Clinical trial NCT03170882
Conditions: Relapsed and/or Refractory Multiple Myeloma
Keywords: Drug therapy
Sponsor: Millennium Pharmaceuticals, Inc.
Start date: 2017-08-01; Completion date: 2021-11-26
Enrollment: 122 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main aim of this study is to learn if ixazomib, given with dexamethasone, stops the cancer from getting worse in people with relapsed or refractory multiple myeloma. It will be compared to another medicine called pomalidomide, given with dexamethasone with people with the same condition. Relapsed means the previous cancer treatment stopped working, over time. Refractory means they did not respond to previous cancer treatment. Another aim is to check for side effects from the study medicines.

At the first visit, the study doctor will check who can take part. Participants who can take part will be picked for 1 of 2 treatments by chance.

* Ixazomib capsules, given with dexamethasone tablets
* Pomalidomide capsules, given with dexamethasone tablets

All participants will take their study medicine on specific days during a 28-day cycle.

The 1st dose of study medicines in each 28-day cycle will take place in the clinic, The other doses of the study medicines will be taken at home. This will happen for 6 cycles. After this, all study medicines will be taken at home.

After treatment, participants will visit the clinic every 12 weeks for a check-up.

If participants cannot attend their clinic for an important reason (for example, due to the COVID-19 pandemic), the clinic will make alternative arrangements using their local procedures.

Detailed description:
The drug being tested in this study is called Ixazomib. Ixazomib is being tested to treat people who have relapsed and/or refractory multiple myeloma (RRMM). This study will compare the efficacy and safety in participants who take ixazomib and dexamethasone to pomalidomide and dexamethasone. It is an open-label, Phase 2 study.

The study will enroll approximately 120 participants. Participants will receive:

* Ixazomib 4 mg + dexamethasone 20 mg (or 10 mg if participant is aged \>=75 years) OR
* Pomalidomide 4 mg + dexamethasone 40 mg (or 20 mg if participant is aged \>=75 years)

All participants will be asked to take either ixazomib plus dexamethasone (in cases where only 4 mg tablets for dexamethasone are available, the following dexamethasone schedule is recommended for participants aged \>=75 years: 12 mg dexamethasone will be given on Days 1, 8, 15, and 22 of every 28-day cycle; and 8 mg dexamethasone will be given on Days 2, 9, 16, and 23 of every 28-day cycle) or pomalidomide 4 mg + dexamethasone 40 mg at recommended doses.

This multi-center trial will be conducted worldwide. The overall time to participate in this study is approximately 28 months after the first participant enters the study.

Participants will make multiple visits to the clinic, and will be contacted for progression free-survival (PFS) follow-up, in case of study drug discontinuation for up to 4 years from first dose administration. After disease progression, participants will be followed-up for overall survival (OS) every 12 weeks until death or up to 4 years.

Alternative methods for administering study procedures/assessments may be considered when it is not possible for the participants to come to the study site due to extenuating circumstances (e.g., due to the COVID-19 pandemic).

Arms: arm 1: Pomalidomide 4 mg, capsules, orally, once daily on Days 1 to 21 of each 28-day cycle, plus dexamethasone 40 mg, (or 20 mg if participant is aged \>=75 years), tablets, orally, once daily on Days 1, 8, 15, and 22 of each 28-day cycle until disease progression, unacceptable toxicity, withdrawal of consent, or sponsor termination of study up to 2 years. arm 2: Ixazomib 4 mg as starting dose, capsules, orally, once daily on Days 1, 8, and 15 of each 28-day cycle, with escalation to 5.5 mg at the start of Cycle 2 for participants who tolerated the 4 mg dose in Cycle 1, plus dexamethasone 20 mg (or 10 mg if participant is aged \>=75 years), tablets, orally, once daily on Days 1, 2, 8, 9, 15, 16, 22, and 23 of every 28-day cycle until disease progression, unacceptable toxicity, withdrawal of consent, or sponsor termination of study up to 2 years.
Interventions: intervention 1: Ixazomib intervention 2: Pomalidomide intervention 3: Dexamethasone
Intervention descriptions: intervention 1: Ixazomib capsules intervention 2: Pomalidomide capsules intervention 3: Dexamethasone tablets

Protocol documents:
Prot_000.pdf: 



Title: A Phase 2, Randomized, Open-Label Study Comparing Oral Ixazomib/Dexamethasone and 
Oral Pomalidomide/Dexamethasone in Relapsed and/or Refractory Multiple Myeloma
NCT Number: NCT03170882
Protocol Approve Date: 31 August 2020
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.


1.0 TITLE PAGE
PROTOCOL 
A Phase 2, Randomized, Open-Label Study Comparing Oral Ixazomib/Dexamethasone and 
Oral Pomalidomide/Dexamethasone in Relapsed and/or Refractory Multiple Myeloma
Sponsor:
Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda 
Pharmaceutical Company Limited
40 Landsdowne Street
Cambridge, MA 02139, USA
Telephone: +1 (617) 679-7000
Note: Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda 
Pharmaceutical Company Limited, may be referred to in this protocol as 
“Millennium,” “Sponsor,” or “Takeda.”
Study Number:
C16029
IND Number:
IND 104,482
EudraCT Number:
2016-004742-28
Compound:
Ixazomib (NINLARO)
Date: 
31 August 2020
Version/Amendment 
Number:
06 (global)
Amendment History:
Date
Amendment 
Number
Amendment Type 
(for Regional Europe Purposes Only)
Region
29 March 2017
Initial protocol
Global
09 August 2017
01
Nonsubstantial
Global
30 January 2019
02
Nonsubstantial
Global
23 April 2019
03
Substantial
United Kingdom
11 June 2019
04
Substantial
Germany
16 September 2019
05
Substantial
Global
31 August 2020
06
Substantial
Global
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1.0
ADMINISTRATIVE 
1.1
Contacts 
A separate contact information list will be provided to each site.
Serious adverse event and pregnancy reporting information is presented in Section 10.0, as is 
information on reporting product complaints and medication errors. 
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines 
provided to the site.
Contact Type/Role
North America
Contact
European Union
Contact
Japan
Contact
Serious adverse event 
and pregnancy reporting
See Section 10.2
See Section 10.2
See Section 10.2
Medical Monitor
(medical advice on 
protocol and 
compound)
See Study Manual
See Study Manual
See Study Manual
Responsible Medical 
Officer 
(carries overall 
responsibility for the 
conduct of the study)
See Study Manual
See Study Manual
See Study Manual
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1.2
Approval
REPRESENTATIVES OF MILLENNIUM 
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 Millennium medical officer (and other signatories, as applicable) 
can be found on the signature page.
Electronic Signatures can be found on the last page of this document.
PPD
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
dance
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INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, package 
insert, 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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1.3
Protocol Amendment 06 Summary of Changes
Rationale for Amendment 06
This document describes the changes in reference to the protocol incorporating Amendment 06. 
The primary reason for this amendment is to modify the study assessments, now that the data 
cutoff date for the study analysis (the only planned formal analysis) has been reached (31 May 
2020). Only patients who continue to demonstrate clinical benefit but who do not have other 
means of access to the study drugs will continue on the study. Because no further formal statistical 
analyses will be performed, only assessments contributing to long-term safety data are required. 
Most study assessments besides safety are discontinued to ease the burden of protocol-mandated 
assessments on patients.
Patients continuing their current study treatment may do so until such time as other means of 
accessing the study drugs are arranged. When possible, patients should complete an End of 
Treatment (EOT) visit and transition onto an alternative supply of (eg, commercially available) 
ixazomib or pomalidomide, as well as dexamethasone, or onto another standard of care treatment. 
Discontinued patients will be treated by their physician per local standard of care.
Upon implementation of Amendment 06, data collection requirements will be limited to collection 
of adverse events (AEs) and serious adverse events (SAEs). All other study assessments are no 
longer required. All central laboratory assessments are discontinued. Quality of life and health care
utilization (HU) assessments and collection of concomitant medications and procedures are 
discontinued. Patients will not be followed for the progression-free survival (PFS) or overall 
survival (OS) follow-up periods, because PFS and OS data are no longer being collected. See the 
updated Schedule of Events in Appendix A for more detailed information (the previous, full 
Schedule of Events is now moved to Appendix L for reference only).
Descriptions of how to manage study procedures during unavoidable circumstances, such as the 
coronavirus disease 2019 (COVID-19) pandemic, have additionally been added.
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 location of the changes, see Appendix M.
Changes in Amendment 06
1. To note that the data cutoff date for the study analysis, which is the only planned formal 
analysis for this study, has now occurred.
2. To note that, now that the data cutoff date for the study analysis has occurred, all central 
efficacy and investigator assessments of response for protocol purposes are now discontinued. 
3. To note that, now that the data cutoff date for the study analysis has occurred, the objective and 
endpoint of the study has changed to solely continue to collect long-term safety data.
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4. To note that as of the current amendment, now that the data cutoff date for the study analysis 
has occurred, only patients who continue to demonstrate clinical benefit but have no access to 
study drugs other than staying in the study may stay in the study.
5. To clarify that, as of the current amendment, the reason for a patient’s treatment 
discontinuation must be recorded in the electronic case report form (eCRF) but no approval by 
the sponsor is required to discontinue treatment.
6. To clarify that local laboratory evaluations are to be used henceforth.
7. To simplify the Schedule of Events to reflect the other changes noted.
8. To clarify that pharmacokinetic (PK) sample collection is now complete.
9. To clarify that the previous, full Schedule of Events and the now-completed PK sampling 
schedule have been moved to a new appendix (Appendix L) for reference only.
10. Identify, as needed, text in the protocol that is no longer applicable as of the current 
amendment, now that the data cutoff date for the study analysis has occurred.
11. To add flexibility in study conduct in unavoidable circumstances (eg, the COVID-19 
pandemic).
12. To indicate that, given the changes in the current amendment, patients remaining on study will 
need to be reconsented.
13. Update language about management of clinical events in patients receiving ixazomib.
14. To clarify details about ixazomib packaging, handling, and storage guidelines.
15. To clarify that PFS and OS data will be analyzed using unstratified tests, among others.
16. To add information about submitting SAE reports.
17. To correct a typographical error and clarify that there is only 1 study analysis planned (and as 
such, no interim analyses).
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TABLE OF CONTENTS
1.0
ADMINISTRATIVE.......................................................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment 06 Summary of Changes ..........................................................5
2.0
STUDY SUMMARY ....................................................................................................13
3.0
STUDY REFERENCE INFORMATION ......................................................................16
3.1
Study-Related Responsibilities.................................................................................16
3.2
Principal Investigator/Coordinating Investigator ......................................................16
3.3
List of Abbreviations ...............................................................................................17
3.4
Corporate Identification...........................................................................................19
4.0
INTRODUCTION.........................................................................................................20
4.1
Background .............................................................................................................20
4.1.1
Ixazomib Clinical Development Program.........................................................20
4.1.1.1
Approval of Ixazomib+Lenalidomide and Dexamethasone for Relapsed 
and/or Refractory Multiple Myeloma.......................................................20
4.1.1.2
Other Clinical Development ....................................................................21
4.1.1.3
Investigator-Initiated Study Relevant to This Protocol .............................21
4.2
Background Information on the Disease to Be Treated.............................................22
4.2.1
Current Medical Treatments for MM ...............................................................22
4.2.2
Unmet Medical Need Addressed by This Clinical Study..................................22
4.2.3
Benefit/Risk Assessment..................................................................................24
4.2.3.1
Benefits ...................................................................................................24
4.2.3.2
Risks .......................................................................................................26
4.3
Rationale for the Proposed Study.............................................................................27
4.3.1
Need for Non-IMiD, Cost-Effective Combination Therapies in RRMM...........27
4.3.2
Need for All-Oral Combination Therapies in Patients With RRMM at Later 
Lines of Therapy..............................................................................................27
4.3.3
Possible Benefit-Risk of Ixa+Dex versus Pom+Dex.........................................28
4.3.4
Ixazomib Dose Rationale.................................................................................29
4.3.5
Summary of Rationale .....................................................................................30
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................31
5.1
Objectives................................................................................................................31
5.1.1
Primary Objective............................................................................................31
5.1.2
Secondary Objectives ......................................................................................31
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5.1.3
Safety Objective ..............................................................................................31
5.1.4
Exploratory Objective......................................................................................31
5.2
Endpoints.................................................................................................................32
5.2.1
Primary Endpoint.............................................................................................32
5.2.2
Secondary Endpoints .......................................................................................32
5.2.3
Safety Endpoint ...............................................................................................32
5.2.4
Exploratory Endpoint.......................................................................................32
6.0
STUDY DESIGN..........................................................................................................33
6.1
Overview of Study Design.......................................................................................33
6.1.1
Study Population .............................................................................................33
6.1.2
Study Therapy Dosing .....................................................................................34
6.1.3
Study Assessments ..........................................................................................34
6.1.3.1
Assessments During the Treatment Period...............................................35
6.1.3.2
Assessments During the Follow-up Periods: PFS and OS.........................36
6.1.3.3
Other Assessment Details ........................................................................38
6.1.4
Statistical Analyses..........................................................................................38
6.2
Number of Patients ..................................................................................................38
6.3
Duration of Study ....................................................................................................38
6.3.1
Duration of an Individual Patient’s Study Participation....................................38
6.3.2
End of Study/Study Completion Definition......................................................38
6.3.3
Timeframes for Primary and Secondary Endpoints to Support Disclosures ......38
6.3.4
Total Study Duration .......................................................................................39
7.0
STUDY POPULATION................................................................................................40
7.1
Inclusion Criteria .....................................................................................................40
7.2
Exclusion Criteria ....................................................................................................42
8.0
STUDY THERAPY ......................................................................................................44
8.1
Investigational Therapy: Ixazomib Administration (Arm A) ....................................44
8.2
Reference/Control Therapy: Pomalidomide Administration (Arm B) .......................45
8.3
Standard of Care Therapy: Dexamethasone Administration (Both Arms).................45
8.4
Dose Modification Guidelines..................................................................................46
8.4.1
Intrapatient Dose Escalation of Ixazomib (Arm A)...........................................46
8.4.2
Criteria for Beginning or Delaying a Subsequent Treatment Cycle...................46
8.4.2.1
Criteria for Beginning the Next Treatment Cycle With Ixa+Dex (Arm A)
................................................................................................................46
8.4.2.2
Criteria for Beginning the Next Treatment Cycle With Pom+Dex (Arm 
B) ............................................................................................................47
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8.4.3
Ixazomib Treatment Modification (Arm A) .....................................................47
8.4.4
Pomalidomide Treatment Modification (Arm B)..............................................50
8.4.5
Dexamethasone Treatment Modification (Both Arms) .....................................50
8.4.6
Criteria for Discontinuation of Study Drug ......................................................51
8.5
Excluded Concomitant Medications and Procedures ................................................52
8.6
Permitted Concomitant Medications and Procedures................................................52
8.7
Precautions and Restrictions ....................................................................................53
8.8
Management of Clinical Events ...............................................................................54
8.8.1
Ixazomib..........................................................................................................54
8.8.2
Pomalidomide..................................................................................................57
8.8.3
Dexamethasone................................................................................................58
8.9
Blinding and Unblinding..........................................................................................58
8.10
Description of Investigational Agents ......................................................................58
8.10.1
Ixazomib..........................................................................................................58
8.10.1.1
Preparation, Reconstitution, and Dispensation .........................................58
8.10.1.2
Packaging and Labeling...........................................................................58
8.10.1.3
Storage, Handling, and Accountability.....................................................58
8.10.2
Pomalidomide (Control Therapy).....................................................................59
8.10.2.1
Preparation, Reconstitution, and Dispensation .........................................59
8.10.2.2
Packaging and Labeling...........................................................................60
8.10.2.3
Storage, Handling, and Accountability.....................................................60
8.10.3
Dexamethasone................................................................................................60
8.10.3.1
Preparation, Reconstitution, and Dispensation .........................................60
8.10.3.2
Packaging and Labeling...........................................................................60
8.10.3.3
Storage, Handling, and Accountability.....................................................60
8.11
Other Protocol-Specified Materials ..........................................................................60
9.0
STUDY CONDUCT......................................................................................................61
9.1
Study Personnel and Organizations..........................................................................61
9.2
Arrangements for Recruitment of Patients................................................................61
9.3
Treatment Group Assignments.................................................................................61
9.4
Study Procedures.....................................................................................................61
9.4.1
Informed Consent ............................................................................................62
9.4.2
Enrollment.......................................................................................................62
9.4.3
Patient Demographics......................................................................................62
9.4.4
Physical Examinations.....................................................................................62
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9.4.5
Medical History and Disease Staging...............................................................62
9.4.6
ECOG Performance Status...............................................................................63
9.4.7
Vital Signs.......................................................................................................63
9.4.8
Height and Weight...........................................................................................63
9.4.9
Electrocardiogram ...........................................................................................63
9.4.10
QOL and HU Assessments...............................................................................63
9.4.10.1
QOL........................................................................................................64
9.4.10.2
HU ..........................................................................................................65
9.4.11
Imaging Disease Assessment ...........................................................................65
9.4.12
Disease Response Assessment by Investigator.................................................66
9.4.13
..............................66
9.4.14
Pregnancy Test ................................................................................................67
9.4.15
Clinical Laboratory Evaluations.......................................................................67
9.4.15.1
Clinical Chemistry and Hematology ........................................................68
9.4.15.2
Clinical Laboratory Evaluations for Disease Assessments........................68
9.4.16
AEs .................................................................................................................69
9.4.17
Concomitant Medications and Procedures........................................................69
9.4.18
PK Samples and Measurements .......................................................................69
9.5
Completion of Study Treatment (for Individual Patients) .........................................70
9.6
Completion of Study (for Individual Patients)..........................................................70
9.7
Discontinuation of Treatment With Study Therapy ..................................................70
9.8
Withdrawal of Patients From Study .........................................................................71
9.9
Study Closure ..........................................................................................................71
9.10
Study Compliance....................................................................................................72
10.0
ADVERSE EVENTS ....................................................................................................73
10.1
Definitions...............................................................................................................73
10.1.1
Pretreatment Event Definition..........................................................................73
10.1.2
AE Definition ..................................................................................................73
10.1.3
SAE Definition................................................................................................73
10.2
Procedures for Recording and Reporting AEs and SAEs..........................................74
10.3
Monitoring of AEs and Period of Observation .........................................................76
10.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events.........76
10.5
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose) ................................................................................................................76
10.6
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities...........77
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................78
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11.1
IDMC ......................................................................................................................78
12.0
DATA HANDLING AND RECORDKEEPING............................................................79
12.1
eCRFs......................................................................................................................79
12.2
Record Retention .....................................................................................................79
13.0
STATISTICAL METHODS..........................................................................................81
13.1
Statistical and Analytical Plans ................................................................................81
13.1.1
Analysis Sets ...................................................................................................81
13.1.2
Analysis of Demographics and Other Baseline Disease Characteristics............81
13.1.3
Efficacy Analysis.............................................................................................81
13.1.3.1
Analyses for Primary Efficacy Endpoint ..................................................82
13.1.3.2
Analyses of Secondary Efficacy...............................................................82
13.1.4
PK Analysis.....................................................................................................83
13.1.5
QOL and HU Analyses....................................................................................83
13.1.6
Safety Analysis................................................................................................83
13.1.6.1
New Primary Malignancy........................................................................85
13.1.7
Control of Overall Type I Error for the Primary Endpoint of PFS ....................85
13.2
Determination of Sample Size..................................................................................85
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................86
14.1
Study-Site Monitoring Visits ...................................................................................86
14.2
Protocol Deviations..................................................................................................86
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................87
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................88
15.1
IRB and/or IEC Approval ........................................................................................88
15.2
Subject Information, Informed Consent, and Subject Authorization .........................89
15.3
Subject Confidentiality ............................................................................................90
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................91
15.4.1
Publication.......................................................................................................91
15.4.2
Clinical Trial Registration................................................................................91
15.4.3
Clinical Trial Results Disclosure......................................................................91
15.5
Insurance and Compensation for Injury....................................................................92
16.0
REFERENCES..............................................................................................................93
LIST OF IN-TEXT TABLES
Table 6.a
Primary and Secondary Endpoints for Disclosures .............................................39
Table 8.a
Dose Reduction Steps for Ixazomib ...................................................................47
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Table 8.b
Ixazomib Dose Modification for Hematologic Toxicities ...................................48
Table 8.c
Ixazomib Dose Modification for Nonhematologic Toxicities..............................49
Table 8.d
Criteria for Ixazomib Retreatment and Cycle Delays Subsequent to 
Hematologic and Nonhematologic Toxicities .....................................................49
Table 8.e
Dose Reduction Steps for Dexamethasone .........................................................50
Table 8.f
Dexamethasone-Related Treatment Modification (Delays, Reductions, and 
Discontinuations) Guidelines Because of AEs [56].............................................51
Table 9.a
Response Assessment.........................................................................................66
Table 9.b
Clinical Chemistry and Hematology Tests..........................................................68
LIST OF IN-TEXT FIGURES
Figure 6.a
Study Schema, From Randomization Through End of Therapy ..........................33
Figure 6.b
Flow of Patients Through Follow-up Periods After the EOT Visit (Only in 
Effect Before Amendment 06)............................................................................37
LIST OF APPENDICES
Appendix A
Updated Schedule of Events...............................................................................99
Appendix B
Responsibilities of the Investigator...................................................................102
Appendix C
Investigator Consent to Use of Personal Information........................................104
Appendix D
Revised IMWG Diagnostic Criteria for MM ....................................................105
Appendix E 
ECOG Scale for Performance Status ................................................................106
Appendix F
ISS Staging Criteria .........................................................................................107
Appendix G
IMWG Uniform Response Criteria for MM .....................................................108
Appendix H
EORTC QLQ-C30 (version 3) .........................................................................110
Appendix I
EORTC QLQ-MY20........................................................................................112
Appendix J
EQ-5D-5L........................................................................................................114
Appendix K
Site HU Data Collection Form .........................................................................117
Appendix L
Previous, Full Schedule of Events and PK Sampling Schedule (Schedules 
Before Implementation of Amendment 06) ......................................................120
Appendix M
Detailed Description of Amendments to Text...................................................127
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2.0
STUDY SUMMARY
Name of Sponsor(s):
Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda 
Pharmaceutical Company Limited
Compound:
Ixazomib (NINLARO)
Title of Protocol: A Phase 2, Randomized, Open-Label Study Comparing Oral Ixazomib/Dexamethasone and Oral 
Pomalidomide/Dexamethasone in Relapsed and/or Refractory Multiple Myeloma
Study Number: C16029
Phase: 2
Study Design: 
Study C16029 is a randomized, open-label, phase 2 study. The 3 stratification factors are International Staging System 
stage (I or II vs III at study entry), prior lines of therapy (2 vs 3 or more), and age (<65 vs ≥65 years). Patients will be 
randomized in a 3:2 ratio to receive ixazomib+dexamethasone (ixa+dex; Arm A) or pomalidomide+dexamethasone 
(pom+dex; Arm B), until first confirmed progressive disease (PD) or unacceptable toxicities.
Primary Objective:
As of Amendment 06, the objective is to continue to collect long-term safety data from patients who are continuing on 
ixazomib and dexamethasone or pomalidomide and dexamethasone because of continuing clinical benefit. Data 
collection for all other study objectives and endpoints is complete and no further formal analyses will be conducted. 
However, the original primary objective is retained below for reference only.
To compare the effect of ixa+dex versus pom+dex on progression-free survival (PFS) in patients with relapsed and/or 
refractory multiple myeloma (RRMM) who have received at least 2 prior lines of therapy, including lenalidomide and 
a proteasome inhibitor, and are refractory to lenalidomide but not refractory to proteasome inhibitors.
Secondary Objectives:
As of Amendment 06, the objective is to continue to collect long-term safety data from patients who are continuing on 
ixazomib and dexamethasone or pomalidomide and dexamethasone because of continuing clinical benefit. Data 
collection for all other study objectives and endpoints is complete and no further formal analyses will be conducted. 
However, the original secondary objectives are retained below for reference only.

