
Change 6: Update the Management of Clinical Events section for ixazomib to reflect evolving data, 
including the addition that ixazomib should be discontinued if SJS occurs.
The change occurs in Section 8.7.1 Ixazomib:
Initial 
wording:
Erythematous Rash With or Without Pruritus
…
The rare risks of Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), 
drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), and 
pemphigus vulgaris have been reported in oncology studies when ixazomib (or 
placebo) was given with concomitant medications that are known to cause rash (eg, 
Bactrim, lenalidomide, aspirin), and/or in the setting of confounding TEAEs. These 
severe, potentially life-threatening or deadly conditions may involve rash with skin 
peeling and mouth sores and should be clinically managed according to standard 
medical practice. Punch biopsies for histopathological analysis are encouraged at the 
discretion of the investigator. Study medications should be discontinued in the event 
of severe, potentially life-threatening rash. Additional information regarding these 
reactions can be found in the IB.
Thrombocytopenia
Blood counts should be monitored regularly as outlined in the protocol, with 
additional testing obtained according to standard clinical practice. 
Thrombocytopenia may be severe but has been manageable with platelet 
transfusions according to standard clinical practice. Ixazomib administration should 
be modified according to dose modification recommendations in the protocol when 
thrombocytopenia occurs (see Table 8.c). Therapy can be reinitiated at a reduced 
level upon recovery of platelet counts. Thrombotic microangiopathy (TMA), 
including thrombotic thrombocytopenia purpura and hemolytic uremic syndrome
(HUS), are rare, serious blood disorders that cause low levels of platelets and red 
blood cells and result in blood clots in small blood vessels. Symptoms may include 
fatigue, fever, bruising, nose bleeds, and decreased urination. These disorders, 
including fatal cases, have been reported in patients receiving ixazomib. TMA 
should be managed according to standard medical practice.
...
Transverse Myelitis
Transverse myelitis has been reported with ixazomib. It is not known whether 
ixazomib causes transverse myelitis; however, because transverse myelitis 
happened to a patient receiving ixazomib, the possibility that ixazomib may have 
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contributed to the transverse myelitis cannot be excluded. Transverse myelitis 
should be managed according to standard medical practice.
Overdose
An overdose is defined as a known deliberate or accidental administration of 
investigational drug, to or by a study subject, at a dose above that which is assigned 
to that individual subject according to the study protocol. If an overdose occurs, 
consider close observation including hospitalization for hemodynamic support. 
Gastric lavage may be considered if instituted within 1 hour of ingestion of an 
ixazomib overdose.
Amended or 
new wording:
Erythematous Rash With or Without Pruritus
…
The rare risks of Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), 
drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), and 
pemphigus vulgaris have been reported in oncology studies when ixazomib (or 
placebo) was given with concomitant medications that are known to cause rash (eg, 
Bactrim, lenalidomide, aspirin), and/or in the setting of confounding TEAEs. These 
severe, potentially life-threatening or deadly conditions may involve rash with skin 
peeling and mouth sores and should be clinically managed according to standard 
medical practice. Punch biopsies for histopathological analysis are encouraged at the 
discretion of the investigator. Study medications should be discontinued in the event 
of severe, potentially life-threatening rash. If Stevens-Johnson syndrome (SJS) 
occurs, ixazomib should be discontinued. Additional information regarding these 
reactions can be found in the IB.
Thrombocytopenia
Blood counts should be monitored regularly as outlined in the protocol, with 
additional testing obtained according to standard clinical practice. 
Thrombocytopenia may be severe but has been manageable with platelet 
transfusions according to standard clinical practice. Ixazomib administration should 
be modified according to dose modification recommendations in the protocol when 
thrombocytopenia occurs (see Table 8.c). Therapy can be reinitiated at a reduced 
level upon recovery of platelet counts. Thrombotic microangiopathy (TMA), 
including thrombotic thrombocytopenia purpura and hemolytic uremic syndrome 
(HUS), are rare, serious blood disorders that cause low levels of platelets and red 
blood cells and result in blood clots in small blood vessels. Symptoms may include 
fatigue, fever, bruising, nose bleeds, and decreased urination. These disorders, 
including fatal cases, have been reported in patients receiving ixazomib. If TMA 
should be managed is suspected, consider withdrawal of the suspected causative 
agent and manage it according to standard medical practice.
...
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Transverse Myelitis
Transverse myelitis has been reported with ixazomib. It is not known whether 
ixazomib causes transverse myelitis; however, because transverse myelitis has 
happened to a patient in patients receiving ixazomib, the possibility that ixazomib 
may have contributed to the transverse myelitis cannot be excluded. Transverse 
myelitis should be managed according to standard medical practice.
Overdose
An overdose is defined as a known deliberate or accidental administration of 
investigational drug, to or by a study subject, at a dose above that which is assigned 
to that individual subject according to the study protocol.
Overdose has been reported in patients taking ixazomib, and the symptoms of 
overdose are generally consistent with the known risks of ixazomib. Reports of 
accidental overdose have been associated with SAEs, such as severe nausea, 
aspiration pneumonia, multiple organ failure, and death.
Health care providers should instruct patients and caregivers that only 1 dose 
of ixazomib should be taken at a time, and only at the prescribed interval (1 
capsule, once a week, on Days 1, 8, and 15 of a 28-day cycle). The importance of 
carefully following all dosage instructions should be discussed with patients 
starting treatment.
There is no known specific antidote for ixazomib overdose. If an overdose 
occurs, consider close observation including hospitalization for hemodynamic 
support admitting the patient to the hospital for IV hydration, monitoring for 
adverse drug reactions, monitoring of vital signs, and appropriate supportive 
care. Gastric lavage and administration of charcoal may be considered if 
instituted within 1 hour of ingestion of an ixazomib overdose.
Rationale for Change: Added management suggestion for erythematous rash with or without 
pruritus (including the addition that ixazomib should be discontinued if SJS occurs), 
thrombocytopenia, removed reference to 1 patient for transverse myelitis, and updated the overdose 
section.
The following sections also contain this change:

Section 8.3.2 Ixazomib Treatment Modification, Table 8.d Ixazomib Dose Modification for
Nonhematologic Toxicities. 
Change 7: Incorporate changes from France-specific Protocol Amendments 01 and 05.
Changes from France-specific Protocol Amendment 01:
#1: The inclusion criterion detailing requirements for female patients has been clarified to state that 
women of childbearing potential must have a negative pregnancy test before the first dose of study 
drug treatment is administered.
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The change occurs in Section 7.1 Inclusion Criteria:
Added text:
Female patients who:
…
–
If they are of childbearing potential, agree to use effective 
contraceptive measures during and for 90 days following treatment. Advise 
women using hormonal contraceptives to also use a barrier method of 
contraception (see Appendix H for details). For women of childbearing 
potential, a pregnancy test should be negative before the first dose of 
study drug treatment is administered.
Rationale for Change: Clarification of the study procedures.
#2: An exclusion criterion has been added to clarify that pregnant women are not permitted to enroll in 
the study.
The change occurs in Section 7.2 Exclusion Criteria:
Added text:

Patient is pregnant.
Rationale for Change: Clarification of the inclusion/exclusion criteria in the study.
#3: Information about the process and timing of obtaining informed consent has been clarified.
The change occurs in Section 9.2 Arrangements for Recruitment of Patients:
Added text:
Recruitment and enrollment strategies for this study may include recruitment 
from the investigator’s local practice or referrals from other physicians. 
Advertisements should be reviewed by the institutional review board 
(IRB)/independent ethics committee (IEC) and Takeda (or designee). In 
France, investigators on the study approached patients who were 
potentially eligible for the study to explain the study and provide further 
information. Patients were provided with a copy of the ICF and had as 
much time as needed for reflection and questions before signing; this was 
expected to be between 1 and 2 weeks.
Rationale for Change: Clarification of the study patient recruitment and informed consent processes.
#4: Footnote "t" and associated reference has been added to the Schedule of Events to clarify the use of 
bone marrow aspirates (BMA).
The change occurs in Section Appendix A Schedule of Events:
Added text:
In France, confirmation of a CR by laboratory criteria is part of the 
standard-of-care evaluation of MM, per the IMWG criteria, to confirm a 
CR. In addition, the IMWG guidance recommends evaluating MRD 
status at a minimum of 1 year following initial confirmation of MRD 
negativity for the response criteria of “sustained MRD-negative status” 
[55].
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Rationale for Change: Clarification of the study procedures.
Change from France-specific Protocol Amendment 05:
#5: To add flexibility in study conduct due to the COVID-19 pandemic.
The change occurs in Section: 14.1 Study-Site Monitoring Visits:
Added text:
In the event a monitor cannot visit the site in a timely manner due to the 
COVID-19 pandemic, alternative monitoring approaches such as remote 
source data verification or telephone contact may be used to ensure data 
quality and integrity and maintain patient safety. Alternative monitoring 
approaches should be used only where allowed by the local health authority 
and permitted by the IRB/IEC, if required. For France, alternative 
monitoring approaches should be used only if approved as a contingency 
measure by ANSM (French Agency for Medicines and Health Products 
Safety) and permitted by the IEC, if required.
Rationale for Change: Clarification of the study procedures.
Rationale for Change: Added the text from the France-specific protocols to the Global protocol.
Change 8: Update the terms of the Posttrial Access program.
The change occurs in Section 6.3.5 Posttrial Access:
Initial 
wording:
6.3.5 Posttrial Access
At the conclusion or termination of the study, participants still on ixazomib 
treatment will be given the opportunity to enroll in a separate open-label rollover 
study in order to continue receiving ixazomib if, in the opinion of the investigator 
and confirmed by the sponsor, they have experienced a clinically important benefit 
from the ixazomib that they received in the study, have no alternative therapeutic 
option, and would be harmed without continued access. 
Duration of Posttrial Access
Continued access to ixazomib for participants will be terminated for those 
individuals who no longer benefit from ixazomib, the benefit-risk no longer favors 
the individual, or ixazomib is available either commercially or via another access 
mechanism, or when an alternative appropriate therapy becomes available. Posttrial 
access may be terminated in a country or geographical region where the marketing 
authorization has been rejected, the development of ixazomib has been suspended or 
stopped by the sponsor, or where ixazomib can no longer be supplied.
Amended or 
new wording:
6.3.5 Posttrial Access
At the conclusion or termination of the study, participants still remaining on 
ixazomib and/or daratumumab treatment will be given the opportunity to enroll in 
a separate open-label rollover study participate in the optional ixazomib
(NINLARO) posttrial access (PTA) program in order to continue receiving 
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ixazomib and/or daratumumab if, in the opinion of the investigator and confirmed 
by the sponsor, they have experienced a clinically important the patient continues
to receive clinical benefit from the ixazomib and/or daratumumab that they 
received in the study, have no alternative therapeutic option, and would be harmed 
without continued access. This is a voluntary program. Alternatively, 
investigators have the option of transferring their patients to standard-of-care 
treatment or treating their patients outside of the PTA program.
Duration of Posttrial Access
Continued access to ixazomib for Participants in the PTA program will be
terminated for those individuals whooffered ixazomib (NINLARO) until they no 
longer benefit from ixazomib, the benefit-risk no longer favors the individual, or 
ixazomib and/or ixazomib is available either commercially or via another access 
mechanism, or when an alternative appropriate therapy becomes available available 
for the indication under study in the participants’ market, and/or the sponsor 
deems the PTA program is no longer viable. The PTA program may also
Posttrial access may be terminated in a country or geographical region where the 
marketing authorization has been rejected, the development of ixazomib has been 
suspended or stopped by the sponsor, or where ixazomib can no longer be supplied.
Rationale for Change: Updated the language to be consistent with the current PTA program.
Change 9: Clarify the daratumumab infusion time period.
The change occurs in Section 8.2.2.2 Daratumumab Schedule and Administration:
Initial 
wording:
Upon implementation of Amendment 04, to prioritize the safety of patients during 
the COVID-19 pandemic, patients may have their infusion duration reduced to 90 
minutes if they did not have a history of an IRR at any time after the third dose 
(Table 8.a and Appendix J).
Amended or 
new wording:
Upon implementation of Amendment 04, to prioritize the safety of patients during 
the COVID-19 pandemic, patients may have their infusion duration reduced to no 
less than 90 minutes if they did not have a history of an IRR at any time after the 
third dose (Table 8.a and Appendix J).
Rationale for Change: Updated the language to clarify that the daratumumab infusion can be reduced
per the guidance in Appendix J.
Table 8.a Infusion Rates for Daratumumab IV Administration also contains this change.
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Statistical Analysis Plan Study C16047
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2.0
TABLE OF CONTENTS
1.0
TITLE PAGE ...........................................................................................................1
1.1
Approval Signatures............................................................................................2
2.0
TABLE OF CONTENTS..........................................................................................3
3.0
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................5
4.0
OBJECTIVES ..........................................................................................................9
4.1
Study Design ......................................................................................................9
4.2
Study Objectives...............................................................................................10
4.2.1
Primary Objectives......................................................................................10
4.2.2
Secondary Objectives..................................................................................10
4.2.3
Exploratory Objectives................................................................................10
5.0
ANALYSIS ENDPOINTS......................................................................................11
5.1
Primary endpoints.............................................................................................11
5.2
Secondary Endpoints ........................................................................................11
5.3
Exploratory Endpoints ......................................................................................11
6.0
DETERMINATION OF SAMPLE SIZE................................................................12
7.0
METHODS OF ANALYSES AND PRESENTATION...........................................12
7.1
General Principles.............................................................................................12
7.1.1
Study Definitions ........................................................................................13
7.1.2
Definition of study days ..............................................................................13
7.1.3
Definition of Study Visit Windows .............................................................13
7.1.4
Conventions for Missing Adverse Event Dates............................................13
7.1.5
Conventions for Missing Concomitant Medication Dates ............................14
7.1.6
Conventions for Missing Initial Diagnosis Dates.........................................15
7.2