To compare overall survival (OS) in patients treated with ixa+dex versus pom+dex.

To compare duration of response, overall response rate (ORR), time to response, and time to progression with 
ixa+dex versus pom+dex.

To obtain health-related quality of life (QOL) data related to physical functioning of patients treated with ixa+dex 
versus pom+dex.

To assess health-related QOL by additional function and symptom domains of the European Organization for 
Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire–Core 30 (EORTC QLQ-C30) 
instrument and by the EORTC Quality of Life Questionnaire–multiple myeloma module (EORTC QLQ-MY20) 
and 5-level classification system of the EuroQol 5-Dimensional Health Questionnaire (EQ-5D-5L) instruments. 

To evaluate health care utilization (HU) by patients receiving ixa+dex versus those receiving pom+dex.

To collect plasma concentration-time data for ixazomib to contribute to population pharmacokinetic 
characterization of ixazomib and to conduct exposure-response analyses for patients receiving ixa+dex.
Safety:

To compare safety/tolerability of ixa+dex to that of pom+dex.
Study Population: Patients with RRMM, aged ≥18 years, for whom pomalidomide is clinically indicated, who have 
had at least 2 prior lines of systemic therapy, including at least 2 consecutive cycles of bortezomib or carfilzomib 
(without having had PD during treatment with or within 60 days after the last dose of bortezomib or carfilzomib), and 
are refractory to lenalidomide.
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Number of Subjects:
Estimated total: approximately 120 patients randomized—approximately 72 in 
Arm A (ixa+dex) and approximately 48 in Arm B (pom+dex).
Number of Sites: 
Estimated total: approximately 
100 globally 
Dose Levels:
Arm A
Ixazomib will be administered at a 4 mg starting dose, with escalation to 5.5 mg at 
Cycle 2 for patients who tolerate the 4 mg dose in Cycle 1 (specifically, patients 
who do not experience any new Grade 1 peripheral neuropathy with pain or other
ixazomib-related Grade ≥2 nonhematologic or Grade ≥3 neutropenia or 
thrombocytopenia in Cycle 1). Patients who have had any dose reductions, holds, 
or delays because of ixazomib toxicities will not dose escalate. Dose escalation 
beyond the start of Cycle 2 is permitted only when dose escalation was 
inadvertently missed at Cycle 2. 
Ixazomib will be administered orally on Days 1, 8, and 15 of each 28-day cycle, 
combined with dexamethasone 20 mg (or 10 mg if patient is aged ≥75 years) orally 
on Days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day cycle until PD. In cases where 
only 4 mg tablets for dexamethasone are available (eg, 4 mg dexamethasone is the 
only dosage available), the following dexamethasone schedule is recommended 
for patients aged ≥75 years: 12 mg dexamethasone will be given on Days 1, 8, 15, 
and 22 of every 28-day cycle; and 8 mg dexamethasone will be given on Days 2, 9, 
16, and 23 of every 28-day cycle.
Arm B
Pomalidomide will be administered at 4 mg orally on Days 1 to 21 of each 28-day 
cycle, combined with dexamethasone 40 mg (or 20 mg if patient is aged ≥75 years) 
orally on Days 1, 8, 15, and 22 of each 28-day cycle until PD.
Route of Administration:
Arm A and Arm B are both 
all-oral therapies.
Duration of Treatment:
Patients will receive study therapy until PD, unacceptable toxicity, withdrawal of 
consent, or sponsor termination of study.
Period of Evaluation:
Up to 28 months 
Main Criteria for Inclusion:

Adult patients (aged ≥18 years) who have been diagnosed with multiple myeloma (MM) according to standard 
criteria.

All patients must have had a relapse or PD after having received 2 or more prior lines of systemic therapy. 
(A line of therapy is defined as 1 or more cycles of a planned treatment program; this may consist of 1 or more 
planned cycles of single-agent therapy or combination therapy, as well as a sequence of treatments administered 
in a planned manner. For example, a planned treatment approach of induction therapy followed by autologous 
stem-cell transplantation, followed by maintenance is considered 1 line of therapy. Typically each line of therapy 
is separated by PD. Discussion with the medical monitor may help clarify the number of prior lines of therapy for 
a prospective study participant.)

All patients must be refractory to lenalidomide, defined as having received at least 2 consecutive cycles of 
lenalidomide as a single agent or within a lenalidomide-containing regimen and having had PD during treatment 
with or within 60 days after the last dose of lenalidomide. The starting dose of lenalidomide should have been 25 
mg (or as low as 10 mg in the case of renal function impairment or other safety concern), and the final dose should 
have been a minimum of 10 mg. 

All patients must have received at least 2 consecutive cycles of a bortezomib- or carfilzomib-containing regimen, 
and either: 
–
Achieved at least a partial response (PR) and did not have PD during treatment with or within 60 days after 
the last dose of bortezomib or carfilzomib, OR
–
Had bortezomib and/or carfilzomib intolerance (defined as discontinuation because of drug-related adverse 
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events (AEs) before completion of the planned treatment course) without PD upon the start of the next 
regimen.

All patients must have an Eastern Cooperative Oncology Group score of 0 to 2.

All patients must have measurable disease defined by serum M-protein ≥1 g/dL (≥10 g/L) or urine M-protein 
≥200 mg/24 hours and must have documented MM isotype by immunofixation (central laboratory). 
Main Criterion for Exclusion: 