Populations for Analysis ...................................................................................15
7.2.1
Safety Population........................................................................................15
7.2.2
Response-Evaluable Population ..................................................................15
7.3
Disposition of Subjects .....................................................................................15
7.3.1
Significant Protocol Deviations...................................................................16
7.4
Demographic and Baseline Characteristics........................................................16
7.4.1
Demographic...............................................................................................16
7.4.2
Disease Specific History .............................................................................16
7.4.3
Baseline Disease Characteristics .................................................................17
7.5
Medical History and Concurrent Medical Conditions........................................18
7.6
Medication History and Concomitant Medications............................................18
7.7
Study Drug Exposure and Compliance..............................................................18
7.8
Efficacy Analysis..............................................................................................19
7.8.1
Primary Efficacy Endpoint..........................................................................19
7.8.2
Secondary Efficacy Endpoints.....................................................................20
7.8.3
Additional Efficacy Endpoint(s)..................................................................21
7.9
Pharmacokinetic Analysis.................................................................................26
7.10
Safety Analysis.................................................................................................26
7.10.1
Adverse Events ...........................................................................................26
7.10.2
Clinical Laboratory Evaluations ..................................................................28
7.10.3
Vital Signs ..................................................................................................29
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7.10.4
12-Lead ECGs.............................................................................................29
7.10.5
Other Observations Related to Safety..........................................................29
7.11
Interim Analysis ...............................................................................................29
7.12
Clinical Study Report........................................................................................30
7.13
Changes in the Statistical Analysis Plan............................................................30
8.0
REFERENCES.......................................................................................................30
LIST OF TABLES
Table 7-1
Handling of Missing Assessments and Censoring for PFS Analysis 
Based on FDA guidance..............................................................................21
Table 7-2
Subscale Scores of EORTC QLQ-C30 ........................................................24
Table 7-3
Definition of Subscale Scores of EORTC QLQ-MY20................................24
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3.0
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
5-HT3
5-hydroxytryptamine 3 serotonin receptor
AE
adverse event
ALL
acute lymphoblastic leukemia
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AML
acute myelogenous leukemia
ANC
absolute neutrophil count
API
active pharmaceutical ingredient
aPTT
activated partial thromboplastin time
Ara-C
Cytarabine
ASCO
American Society of Clinical Oncology
ASCT
autologous stem cell transplant 
AST
aspartate aminotransferase
AUC
area under the plasma concentration versus time curve
BCRP
breast cancer resistance protein
hCG
beta-human chorionic gonadotropin
BID
bis in die; twice a day
BM
bone marrow
BSA
body surface area
BUN
blood urea nitrogen
BZD
Benzodiazepines
CBC
complete blood count
CDF
cumulative distribution function
CFR
Code of Federal Regulations
Cmax
maximum (peak) concentration
CNS
central nervous system
CO2
carbon dioxide
CR
complete response
CRM
continual reassessment method
CRP
C-reactive protein
CSF-1R
colony-stimulating factor 1 receptor
CT
computed tomography
CV
coefficient of variation or cardiovascular 
CYP
cytochrome P450
DLT
dose-limiting toxicity
DME
drug metabolizing enzymes
DNA
deoxyribonucleic acid
DOR
duration of response
ECG
Electrocardiogram
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Abbreviation
Term
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
ELISA
enzyme-linked immunosorbent assay
EORTC QLQ-C30
European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire-Core Module 30
EORTC QLQ-MY20
European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire-Multiple Myeloma Module 20
EOS
End of Study (visit)
EOT
End of Treatment (visit)
EU
European Union
FDA
United States Food and Drug Administration
GCP
Good Clinical Practice
G-CSF
granulocyte colony stimulating factor
GGT
gamma glutamyl transferase
GI
Gastrointestinal
GLP
Good Laboratory Practices
GM-CSF
granulocyte macrophage-colony stimulating factor
GMP
Good Manufacturing Practice
Hb
Hemoglobin
Hct
Hematocrit
HDPE
high-density polyethylene
HDT
high-dose therapy
hERG
human ether-à-go-go related gene
HIV
human immunodeficiency virus
HNSTD
highest nonseverely toxic dose
IB
Investigator’s Brochure
IC50
concentration producing 50% inhibition
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IMiD
immunomodulating drugs
inc
Including
IR
Immunophenotype
IRB
institutional review board
ITT
intent-to-treat
IV
intravenous; intravenously
IVRS
interactive voice response system
Ki
inhibition constant
KPS
Karnofsky Performance Status
LDH
lactate dehydrogenase
LFT
liver function test(s)
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Abbreviation
Term
Ixazomib
generic name of MLN9708
MID
minimally important difference
MM
multiple myeloma
MRD
minimal residual disease
MRI
magnetic resonance imaging
MRU
medical resource utilization
MTD
maximum tolerated dose
MUGA
multiple gated acquisition (scan)
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NDMM
newly diagnosed multiple myeloma 
NPO
nothing by mouth
nCR
nearly complete response
NYHA
New York Heart Association
ORR
overall response rate
OS
overall survival 
PBMC
peripheral blood mononuclear cell
PCR
polymerase chain reaction
PD
progressive disease (disease progression)
PFS
progression-free survival 
P-gp
P-glycoprotein
PK
pharmacokinetic(s)
PN
peripheral neuropathy
PO
per os; by mouth (orally)
POEMS
polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and 
skin changes
PR
partial response
PRO
patient-reported outcome
PSA
prostate-specific antigen
QD
quaque die; each day; once daily
QID
quater in die; 4 times a day
QOD
quaque altera die; every other day
QOL
quality of life
QTc
rate-corrected QT interval (millisec) of electrocardiograph
RBC
red blood cell
RECIST
Response Evaluation Criteria in Solid Tumors
RRAL
relapsed and/or refractory systemic light chain amyloidosis
RRMM
refractory multiple myeloma 
SAE
serious adverse event
SC
Subcutaneous
sCR
stringent complete response
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Abbreviation
Term
SCT
stem cell transplant 
SD
stable disease
SmPC
Summary of Product Characteristics
t1/2
terminal disposition half-life
TGI
tumor growth inhibition
Tmax
first time of occurrence of maximum (peak) concentration
TTP
time-to-progression 
UK
United Kingdom
ULN
upper limit of the normal range
US
United States
VGPR
very good partial response
VMP
VELCADE to melphalan and prednisone 
WBC
white blood cell
WHO
World Health Organization
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4.0
OBJECTIVES
4.1
Study Design
This is an open-label, multicenter, phase 2 study designed to evaluate the safety and efficacy 
of oral ixazomib in combination with daratumumab and dexamethasone in adult patients 
with MM who have received at least 1 prior therapy. All patients must have documented 
evidence of PD as defined by IMWG criteria on or after their last regimen. 
The study treatment regimen is defined as the combination of ixazomib, daratumumab, and 
dexamethasone. All cycles are approximately 28 days with treatment given until PD or 
unacceptable toxicity. Ixazomib will be administered at 4 mg orally on Days 1, 8, and 15 of 
each 28-day cycle. In Cycle 1, ixazomib will be given after the daratumumab infusion; in 
subsequent cycles, if there have been no Grade 3 or higher infusion-related reactions (IRRs) 
in the previous cycle, ixazomib can be given prior to or at approximately the same time as 
the premedications that are administered prior to daratumumab infusion. Daratumumab will 
be administered intravenously at 16 mg/kg. Daratumumab will be given on Days 1, 8, 15, 
and 22 in Cycles 1 and 2; on days 1 and 15 in Cycles 3 to 6; on Day 1 in Cycles 7 and 
beyond. dexamethasone will be given weekly in split doses, ie, 20 mg the day before and 
after each daratumumab IV infusion. 
At close/termination of the study, the patients still on ixazomib treatment will have the 
option to enroll in a separate open-label rollover study to continue receiving ixazomib if, in 
the opinion of the investigator and sponsor, that they have experienced a clinically important 
benefit from the ixazomib received in the study, have no alternative therapeutic option and 
would be harmed without continued access.  
Patients will attend an End-of-Treatment (EOT) visit up to 30 days after receiving their last 
dose of study therapy. All study procedures outlined for the EOT visit will be completed as 
specified in the protocol. Patients who stop treatment for any reason other than PD will 
continue to have PFS follow-up visits. The PFS follow-up visits should occur every 4 weeks 
from EOT until the occurrence of PD or death, or the patient withdraws consent for further 
follow-up, whichever comes first. After PD occurs, the patient will enter into the OS follow-
up period, in which the patient will be followed every 12 weeks until death or termination of 
the study.
The study will be conducted to evaluate the safety and efficacy of the study drug regimen 
and to evaluate treatment effects on patient-reported quality of life (QOL); PK data collected 
in this study will contribute to future population PK analyses of ixazomib. 
 
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4.2
Study Objectives
4.2.1
Primary Objectives
The primary objective is to evaluate the proportions of patients with a response of VGPR or 
better to IDd treatment. 
4.2.2
Secondary Objectives
The secondary objectives are:

To measure PFS, TTP, and OS

To measure ORR, time to response (TTR), and DOR

To collect plasma concentration-time data for ixazomib to contribute to population 
PK analyses. 

To evaluate the safety/tolerability of IDd administered in a 28-day cycle.
4.2.3
Exploratory Objectives
 
 
 
 
 
 
 
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5.0
ANALYSIS ENDPOINTS
5.1
Primary endpoints
The primary endpoint is the rate of VGPR or better response as evaluated by the investigator 
according to IMWG criteria, in patients that are response evaluable. 
5.2
Secondary Endpoints
The secondary endpoints are:

PFS, defined as the time from the date of first dose of any study drug treatment to 
the date of first documentation of progressive disease (PD) as evaluated by the 
investigator per IMWG criteria, or death due to any cause, whichever occurs first. 

TTP, defined as the time from the date of first dose of any study drug treatment to 
the date of first documented evidence of PD. 

OS, defined as the time from the date of first dose of any study drug treatment to the 
date of death.

ORR (defined as CR, VGPR, plus partial response [PR], per IMWG criteria) during 
or after the study treatment, but before subsequent therapy or PD. 

TTR, defined as the time from the date of first dose of any study drug treatment to 
the date of first documented PR or better. 