Patients must not have received prior ixazomib or pomalidomide and must not have participated in a previous 
ixazomib clinical study.
Main Criteria for Evaluation and Analyses:
The primary endpoint for this study is PFS, defined as the time from randomization to the first occurrence of 
confirmed PD, as evaluated by investigators on the basis of central laboratory results according to International 
Myeloma Working Group (IMWG) criteria, or death from any cause, whichever occurs first.
The secondary endpoints are OS; ORR (defined as complete response, very good partial response (VGPR), or PR [per 
IMWG criteria]); duration of response; time to response; time to progression (TTP); health-related QOL as measured 
by the physical functioning domain of the EORTC QLQ-C30; health-related QOL as measured by other domains of 
the EORTC QLQ-C30, by the EORTC QLQ-MY20, and by the EQ-5D-5L; health care utilization as measured by the 
number and duration of medical encounters; and safety/tolerability. 
After the data cutoff date for the study analysis (including for PFS) has occurred, all central efficacy and investigator 
assessments of response for protocol purposes will be discontinued.
As of Amendment 06, the data cutoff date for the study analysis (31 May 2020) has been reached. Only patients who 
continue to demonstrate clinical benefit but who do not have other means of access to the study drugs will continue on 
the study. As no further formal statistical analyses will be performed, only assessments contributing to long-term 
safety data are required. Most study assessments besides safety are discontinued to ease the burden of 
protocol-mandated assessments on patients.
Patients continuing their current study treatment may do so until such time as other means of accessing the study drugs 
are arranged. When possible, patients should complete an End of Treatment visit and transition onto an alternative 
supply of (eg, commercially available) ixazomib or pomalidomide, as well as dexamethasone, or onto another 
standard of care treatment. Discontinued patients will be treated by their physician per local standard of care.
Upon implementation of Amendment 06, data collection requirements will be limited to collection of AEs and serious 
AEs. All other study assessments are no longer required. All central laboratory assessments are discontinued. Quality 
of life and health care utilization assessments and collection of concomitant medications and procedures are 
discontinued. Patients will not be followed for the PFS or OS follow-up periods, as PFS and OS data are no longer 
being collected.
Statistical Considerations:
There will be 1 study analysis for PFS and secondary endpoints.
Sample Size Justification:
Approximately 120 patients will be enrolled in total. 
The primary endpoint is PFS. Approximately 81 PFS events would be needed to provide 80% power at a 2-sided 0.20 
level of significance with an HR of 0.62.
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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. 
3.2
Principal Investigator/Coordinating Investigator 
Millennium 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
ANC
absolute neutrophil count
ASCT
autologous stem cell transplantation
CFR
Code of Federal Regulations
CR
complete response
CRO
contract research organization
CT
computed tomography
DRESS
Drug Reaction with Eosinophilia and Systemic Symptoms 
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EORTC QLQ-C30
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire–Core 30
EORTC QLQ-MY20
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire–multiple myeloma module
EOT
End of Treatment
EQ-5D-5L
5-level classification system of the EuroQol 5-Dimensional Health Questionnaire
EQ VAS
EuroQol visual analogue scale
EU
European Union
FDA
Food and Drug Administration
G-CSF
granulocyte colony stimulating factor
GCP
Good Clinical Practice
HR
hazard ratio
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
IDMC
independent data monitoring committee
IEC
independent ethics committee
IMiD
immunomodulatory drug
IMWG
International Myeloma Working Group
IRB
institutional review board
IRT
interactive response technology
ISS
International Staging System
ITT
intent-to-treat
IV
intravenous
ixa+dex
ixazomib+dexamethasone (investigational study therapy, given in Arm A)
KM
Kaplan-Meier
LenDex
lenalidomide and dexamethasone
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line of therapy
1 or more cycles of a planned treatment program; this may consist of 1 or more planned 
cycles of single-agent therapy or combination therapy, as well as a sequence of treatments 
administered in a planned manner. For example, a planned treatment approach of 
induction therapy followed by ASCT, followed by maintenance is considered 1 line of 
therapy) [1]. Typically, each line of therapy is separated by PD. Discussion with the 
medical monitor may help clarify the number of prior lines of therapy for each prospective 
study participant.
MedDRA
Medical Dictionary for Regulatory Activities
MM
multiple myeloma
MRI
magnetic resonance imaging
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NDMM
newly diagnosed multiple myeloma
NSAIDs
nonsteroidal anti-inflammatory drugs
ORR
overall response rate
OS
overall survival
PD
progressive disease
PET
positron emission tomography
PFS
progression-free survival
PK
pharmacokinetic
pom+dex
pomalidomide+dexamethasone (control study therapy; given in Arm B)
PP
per-protocol
PR
partial response
QOL
quality of life
REMS
Risk Evaluation and Mitigation Strategies
RRAL
relapsed and/or refractory systemic light-chain amyloidosis
RRMM
relapsed and/or refractory multiple myeloma
SAE
serious adverse event
SJS
Stevens-Johnson syndrome 
SmPC
Summary of Product Characteristics
SPEP
serum protein electrophoresis
SUSARs
suspected unexpected serious adverse reactions
TEAE
treatment-emergent adverse event
TEN
toxic epidermal necrolysis 
TMA
thrombotic microangiopathy
TTP
time to progression
ULN
upper limit of normal
UPEP
urine protein electrophoresis
US
United States
VD
bortezomib with dexamethasone
VGPR
very good partial response
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3.4
Corporate Identification 
Millennium
Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda 
Pharmaceutical Company Limited
TDC Japan
Takeda Development Center Japan
TDC Asia
Takeda Development Center Asia, Pte Ltd
TDC Europe
Takeda Development Centre Europe Ltd
TDC Americas
Takeda Development Center Americas, Inc
TDC
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable
Takeda
Millennium Pharmaceuticals, Inc, TDC Japan, TDC Asia, TDC Europe and/or TDC 
Americas, as applicable
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4.0
INTRODUCTION
4.1
Background
4.1.1
Ixazomib Clinical Development Program
Ixazomib, an oral inhibitor of the 20S proteasome, is under development for the treatment of 
multiple myeloma (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, 
Millennium Pharmaceuticals, Inc’s first-in-class proteasome inhibitor [2].
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).
4.1.1.1
Approval of Ixazomib+Lenalidomide and Dexamethasone for Relapsed and/or 
Refractory Multiple Myeloma
Ixazomib in combination with lenalidomide and dexamethasone (LenDex) was approved (under 
the brand name NINLARO) by the United States (US) Food and Drug Administration (FDA) in 
November 2015 for the treatment of patients with MM who have received at least 1 prior therapy 
[3,4], with approvals subsequently in Canada, Israel, Australia, the European Union (EU), and 
Singapore and in Switzerland for patients who have received at least 1 prior therapy and have 
high-risk characteristics or have received at least 2 prior therapies. Additionally, NINLARO is 
approved as a Medical Service Product in Venezuela.
The pivotal phase 3 Study C16010 was the basis for the approval, involving 722 patients with 
relapsed and/or refractory multiple myeloma (RRMM) [4]. The primary endpoint of PFS was met 
in the intent-to-treat (ITT) population at the primary analysis, with a significant 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. At a median follow-up of 
approximately 23 months, the median OS had not been reached in either regimen. The rates of 
SAEs were similar in the 2 regimens (47% with ixazomib, 49% with placebo), as were the rates of 
death during the study period (4% and 6%, respectively); Grade ≥3 AEs occurred in 74% and 69% 
of the patients, respectively. Overall, the addition of ixazomib to LenDex did not add substantial 
toxicity. 
The PFS benefit and safety profile seen in global Study C16010 have been substantiated in the 
China Continuation study, a second double-blind, placebo-controlled study of similar design and 
the same inclusion criteria, with 115 patients with RRMM, all enrolled in China [5]. In addition, an 
OS benefit in favor of the ixazomib+LenDex group was observed at the final analysis [6]. 
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More details are given in Section 4.2.3.1.
4.1.1.2
Other 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. Regardless of the route of administration, in the twice-weekly dosing schedule, 
ixazomib is given on Days 1, 4, 8, and 11 of a 21-day cycle, and in the weekly dosing schedule, 
ixazomib is given on Days 1, 8, and 15 of a 28-day cycle. 
Phase 1, phase 1/2, and phase 2 studies are ongoing in MM, relapsed and/or refractory systemic 
light-chain amyloidosis (RRAL), solid tumors, and lymphoma. In addition, phase 1 studies have 
been completed in patients with renal impairment who have RRMM or advanced solid tumors 
(Study C16015); patients with hepatic impairment who have advanced solid tumors or 
hematologic malignancies (Study C16018); and in an absorption, distribution, metabolism, and 
excretion study in patients with advanced solid tumors or lymphoma (Study C16016). Phase 3 
studies in RRMM, newly diagnosed multiple myeloma (NDMM), and RRAL are under way. 
As of 27 March 2016, for SAE and fatality incidences, a total of 3346 patients have been exposed 
to ixazomib. Specifically, data are available from 929 patients known to have received at least 1 
dose of either the IV or oral ixazomib formulations across the clinical development program; in 
addition, 2417 patients have been enrolled in the following phase 3 clinical trials:
!
Double-blind, placebo-controlled Study C16010 and Study C16010 China Continuation study 
of ixazomib versus placebo in combination with LenDex in patients with RRMM (described in 
Section 4.1.1.1).
!
Double-blind, placebo-controlled Study C16014 and Study C16014 extension in South Korea 
of ixazomib versus placebo in combination with LenDex in patients with NDMM. 
!
Double-blind, placebo-controlled Study C16019 of ixazomib versus placebo as maintenance in 
patients with NDMM who have undergone autologous stem cell transplantation (ASCT) 
before entering the study.
!
Double-blind, placebo-controlled Study C16021 of ixazomib versus placebo as maintenance in 
patients with NDMM who have not undergone ASCT.
!
Open-label Study C16011 of ixazomib and dexamethasone (ixa+dex) versus physician’s 
choice of a dexamethasone-containing regimen in patients with RRAL. 
4.1.1.3
Investigator-Initiated Study Relevant to This Protocol
Results of the investigator-initiated study of ixa+dex in patients with RRMM (MC1181, 
NCT01415882; principal investigator, 
) are of particular importance for 
Study C16029, the focus of this protocol [7,8]. In that study, patients with relapsed MM were 
treated with ixazomib 4.0 or 5.5 mg weekly for 3 of 4 weeks and with dexamethasone 40 mg 
weekly. The overall response rate (ORR) was 31% for the 4.0 mg arm and 54% for the 5.5 mg arm. 
Both arms had manageable toxicities. See Section 4.3.4 for more information.
PPD
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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4.2
Background Information on the Disease to Be Treated
MM is a clonal disease of plasma cells that is characterized by the accumulation of plasma cells in 
the bone marrow (and other organs) and sometimes results in bone marrow failure, bone 
destruction, hypercalcemia, anemia, infection, and renal failure. It is the second most common 
hematological malignancy, constituting approximately 1% of all reported neoplasms and 
approximately 13% of hematologic cancers worldwide [9]. The incidence of MM is expected to 
increase over the next decade, which highlights the need for more effective MM therapies [10]. 
Moreover, to a greater extent in the future than now, MM will be a disease that primarily affects 
older persons (those aged 64 to 84 years) [11], who generally have a worse prognosis than younger 
persons. 
4.2.1
Current Medical Treatments for MM
Although MM is considered a fatal disease, duration of survival has improved dramatically over 
the last 2 decades because of advances in understanding the disease biology as well as 
improvements in treatment and supportive care strategies. Between 1990 and 2007, the cancer 
death rate for people with MM in the United States decreased by approximately 9% for men and 
13% for women, owing to the introduction of stem cell transplantation and the novel agents 
bortezomib, thalidomide, and lenalidomide [12]. Correspondingly, 5-year survival improved from 
25% in 1975 to 39% in 2006 [13]. Similar improvements in survival rates among European 
patients with MM have been shown, particularly among younger patients [14,15]. Moreover, 
newer agents continue to be introduced, including carfilzomib, pomalidomide, elotuzumab, and 
daratumumab. These newer agents have been shown to improve survival among older patients, 
with the 6-year OS among patients older than 65 years increasing from 31% among those 
diagnosed in 2001-2005 to 56% among those diagnosed in 2006-2010 (p<0.001) [16]. Nonetheless, 
responses to currently available therapies are temporary, and most patients receive multiple 
therapies and combination therapies over the course of their disease.
First-line treatment options are determined by a patient’s eligibility, or lack thereof, for ASCT 
[17,18]. Regardless of whether the patient is transplant eligible, MM is sensitive to a number of 
cytotoxic drugs, including proteasome inhibitors such as bortezomib and carfilzomib, alkylating 
agents, immunomodulatory drugs (IMiDs) (eg, thalidomide and lenalidomide), corticosteroids, 
and monoclonal antibodies (eg, elotuzumab and daratumumab) [19-24]. However, even with such 
advances and risk-adapted approaches, nearly all patients eventually relapse or become refractory 
and require subsequent treatment [25,26]; thus, new treatment options are urgently needed. In 
particular, new therapies with less toxicity are needed for elderly patients to continue to improve 
the prognosis of this population that comprises most MM patients [16].
4.2.2
Unmet Medical Need Addressed by This Clinical Study
MM remains an incurable disease for most patients and development of RRMM is an inevitable 
reality for almost all patients. While there is no widely accepted standard of care for RRMM, 
patients typically receive several lines of therapy with combinations of drugs over the course of 
their disease. Further, MM is heterogeneous, and no single treatment regimen will be effective for 
all patients [27]. Consequently, treatment decisions are carefully based on patient and disease 
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characteristics. Historically, with each subsequent recurrence of MM, patients have a lower 
probability of responding to therapy [28-33]. Therefore, there is a need for regimens that are 
effective in later therapies. In addition, patients who require treatment after receiving 2 prior lines 
of therapy may experience long-term side effects as a consequence of being exposed to multiple 
cytotoxic drugs with varying toxicity profiles (eg, neuropathy, decreased bone marrow reserve). 
Many patients in their third or later line of therapy are not able to tolerate the toxicity of a 3-drug 
regimen and would benefit from a less toxic doublet (see Section 4.3.3). (A line of therapy is 
defined as 1 or more cycles of a planned treatment program; this may consist of 1 or more planned 
cycles of single-agent therapy or combination therapy, as well as a sequence of treatments 
administered in a planned manner. For example, a planned treatment approach of induction 
therapy followed by ASCT, followed by maintenance is considered 1 line of therapy [1]. Typically, 
each line of therapy is separated by progressive disease [PD]. Discussion with the medical monitor 
may help clarify the number of prior lines of therapy for each prospective study participant.) 
As the incidence of MM in older patients increases, so does the need for therapy that is effective 
but also tolerable and that maintains quality of life (QOL) [34]. At first relapse, the goal of therapy 
is often similar to that for newly diagnosed patients, with a focus on a more aggressive treatment 
and a higher acceptance for toxicity, but at later stages and with older age, therapeutic goals may 
change significantly, toward an increased emphasis on QOL, safety, tolerability, and convenience, 
in addition to efficacy. Patients typically value spending time away from the hospital and clinic as 
their disease advances. Therefore, these patients may prefer an entirely oral treatment regimen. In 
addition, many elderly patients may also be unable to tolerate more-toxic 3-drug combinations and 
thus would benefit from an efficacious but less toxic doublet.
Real-world clinical practice data illustrate a significant correlation between duration of therapy 
and probability of survival. Recently, this was documented with real-world electronic medical 
record data from a US-based study showing that each additional month of treatment in second-line 
RRMM was associated with a reduced risk of death at 1 year after initiation of second-line therapy 
(HR=0.67; 95% CI] 0.59, 0.77) [35].
Further, currently available therapies have been associated with dose-limiting toxicities and added 
treatment burdens to patients and their caregivers. For example, proteasome inhibitors approved in 
the relapsed setting require frequent hospital visits for IV (bortezomib and carfilzomib) or 
subcutaneous (bortezomib) administration [2,36]. Similarly, newly approved monoclonal 
antibodies such as daratumumab require frequent, prolonged IV infusions [37]. IV infusions of 
anticancer agents, or any parenteral agents, require administration in a hospital or clinic setting and 
add more than drug costs to the health economic burden, including, but not limited to, the cost of 
the use of the facility and its staff plus the cost of transportation to the facility in addition to the 
overall costs associated with therapy. Moreover, AEs that are associated with currently available 
agents impact a patient’s QOL and can lead to dose reductions and/or early treatment 
discontinuation, which in turn result in suboptimal treatment as well as potential loss of time able 
to perform work. Such AEs include peripheral neuropathy and hypotension (bortezomib), second 
primary malignancies (lenalidomide), neutropenia, allergic reactions, infusion-related reactions 
(daratumumab), vascular events (carfilzomib), thrombotic events (lenalidomide and 
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pomalidomide), and myelosuppression (pomalidomide) [2,17,36-42]. Finally, concern regarding 
the risk of teratogenicity of the IMiDs (including pomalidomide) has led to creation of the 
Pregnancy Prevention Programme in the European Union and the Risk Evaluation and Mitigation 
Strategies (REMS) programs in the United States. These programs increase the burdens placed on 
patients, health care providers, and health care clinics.
Consideration of the toxicity and the treatment burden to patients is important in this population 
because patients with relapsed MM are often sicker and carry with them some of the residual 
effects of their initial therapy [43]. Minimizing potential long-term adverse effects while 
maintaining efficacy is an important goal in the treatment of RRMM [43,44]. However, currently 
available therapies do not provide sustained improvements in disease control. For example, the 
median PFS for pomalidomide+dexamethasone (pom+dex) in patients in their third or later line of 
therapy in the registration-enabling MM-003 study (NIMBUS) [45] was 3.8 months (95% CI, 
3.4-4.6 months) versus 1.9 months (95% CI 1.9-2.1 months) with high-dose dexamethasone. 
Although the 3.8 months was a clinically meaningful and statistically significant improvement 
over the 1.9 months, it was not a prolonged response. In that same study, pom+dex provided a 
4.1-month improvement in OS. In addition, a study of single-agent daratumumab used to treat a 
similar population—US and EU patients with RRMM—showed a median PFS of 3.7 months and 
an ORR of 29.2% [46]. These survival and response findings support the observation that 
advanced MM continues to be an area of high unmet need, including a need for treatment 
approaches that prolong disease control while minimizing burden to patients (safety, oral 
convenience) and to the health care system. 
The convenience of the all-oral ixazomib regimen benefits active working patients in addition to 
those elderly or frail patients who would prefer to avoid traveling for frequent long hospital visits. 
Furthermore, the nursing time involved with administration of IV regimens as compared with the 
all-oral ixazomib regimen is an important consideration, while the safety profile speaks to patients’ 
ability to have a long-term regimen with maintenance of disease control.
4.2.3
Benefit/Risk Assessment
4.2.3.1
Benefits
Ixazomib in combination with LenDex has been approved by the US FDA and other agencies for 
the treatment of patients with MM who have received at least 1 prior therapy [3,4]. The 
exploration of ixazomib for other therapeutic areas is ongoing. To date, activity in MM has been 
seen with single-agent ixazomib and with ixazomib combined with established therapies. In 
addition, single-agent activity has been observed in relapsed amyloidosis and indolent 
non-Hodgkin lymphoma.
The pivotal phase 3 Study C16010 was the basis for the approval, involving 722 patients with 
RRMM [4]. The primary endpoint of PFS was met in the ITT population at the primary analysis, 
with a significant PFS benefit for patients receiving ixazomib+LenDex versus placebo+LenDex 
(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: ORR (78% vs 
72%), time to progression (TTP) (median, 21.4 vs 15.7 months), and duration of response (median, 
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20.5 vs 15.0 months) at the primary analysis. At a median follow-up of approximately 23 months, 
the median OS had not been reached in either regimen; nevertheless, the 2-year OS rate was 77.5%, 
which is one of the largest achieved to date in phase 3 studies of RRMM. 
The PFS benefit seen in global Study C16010 has been substantiated in the China Continuation 
study, a second double-blind, placebo-controlled study of similar design and the same inclusion 
criteria, with 115 patients with RRMM, all enrolled in China [5]. In this study, the primary 
endpoint of PFS was significantly improved in the ixazomib regimen as compared with the 
placebo regimen, with HR=0.598 and p=0.035 (with a median follow-up of approximately 
8 months, the median PFS was 6.7 vs 4.0 months, respectively). The PFS benefit in the ixazomib 
regimen was supported by improvements with the ixazomib regimen versus the placebo regimen 
in ORR (56% vs 31%) and TTP (median 7.3 vs 4.1 months). The reasons for the shorter median 
PFS in the China Continuation population than in the Study C16010 ITT population are likely the 
fact that Chinese patients are diagnosed with MM when their disease is more advanced as 
compared with the global population [47,48] and that the China Continuation patients were more 
frequently refractory to thalidomide (54% vs 12%, respectively), which can cause reduced efficacy 
of subsequent lenalidomide-containing regimens [49]. At the final analysis, an OS benefit in favor 
of the ixazomib+LenDex combination was observed [6]. In summary, the data from the China 
Continuation study support Study C16010 data, showing a positive treatment effect with the 
ixazomib regimen.
The Study C16010 and China Continuation findings are supportive of the current study. In both 
studies, the addition of ixazomib to LenDex was associated with a survival benefit; notably, all 
patients had RRMM that could have been pretreated with, but not refractory to, IMiDs and 
proteasome inhibitors. In Study C16010 [4], the IMiD-pretreated population had a similar PFS 
benefit with ixazomib as did the IMiD-naïve population (HRs, 0.74 and 0.70), and the proteasome 
inhibitor-pretreated population had a similar PFS benefit as did the proteasome inhibitor-naive 
population (HRs, 0.74 and 0.75). Thus, there is randomized evidence of an ixazomib treatment 
effect in patients with at least 2 prior lines of therapy, including prior IMiD treatment and prior 
proteasome inhibitor treatment, similar to the patients who will be enrolled in the current study. On 
the basis of these findings, as well as support for doublet (rather than triplet) therapy (eg, [50], and 
the approval of pom+dex for RRMM), this study is being conducted to test the hypothesis that 
ixazomib in combination with a corticosteroid may be an effective treatment of RRMM.
Overall, ixazomib shows 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 newly diagnosed MM, and prolongs stabilization of the underlying disease in other 
patients across all ongoing studies. Though additional data continue to be obtained to further 
establish the clinical benefit of this drug, the emerging data support the continued development of 
ixazomib for the treatment of patients with hematologic and solid tumor malignancies as well as 
ixazomib as part of doublet therapy for RRMM.
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4.2.3.2
Risks
Safety data supporting the higher ixazomib dose (5.5 mg weekly for 3 weeks in each 28-day cycle) 
are available from 
 and colleagues at the Mayo Clinic [7,8]. The initial group of this study 
investigated single-agent oral ixazomib administered at 5.5 mg weekly for 3 weeks of a 28-day 
cycle with dexamethasone added if a patient had a suboptimal response (minimal response by end 
of Cycle 2 or lack of partial response [PR] at end of Cycle 4) or PD. Results observed in this initial 
experience with 5.5 mg ixazomib led to study modification, with the addition of a randomized 
portion, consisting of 2 treatment groups comparing oral ixazomib doses of 4 and 5.5 mg, each in 
combination with dexamethasone. These 2 groups inform the comparative safety, tolerability, and 
efficacy of ixazomib (4 or 5.5 mg) administered weekly for 3 weeks of a 28-day cycle plus oral 
dexamethasone (20 mg) administered on Days 1, 2, 8, 9, 15, and 16 of the 28-day cycle in adults 
with measurable MM who have received ≥1 prior lines of therapy and who are not refractory to 
proteasome inhibitor therapy.
Patients received a median of 7 cycles of therapy (range, 1-31 cycles) across the study; 53 (76%) 
and 34 (49%) patients received at least 4 and 8 cycles, respectively, and 21 (30%) patients 
continued in the study for >12 cycles. The median number of treatment cycles was similar for the 2 
groups: 8 (range, 1-28) and 7 (range, 1-31) for the 4 mg and 5.5 mg dose groups, respectively. The 
total number of cycles delivered was similar between the 2 groups, with 347 cycles administered to 
the 4 mg dose group and 341 for the 5.5 mg dose group.
Dose modifications for ixazomib were required in a higher proportion of patients in the 5.5 mg 
dose group compared with the 4 mg dose group (43% vs 17%), while dose modifications for 
dexamethasone occurred in 34% and 23%, respectively. Thus, more than half the patients starting 
treatment at 5.5 mg ixazomib continued treatment without dose modification. Treatment delays 
were equivalent between the 2 ixazomib dose levels, with 26% and 29% of patients requiring dose 
delays in the 4 mg and 5.5 mg ixazomib groups, respectively. In terms of delivered dose, 95% of 
the intended dose of ixazomib was delivered in the 4 mg group compared with 85% of the intended 
dose in the 5.5 mg group.
An AE of any grade that was considered at least possibly related was reported in 100% of the 
patients in both groups. There were no treatment-related deaths in either group; 2 patients died on 
study in the 4 mg ixazomib group (respiratory syncytial virus and multiorgan failure 
approximately 10 months after first dose; pancreatic cancer approximately 2 years after first dose; 
all were assessed as unrelated to study medication). Grade 3 or 4 AEs considered at least possibly 
related to study treatment were reported for 9 (26%) and 2 (6%) patients in the lower-dose group 
and in 19 (54%) and 2 (6%) patients in the higher-dose group, respectively. Both of the Grade 4 
events reported in the 5.5 mg ixazomib group were considered related to study treatment. The most 
common Grade ≥2 AEs included fatigue, neutropenia, thrombocytopenia, and diarrhea. Peripheral 
neuropathy that was considered at least possibly related to study treatment was seen in 33 patients 
(Grade 1), 8 patients (Grade 2), and 2 patients (Grade 3; both in the 5.5 mg dose group). No 
cumulative hematological toxicity was observed in either group of the study, and the reported 
thrombocytopenia AEs usually resolved before the next cycle. Overall, the majority of AEs were 
Grade 3 or less in both the 4 mg and 5.5 mg ixazomib dose groups. Five patients discontinued the
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study because of an AE (2 in the 4 mg ixazomib group; 3 in the 5.5 mg ixazomib group); these 
events included continued Grade 2 neuropathy and heart failure.
These data indicate that there is a subpopulation of patients who are able to tolerate 5.5 mg ixa+dex. 
In the current study design, the intent is to identify this subpopulation based on excellent 
tolerability of ixazomib 4 mg in the first cycle and have the potential to dose escalate.
The investigators in the 
 study recommended that careful attention be given to the toxicity 
associated with the higher dose and that timely dose reductions be considered to mitigate the 
adverse effects [7,8]. Indeed, to mitigate the inherent risks in clinical studies of ixazomib, patients 
are monitored closely for anticipated toxicities. Guidance for the management of AEs (see 
Section 8.8) and procedures for reducing doses (see Section 8.4) are provided, and drug dosage 
can be reduced either by decreasing the dose administered or by holding of the scheduled treatment. 
Further information is provided in the IB.
4.3
Rationale for the Proposed Study
4.3.1
Need for Non-IMiD, Cost-Effective Combination Therapies in RRMM
With the recent approval of lenalidomide in front-line MM both in the United States and the 
European Union, the use of this IMiD as primary therapy will become increasingly prevalent. 
Because all patients with MM will ultimately relapse and most will develop lenalidomide-resistant 
disease, alternatives to lenalidomide will be required in later lines of therapy. Also, use of a 
non-IMiD combination in this setting will lower the burdens placed on patients, health care 
providers, and health care clinics, because a Pregnancy Prevention Programme (European Union) 
or a REMS program (United States) will no longer be required.
Although the typical later-line therapy for patients with RRMM is triplet therapy, some triplet 
combinations have not shown superior efficacy over doublets involving dexamethasone 
(eg, bortezomib, melphalan, and prednisone [VMP] or bortezomib, thalidomide, and 
dexamethasone [VTD] vs bortezomib with dexamethasone [VD])—even among elderly patients 
being treated in community practices [50]. Dexamethasone-based doublets like VD have also been 
shown as effective and tolerable for elderly patients with RRMM [51]. Ixa+dex is a new 
potentially beneficial doublet therapy for RRMM patients. Furthermore, many elderly and/or 
heavily pretreated patients may not be able to tolerate the toxicity of a triplet drug combination.
4.3.2
Need for All-Oral Combination Therapies in Patients With RRMM at Later Lines of 
Therapy
Both ixa+dex and the comparator, pom+dex, are particularly compelling options for third-line 
RRMM patients because many of these heavily pretreated patients, who are in the later stages of 
their disease, may prefer an all-oral regimen. Such a regimen will benefit patients who are not able 
or do not wish to travel to treatment clinics for weekly or more-frequent IV infusions. An entirely 
oral treatment option may therefore afford patients a better QOL. Furthermore, because the 
investigational regimen is an entirely oral therapy, an all-oral, standard-of-care comparator, 
pom+dex, provides a balanced treatment burden between the 2 regimens.
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A recently published study [52] summarizes cross-sectional data from >7000 patients with MM 
who were being treated across 7 European countries in 2014. In that study, bortezomib-based 
therapies were the most commonly used induction regimens, and 61% of patients who received 
bortezomib at first line went on to receive lenalidomide at second line. Third-line therapy was 
more variable, with the therapies divided among pomalidomide, other agents (eg, bendamustine), 
and bortezomib retreatment (used in 43% of patients who had received it at first line). In the 
third-line setting, salvage therapy with either regimen in Study C16029—that is, an entirely oral 
combination of either pom+dex or ixa+dex—may be preferred by some patients to retreatment 
with bortezomib (either IV or subcutaneous) or treatment with another IV therapy, such as 
daratumumab, recently approved by both the FDA and European Medicines Agency in the salvage 
setting after treatment with a proteasome inhibitor and an IMiD [37,53].
Furthermore, the efficacy of available therapies could be improved upon for this patient population. 
As noted above, in the NIMBUS study, use of pom+low-dose dex resulted in a median PFS of only 
4.0 months (95% CI, 3.6-4.7 months). Similarly, the median PFS with daratumumab was 4.0 
months (95% CI, 2.8-5.6 months) [54]. For this study, daratumumab was considered as a potential 
comparator; however, given that treatment with daratumumab requires travel to a clinic for IV 
infusion and premedication, an entirely oral combination was determined to be a more appropriate 
control for this study. In addition, a comparison of ixa+dex to daratumumab single agent would 
not allow for the characterization of the ixazomib contribution to the observed treatment effect, 
unlike a comparison of ixa+dex to pom+dex, in which the dexamethasone contribution would be 
similar in both treatment groups. For this reason, this study will compare an experimental regimen 
including ixazomib, which typically has been studied in combination with LenDex, but here will 
be combined with dexamethasone only. As a control regimen, pomalidomide will be used in 
combination with dexamethasone. 
4.3.3
Possible Benefit-Risk of Ixa+Dex versus Pom+Dex
Preliminary data suggest that, under some circumstances, ixa+dex may have favorable efficacy as 
compared with pom+dex. 
 and colleagues at the Mayo Clinic have conducted an 
investigator-initiated phase 2 study of ixazomib in patients with RRMM who were considered not 
refractory to bortezomib [7,8]. The preliminary data suggested that greater clinical benefit may be 
achieved with the use of ixa+dex, with 4 mg and 5.5 mg doses of ixazomib, compared with 
historical data with pom+dex (described in Section 4.2.2 above). Therefore, this 
company-sponsored study is intended to provide further assessment on the feasibility and safety of 
the dose escalation of 4 mg to 5.5 mg ixazomib after the first cycle.
Pomalidomide is indicated for use in combination with dexamethasone in adults with RRMM who 
have received ≥2 prior treatment regimens, including both lenalidomide and bortezomib, and have 
demonstrated PD on the last therapy. In this study, pom+dex will be administered to patients who 
have received ≥2 prior lines of therapy, have been exposed but are not refractory to a proteasome 
inhibitor, and are refractory to lenalidomide. This is a subgroup of the population of patients for 
whom pomalidomide is currently approved and who may derive particular benefit from a 
proteasome inhibitor. Pomalidomide given with dexamethasone is an accepted standard of care for 
this patient population.
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The risks of both pomalidomide and ixazomib in the patient population eligible for this study 
appear manageable with appropriate prophylaxis, dose holds, and/or dose modification. In 
summary, patients receiving pomalidomide are likely to have greater risks of thromboembolic 
events and neutropenia, while those receiving ixazomib are more at risk of experiencing 
thrombocytopenia and gastrointestinal events—all of which appear to be largely manageable with 
appropriate monitoring, prophylaxis, dose holds, and/or dose modifications.
4.3.4
Ixazomib Dose Rationale
The ixazomib dosing regimen for this study was informed by the phase 2 Mayo Clinic study 
(conducted by 
 and colleagues [7,8] and described in Section 4.2.3.2) of ixazomib in 
combination with dexamethasone conducted in patients with relapsed MM who were not 
refractory to bortezomib. In the randomized portion of the study with 2 treatment groups, patients 