DOR, measured as the time from the date of first documentation of PR or better to 
the date of first documented progression among those patients that responded. 
5.3
Exploratory Endpoints
 
 
 
 
 
 
 
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6.0
DETERMINATION OF SAMPLE SIZE
The statistical assumption is based on observed CR+VGPR rates in historical clinical studies 
with ixazomib[1], bortezomib[2], and daratumumab[3]. The sample size is calculated using the 
binomial exact test for single proportion based on the rate of VGPR or better of the IDd 
treatment regimen. With 54 response-evaluable patients, there will be 95% power to test a 
null hypothesis of a rate of VGPR or better of 30% and an alternative hypothesis of a rate of 
VGPR or better of 55% at 2-sided significance level of α=0.05. Therefore, assuming 10% of 
patients are not response-evaluable, the total enrollment will be approximately 60 patients.
7.0
METHODS OF ANALYSES AND PRESENTATION
7.1
General Principles
In general, summary tabulations will display the number of observations, mean, standard 
deviation, median, minimum, and maximum for continuous variables, and the number and 
percentage per category for categorical data. The Kaplan-Meier survival curves and 25th, 
50th (median), and 75th percentiles will be provided along with their 95% confidence 
intervals (CIs) for time-to-event data.
Baseline is defined as the value collected at the time closest to, but prior to, the start of any 
study drug administration, unless otherwise stated
All statistical analyses will be conducted using SAS® Version 9.4, or higher.
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7.1.1
Study Definitions
7.1.2
Definition of study days
Study Day 1 is defined as the date on which a subject is administered their first dose of the 
medication. Other study days are defined relative to the Study Day 1 with Day 1 being Study 
Day 1 and Day -1 being the day prior to Study Day 1.
7.1.3
Definition of Study Visit Windows
All data will be categorized based on the scheduled visit at which it was collected. These 
visit designators are predefined values that appear as part of the visit tab in the CRF.
7.1.4
Conventions for Missing Adverse Event Dates
Every effort will be made to avoid missing/partial dates in on-study data. 
Adverse events with stop dates that are completely or partially missing will be imputed as 
follows:
1. If the stop date has a month and year but the day is missing, the last day of the month 
will be imputed. 
2. If the stop date has year, but day and month are missing, the 31th of December will 
be imputed. 
After the imputation, the imputed dates will be compared against the date of death, if 
available. If the date is later than the date of death, the date of death will be used as the 
imputed date instead.
Adverse events with start date completely or partially missing will be imputed as follows: 
1. If the start date has month and year but day is missing, the first day of the month will 
be imputed. 
a.
If this date is earlier than the first dose date, then the first dose date will be used.
b. If this date is later than the stop date (possibly imputed), then the stop date will 
be used instead.
2. If the start date has a year, but day and month are missing, then 15th of June will be 
imputed. 
a.
If this date is earlier than the first dose date, then the first dose date will be used 
instead. 
b. If this date is later than the stop date (possibly imputed), then the stop date will 
be used instead. 
3. If the start date is completely missing then the first dose date will be used. 
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7.1.5
Conventions for Missing Concomitant Medication Dates
Every effort will be made to avoid missing/partial dates in on-study data. 
Concomitant therapies with start date that are completely or partially missing will be 
analyzed as follows:
1. If the start date has a month and year but the day is missing, the event will be 
considered concomitant if the month and year of the start date of the event are: 
a.
On or after the month and year of the date of the first dose of study drug
and 
b. On or before the month and year of the date of the last dose of study drug plus 30 
days
2. If the start date has a year, but the day and month are missing, the event will be 
considered concomitant if the year of the start date of the event is:
c.
On or after the year of the date of the first dose of study drug
and 
d. On or before the year of the date of the last dose of study drug plus 30 days
3. If the start date of an event is completely missing, then the event is assumed to be 
concomitant.
Subsequent therapies with start date that are completely or partially missing will be analyzed 
as follows:
1. When month and year are present and the day of the month is missing, 
a.
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. 
b. 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. 
2. When only a year is present, 
a.
If the onset year is the same as the year of last dose with study drug, the date 
of last dose + 1 will be imputed. 
b. If the onset year is not the same as the year of last dose with study drug, the 
first day of the year is imputed. 
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3. If no components of the onset date are present the date of last dose + 1 will be 
imputed.
7.1.6
Conventions for Missing Initial Diagnosis Dates
1
If only day is missing but year and month are present, set day=15;
2
If only a year is present, and it is the same as the year of the first dose of study drug, 
the 15th of January will be used unless it is later than the first dose date, in which 
case the date of the first of January will be used, unless other data indicate that the 
date is earlier. If only a year is present, and it is not the same as the year of the first 
dose of study drug, the 15th of June will be used, unless other data indicate that the 
date is earlier.
3
If completely missing, set to null.
7.2
Populations for Analysis
7.2.1
Safety Population
The safety population is defined as all patients who receive at least 1 dose of any study drug.
The safety population will be used for safety related analyses such as AE, concomitant 
medication, laboratory tests, vital signs and ECG. In addition, it will also be used for the 
analyses of TTP, PFS, OS and QOL data.
7.2.2
Response-Evaluable Population
The response evaluable population is defined as patients who receive at least 1 dose of
ixazomib, have measurable disease either during screening or prior to first dose of study 
drug and at least 1 post-baseline disease assessment. The response-evaluable population will 
be used for the analyses of primary endpoint, overall response rates (ORR), time to response 
(TTR), and duration of response (DOR). Measurable disease is defined by the 
documentation of at least 1 of the following 2 measurements:

Serum M-protein 1 g/dL (10 g/L).