received ixazomib at either 4 mg or 5.5 mg on Days 1, 8, and 15 of each 28-day cycle, in 
combination with 20 mg dexamethasone on Days 1, 2, 8, 9, 15, and 16 of each cycle. Thirty-five 
patients were randomized to each group.
The ORR for patients randomized to receive ixazomib at 5.5 mg was found to be higher (54%) 
than that for the 4 mg patients (31%). Additionally, a trend was observed between the average 
ixazomib dose (calculated to first best response [PR or better]) and the probability of ≥PR 
(p=0.0795, N=70), suggesting that higher doses of ixazomib may result in higher ORR. Event-free 
survival was similar across the tertiles of average ixazomib dose; however, it should be noted that 
this small study was not powered to detect a statistically significant difference in event-free 
survival.
As noted in Section 4.2.3.2, a higher frequency of Grade ≥3 AEs that were considered at least 
possibly related to study therapy was observed in the 5.5 mg ixazomib group than in the 4 mg 
ixazomib group (54% vs 26%). Dose reductions for ixazomib were also required for a higher 
percentage of patients in the 5.5 mg ixazomib group (43%, vs 17% in the 4 mg ixazomib group).
Collectively, the available data from the randomized phase 2 study [7,8] indicate that both the 
4 mg and 5.5 mg doses of ixazomib are active, with the 5.5 mg dose being associated with a higher 
ORR, although it is not yet known whether this dose will result in longer PFS. The 5.5 mg dose 
was associated with a higher frequency of AEs and more dose modifications.
As a result, in an effort to provide an opportunity for maximum clinical benefit without excessive 
toxicity, a 4 mg starting dose for ixazomib will be used in this study, with escalation to 5.5 mg at 
the start of Cycle 2 for those patients who tolerate the 4 mg dose in Cycle 1 (as specified in Section 
8.4.1). Because the study population is patients with advanced disease in later-line therapy, the 
timing of dose escalation at the start of Cycle 2 was selected so that patients who appear to be 
tolerating ixazomib can escalate quickly to a higher dose and potentially improve their chance of 
achieving disease control before experiencing PD. Also, the main potential AEs (eg, 
thrombocytopenia, gastrointestinal events, rash) are acute AEs that are expected to be seen early in 
the treatment course, further providing a rationale for an intrapatient dose escalation decision after 
Cycle 1.
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4.3.5
Summary of Rationale
A typical patient eligible for this study will have received a proteasome inhibitor other than 
ixazomib in the first or second line without having developed resistance and will have developed 
resistance to lenalidomide in the second or later line. This study is designed to determine whether 
there is a subpopulation of patients for whom pom+dex is clinically indicated but who may 
preferentially benefit from ixa+dex.
The sponsor expects there to be a significant number of patients in the United States and European 
Union who would qualify for third-line salvage therapy in this study and would potentially benefit 
from either of these all-oral, doublet study therapies.
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5.0
STUDY OBJECTIVES AND ENDPOINTS
As of Amendment 06, the objective and endpoint are to continue to collect long-term safety data 
from patients who are continuing on ixazomib and dexamethasone or pomalidomide and 
dexamethasone because of continuing clinical benefit. Data collection for all other study 
objectives and endpoints is complete and no further formal analyses will be conducted. However, 
the original lists of objectives and endpoints are retained below for reference only.
5.1
Objectives
5.1.1
Primary Objective
The primary objective is to compare the effect of ixa+dex versus pom+dex on PFS in patients with 
RRMM who have received at least 2 prior lines of therapy, including lenalidomide and a 
proteasome inhibitor, and are refractory to lenalidomide but not refractory to proteasome 
inhibitors.
5.1.2
Secondary Objectives
Secondary objectives are: 
!
To compare OS in patients treated with ixa+dex versus pom+dex.
!
To compare duration of response, ORR, time to response, and time to progression with 
ixa+dex versus pom+dex.
!
To obtain health-related QOL data related to physical functioning of patients treated with 
ixa+dex versus pom+dex. 
!
To assess health-related QOL by additional function and symptom domains of the European 
Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire–
Core 30 (EORTC QLQ-C30) instrument and by the EORTC Quality of Life Questionnaire–
multiple myeloma module (EORTC QLQ-MY20) and 5-level classification system of the
EuroQol 5-Dimensional Health Questionnaire (EQ-5D-5L) instruments in patients receiving 
ixa+dex versus those receiving pom+dex.
!
To evaluate HU by patients receiving ixa+dex versus those receiving pom+dex.
!
To collect plasma concentration-time data for ixazomib to contribute to population PK 
characterization of ixazomib and to conduct exposure-response analyses for patients receiving 
ixa+dex.
5.1.3
Safety Objective
The safety objective is to compare the safety/tolerability of ixa+dex to that of pom+dex.
5.1.4
Exploratory Objective
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5.2
Endpoints
5.2.1
Primary Endpoint
The primary endpoint is PFS, defined as the time from randomization to the first occurrence of 
confirmed PD, as evaluated by the investigator, according to International Myeloma Working 
Group (IMWG) criteria [55], or death from any cause, whichever occurs first.
5.2.2
Secondary Endpoints
Secondary endpoints are:
!
OS, measured as the time from randomization to death from any cause.
!
ORR, defined as PR, very good partial response (VGPR), or complete response (CR), as 
evaluated by the investigator, according to IMWG criteria [55].
!
Duration of response, defined as the time from the first documentation of PR or better to first 
documentation of PD.
!
Time to response, defined as the time from randomization to the first documentation of PR or 
better. 
!
TTP, defined as the time from randomization to first documentation of PD.
!
Health-related QOL as measured by the physical functioning domain of the EORTC 
QLQ-C30.
!
Health-related QOL as measured by other domains of the EORTC QLQ-C30, by the EORTC 
QLQ-MY20, and by the EQ-5D-5L.
!
HU as measured by the number and duration of medical encounters.
5.2.3
Safety Endpoint
The safety endpoint is the safety/tolerability of ixa+dex versus pom+dex.
5.2.4
Exploratory Endpoint
PPD
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6.0
STUDY DESIGN
6.1
Overview of Study Design
This is a prospective open-label, randomized, 2-arm, multicenter phase 2 study of patients with 
RRMM who have received at least 2 prior lines of therapy. Eligible patients will be randomized to 
receive ixa+dex (Arm A) or pom+dex (Arm B) in a 3:2 ratio via interactive response technology 
(IRT). The study design is illustrated in Figure 6.a.
Figure 6.a
Study Schema, From Randomization Through End of Therapy
Ixa=ixazomib; pom=pomalidomide; RRMM=relapsed and/or refractory multiple myeloma.
Note: There are 3 stratification factors in the study: International Staging System stage (I or II vs III at study entry), 
prior lines of therapy (2 vs 3 or more), and age (<65 vs ≥65 years).
6.1.1
Study Population
The patient population will consist of adult patients (aged ≥18 years) who have an Eastern 
Cooperative Oncology Group (ECOG) score of 0, 1, or 2; who have been diagnosed with MM 
according to IMWG criteria [55]; and who have measurable disease and documentable isotype. All 
patients must have had a relapse or PD after having received 2 or more prior lines of systemic 
therapy. (A line of therapy is defined as 1 or more cycles of a planned treatment program; this may
consist of 1 or more planned cycles of single-agent therapy or combination therapy, as well as a 
sequence of treatments administered in a planned manner. For example, a planned treatment 
approach of induction therapy followed by autologous SCT, followed by maintenance is 
considered 1 line of therapy [1]. Typically, each line of therapy is separated by PD. Discussion 
with the medical monitor may help clarify the number of prior lines of therapy for each prospective 
study participant.)
1. All patients must be refractory to lenalidomide, defined as having received at least 
2 consecutive cycles of lenalidomide as a single agent or within a lenalidomide-containing 
regimen and having had PD during treatment with or within 60 days after the last dose of 
lenalidomide. The starting dose of lenalidomide should have been 25 mg (or as low as 10 mg in 
the case of renal function impairment or other safety concern), and the final dose should have 
been a minimum of 10 mg. In addition, all patients must have received at least 2 consecutive 
cycles of a bortezomib- or carfilzomib-containing regimen. Further, all patients must not be 
refractory to proteasome inhibitors (ie, must have achieved at least a PR and not have had PD 
during treatment with or within 60 days after the last dose of bortezomib or carfilzomib) or 
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have bortezomib and/or carfilzomib intolerance (ie, must have discontinued because of 
drug-related AEs before completion of the planned treatment course) without PD before the 
start of the next regimen. A Millennium project clinician or designee will confirm patient 
eligibility before randomization by the investigator.
2. Patients with a prior allogenic bone marrow transplantation in any prior line of therapy are 
excluded. Patients with a prior autologous SCT in the last prior line of therapy are excluded, 
unless the autologous SCT was done a year or more before disease progression. Exclusion of 
patients on this basis aims not to interfere with the immune profiling endpoint. 
The 3 stratification factors that will be used are ISS stage (I or II vs III) at study entry, prior lines of 
therapy (2 vs 3 or more), and age (<65 vs ≥65 years).
6.1.2
Study Therapy Dosing
Patients randomized to Arm A will receive oral ixazomib on Days 1, 8, and 15 of every 28-day 
cycle, as well as 20 mg oral dexamethasone (or 10 mg if patient is aged ≥75 years) on Days 1, 2, 8, 
9, 15, 16, 22, and 23 of every 28-day cycle. In cases where only 4 mg tablets for dexamethasone 
are available (eg, 4 mg dexamethasone is the only dosage available), the following dexamethasone 
schedule is recommended for patients aged ≥75 years: 12 mg dexamethasone will be given on 
Days 1, 8, 15, and 22 of every 28-day cycle; and 8 mg dexamethasone will be given on Days 2, 9, 
16, and 23 of every 28-day cycle.
For Cycle 1, all patients will receive a starting dose of 4 mg of ixazomib. Patients who do not 
experience any new Grade 1 peripheral neuropathy with pain or other ixazomib-related Grade ≥2 
nonhematologic or Grade ≥3 neutropenia or thrombocytopenia in Cycle 1 will dose escalate to 5.5 
mg of ixazomib on the same schedule at the start of Cycle 2. Patients who have had any dose 
reductions, holds, or delays because of ixazomib toxicities will not dose escalate. Dose escalation 
beyond the start of Cycle 2 is permitted only when dose escalation was inadvertently missed at 
Cycle 2 and will require consultation with a Millennium project clinician or designee.
Patients randomized to Arm B will receive oral pomalidomide at a dose of 4 mg daily on Days 1 to 
21 of each 28-day cycle, as well as 40 mg oral dexamethasone (or 20 mg if patient is aged 
≥75 years) on Days 1, 8, 15, and 22 of each 28-day cycle until PD. 
Neither pomalidomide nor dexamethasone will be dose escalated in this study.
6.1.3
Study Assessments
Section 9.4 provides more information on study procedures, and Appendix A contains the detailed, 
updated Schedule of Events for this study (the previous, full Schedule of Events is now moved to 
Appendix L for reference only).
Only patients who continue to demonstrate clinical benefit but who do not have other means of 
access to the study drugs will continue on the study. As no further formal statistical analyses will 
be performed, only assessments contributing to long-term safety data are required. Most study 
assessments besides safety are discontinued to ease the burden of protocol-mandated assessments 
on patients.
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Patients continuing their current study treatment may do so until such time as other means of 
accessing the study drugs are arranged. When possible, patients should complete an EOT visit and 
transition onto an alternative supply of (eg, commercially available) ixazomib or pomalidomide, 
as well as dexamethasone, or onto another standard of care treatment. Discontinued patients will 
be treated by their physician per local standard of care.
Upon implementation of Amendment 06, data collection requirements will be limited to collection 
of AEs and SAEs. All other study assessments are no longer required. All central laboratory 
assessments are discontinued. Quality of life and HU assessments are discontinued. Patients will 
not be followed for the PFS or OS follow-up periods, because PFS and OS data are no longer being 
collected. See the updated Schedule of Events in Appendix A (the previous, full Schedule of 
Events is now moved to Appendix L for reference only).
6.1.3.1
Assessments During the Treatment Period
Assessments Effective Only Before Amendment 06
Patients will have study assessments performed at regular intervals while they are participating in 
the study: weekly (Days 1 and 15) for 2 cycles and then once a cycle (on Day 1) for the remainder 
of the Treatment period, until PD or discontinuation. In addition, in Arm B only, on Day 8 and 
Day 22 of Cycles 1 and 2, hematologic laboratory assessments will be performed. Patients will 
receive study therapy until documented, confirmed PD (on the basis of the IMWG criteria), 
intolerable toxicities, withdrawal of consent, or sponsor termination of study, whichever comes 
first. 
Patients will be assessed for disease response and progression, according to the IMWG criteria by 
the investigator, for the purpose of treatment decisions, at every cycle during the Treatment period.
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, and QOL data, 
with an emphasis on tolerability and symptom burden, will be collected. 
QOL assessments will be collected at Screening. QOL and HU assessments will be collected on 
Day 1 of every treatment cycle and at the EOT visit (as well as during the PFS Follow-up period 
and, for EQ-5D-5L only, the OS Follow-up period; see next section). QOL and HU assessments 
should be completed on the same day as the study visit, before any other study procedures are 
performed or study therapy is administered. 
Assessments Still in Effect as of Amendment 06
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 EOT visit 30 days (+1 week) after receiving their last dose of study therapy 
or prior to the start of a new line of anti-myeloma treatment, should that line start within 30 days of 
the last dose. In the event a patient withdraws consent or has a death prior to the EOT visit, the last 
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date of contact with the patient will be utilized as the EOT visit date. AEs/SAEs will be monitored
for all patients up to 30 days after administration of the last dose of study therapy regardless of 
whether a patient starts a new line of therapy. 
Note: Related SAEs occurring during follow-up periods after the EOT visit must be reported to the 
Global Pharmacovigilance department or designee. This includes deaths that the investigator 
considers related to study therapy that occur during posttreatment follow-up. In addition, new 
primary malignancies that occur during follow-up periods, irrespective of causality to study 
therapy, must be reported to the Global Pharmacovigilance department or designee. Refer to 
Section 10.0 for details regarding definitions, documentation, and reporting of SAEs.
6.1.3.2
Assessments During the Follow-up Periods: PFS and OS
The following section describes the study design before Amendment 06 was implemented and is 
no longer relevant after that time but is retained below for reference only.
After a patient completes the EOT visit or a patient discontinues study therapy before confirmed 
PD, he/she will enter either a PFS or OS follow-up period (Figure 6.b). Information about any new 
primary malignancies will be collected during the study, including during both follow-up periods. 
Patients who have stopped treatment for any reason other than PD will enter the PFS Follow-up 
period. Patients who have PD while on study therapy will skip the PFS Follow-up period and will 
enter directly into the OS Follow-up period. Patients in the PFS Follow-up period who have PD or 
start subsequent anticancer therapy during this follow-up period will end PFS Follow-up and will 
enter into the OS Follow-up period.
Figure 6.b provides more detail about both follow-up periods.
QOL and HU assessments will be collected during the PFS Follow-up period at every PFS 
Follow-up visit. QOL and HU assessments should be completed on the same day as the follow-up 
visit, before any other study procedures are performed. 
The only QOL assessment collected during the OS Follow-up period is the EQ-5D-5L assessment. 
This assessment will be collected during the OS Follow-up period at every OS Follow-up visit. 
The assessment should be completed on the same day as the follow-up visit, before any other study 
procedures are performed. 
All assessments during the OS Follow-up period (including the EQ-5D-5L) may be made over the 
telephone by trained site staff and do not require a clinic visit. Data may be collected by methods 
that include, but are not limited to, telephone, email, mail, and social security indexes. Both the 
patient and the current treating physician will be contacted during the OS Follow-up period to 
provide information about all MM treatments (best response, date of progression, drug regimen, 
start/stop date).
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Figure 6.b
Flow of Patients Through Follow-up Periods After the EOT Visit (Only in 
Effect Before Amendment 06)
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6.1.3.3
Other Assessment Details
An independent data monitoring committee (IDMC) will review safety data at regular intervals, 
approximately every 6 months or per IDMC request. 
After the data cutoff date for the study analysis has occurred, no further analyses are planned, and 
all central efficacy and investigator assessments of disease response (ie, PFS, response rates, and 
TTP) for protocol purposes will be discontinued. As such, no further laboratory samples related to 
response assessments will be sent to the central laboratory.
6.1.4
Statistical Analyses
Upon completion of this study, approximately 120 patients will have been enrolled globally. The 
study analysis for PFS will occur after approximately 81 PFS events have been observed (after 
approximately 28 months from first patient enrollment), for 80% power at a 2-sided 0.20 level of 
significance. Analysis of all secondary endpoints will occur at the same time as this study analysis, 
which is the only planned formal analysis for this study; no further formal analyses are planned. 
Long-term safety data collected after the data cutoff date for the study analysis will be summarized 
descriptively in a clinical study report addendum.
See Section 13.0 for more information.
6.2
Number of Patients
Upon completion of this study, approximately 120 patients will have been enrolled at 
approximately 100 study sites globally: approximately 72 in Arm A (ixa+dex) and approximately 
48 in Arm B (pom+dex). Enrollment is defined as randomization to a study therapy.
6.3
Duration of Study
6.3.1
Duration of an Individual Patient’s Study Participation
Patients, including those who achieve a clinical response, may receive study therapy until they 
experience PD, have an unacceptable toxicity, or withdraw consent, or until the sponsor terminates 
the study.
6.3.2
End of Study/Study Completion Definition
The study will be considered complete after the study analysis (for PFS and all secondary 
endpoints) has been completed or the study has been terminated by the sponsor. The estimated 
time frame for study completion is approximately 28 months. 
6.3.3
Timeframes for Primary and Secondary Endpoints to Support Disclosures
Refer to Table 6.a for disclosures information for all primary and secondary endpoints.
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Table 6.a
Primary and Secondary Endpoints for Disclosures
Endpoint
Definition
Maximum Time Frame
Primary: PFS
The time from randomization to the first occurrence of 
confirmed PD, as evaluated by the investigator, according to 
IMWG criteria [55], or death from any cause, whichever occurs 
first
Up to 4 years
Secondary: OS
The time from randomization to death from any cause
Up to 4 years
Secondary: ORR
PR, VGPR, or CR, as evaluated by the investigator, according 
to IMWG criteria
Up to 4 years
Secondary: Duration 
of response
The time from the first documentation of PR or better to first 
documentation of PD
Up to 4 years
Secondary: Time to 
response
The time from randomization to the first documentation of PR 
or better
Up to 4 years
Secondary: TTP
The time from randomization to first documentation of PD
Up to 4 years
Secondary: 
Health-related QOL 
related to physical 
functioning
The physical functioning domain of the EORTC QLQ-C30
Up to 4 years
Secondary: Other 
health-related QOL
Health-related QOL as measured by other domains of the 
EORTC QLQ-C30, by the EORTC QLQ-MY20, and by the 
5-level classification system of the EQ-5D-5L
Up to 4 years
Secondary: Health 
care utilization (HU)
HU as measured by the number and duration of medical 
encounters
Up to 4 years
EORTC QLQ-C30: European Organization for Research and Treatment of Cancer Quality of Life Questionnaire–
Core 30; EORTC QLQ-MY20: European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire–multiple myeloma module; IMWG: International Myeloma Working Group; ORR: overall response 
rate; OS: overall survival; PD: progressive disease; PFS: progression-free survival; TTP: time to progression; QOL: 
quality of life. 
6.3.4
Total Study Duration
It is anticipated that this study will last for approximately 28 months. However, the study duration 
is dependent on rate of accrual and of maturation of the different endpoints.
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7.0
STUDY POPULATION
7.1
Inclusion Criteria
Each patient must meet all of the following inclusion criteria to be enrolled in the study:
1. Male or female patients aged 18 years or older.
2. Must have a confirmed diagnosis of MM requiring therapy according to IMWG criteria (see 
Appendix D).
3. ECOG performance status of 0 to 2 (see Appendix E). 
4. Must have had a relapse or PD after having received 2 or more prior lines of systemic therapy.
Note: A line of therapy is defined as 1 or more cycles of a planned treatment program; this may 
consist of 1 or more planned cycles of single-agent therapy or combination therapy, as well as 
a sequence of treatments administered in a planned manner. For example, a planned treatment 
approach of induction therapy followed by autologous SCT, followed by maintenance is 
considered 1 line of therapy [1]. Typically, each line of therapy is separated by PD. Discussion 
with the medical monitor may help clarify the number of lines of therapy that a prospective 
study participant had.
5. Must be refractory to lenalidomide, defined as having received at least 2 consecutive cycles of 
lenalidomide as a single agent or within a lenalidomide-containing regimen and having had PD 
during treatment with or within 60 days after the last dose of lenalidomide. The starting dose of 
lenalidomide should have been 25 mg (or as low as 10 mg in the case of renal function 
impairment or other safety concern), and the final dose should have been a minimum of 10 mg.
6. Must have received at least 2 consecutive cycles of a bortezomib- or carfilzomib-containing 
regimen, and either:
–
Achieved at least a PR and did not have PD during treatment with or within 60 days after 
the last dose of bortezomib or carfilzomib, OR
–
Had bortezomib and/or carfilzomib intolerance (defined as discontinuation because of 
drug-related AEs before completion of the planned treatment course) without PD before 
the start of the next regimen.
7. Patients must have measurable disease defined by: 
–
Serum M-protein ≥1 g/dL (≥10 g/L), OR
–
Urine M-protein ≥200 mg/24 hours and must have documented MM isotype by 
immunofixation (central laboratory).
8. Patients must meet all of the following clinical laboratory criteria:
–
Absolute neutrophil count (ANC) ≥1000/mm3 and platelet count ≥75,000/mm3, without 
growth factor or transfusion support.
–
Total bilirubin ≤1.5 times the upper limit of normal (ULN).
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–
Alanine aminotransferase and aspartate aminotransferase ≤3×ULN.
–
Calculated creatinine clearance ≥30 mL/min (see Section 9.4.15.1).
9. Female patients who:
–
Are postmenopausal for at least 1 year before the Screening Visit, OR
–
Are surgically sterile, OR
–
If they are of childbearing potential, agree to practice 1 highly effective method of 
contraception and 1 additional effective (barrier) method at the same time, for 4 weeks 
before signing the informed consent through 90 days after the last dose of study therapy, 
OR
–
Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle 
of the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.), AND
–
In women of childbearing potential (if randomized to Arm B), agree to have 2 negative 
pregnancy tests before initiating therapy, with 1 or both being a serum test (the first test 
should be performed within 10-14 days before; the second, within 24 hours before); then 
have a negative pregnancy test weekly during the first month and monthly thereafter in 
women with regular menstrual cycles or every 2 weeks thereafter in women with irregular 
menstrual cycles; and have a negative pregnancy test 4 weeks after the last dose of study 
therapy.
10. Male patients, even if surgically sterilized (ie, status postvasectomy), who:
–
Agree to practice effective barrier contraception during the entire study Treatment period 
and through 90 days after the last dose of study therapy, OR
–
Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle 
of the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.), AND
–
Do not donate semen or sperm during treatment and for 90 days after the last dose of study 
therapy.
11. 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.
12. Suitable venous access for the study-required blood sampling, including PK sampling.
13. Patient is willing and able to adhere to the study visit schedule and other protocol requirements 
including blood sampling and bone marrow aspiration.
14. Recovered (ie, Grade ≤1 nonhematologic toxicity) from the reversible effects of prior 
anticancer therapy.
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15. Patients must be willing and able to adhere to pomalidomide-related risk mitigation activities if 
randomized to the pom+dex arm (eg, REMS, pregnancy prevention programs).
7.2
Exclusion Criteria 
Patients meeting any of the following exclusion criteria are not to be enrolled in the study:
1. Patients must not have received prior ixazomib or pomalidomide and must not have been a 
participant in a previous ixazomib clinical study.
2. Prior allogenic bone marrow transplantation in any prior line of therapy or prior autologous 
SCT in the last prior line of therapy—unless the autologous SCT was performed a year or more 
before disease progression. 
3. Female patients who are lactating and breastfeeding or have a positive serum pregnancy test 
during the Screening period. 
4. Any serious medical or psychiatric illness that could, in the investigator’s opinion, potentially 
interfere with the completion of treatment according to this protocol, such as life-threatening 
illness unrelated to cancer.
5. Diagnosed with or treated for another malignancy within 2 years before randomization, or 
previously diagnosed with another malignancy and have any evidence of residual, persistent, 
or recurrent disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type 
are not excluded if they have undergone complete resection.
6. Diagnosis of smoldering MM (see Appendix D), Waldenström’s macroglobulinemia, POEMS 
(polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin 
changes) syndrome, plasma cell leukemia, primary amyloidosis, myelodysplastic syndrome, 
or myeloproliferative syndrome.
7. Known allergy to any of the study medications or their analogues, or excipients in the various 
formulations.
8. Peripheral neuropathy Grade 1 with pain or Grade 2 or higher peripheral neuropathy of any 
cause on clinical examination during the Screening period.
9. Treatment with any investigational products or with chimeric or fully human monoclonal 
antibodies within 30 days before randomization, systemic anticancer therapy or radiotherapy 
within 14 days before randomization (Note: “spot” radiation for areas of pain is permitted), and 
major surgery within 14 days before randomization.
10. Known gastrointestinal disease or gastrointestinal procedure that could interfere with the oral 
absorption or tolerance of study therapy, including difficulty swallowing.
11. Serious infection requiring parenteral antibiotic therapy or any other serious infection within 
14 days before randomization.
12. Central nervous system involvement with MM (by clinical symptoms and signs).
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13. Ongoing or active systemic infection, known human immunodeficiency virus-RNA positive, 
known hepatitis B surface antigen seropositive, or known hepatitis C virus-RNA positive.
Note: Patients who have positive hepatitis B core antibody can be enrolled but must have 
hepatitis B virus-DNA negative. Patients who have positive hepatitis C antibody can be 
enrolled but must have hepatitis C virus-RNA negative.
14. Systemic treatment with strong cytochrome P-450 3A inducers (rifampin, rifapentine, rifabutin, 
carbamazepine, phenytoin, phenobarbital) or use of St. John’s wort within 14 days before 
randomization.
15. Admission or evidence of illicit drug use, drug abuse, or alcohol abuse.
16. History of severe cutaneous reactions, including hypersensitivity reactions such as 
Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with 
eosinophilia and systemic symptoms (DRESS), in the context of treatment with lenalidomide 
or thalidomide (see Section 8.7 for more information).
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8.0
STUDY THERAPY
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). One cycle of study therapy at a time 
will be dispensed for oral dosing at home as directed in the Schedule of Events (Appendix A). 
Patients may take study therapy at home as directed. The date and time of each dose of study 
therapy should be recorded by the patient in the patient diary. Refer to the Study Manual for 
additional instructions regarding study therapy administration.
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.
Each AE should be attributed to a specific drug (ie, ixazomib, pomalidomide, or dexamethasone), 
if possible, so that dose modifications can be made accordingly. Only 1 dose adjustment per cycle 
will be performed for a given agent when toxicity is suspected to be related primarily to that agent. 
Reduction of 1 agent and not the other is appropriate if the toxicity is suspected to be related 
primarily to that 1 agent.
8.1
Investigational Therapy: Ixazomib Administration (Arm A)
Ixazomib capsules will be supplied by the sponsor as single capsules at 4 different dose strengths, 
containing 5.5, 4.0, 3.0, and 2.3 mg of ixazomib. The dose strengths will allow for delivery of the 
unit starting dose (4.0 mg), dose escalation to 5.5 mg, or dose reductions (2.3, 3.0 mg) as needed 
during treatment.
In patients randomized to Arm A, ixazomib will be given as a single, oral dose weekly (Days 1, 8, 
and 15) for 3 weeks, followed by 1 week without ixazomib in a 28-day cycle. Day 1 dosing in 
Cycle 1 through Cycle 6 must be administered in the clinic, as must the first cycle of dose 
escalation to 5.5 mg of ixazomib; other cycle doses may be taken at home. Refer to Section 
8.10.1.3 and the Study Manual for additional instructions regarding study therapy administration.
The starting dose for ixazomib is 4 mg, with escalation to 5.5 mg at the start of Cycle 2 for patients 
who tolerate the 4 mg dose in Cycle 1 (specifically, patients who do not experience any new Grade 
1 peripheral neuropathy with pain or other ixazomib-related Grade ≥2 nonhematologic or Grade 
≥3 neutropenia or thrombocytopenia in Cycle 1). Patients who have had any dose reductions, holds, 
or delays because of ixazomib toxicities will not dose escalate. Dose escalation beyond the start of 
Cycle 2 is permitted only when dose escalation was inadvertently missed at Cycle 2 and will 
require consultation with a Millennium project clinician or designee.
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 a sip of water. A total of 
approximately 240 mL 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 
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dose, the patient should not repeat the dose but should resume dosing at the time of the next 
scheduled dose.
It is recommended that dexamethasone be taken at least 2 hours before the ixazomib dose on the 
ixazomib dosing days (see Section 8.3).
8.2
Reference/Control Therapy: Pomalidomide Administration (Arm B)
Patients randomized to Arm B will be dosed with pomalidomide per local prescribing information 
[41,42]: oral pomalidomide at a dose of 4 mg daily on Days 1 to 21 of each 28-day cycle. 
Thromboprophylaxis is recommended (see Section 8.8.2). Also see local prescribing information
[41,42] for further dosing instructions.
8.3
Standard of Care Therapy: Dexamethasone Administration (Both Arms)
Each treatment arm will receive 40 mg of dexamethasone per week, with a difference in dosing 
schedule across study arms. Patients in Arm A will receive a total of 40 mg dexamethasone split 
across 2 consecutive days (to maximize the prophylactic anti-emetic effect around the ixazomib 
dosing) and patients in Arm B will receive a 40 mg dexamethasone dose in 1 day (as per the 
pomalidomide prescribing information), as detailed below. 
Patients randomized to Arm A will receive 20 mg oral dexamethasone (or 10 mg if patient is aged 
≥75 years) on Days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day cycle. In cases where only 4 mg 
tablets for dexamethasone are available (eg, 4 mg dexamethasone is the only dosage available), the 
following dexamethasone schedule is recommended for patients aged ≥75 years: 12 mg 
dexamethasone will be given on Days 1, 8, 15, and 22 of every 28-day cycle; and 8 mg 
dexamethasone will be given on Days 2, 9, 16, and 23 of every 28-day cycle.
Patients randomized to Arm B will receive 40 mg oral dexamethasone (or 20 mg if patient is aged 
≥75 years) on Days 1, 8, 15, and 22 of each 28-day cycle, per the pomalidomide local prescribing 
information that specifies dexamethasone dosing when used in combination with pomalidomide 
[41,42].
The dexamethasone dose will be determined by the patient’s age at time of randomization. In the 
event that a patient is aged 74 years or younger at randomization and turns 75 or older while taking 
part in the study, the patient’s dexamethasone dose will only be changed from the dose at 
randomization in the event of dexamethasone-related AEs.
Dexamethasone should 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.
In patients randomized to Arm A, it is recommended that dexamethasone be administered at least 2 
hours before the ixazomib dose on the ixazomib dosing days (to maximize the potential antiemetic 
effect).
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8.4
Dose Modification Guidelines
In general, if ixazomib, pomalidomide, or dexamethasone are delayed or held due to AEs or other 
safety findings, then the corresponding study therapy should also be delayed or held, given that 
study treatment is combination therapy. Therefore, if ixazomib is held, dexamethasone should also 
be held. Likewise, if pomalidomide is held, dexamethasone should be held. If dexamethasone is 
held, either ixazomib or pomalidomide should be held, based on the patient’s treatment group 
determined at randomization.
8.4.1
Intrapatient Dose Escalation of Ixazomib (Arm A)
A starting dose of 4 mg of ixazomib will be used at Cycle 1 for all patients in Arm A. Patients who 
do not experience any new Grade 1 peripheral neuropathy with pain or other ixazomib-related 
Grade ≥2 nonhematologic or Grade ≥3 neutropenia or thrombocytopenia in Cycle 1 will dose 
escalate to 5.5 mg of ixazomib on the same schedule at the start of Cycle 2. Patients who have had 
any dose reductions, holds, or delays because of ixazomib toxicities will not dose escalate. Dose 
escalation beyond the start of Cycle 2 is permitted only when dose escalation was inadvertently 
missed at Cycle 2 and will require consultation with a Millennium project clinician or designee. 
8.4.2
Criteria for Beginning or Delaying a Subsequent Treatment Cycle
8.4.2.1
Criteria for Beginning the Next Treatment Cycle With Ixa+Dex (Arm A)
Treatment with ixazomib will be repeated every 28 days in Arm A. 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.