Urine M-protein 200 mg/24 hours.
7.3
Disposition of Subjects
Patient disposition includes the number and percentage of patients for the following 
categories: patients discontinued from the treatment, primary reason to discontinue the 
treatment, patients discontinued from the study, and primary reason to discontinue from the 
study.
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A listing will be generated to present patient disposition variables.
7.3.1
Significant Protocol Deviations
Significant protocol deviations will be presented by patient in a listing, which will include, 
but will not necessarily be limited to, the following:
Any inclusion/exclusion criteria not met by an enrolled patient.
Use of or administration of excluded and/or restricted medications, not in accordance 
with the study protocol. 
Study procedures not performed as per the clinical study protocol to the extent that 
the deviation may confound interpretation of primary clinical study objectives and/or 
affect patient safety.
Dispensing of incorrect treatment and/or incorrect dose of clinical study medication.
Any occasion that withdrawal criterion is met but the patient is not withdrawn.
Protocol deviations will be listed using the safety population. COVID-related deviation will 
be listed separately
7.4
Demographic and Baseline Characteristics
Demographic and baseline characteristics will be summarized using safety population. 
7.4.1
Demographic
Demographic data will be summarized using the safety set. Summaries will include age, age 
group (<65, >=65 - <75, >=75), sex, race, ethnicity, height, weight, and other parameters as 
appropriate. Age will be calculated from date of birth to date of informed consent. 
7.4.2
Disease Specific History
Disease specific history (collected on the Disease Characteristics, Prior Therapy and Prior 
Radiation, Prior Transplant, and Prior Surgery CRF pages) will be summarized for all 
patients as appropriate, including type of myeloma at diagnosis (both heavy and light chain 
type), Durie-Salmon stage at diagnosis, International Stage System (ISS) at diagnosis, 
evidence of lytic bone disease and extramedullary disease, and the prior therapies (lines of 
prior therapies, best hematological response to prior therapy, type of prior therapy in the 
format of therapy contained, months from initial diagnosis to first dose of ixazomib). The 
months from prior diagnosis to the first dose of study drug is calculated as
first dose date - date of diagnosis +1  
365.25/12
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7.4.3
Baseline Disease Characteristics
Baseline disease characteristics will be summarized, including type of myeloma at study 
entry, which will be derived using baseline measurements of laboratory data. These include 
serum M-protein, urine M-protein, serum free light chain (FLC), serum free light chain ratio,
involved FLC,
2
-microglobin and its categories (i.e., < 3.5, 3.5-5.5, > 5.5 mg/L), serum 
creatinine and its categories, (<=2, >2 mg/dL), calculated creatinine clearance and its 
categories (<30, 30-<60, 60-<90, >=90 mL/min), serum albumin and its categories (i.e., 
<3.5, >=3.5 g/dL), corrected calcium, and Oncology Group (ECOG) performance status. 
Corrected calcium is calculated as:
Serum calcium [mg/dL] + 0.8 x (4 - serum albumin [g/dL])
The following categories of extent of disease at baseline will also be summarized: number of 
patients with bone marrow aspirate, bone marrow aspirate results (% plasma cells, 
%Kappa/Lambda ratio performed, Kappa/Lambda ratio), number of patients with bone 
marrow aspirate/biopsy, bone marrow aspirate/biopsy results (% plasma cells, % cellularity, 
type of cellularity, Kappa/Lambda ratio), number and percentage of lytic bone lesions
presenting in imaging, and number and percentage of extramedullary plasmacytoma present 
in imaging
Creatinine clearance will be calculated using the Cockcroft-Gault formulas as follows:
For male patients: 
For female patients:
Integer values will be used. 
For patients with heavy chain, the patient’s type of myeloma is determined by the 
combination of heavy chain type (IgG, IgA, IgM, IgD, and other) and light chain type 
[mg/dL])
creatinine
(serum
72
weight[kg]
Age[yrs])
(140
clearance
creatinine




[mg/dL])
creatinine
(serum
72
weight[kg]
Age[yrs])
(140
85
.0
clearance
creatinine





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(Kappa, Lambda, and biclonal). In descriptive summaries, the disease will be categorized by 
the heavy chain type first, then within each of these categories, patients will be further 
classified according to their light chain type. For patients with light chain only, patients will 
be summarized separately
Percentages for all categorical summarizations for bone marrow biopsy and aspirate is based 
on patients with an adequate sample for the specified test.
7.5
Medical History and Concurrent Medical Conditions
General medical history will be summarized (as frequency and percentage), using the safety 
population by Medical Dictionary for Regulatory Activities (MedDRA) system organ class, 
high level term, and preferred term. A patient is counted only once within each MedDRA. 
Percentages are based on the number of patients in the safety population.
General medical history will be listed for all patients. 
7.6
Medication History and Concomitant Medications
Prior and concomitant medications will be listed for all patients in the safety population. 
Concomitant medications will be summarized (as frequency and percentage) by World 
Health Organization Drug (WHODrug) Dictionary anatomical main group and preferred 
term. A patient is counted only once within each WHODrug category. Percentages are based 
on the number of patients in the safety population.
7.7
Study Drug Exposure and Compliance
Eligible patients will take ixazomib in combination with daratumumab and dexamethasone
at the following dose levels and schedules:

ixazomib 4 mg oral on Days 1, 8, and 15 of each 28-day cycle

daratumumab 16 mg/kg on Days 1, 8, 15 and 22 in cycles 1 and 2; on Days 1 and 15 
in cycles 3 to 6; on Day 1 in cycles 7 and beyond

dexamethasone 20 mg on Days 1, 2, 8, 9, 15, 16, 22 and 23 of each 28-day cycle
Patients will be treated with IDd until progression of disease or unacceptable toxicity 
leading to a discontinuation of treatment or study termination. At that time, an EOT 
assessment will be completed and patients will then enter the follow-up phase of the study.
Overall exposure to the treatment regimen and exposure to each study drug will be 
summarized. Summaries will be for the overall IDd regimen and by each study drug, and 
will include the number of treatment cycles, total amount of drug taken (in mg), total 
number of doses taken, extent of exposure, number and percentage of patients by treatment 
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cycle, and drug compliance. An aggregate summary of the numbers and percentages of 
patients who had cycles 1-6, 7-13, 14-20 and >20 will also be presented. 
A treatment cycle is defined as a cycle in which the patient received any amount of study 
drug. A treatment cycle for a specific drug is defined as a cycle in which the patient received 
any amount of that drug. 
Extent of Exposure (days) is calculated as (Last Dose Date of study drug – First Dose Date 
of study drug + 1).
Drug compliance is presented by relative dose intensity (RDI) and calculated as follows:
Relative dose intensity (RDI) (%) = 100 × (total amount of dose taken (mg)) / (sum of the 
planned dose over all treatment cycles).
RDI will also be displayed as <50%, >=50% - < 80%, >=80% - < 100%, = 100% and > 
100%.
The actions on each study drug (dose reduction, held, missed, increased, delayed, 
discontinued permanently, etc) will be summarized for all patients., and by each cycle, 
aggregated for Cycles 1-6, 7-12, 13-20 and >20 if there is sufficient data for analysis. 
Exposure data will also be presented in a by-patient listing.
7.8
Efficacy Analysis
Response will be assessed according to the International Myeloma Working Group (IMWG) 
criteria (in protocol appendix section) for all patients at every cycle during the treatment 
period and subsequently every 4 weeks during the PFS follow-up period until disease 
progression or patient is off the study. A response assessment (sCR, CR, VGPR, PR, SD) is 
considered confirmed if the next evaluable response assessment is the same or better. A 
response assessment of PD is considered confirmed if the next assessment is PD. In case 
there is only one PD as the last assessment, this PD is considered confirmed if either the 
EOT reason is PD or alternate therapy immediately follows the last assessment.
7.8.1
Primary Efficacy Endpoint 
The primary endpoint is the combined best confirmed response rate of CR + VGPR. The 
primary efficacy analysis will be based on the response-evaluable population.
Estimates of combined best confirmed response of CR + VGPR rates will be presented with 
2-sided 95% exact binomial confidence intervals. 
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Additionally, the best response rate will be summarized by cycle. Best response rates at the 
end of a cycle are based on the number of subjects treated for at least that many cycles. Best 
response at the end of a cycle is the best response (confirmed or unconfirmed) at or before 
the cycle for subjects who have been treated for at least that many cycles.”
7.8.2
Secondary Efficacy Endpoints
The secondary efficacy parameters include PFS, TTP, OS, ORR, TTR and DOR.
Progression Free Survival 
PFS is defined as the time from the date of the first administration of any study drug 
treatment to the date of the first documentation of disease progression based on the 
investigator’s assessment or death due to any cause, whichever occurs first. Patients without 
documentation of PD or death will be censored at the date of last response assessment that is 
SD or better. 
Time to Progression
TTP is defined as the time from the date of the first administration of any study drug 
treatment to the date of the first documentation of disease progression based on the 
investigator’s assessment. Patients without documentation of PD will be censored at the date 
of last response assessment that is SD or better.
Overall Survival
OS is defined as the time from the date of first dose of any study drug treatment to death due 
to any cause. A patient without documentation of death at the time of analysis will be 
censored at the last visit at which s/he was known to be alive. 
Overall Response Rate
ORR is defined as the rate of patients with response of CR + VGPR + PR before PD or 
subsequent therapy and will be analyzed in the response evaluable population.
Time to Response
TTR is defined as the time from the date of first dose of any study drug treatment to the date 
of first documented PR or better and will be analyzed in the response evaluable population.
Duration of Response
DOR is defined as the time from the first documentation of PR or better to the date of first 
documented progression among those patients that responded. Responders without 
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documentation of PD will be censored at the date of last response assessment that is SD or 
better prior to the start of alternative therapy. DOR will be analyzed in the response 
evaluable population of patients with a confirmed response of PR or better.
PFS, TTP and OS will be analyzed in the safety population. Kaplan-Meier (KM) analysis
will be used to estimate PFS, TTP and OS if applicable. The quartiles (if estimable) and 
median follow-up, along with their 2-sided 95% CIs, will be provided. For patients who 
were censored, the reason for censoring will be summarized. The KM survival curves will 
also be produced.
The details regarding the handling of missing assessments and censoring for the PFS 
analysis are presented in the table below.
Table 7-1
Handling of Missing Assessments and Censoring for PFS Analysis 
Based on FDA guidance 
Situation
Date of Progression or Censoring
Outcome
No baseline and/or no post baseline assessment, no 
subsequent anticancer therapy after study 
treatment, no death
Date of Randomization 
Censored
Disease progression documented between 
scheduled visits 
Date of next scheduled visit
Progressed
No documented death or disease progression 
Date of last adequate assessmenta
Censored
Lost to follow-up, withdraw consent before any 
documented death or disease progression
Date of last adequate assessmenta
Censored 
Death or progression after more than 1 missed 
visitb
Date of last adequate assessmenta
Censored
Alternate antineoplastic therapy started prior to 
disease progression 
Date of last adequate assessment prior 
to starting alternate antineoplastic 
therapy
Censored
Death before first assessment
Date of death
Progressed
Death between adequate assessment visits
Date of death
Progressed
a Adequate disease assessment is defined as there being sufficient data to evaluate a patient’s disease 
status.
b Death or progression occurs more than 90 days from the previous adequate assessment.
7.8.3
Additional Efficacy Endpoint(s)
 
 
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7.9
Pharmacokinetic Analysis
The ixazomib plasma concentration-time data will be listed and summarized by time point 
using descriptive statistics. PK data collected in this study will contribute to future population 
PK analyses of ixazomib. These analyses may include data from other ixazomib clinical 
studies. The analysis plan for the population PK analysis will be defined separately and the 
results will be reported separately. The PK data collected in this study may also contribute to 
exposure-response analyses. The results of any exposure-response analyses will be reported 
separately. 
7.10
Safety Analysis
Safety will be evaluated by the incidence, intensity, types of adverse events (AEs), clinically 
significant changes in the patient’s vital signs, weight, and clinical laboratory results in the 
safety population. 
7.10.1
Adverse Events
7.10.1.1
Adverse Events
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
Version 21.0 or higher. All AEs will be presented in a by-patient listing. 
Treatment-emergent AEs are AEs that occur after administration of the first dose of any 
study drug and through 30 days after the last dose of any study drug. 
AEs will be tabulated according to MedDRA by system organ class, high level terms and 
preferred terms and will include the following categories: 

TEAEs

Drug-related TEAEs
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
Grade 3 TEAEs

Grade 3 drug-related TEAEs

Grade 4 or higher TEAEs

Grade 4 or higher drug-related TEAEs

The most commonly reported TEAEs (ie, those reported by ≥10% of all patients)

All SAEs

New primary malignancies

Any AE resulting in dose modification or discontinuation of any study therapy.