All nonhematologic toxicity considered to be related to treatment with study therapy must have 
resolved to Grade ≤1 or 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 
ixa+dex 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 to not meet 
the previously cited criteria, delay ixa+dex 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, 
the ixa+dex doses will be reduced by 1 dose level when therapy resumes. Should ixa+dex need to 
be delayed for 4 weeks because of incomplete recovery from treatment-related toxicity, ixa+dex
should be discontinued or dose reduction of 1 or more than 1 dose levels should be considered if, in 
the investigator’s view, therapy still has a reasonable probability of providing a benefit. 
Resumption of cycles after 4 weeks must be discussed with the Millennium project clinician or 
designee.
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8.4.2.2
Criteria for Beginning the Next Treatment Cycle With Pom+Dex (Arm B)
Treatment with pom+dex will be repeated every 28 days in Arm B. The criteria for toxicity 
recovery before the patient can begin the next cycle are outlined in the pom+dex local prescribing 
information [41,42].
8.4.3
Ixazomib Treatment Modification (Arm A)
Patients experiencing AEs attributed to ixazomib may continue in the study but may have doses of 
ixazomib held or reduced by at least 1 dose level as shown in Table 8.a. When a dose reduction of 
ixazomib is required because of toxicity, no dose re-escalation will be permitted.
Treatment modifications because of to ixazomib-related AEs are outlined in Table 8.b for 
hematologic toxicities and in Table 8.c for nonhematologic toxicities. Table 8.d provides the 
criteria for retreatment and cycle delays. 
Table 8.a
Dose Reduction Steps for Ixazomib
Current 
Dose
First Dose 
Reduction
Second Dose 
Reduction
Third Dose Reduction
Fourth Dose Reduction
4 mg
3 mg
2.3 mg
Discontinue ixazomib
--
5.5 mg
4 mg
3 mg
2.3 mg
Discontinue ixazomib
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Table 8.b
Ixazomib Dose Modification for Hematologic Toxicities
Criteria
Action
Within-Cycle Dose Modifications
If platelet count ≤50109/L or ANC 
≤0.75109/L on an ixazomib dosing day 
(other than Day 1)
Ixazomib dose should be withheld. Complete blood count with 
differential should be repeated at least weekly or more frequently until 
the ANC and/or platelet counts have exceeded the prespecified values 
(ANC ≥1.0×109/L; platelet count ≥75×109/L). Upon recovery, 
ixazomib may be reinitiated and reduced by 1 dose level in 
accordance with reductions outlined in Table 8.a.
Dose Modifications for Subsequent 
Treatment Cycles 
Delay of ≥2 weeks at the start of a 
subsequent cycle because of lack of toxicity 
recovery as defined in Section 8.4.2: 
ANC <1.0109/L; platelet count <75109/L 
(Or other nonhematologic toxicities Grade 
>1 or not to the patient’s baseline condition)
Hold ixazomib until resolution per criteria.
Reduce ixazomib by 1 dose level as outlined in Table 8.a.
The maximum delay before treatment should be discontinued will be 
4 weeks (except in the case of investigator-determined clinical benefit 
and discussion with the project clinician or designee, at which time a 
reduction of 1 or more dose levels should be made).
All hematologic toxicities
For hematologic toxicity that occurs during a cycle but recovers in 
time for the start of the next cycle:
If dose was reduced within the cycle, start the next cycle at that same 
dose.
If because of timing–ie, a toxicity after Day 15 dosing such that a dose 
reduction was not required at that point in the cycle–then reduce 
ixazomib by 1 dose level at the start of the cycle.
Do not reduce the dose both within a cycle and at the start of the cycle 
for the same most severe toxicity.
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Table 8.c
Ixazomib Dose Modification for Nonhematologic Toxicities
Criteria
Action
Peripheral Neuropathy
Grade 1 peripheral 
neuropathy 
No action
Grade 1 signs and symptoms: asymptomatic, 
without pain or loss of function, clinical or 
diagnostic observations only
Worsening Grade 1 
peripheral neuropathy (ie, 
Grade 1 with pain) or 
Grade 2
Hold ixazomib until resolution to 
Grade ≤1 without pain or baseline.
Grade 2 signs and symptoms: moderate 
symptoms, limiting instrumental activities of 
daily living
New or worsening Grade 2 
peripheral neuropathy with 
pain or Grade 3
Hold ixazomib until resolution to 
Grade ≤1 or baseline.
Reduce ixazomib to next lower dose 
upon recovery as outlined in 
Table 8.a.
Grade 3 signs and symptoms: severe 
symptoms, limiting self-care activities of daily 
living, assistive device indicated
New or worsening Grade 4 
peripheral neuropathy
Discontinue ixazomib.
Grade 2 Rash
Symptomatic recommendations per Section 8.8. The investigator and project clinician 
or designee may discuss considerations for dose modifications and symptom 
management.
All other Grade ≥2 
nonhematologic toxicities
Hold ixazomib until resolution to Grade ≤1 or baseline.
Reduce ixazomib by 1 dose level as outlined in Table 8.a.
Note: A dose level reduction will be made either on the basis of within-cycle criteria or 
subsequent cycle criteria but not both for the same cycle.
Grade 4 nonhematologic 
toxicities 
Consider permanently discontinuing ixazomib, except in the case where the investigator 
determines that the patient is obtaining a clinical benefit and has discussed this with the 
project clinician or designee. If ixazomib is continued, the dose should be reduced by at 
least 1 level.
ANC: absolute neutrophil count. 
Table 8.d
Criteria for Ixazomib Retreatment and Cycle Delays Subsequent to 
Hematologic and Nonhematologic Toxicities
Criteria
Action
Both hematologic and 
nonhematologic 
events
Delay ixazomib for 1 week.
Re-evaluate patient; if still not resolved, delay ixazomib for 1 additional week.
Hematologic and 
nonhematologic 
events not resolved 
after 1-week treatment 
delay
If initiation of subsequent therapy needs to be delayed for more than 2 weeks because of 
incomplete recovery from treatment-related toxicity, the dose of ixazomib will be reduced 
by 1 dose level as outlined in Table 8.a when treatment resumes.
The maximum delay before treatment should be discontinued will be 4 weeks (except in the 
case of investigator-determined clinical benefit and discussion with the project clinician or 
designee at which time dose reduction by at least 1 dose level should be considered). 
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8.4.4
Pomalidomide Treatment Modification (Arm B)
All pomalidomide treatment modifications are according to the local prescribing information 
[41,42]. 
Patients experiencing AEs attributed to pomalidomide may have doses of pomalidomide held or 
reduced by at least 1 dose level as noted in the local prescribing information [41,42]. When a dose 
reduction of pomalidomide is required because of toxicity, no dose re-escalation will be permitted. 
If a patient experiences angioedema, skin exfoliation, bullae, or any other severe cutaneous 
reaction such as SJS, TEN, or DRESS, treatment with pomalidomide should be immediately and 
permanently discontinued. The patient should additionally discontinue treatment with 
dexamethasone and remain on study for PFS and OS follow-up. 
8.4.5
Dexamethasone Treatment Modification (Both Arms)
Patients experiencing AEs attributed to dexamethasone may have doses of dexamethasone held or 
reduced by at least 1 dose level as shown in Table 8.e. When a dose reduction of dexamethasone is 
required because of toxicity, no dose re-escalation will be permitted. 
Treatment modifications because of dexamethasone-related AEs are outlined in Table 8.f.
Table 8.e
Dose Reduction Steps for Dexamethasone
Starting Dose
First Dose 
Reduction
Second Dose Reduction
Third Dose 
Reduction
Arm A
For patients aged <75 yr
20 mg 
on Days 1, 2, 8, 9, 15, 16, 22, and 23
20 mg
on Days 1, 8, 15, and 
22
10 mg
on Days 1, 8, 15, and 22
OR, if only 4 mg tablets are available
12 mg on Day 1, 8 mg on Day 8, 12 mg 
on Day 15, and 8 mg on Day 22
Discontinue 
dexamethasone
For patients aged ≥75 yr
10 mg
on Days 1, 2, 8, 9, 15, 16, 22, and 23
OR, if only 4 mg tablets are available
12 mg on Days 1, 8, 15, and 22
8 mg on Days 2, 9, 16, and 23
12 mg
on Days 1, 8, 15, and 
22
8 mg
on Days 1, 8, 15, and 22
Discontinue 
dexamethasone
Arm B (per pomalidomide local 
prescribing information)
For patients aged <75 yr
40 mg
on Days 1, 8, 15, and 22
20 mg
on Days 1, 8, 15, and 
22
10 mg
on Days 1, 8, 15, and 22
OR, if only 4 mg tablets are available
12 mg on Day 1, 8 mg on Day 8, 
12 mg on Day 15, and 8 mg on Day 22
Discontinue 
dexamethasone
For patients aged ≥75 yr
20 mg
on Days 1, 8, 15, and 22
12 mg
on Days 1, 8, 15, and 
22
8 mg
on Days 1, 8, 15, and 22
Discontinue 
dexamethasone
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Table 8.f
Dexamethasone-Related Treatment Modification (Delays, Reductions, and 
Discontinuations) Guidelines Because of AEs [56]
AE (Severity)
Action on Dexamethasone a
Gastrointestinal
Dyspepsia, gastric, or duodenal ulcer, 
gastritis Grade 1-2 (requiring medical 
management)
Treat with histamine-2 blockers, sucralfate, or 
omeprazole. If symptoms persist despite these 
measures, decrease dexamethasone by 1 dose level.
Grade ≥3 (requiring hospitalization or 
surgery)
Hold dexamethasone until symptoms adequately 
controlled. Restart and decrease 1 dose level of 
current dose along with concurrent therapy with 
histamine-2 blockers, sucralfate, or omeprazole. If 
symptoms persist despite these measures, discontinue 
dexamethasone and do not resume.
Acute pancreatitis
Discontinue dexamethasone and do not resume.
Cardiovascular
Edema Grade >2 (limiting function and 
unresponsive to therapy or anasarca)
Diuretics as needed and decrease dexamethasone by 1 
dose level. If edema persists despite these measures, 
decrease dose another level. Discontinue 
dexamethasone and do not resume if symptoms persist 
despite second reduction.
Neurological
Confusion or mood alteration Grade >2 
Hold dexamethasone until symptoms resolve. Restart 
with 1 dose level reduction. If symptoms persist 
despite these measures, discontinue dexamethasone 
and do not resume.
Musculoskeletal
Muscle weakness Grade >2 (interfering 
with function interfering with 
activities of daily living)
Decrease dexamethasone dose by 1 dose level. If 
weakness persists despite these measures, decrease 
dose by 1 dose level. Discontinue dexamethasone and 
do not resume if symptoms persist.
Metabolic
Hyperglycemia Grade ≥3 
Treatment with insulin or oral hypoglycemics as 
needed. If uncontrolled despite these measures, 
decrease dose by 1 dose level until levels are 
satisfactory.
Other: Grade 3 dexamethasone-related events
Hold dexamethasone until symptoms resolve to Grade 
≤2; then resume with dose reduced by 1 dose level.
AE: adverse event.
a If recovery from toxicities does not occur within 14 days, then the dose of dexamethasone will be decreased by 
1 dose level.
8.4.6
Criteria for Discontinuation of Study Drug
Grade 4 nonhematologic toxicities (considered related to treatment) will, in general, require that 
treatment with study therapy be permanently discontinued. If, in the opinion of the investigator 
and the project clinician or designee, it is in the patient’s best interest to continue treatment with 
study therapy, then the dose of study therapy will be reduced by at least 1 dose level in subsequent 
cycles of treatment after recovery of the toxicity or toxicities in question to Grade 1 or to baseline 
values. 
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8.5
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 pomalidomide 
[41,42].
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).
8.6
Permitted Concomitant Medications and Procedures
All necessary supportive care consistent with optimal patient care will be available to patients, as 
necessary. All blood products and concomitant medications received from the signing of the 
informed consent form until 30 days after the final dose of study therapy will be recorded in the 
eCRFs. 
The following medications and procedures are permitted during the study: 

Myeloid growth factors (eg, granulocyte colony stimulating factor [G-CSF], granulocyte 
macrophage-colony stimulating factor) are permitted. Their use should follow the local 
prescribing information, published guidelines, and/or institutional practice; however, 
alternative usage may be reviewed with the Millennium project clinician or designee. 
Long-acting growth factors (eg, pegylated G-CSF) are not permitted, however. Myeloid 
growth factors may not be used during the Screening period to meet the neutrophil eligibility 
requirements.

Erythropoietin will be allowed in this study. The use of erythropoietic agents carries a risk of
thrombotic events including thromboembolism. Therefore, erythropoietic agents, as well as 
other agents that may increase the risk of thromboembolic events, should be used with caution 
in combination with pomalidomide therapy (Arm B).

Patients should be transfused with red cells and platelets as clinically indicated. Platelet 
transfusions may not be used during the Screening period to meet the platelet eligibility 
requirements.

Patients who are receiving bone-healing agents, such as bisphosphonates or denosumab, for 
previously identified lytic destruction of bone or with osteopenia may continue treatment 
according to the American Society of Clinical Oncology Clinical Practice Guidelines or 
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institutional practice in accordance with the local prescribing information, unless specifically 
contraindicated. If bone-healing–agent therapy was not started before the study start, initiation 
of treatment should be discussed with the Millennium project clinician or designee. 

Supportive measures consistent with optimal patient care may be given throughout the study.
8.7
Precautions and Restrictions
Fluid deficit should be promptly corrected before initiation of, and during treatment with, 
ixazomib (in Arm A).
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.
It is not known what effects ixazomib and pomalidomide 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 practice 1 highly effective method of 
contraception and one additional effective (barrier) method at the same time, for 4 weeks 
before signing the informed consent through 90 days after the last dose of study therapy, OR

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of 
the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.), AND

In women of childbearing potential who are randomized to Arm B (pom+dex), have 2 negative 
pregnancy tests before initiating therapy, with 1 or both being a serum test (the first test should 
be performed within 10-14 days before; the second, within 24 hours before); then have a 
negative pregnancy test weekly during the first month and monthly thereafter in women with 
regular menstrual cycles or every 2 weeks thereafter in women with irregular menstrual cycles; 
and have a negative pregnancy test 4 weeks after the last dose of study therapy.
Male patients, even if surgically sterilized (ie, status postvasectomy), who:

Agree to practice effective barrier contraception during the entire study Treatment period and 
through 90 days after the last dose of study therapy, OR
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
Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of 
the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.), AND