Any other AEs that in the opinion of the investigator is a clinically significant event.
Patients reporting 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.
Drug-related, treatment-emergent AEs will also be summarized by the National Cancer 
Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) using the most 
current published version. Patients reporting 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 
all patients) will be tabulated by preferred term. Patients reporting the same AE more than 
once will have that event counted only once within each preferred term.
AECI table (TEAE of Clinical Importance) will also be tabulated by System Organ Class 
and Preferred Term
An overall summary AE table will include numbers and percentages of patients who had any 
AE, drug-related AE, Grade 3 AE, Grade 3 or higher AE, Grade 3 drug-related AE, Grade 3 
or higher drug-related AE, Grade 4 or higher AE, Grade 4 or higher drug related AE,serious 
adverse event (SAE), drug-related SAE, AE resulting in study drug 
modification/discontinuation/reduction, and on-study deaths. An on-study death is defined 
as a death that occurs between the first dose of any study drug and within 30 days of the last 
dose of any study drug. 
A by-patient listing of treatment-emergent AEs resulting in discontinuation of study drug 
regimen will be presented.
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7.10.1.2
Serious Adverse Events
The number and percentage of patients experiencing at least one treatment-emergent SAE 
will be summarized by MedDRA primary system organ class, high level term, and preferred 
term. Drug-related SAE will be summarized similarly.
In addition, a by-patient listing of the SAEs will be presented (the patient listing will contain 
all SAEs regardless of treatment-emergent AE status).
7.10.1.3
Deaths
A by-patient listing of deaths will be presented. All deaths occurring on-study and during 
follow-up will be displayed (regardless of treatment-emergent AE status). 
7.10.1.4
Adverse Events Resulting in Discontinuation of Study Drug
A by-subject listing of TEAEs resulting in discontinuation of any study drug or any dose 
modification will be presented. 
7.10.2
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 
(e.g., 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. However, 
for the bone marrow plasma cell percentage, the convention of (x-1)% (mainly for 5% for 
CR) will be used.
Laboratory test results from the central laboratory will be used when they are available.
Laboratory test results from local laboratory will only be used when no central laboratory 
test results exist at the same scheduled sample collection time point.
If a patient has repeated laboratory values for a given time point, the value from the last 
evaluation will be used. The test closest to the first dose will be considered baseline.
Laboratory test results will be summarized according to the scheduled sample collection 
time point. Change from baseline will also be presented. The parameters to be analyzed are 
as follows:

Hematology: hemoglobin, neutrophils (ANC), lymphocytes, monocytes, eosinophils 
and basophils, platelets, WBC

Serum chemistry: albumin, alkaline phosphatase, AST, ALT, blood urea nitrogen 
(BUN), beta-microglobin, total bilirubin, creatinine, , uric acid, 

LDH, glucose, calcium, sodium, potassium, magnesium, phosphate, CO2, and
chloride.
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Mean laboratory values over time will be plotted for the above laboratory parameters
Shift tables will be constructed for laboratory parameters to tabulate changes in NCI 
CTCAE for toxicity from baseline to post baseline worst CTC grade. the most current 
published CTCAE version will be used, Parameters to be tabulated will include:

Hematology: hemoglobin, platelets, WBC, ANC, Lymphocyte, leukocyte

Serum chemistry: ALT, AST, alkaline phosphatase, creatinine, total bilirubin, 
calcium, magnesium, potassium, sodium, and phosphate,blood urea nitrogen (BUN), 
albumin
Scatter plots of baseline versus worst postbaseline values for the above parameters will be 
generated.
By-patient listings to be presented include hematology, serum chemistry. Unscheduled 
laboratory test results will be listed and included in laboratory shift tables. 
7.10.3
Vital Signs
The actual values of vital sign parameters including oral temperature, pulse rate, systolic and 
diastolic blood pressure, and weight, will be summarized over time. Change from Baseline 
will also be presented. 
A by-patient listing will be presented.
7.10.4
12-Lead ECGs
Descriptive statistics for the actual values and changes from baseline in ECGs (PR Interval, 
QRS interval, QT interval, and Ventricular Rate) will be tabulated by time point.
ECG abnormalities will be presented in a data listing.
7.10.5
Other Observations Related to Safety
Eastern Cooperative Oncology Group (ECOG) performance status and change from 
Baseline will be summarized. Shifts from Baseline to the worst post-Baseline score will be 
tabulated by treatment arm.
Pregnancy testing results will be presented in a by-patient listing.
Additional safety analyses may be performed to further define the safety profile of ixazomib 
and daratumumab.
7.11
Interim Analysis
An interim safety review will be conducted after the first 15 patients have been enrolled and 
have had the chance to have been treated for 4 cycles. First interim analysis will be 
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conducted 6 months after last patient is enrolled. Second interim analysis will be conducted 
after 50% of PFS events have occurred.
No formal statistical analysis is planned for the safety review. A DSMB is not indicated at 
this time for the study. However, the decision to convene a DSMB could be made an any 
time during the conduct of the study. A steering committee is planned and will review the
safety data, a recommendation may be provided by the steering committee regarding the 
trial conduct.
7.12
Clinical Study Report
The first interim analysis on the best confirmed response rate of CR+VGPR will be 
conducted 6 months after the last patient is enrolled. At that time, all relevant data will be 
queried and cleaned; a database snapshot will be taken. If the study is claimed successful, 
CSR would be written prior to study completion.
Second interim analysis will be performed after 50% patients have experienced 
progression/death events. The safety analysis may be updated based on the available data. 
An addendum to the CSR may be written if warranted based on these analyses.
Final analysis will be conducted 1 year after 50% of the PFS events have occurred, and a 
CSR will be written following this analysis if not done so earlier.
7.13
Changes in the Statistical Analysis Plan
This is statistical analysis plan amendment 1 which clarifies that there are 2 interim analyses 
and one final analysis. There are no major change in statistical analysis method. 
8.0
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