Do not donate semen or sperm during treatment and for 90 days after the last dose of study 
therapy.
Special warnings and precautions for use of pomalidomide were added in Amendment 05 on the 
basis of the updated Summary of Product Characteristics (SmPC) of pomalidomide (Imnovid) [57]. 
Management of current study patients and enrollment of future study patients who have a history 
of severe cutaneous reactions, including hypersensitivity reactions, in the context of treatment 
with pomalidomide, lenalidomide, or thalidomide, is required as follows: 
a.
For all patients assigned to pomalidomide+dexamethasone treatment and who were 
enrolled prior to the C16029 protocol amendment 05 effective date:
i. Inform patients of the newly identified safety risk and document this step 
clearly within the patient's source documentation. 
ii. Obtain medical history regarding severe cutaneous reactions to 
lenalidomide, thalidomide, or pomalidomide (on-study) and immediately 
discontinue treatment with pomalidomide in those patients with a positive 
history of skin reactions consistent with angioedema, skin exfoliation, 
bullae, or any other severe cutaneous reactions such as SJS, TEN, or 
DRESS; do not resume therapy.
b. For all patients currently in screening and all future screened patients after the 
C16029 protocol amendment 05 effective date:
i. Inform patients of this newly identified safety risk and document this step 
clearly within the patient's source documentation.
ii. If a patient has experienced a severe cutaneous reaction as part of prior 
treatment with lenalidomide or thalidomide, the patient must be excluded 
from Study C16029.
8.8
Management of Clinical Events
AEs associated with an overdose will be documented on AE eCRF according to Section 10.0. 
SAEs associated with overdose should be reported according to the procedure outlined in 
Section 10.2.
8.8.1
Ixazomib
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. Prophylactic antiviral therapy, such as acyclovir, valacyclovir, or other antivirals, 
are recommended unless clinically contraindicated. 
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Nausea or Vomiting
Prophylaxis with standard antiemetics, including serotonin 5-hydroxytryptamine 3 receptor 
antagonists, is recommended for emesis. In addition, it is recommended that the dexamethasone 
dose be administered at least 2 hours before ixazomib to maximize the potential antiemetic effect 
(see Section 8.3). 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.
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 (eg, prednisone ≤10 mg per day or equivalent) is permitted. 
Management of a Grade 3 rash may require IV antihistamines or corticosteroids. Administration of 
ixazomib (and other causative agent if given in combination) should be modified per protocol and 
reinitiated at a reduced level from where rash was noted (also per protocol).
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, 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 treatment-emergent 
adverse events (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. 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 
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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 Section 8.4.3). Therapy can be reinitiated at a 
reduced level upon recovery of platelet counts. Thrombotic microangiopathy (TMA), including
thrombotic thrombocytopenia purpura (TTP) 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.
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 in the 
protocol when neutropenia occurs (see Section 8.4.3). 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 
(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.
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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 happened to a patient 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. If overdose occurs, consider close observation including hospitalization for 
hemodynamic support. Gastric lavage may be considered if instituted within 1 hour of ingestion of 
ixazomib overdose.
8.8.2
Pomalidomide
See the pomalidomide local prescribing information for more information [41,57].
Arterial and Venous Thromboembolism
Venous thromboembolic events (deep venous thrombosis and pulmonary embolism) and arterial 
thromboembolic events (myocardial infarction and stroke) have been observed in patients treated 
with pomalidomide. Patients with known risk factors, including prior thrombosis, may be at
greater risk, and actions should be taken to try to minimize all modifiable factors 
(eg, hyperlipidemia, hypertension, smoking).
Thromboprophylaxis is recommended, and the choice of regimen should be based on assessment 
of the patient’s underlying risk factors and local practice guidelines. Patients should be instructed 
to seek medical care if they develop symptoms such as shortness of breath, chest pain, arm or leg 
swelling. Anticoagulation therapy (eg, acetylsalicylic acid, warfarin, heparin or clopidogrel) is 
recommended unless contraindicated, especially in patients with additional thrombotic risk 
factors.
The use of erythropoietic agents carries a risk of thrombotic events including thromboembolism. 
Therefore, erythropoietic agents, as well as other agents that may increase the risk of 
thromboembolic events, should be used with caution.
Erythematous Rash With or Without Pruritus 
Pomalidomide hold or discontinuation should be considered for Grade 2 to 3 skin rash. 
Pomalidomide must be discontinued permanently for any Grade 4 rash.
Severe Cutaneous Reactions
Pomalidomide administration should be immediately and permanently discontinued for 
angioedema, skin exfoliation, bullae, or any other severe cutaneous reaction such as SJS, TEN, or 
DRESS.
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Thrombocytopenia
Pomalidomide administration should be modified according to dose modification 
recommendations in the protocol when thrombocytopenia occurs (see Section 8.4.4). 
Neutropenia
Pomalidomide administration should be modified according to dose modification 
recommendations in the protocol when neutropenia occurs (see Section 8.4.4). Therapy can be 
reinitiated at a reduced level upon recovery of ANC. In case of neutropenia, growth factor use 
should be considered.
8.8.3
Dexamethasone
See the dexamethasone local prescribing information for management of any 
dexamethasone-related clinical events [58].
8.9
Blinding and Unblinding
This is an open-label study. 
8.10
Description of Investigational Agents
8.10.1 Ixazomib
The ixazomib capsule formulation consists of the drug substance (ixazomib citrate), 
microcrystalline cellulose, talc, and magnesium stearate. There are 4 capsule strengths: 2.3, 3.0, 
4.0, and 5.5 mg. Each strength is differentiated by a unique capsule color. Dosage strength is stated 
as ixazomib. Ixazomib capsules are individually packaged in blisters.
For additional details, please see the ixazomib IB and Pharmacy Manual.
8.10.1.1 Preparation, Reconstitution, and Dispensation
Ixazomib is dispensed in a blister pack in a child-resistant carton. For the 2.3, 3.0, 4.0, and 5.5 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.
8.10.1.2 Packaging and Labeling
Ixazomib will be provided by Millennium. The ixazomib local prescribing information will fulfill 
all requirements specified by governing regulations.
8.10.1.3 Storage, Handling, and Accountability
On receipt at the investigative site, ixazomib should remain in the blister pack 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 
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sponsor’s attention for assessment and authorization for continued use. Ensure that the drug is used 
before the retest expiry date provided by Millennium. 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 study drug 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 who are receiving take-home 
medication should be given only 1 cycle of medication at a time. Comprehensive instructions 
should be provided to the patient to ensure compliance with dosing procedures. Patients should be 
instructed to store the medication as indicated in the Pharmacy Manual or equivalent. Patients 
should be instructed to 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 their next visit for take-home medication. In case of 
extenuating circumstances that prevent a patient from attending the study site (eg, the COVID-19 
pandemic), 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 clean-up operation. 
The product may be harmful by inhalation, ingestion, or skin absorption. Gloves and protective 
clothing should be worn during clean-up 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 is to be taken as intact capsules.
Refer to the Pharmacy Manual for this study for additional instructions.
8.10.2 Pomalidomide (Control Therapy)
8.10.2.1 Preparation, Reconstitution, and Dispensation
Pomalidomide is dispensed as a capsule as described in the local prescribing information [41,42].
Pomalidomide is an anticancer drug, and as with other potentially toxic compounds, caution 
should be exercised during handling.
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8.10.2.2 Packaging and Labeling
Pomalidomide will be supplied from commercial sources.
8.10.2.3 Storage, Handling, and Accountability
Pomalidomide capsules should be stored according to the instructions provided in the 
manufacturer’s package insert.
8.10.3 Dexamethasone
8.10.3.1 Preparation, Reconstitution, and Dispensation
Dexamethasone is dispensed as a tablet as described in the local prescribing information [58].
8.10.3.2 Packaging and Labeling
Dexamethasone will be supplied from commercial sources.
8.10.3.3 Storage, Handling, and Accountability
Dexamethasone tablets should be stored according to the instructions provided in the 
manufacturer’s package insert. 
8.11
Other Protocol-Specified Materials
No other drugs or ancillary material are supplied for use in this study.
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9.0
STUDY CONDUCT
This trial will be conducted in compliance with the protocol, Good Clinical Practice (GCP), 
applicable regulatory requirements, and International Conference on Harmonisation (ICH) 
guidelines.
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.
9.2
Arrangements for Recruitment of Patients
Recruitment and enrollment strategies for this study may include recruitment from the 
investigator’s local practice or referrals from other physicians. If advertisements become part of 
the recruitment strategy, they will be reviewed by the institutional review board 
(IRB)/independent ethics committee (IEC). It is not envisioned that prisoners (or other populations 
that might be subject to coercion or exploitation) will be enrolled into this study.
9.3
Treatment Group Assignments
After written informed consent has been obtained, the patient will be randomized to a treatment 
arm using IRT. Patient eligibility will be confirmed by a Millennium project clinician or designee 
before randomization into the study. Centralized randomization via IRT will be used. 
9.4
Study Procedures
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 or a longer window after discussion with the Millennium project clinician or designee. If 
the study schedule is shifted, assessments must be shifted to ensure that collection of assessments 
is completed before dosing. 
Refer to the Schedule of Events (Appendix A) for timing of assessments. Additional details are 
provided as necessary in the sections that follow. (For the timing of assessments performed before 
implementation of Amendment 06, please refer to the previous, full Schedule of Events and 
Pharmacokinetic Sampling Schedule in Appendix L.)
In acknowledgement of hospital, local, state, or national government restrictions, or other 
site-related factors caused by unavoidable circumstances (eg, 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
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are impacted by these unavoidable circumstances, any procedures not conducted per the study 
protocol will be documented in the eCRF.
If a patient misses an in-person study visit, the investigator/study team staff will speak directly 
with the patient by telephone or other medium (eg, a computer-based video communication) 
during each visit window to assess subject safety and overall clinical status. During this contact 
with the patient, the study site physician or other qualified site staff should at minimum conduct 
AE collection and an assessment of clinical symptoms. Other study assessments may be collected 
remotely as is feasible and may involve audio or video recording. Assessments/procedures that 
cannot be completed during the protocol-specified window because a site visit is done remotely (ie, 
symptom-directed physical examination, hematology, clinical chemistry) are waived.
9.4.1
Informed Consent
Each patient must provide written informed consent before any study-required procedures are 
conducted, unless those procedures are performed as part of the patient’s standard care.
As of Amendment 06, 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.
9.4.2
Enrollment
A patient is considered to be enrolled in the study when he/she has been randomized to a study 
therapy. Procedures for completion of the enrollment information are described in the Study 
Manual.
9.4.3
Patient Demographics
The date of birth, race, ethnicity, and sex of the patient are to be recorded during Screening.
9.4.4
Physical Examinations
A complete physical examination and symptom-directed physical examination, including 
examination for rash, performance status, and peripheral neuropathy, will be conducted at the time 
points specified in the Schedule of Events (Appendix A). Please refer to the previous, full 
Schedule of Events (Appendix L) for the timing of assessments before implementation of 
Amendment 06.
9.4.5
Medical History and Disease Staging
During the Screening period, a complete medical history will be compiled for each patient 
including the diagnosis and initial staging; a review of all current medications, prior radiation, 
and/or antineoplastic therapy; and the patient’s current smoking status.

Diagnosis of MM (Appendix D) and initial ISS staging (based on serum albumin and 
β2-microglobulin levels; Appendix F), myeloma isotyping (IgG, IgA, IgM, IgD, IgE, light 
chain kappa or lambda), and initial cytogenetic information, if known. Note: Cycle 1 Day 1 
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dosing may proceed if MM isotype testing has been submitted to, but not yet analyzed at, the 
central laboratory.

MM-directed therapy including initial and subsequent therapies, responses, dates and 
clinically significant toxicities. 

Review of all current medications, prior radiation (as permitted >14 days before randomization 
for symptomatic bone lesion or >5 years before randomization for another malignancy), and 
the patient’s current smoking status.
9.4.6
ECOG Performance Status 
Performance status will be assessed using the ECOG Performance Scale (see Appendix E) at every 
cycle, as well as other times, as indicated in the previous, full Schedule of Events (Appendix L). 
Upon implementation of Amendment 06, ECOG data will no longer be collected.
9.4.7
Vital Signs 
Measurements of temperature and respiratory rate are to be performed at Screening, and thereafter, 
only as clinically indicated. Measurements of blood pressure and heart rate are to be performed at 
Screening and during the Treatment period as indicated in the previous, full Schedule of Events 
(Appendix L). Upon implementation of Amendment 06, vital signs data will no longer be 
collected.
9.4.8
Height and Weight 
Height will be measured only during Screening. Weight will be measured during Screening as well 
as other times, as indicated in the previous, full Schedule of Events (Appendix L). Upon 
implementation of Amendment 06, weight data will no longer be collected.
9.4.9
Electrocardiogram
A 12-lead electrocardiogram (ECG) will be conducted at Screening. It may be repeated as 
clinically indicated during the study at the discretion of the investigator. ECG data to be obtained 
include PR interval, QRS interval, and QT interval. 
9.4.10 QOL and HU Assessments
QOL and HU assessments will be performed per the previous, full Schedule of Events 
(Appendix L), also described in this section. All QOL and HU assessments will be completed 
before any other study procedures are performed or study therapy is administered. The order of 
assessments will be the EORTC QLQ-C30 (Appendix H), EORTC QLQ-MY20 (Appendix I), and 
EQ-5D-5L (Appendix J), followed by the HU assessment (Appendix K). Upon implementation of 
Amendment 06, PRO data will no longer be collected.
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9.4.10.1 QOL
The patient-reported health-related QOL will be directly self-reported by patients on paper 
versions of the EORTC QLQ-C30 (Appendix H), EORTC QLQ-MY20 (Appendix I), and 
EQ-5D-5L (Appendix J), at multiple points throughout the study: at the Screening visit, on Day 1 
visits of every cycle during the Treatment period, at the EOT visit, and at the PFS Follow-up visits, 
every 4 (±1) weeks during the PFS Follow-up period (see the previous, full Schedule of Events in 
Appendix L. Upon implementation of Amendment 06, PRO and PFS data will no longer be 
collected.
The EQ-5D-5L will also be assessed at the OS Follow-up visits, every 12 (±1) weeks during the 
OS Follow-up period; however, if a patient is unable to attend a study visit during the OS 
Follow-up period, EQ-5D-5L assessments may be collected from the patients via a telephone 
interview by trained site staff, who record the patient’s responses on the patient’s behalf. Upon 
implementation of Amendment 06, PRO and OS data will no longer be collected.
EORTC QLQ-C30
Cancer-specific health-related QOL will be assessed using the EORTC QLQ-C30 [59]
(Appendix H). The EORTC QLQ-C30 contains 30 items across 5 functional scales (physical, role, 
cognitive, emotional, and social), 9 symptom scales (fatigue, nausea and vomiting, pain, dyspnea, 
sleep disturbance, appetite loss, constipation, diarrhea, and financial difficulties) and a global 
health status/QOL scale. Most of the 30 items have 4 response levels (not at all, a little, quite a bit, 
and very much), with 2 questions relying on a 7-point numeric rating scale. Raw scores are 
converted into scale scores ranging from 0 to 100. For the functional subscales and the global 
health status/QOL subscale, higher scores represent better QOL; for the symptom subscales, lower 
scores represent better QOL.
The physical functioning domain of EORTC QLQ-C30 consists of 5 items covering the patient’s 
daily physical activities. It has been validated to measure physical activity changes in patients with 
MM [60,61]. Because of the relevance of physical function in MM, the physical functioning 
domain of EORTC QLQ-C30 has been used as a primary endpoint in some MM studies [61]. 
Upon implementation of Amendment 06, PRO data will no longer be collected.
EORTC QLQ-MY20
The EORTC QLQ-MY20 is an MM disease-specific 20-item questionnaire module, designed to 
assess the QOL of MM patients with EORTC QLQ-C30. The 20 items are across 2 functional 
subscales and 2 symptom subscales (Appendix I). The EORTC QLQ-MY20 has also been 
validated and used in clinical studies of MM and has been demonstrated to have excellent 
measurement properties (validity, reliability, responsiveness). 
Raw scores are converted into scale scores ranging from 0 to 100. For the functional subscales, 
higher scores represent better QOL; for the symptom subscales, lower scores represent better 
QOL.
Upon implementation of Amendment 06, PRO data will no longer be collected.
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EQ-5D-5L
The EQ-5D-5L consists of 2 pages: the EQ-5D-5L descriptive system and the EuroQol visual 
analogue scale (EQ VAS) (Appendix J). The descriptive system comprises 5 dimensions (mobility, 
self-care, usual activities, pain/discomfort, and anxiety/depression), each rated on 5 levels. The 
EQ VAS records the respondent’s self-rated health on a 20 cm, vertical, visual analogue scale 
ranging from 0 (worst imaginable health state) to 100 (best imaginable health state).
Upon implementation of Amendment 06, PRO data will no longer be collected.
9.4.10.2 HU
HU data will be collected on Day 1 visits of every cycle during the Treatment period, at the EOT 
visit, and at the PFS Follow-up visits, every 4 (±1) weeks during the PFS Follow-up period (see the 
previous, full Schedule of Events (Appendix L). Only non-protocol-directed health care 
encounters (ie, those not scheduled per this study protocol) are to be entered into the HU form 
(Appendix K). The form is to include all hospitalizations, emergency room visits, and 
non-protocol-directed outpatient visits (eg, physician/clinic visits, 
laboratory/pathology/radiology/biomedical imaging workups); missed work by the patient and/or 
caregiver is also collected on the form. 
Note that the HU form is NOT intended to be completed by patient directly. At each HU 
assessment, the data collection recall timeframe is from the time of the previous study visit. 
Upon implementation of Amendment 06, HU and PFS data will no longer be collected.
9.4.11 Imaging Disease Assessment
Imaging to assess status of bone disease will be performed at Screening (within 8 weeks before 
randomization) for all patients by means of skeletal survey, CT, MRI, or positron emission 
tomography (PET)-CT. Additional assessments 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. At 
least the following areas should be assessed: head, neck, chest, abdomen, pelvis, arms, and legs.
Imaging to assess extramedullary disease will be done at Screening (within 8 weeks before 
randomization) 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 1 Day 1 and every 3 cycles thereafter, unless the Screening assessment is 
completed before 14 days before Cycle 1 Day 1; then the next assessment can be on Cycle 3 Day 1.
Imaging assessments will be analyzed locally and reports maintained with the patient record for 
review during monitoring visits.
Upon implementation of Amendment 06, imaging will no longer be performed at specified times 
per the Schedule of Events.
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9.4.12 Disease Response Assessment by Investigator
Patients will be assessed for disease response according to the IMWG uniform response criteria, 
version 2011 (see Appendix G), until the data cutoff date for the study analysis (including for PFS) 
has occurred. At that time, all central efficacy and investigator assessments of disease response for 
protocol purposes will be stopped. Details of the clinical laboratory evaluations for disease 
assessment are given in Section 9.4.15.2.
Response categories are in Table 9.a.
Table 9.a
Response Assessment
Complete response
CR
Subcategory: stringent complete response
sCR
Very good partial response 
VGPR
Partial response
PR
Stable disease
SD
Progressive disease
PD
CR must be confirmed with follow-up assessments of serum protein electrophoresis, urine protein 
electrophoresis, immunofixation of blood and urine, and serum free light chains as outlined in 
Section 9.4.15.2. One bone marrow assessment must occur to document CR; no second bone 
marrow confirmation of CR is needed.
Note: To determine a response of stringent CR, bone marrow immunohistochemistry or 
immunofluorescence for kappa/lambda ratio should be performed for all patients suspected to be 
in CR to meet this response category’s requirements. 
The duration of stable disease should be collected.
At any point during treatment, patients suspected of having PD will have response assessments 
repeated to confirm PD. Per IMWG criteria, 2 consecutive response assessments are required to 
document PD. These assessments must be performed at the central laboratory in order to document
PD. Before an investigator discontinues a patient from treatment for PD, the Progressive Disease 
Review form must be completed and sent as soon as possible, permitting pertinent data to be 
confirmed by a Millennium project clinician or designee. 
Upon implementation of Amendment 06, only patients who continue to demonstrate clinical 
benefit but who do not have other means of access to the study drugs will continue on the study. 
The reason for treatment discontinuation must be recorded in the eCRF but no approval is
required.
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9.4.14 Pregnancy Test
In Arm A, 3 serum pregnancy tests must be performed for women of childbearing potential: one at 
Screening, one at Cycle 1 Day 1, and one at the EOT visit. The Cycle 1 Day 1 pregnancy test may 
be collected up to 3 days before dosing and results must be available and negative before dosing. 
In Arm B, for women of childbearing potential, 2 pregnancy tests (with 1 or both being serum 
tests) must be performed before starting pom+dex and results must be available and negative 
before dosing: the first within 10 to 14 days before dosing and the second within 24 hours before 
dosing. Then testing must be performed weekly during the first month and monthly thereafter in 
women with regular menstrual cycles, or every 2 weeks (at Day 15) in women with irregular 
menstrual cycles. In Arm B at the EOT visit, the test must be a serum pregnancy test. The results of 
each test must be available and negative before the study therapy is administered.
Pregnancy tests may also be repeated during the study upon request by IECs/IRBs or if required by 
local regulations.
9.4.15
Clinical Laboratory Evaluations
If the Screening laboratory tests were performed more than 14 days before the first dose (Cycle 1 
Day 1), the tests will be repeated before dosing. The test closest to the first dose will be considered 
Baseline.
Hematology and chemistry laboratory samples will be collected locally and may be collected up to 
3 days before Day 1 of each cycle or prior to dosing on Day 1. For Cycles 1 and 2, the laboratory 
samples may be collected 24 hours prior to dosing on Day 15 for Arm A (ixa+dex) or before 
dosing on Day 15. For Arm B (pom+dex); hematology samples only will be collected at Cycle 1 
and at Cycle 2, Days 8 and 22. Samples may be collected 24 hours before, or prior to dosing on, 
Days 8 and 22. Laboratory reports must be reviewed by the investigator prior to dosing for all 
cycle visits, and clinical significance must be indicated. In addition, the investigator must assess 
any AEs or concomitant medication changes prior to dosing. Local laboratory evaluations may be 
done more frequently at the investigator’s discretion (ie, for acute management of TEAEs). 
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9.4.15.1 Clinical Chemistry and Hematology
Upon implementation of Amendment 06, centralized clinical laboratory evaluations are no longer 
required and local laboratories are to be used. Local laboratory evaluations should be entered into 
the eCRF only if required to understand 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. These 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.
Blood samples for analysis of the clinical chemistry and hematological parameters shown in 
Table 9.b will be obtained and recorded in the eCRFs as specified in the updated Schedule of 
Events (Appendix A). (For the previous, full Schedule of Events, see Appendix L.) 
Table 9.b
Clinical Chemistry and Hematology Tests 
Hematology
Serum Chemistry
Hemoglobin
Leukocytes with differential
Neutrophils ANC
Platelet (count)
Albumin
Alkaline phosphatase
Alanine aminotransferase
Aspartate aminotransferase
%2-microglobulin (at Screening only)
Bilirubin (total)
Blood urea nitrogen
Calcium
Creatinine
Gamma glutamyl transferase
Lactate dehydrogenase (at Screening 
only)
Magnesium
Potassium
Urate
C-reactive protein
Quantification of B cells, T cells, and natural killer cells 
Measles
Varicella-zoster virus
Tetanus
If creatinine clearance is to be estimated, the Cockcroft-Gault formula will be employed as 
follows:
For female patients, the result of the formula above should be multiplied by 0.85. 
9.4.15.2 Clinical Laboratory Evaluations for Disease Assessments 
Upon implementation of Amendment 06, all central laboratory assessments are no longer required.
See the updated Schedule of Events (Appendix A) for more information.
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A blood sample will be collected during Screening for measurement of serum 2-microglobulin 
and albumin for determination of disease stage according to the ISS; these results will be analyzed 
centrally and recorded on the eCRF.
Clinical laboratory evaluations for disease assessments (serum protein electrophoresis [SPEP], 
urine protein electrophoresis [UPEP], serum free light chain, immunofixation, and 
immunoglobulin) must be sent to the central laboratory for evaluation.
Immunofixation will also 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. Blood samples for IgM, IgG, and IgA will be obtained at 
Screening and throughout the study at the time points specified in the as indicated in the previous, 
full Schedule of Events (Appendix L). Note that 24-hour urine collection is permitted before 
Screening if it is part of standard clinical practice at the site. Quantitative IgD and IgE will be done 
at Screening (and Baseline if needed) 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.
Bone marrow aspirate or biopsy disease assessment is to be performed at a local laboratory to 
assess disease status at Screening and 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 bone marrow aspirate or biopsy drawn prior to consent is acceptable for the 
Baseline assessment provided that it is collected within 42 days before the first dose.
9.4.16 AEs
Monitoring of AEs, serious and nonserious, will be conducted throughout the study as specified in 
the Schedule of Events (Appendix A). Refer to Section 10.0 for details regarding definitions, 
documentation, and reporting of pretreatment events, AEs, and SAEs.
When peripheral neuropathy occurs, each subsequent monthly evaluation will record the grade of 
peripheral neuropathy at that visit. (This is in contrast to other AEs where only increases in grade 
are recorded until the maximum grade is reached and then followed at that grade until complete 
resolution or return to Baseline.) Peripheral neuropathy will be followed monthly until: 
1) resolution of peripheral neuropathy, 2) the start of a second-line alternative antineoplastic 
treatment, or 3) 6 months after PD has occurred, whichever occurs first.
9.4.17 Concomitant Medications and Procedures
Concomitant medications and therapeutic procedures will be recorded in the eCRFs as specified in 
the Schedule of Events (Appendix A). See Section 8.5 and Section 8.6 for a list of medications and 
therapies that are prohibited and allowed, respectively, during the study.
9.4.18
PK Samples and Measurements
PK data will be collected in Arm A (ixa+dex) only, as indicated Table A of the previous, full 
Schedule of Events (Appendix L). Plasma concentrations of ixazomib (the complete hydrolysis 
product of ixazomib citrate) will be measured using a validated liquid chromatography 
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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 (the complete hydrolysis product of ixazomib citrate) will be 
collected during Cycles 1 through 4. The exact date and time of each PK sample collection should 
be recorded in the source documents and eCRF.
Upon implementation of Amendment 06, PK sample collection will be considered complete and 
no additional PK samples will be collected or quantified.
9.5
Completion of Study Treatment (for Individual Patients)
Patients will be considered to have completed study treatment if they experience PD, discontinue 
treatment because of unacceptable toxicity, or withdraw consent for any reason. Before an 
investigator discontinues a patient from treatment for PD, the pertinent data must be confirmed by 
a Millennium project clinician or designee. Patients will attend an EOT visit 30 days (+1 week) 
after receiving their last dose of study therapy or prior to the start of a new line of anti-myeloma 
treatment. In the event a patient withdraws consent or has a death prior to the EOT visit, the last 
date of contact with the patient will be utilized as the EOT visit date. AEs/SAEs will be monitored 
for all patients up to 30 days post last study drug dose regardless if a patient starts a new line of 
therapy. Patients will continue to be followed for other follow-up assessments specified in Section 
6.1.3.2. Also refer to the updated Schedule of Events (Appendix A) for EOT visit assessments.
Upon implementation of Amendment 06, only patients who continue to demonstrate clinical 
benefit but who do not have other means of access to the study drugs will continue on the study. 
Patients continuing their current study treatment may do so until such time as other means of 
accessing the study drugs are arranged. When possible, patients should complete an EOT visit and 
transition onto an alternative supply of (eg, commercially available) ixazomib or pomalidomide, 
as well as dexamethasone, or onto another standard of care treatment. Discontinued patients will 
be treated by their physician per local standard of care. The reason for treatment discontinuation 
must be recorded in the eCRF but no approval is required.
9.6
Completion of Study (for Individual Patients)
Patients will be considered to have completed the study when the analysis for the study (PFS and 
secondary endpoints) is completed or when the sponsor terminates the study. The study will be 
considered complete after the study analysis is completed or the study has been terminated (see 
Section 9.9).
9.7
Discontinuation of Treatment With Study Therapy
Study therapy must be permanently discontinued for patients who become pregnant.
Treatment with study therapy may also be discontinued for any of the following reasons:

AE.

Protocol deviation.
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
Study terminated by sponsor.

Withdrawal by subject.

Lost to follow-up.

Pregnancy (patient must be discontinued).

Progressive disease.

Death.

Other.
Upon implementation of Amendment 06, only patients who continue to demonstrate clinical 
benefit but who do not have other means of access to the study drugs will continue on the study. 
Patients continuing their current study treatment may do so until such time as other means of 
accessing the study drugs are arranged. When possible, patients should complete an EOT visit and 
transition onto an alternative supply of (eg, commercially available) ixazomib or pomalidomide, 
as well as dexamethasone, or onto another standard of care treatment. Discontinued patients will 
be treated by their physician per local standard of care. The reason for treatment discontinuation 
must be recorded in the eCRF but no approval is required.
9.8
Withdrawal of Patients From Study
A patient will be withdrawn from the study for any of the following reasons:

Study terminated by sponsor.

Withdrawal by subject.

Lost to follow-up. 

Other.
Upon implementation of Amendment 06, PFS and OS follow-up will no longer be performed. 
Patients will now complete the study immediately following the EOT visit. The consequence of 
study withdrawal is that no new information will be collected from the withdrawn patient and 
added to the existing data or any database.
9.9
Study Closure
The study will be considered complete after the study analysis is completed or the study has been 
terminated. In addition to PFS, at the time of the study analysis, OS and other secondary endpoints 
will be assessed, with no later analyses to follow. Only patients who continue to demonstrate 
clinical benefit but who do not have other means of access to the study drugs will continue on the 
study. Patients continuing their current study treatment may do so until such time as other means 
of accessing the study drugs are arranged. When possible, patients should complete an EOT visit 
and transition onto an alternative supply of (eg, commercially available) ixazomib or 
pomalidomide, as well as dexamethasone, or onto another standard of care treatment. 
Discontinued patients will be treated by their physician per local standard of care.
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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 Millennium, there is sufficient reasonable cause. Written notification 
documenting the reason for study termination will be provided to the investigator or Millennium 
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.

Insufficient, incomplete, and/or unevaluable data.

Determination of efficacy based on the study analysis.

Plans to modify, suspend, or discontinue the development of the study drug.
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 
Millennium once the site’s participation in the study has concluded.
Within 15 days after premature closure, Millennium must notify the competent authorities and 
IECs of any member state where the study is being conducted, providing the reasons for study 
closure. 
9.10
Study Compliance
Study therapy 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 therapy receipt and dispensing.
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10.0
ADVERSE EVENTS
10.1
Definitions
10.1.1 Pretreatment Event Definition
A pretreatment event is defined as any untoward medical occurrence in a patient or subject who 
has signed informed consent to participate in a study but before administration of any study 
medication; it does not necessarily have to have a causal relationship with study participation.
10.1.2 AE Definition
AE means any untoward medical occurrence in a patient or subject administered a pharmaceutical 
product; the untoward medical occurrence does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product whether or not it is related to the medicinal product. This includes any 
newly occurring event, or a previous condition that has increased in severity or frequency since the 
administration of study therapy.
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is considered 
by the investigator to be a clinically significant change from baseline.
10.1.3 SAE Definition
SAE means any untoward medical occurrence that at any dose:

Results in death.

Is life-threatening (refers to an AE in which the patient was at risk of death at the time of the 
event. It does not refer to an event which hypothetically might have caused death if it were 
more severe).

Requires inpatient hospitalization or prolongation of an existing hospitalization (see 
clarification in the paragraph in Section 10.2 on planned hospitalizations).

Results in persistent or significant disability or incapacity. (Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions).

Is a congenital anomaly/birth defect.

Is a medically important event. This refers to an AE that may not result in death, be 
immediately life threatening, or require hospitalization, but may be considered serious when, 
based on appropriate medical judgment, may jeopardize the patient, require medical or 
surgical intervention to prevent 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 
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development of drug dependency or drug abuse; any organism, virus, or infectious particle 
(eg, prion protein transmitting transmissible spongiform encephalopathy), pathogenic or 
nonpathogenic, is considered an infectious agent.
In this study, intensity for each AE, including any laboratory abnormality, will be determined 
using the NCI CTCAE, Version 4.03, effective date 14 June 2010 [62]. Clarification should be 
made between an SAE and an AE that is considered severe in intensity (Grade 3 or 4), because the 
terms serious and severe are NOT synonymous. The general term severe is often used to describe 
the intensity (severity) of a specific event; the event itself, however, may be of relatively minor 
medical significance (such as a Grade 3 headache). This is NOT the same as serious, which is 
based on patient/event outcome or action criteria described above, and is usually associated with 
events that pose a threat to a patient’s life or ability to function. A severe AE (Grade 3 or 4) does 
not necessarily need to be considered serious. For example, a white blood cell count of 1000/mm3
to less than 2000 is considered Grade 3 (severe) but may not be considered serious. Seriousness 
(not intensity) serves as a guide for defining regulatory reporting obligations.
10.2
Procedures for Recording and Reporting AEs and SAEs
All AEs spontaneously reported by the patient and/or in response to an open question from study 
personnel or revealed by observation, physical examination, or other diagnostic procedures will be 
recorded on the appropriate page of the eCRF (see Section 10.3 for the period of observation). Any 
clinically relevant deterioration in laboratory assessments or other clinical finding is considered an 
AE. When possible, signs and symptoms indicating a common underlying pathology should be 
noted as 1 comprehensive event.
Regardless of causality, SAEs and serious pretreatment events (as defined in Section 10.1) must be 
reported (see Section 10.3 for the period of observation) by the investigator to the Millennium 
Global Pharmacovigilance department or designee (contact information provided below). This 
should be done by faxing the SAE Form within 24 hours after becoming aware of the event. The 
SAE Form, created specifically by Millennium, will be provided to each clinical study site. A 
sample of the SAE Form may be found in the Study Manual. Follow-up information on the SAE or 
serious pretreatment event may be requested by Millennium. SAE report information must be 
consistent with the data provided on the eCRF.
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.
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SAE Reporting Contact Information
US and Canada
Japan
Emergency Center for Safety Information (available 24 hours a day, 365 days a year)
Planned hospital admissions or surgical procedures for an illness or disease that existed before 
study therapy 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 therapy administration. For serious 
pretreatment events, the investigator must determine both the severity (toxicity grade) of the event 
and the causality of the event in relation to study procedures.
Severity (toxicity grade) for each AE, including any laboratory abnormality, will be determined 
using the NCI CTCAE, Version 4.03, effective date 14 June 2010 [62]. The criteria are provided in 
the Study Manual.
Relationship of the event to study therapy 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 therapy?”
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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 regardless of whether a patient starts a new line 
of therapy and recorded in the eCRFs. AEs 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); the exception is peripheral neuropathy, which will be followed 
monthly until 1) resolution of peripheral neuropathy, 2) the start of a second-line alternative 
antineoplastic treatment, or 3) 6 months after PD has occurred, whichever occurs first.

SAEs
–
Serious pretreatment events will be reported to the Millennium Global Pharmacovigilance 
department or designee from the time of the signing of the informed consent form up to 
first dose of study therapy, and will also be recorded in the eCRF. 
–
Related and unrelated treatment-emergent SAEs will be reported to the Millennium Global 
Pharmacovigilance department or designee from the first dose of study therapy through 30 
days after administration of the last dose of study therapy regardless of whether a patient 
starts a new line of therapy and recorded in the eCRF. After this period, only related SAEs 
must be reported to the Millennium 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); 
the exception is peripheral neuropathy, which will be followed monthly until 1) resolution 
of peripheral neuropathy, 2) the start of a second-line alternative antineoplastic treatment, 
or 3) 6 months after PD has occurred, whichever occurs first.
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 therapy. The sponsor 
must also be contacted immediately by faxing a completed Pregnancy Form to the Millennium 
Global Pharmacovigilance department or designee (see Section 10.2). The pregnancy must be 
followed for the final pregnancy outcome.
If a female partner of a male patient becomes pregnant during the male patient’s participation in 
this study, the sponsor must also be contacted immediately by faxing a completed Pregnancy Form 
to the Millennium Global Pharmacovigilance department or designee (see Section 10.2). Every 
effort should be made to follow the pregnancy for the final pregnancy outcome.
10.5
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose)
A product complaint is defined as a verbal, written, or electronic expression that implies 
dissatisfaction regarding the identity, strength, purity, quality, or stability of a drug product. 
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Individuals who identify a potential product complaint situation should immediately report this via 
the phone numbers or email addresses provided below.
A medication error is defined as 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 number or email address provided below.
Product
Call center
Phone number
Email
Fax
NINLARO 
(ixazomib)
Product complaints or medication errors in and of themselves are not AEs. If a product complaint 
or a medication error results in an SAE, an SAE Form should be completed and sent to 
 
(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 European 
Medicines Agency, investigators and IRBs or IECs, as applicable, in accordance with national 
regulations in the countries where the study is conducted. Relative to the first awareness of the 
event by/or further provision to the sponsor or sponsor’s designee, SUSARs will be submitted to 
the regulatory authorities as an expedited report within 7 days for fatal and life-threatening events 
and 15 days for other serious events, unless otherwise required by national regulations. The 
sponsor will also prepare an expedited report for other safety issues where these might materially
alter the current benefit-risk assessment of an investigational medicinal product or that would be 
sufficient to consider changes in the investigational medicinal product’s administration or in the 
overall conduct of the trial. The investigational site also will forward a copy of all expedited 
reports to his or her IRB or IEC in accordance with national regulations.
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11.0
STUDY-SPECIFIC COMMITTEES
An IDMC will be used in this study. 
11.1
IDMC
An IDMC supported by an independent statistician will review safety data, including the 
feasibility and safety of the intrapatient dose escalation of ixazomib from 4 mg to 5.5 mg at 
regularly scheduled meetings prespecified in the IDMC charter.
The IDMC will provide a recommendation regarding study continuation based on the safety 
parameters. If the study is terminated early based on the IDMC recommendation, Millennium will 
notify the appropriate regulatory authorities.
Study accrual will not be interrupted because of the scheduled safety reviews. The IDMC or 
ixazomib study team may request an ad hoc meeting for any reason, including a significant 
unexpected safety event, unplanned unblinding of study results, follow-up of an observation 
during a planned IDMC meeting, or a report external to the study, such as publication of study 
results from a competing product. At each review, subject incidence rates of AEs (including all 
SAEs, treatment-related AEs, serious treatment-related events, and events requiring the 
discontinuation of study therapy) will be tabulated by system organ class, preferred term, and 
severity grade. Listings and/or narratives of on-study deaths and other serious and significant AEs, 
including any early withdrawals because of AEs, will be provided. Records of all meetings will be 
archived. The IDMC will communicate major safety concerns and recommendations regarding 
study modification or termination to Millennium. Further details will be provided in the IDMC 
charter. 
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12.0
DATA HANDLING AND RECORDKEEPING 
The full details of procedures for data handling will be documented in the Data Management Plan. 
If selected for coding, AEs, pretreatment events, medical history, and concurrent conditions will 
be coded using the Medical Dictionary for Regulatory Activities (MedDRA). Drugs will be coded 
using the World Health Organization Drug Dictionary.
12.1
eCRFs 
Completed eCRFs are required for each subject who signs an informed consent form.
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 Millennium 
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.
12.2
Record Retention
The following procedure is applied for the countries except for Japan. 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 informed consent forms, subject authorization forms regarding the use of personal 
health information (if separate from the informed consent forms), 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 
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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.
The following procedure is applied for Japanese sites only. The investigator and the head of the
institution agree 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 informed consent forms, subject authorization forms regarding the use of 
personal health information (if separate from the informed consent forms), electronic copies 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 and the head of the institution 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/or the head of the institution and sponsor. Refer to the Clinical Study 
Site Agreement for the sponsor’s requirements on record retention. The investigator and the head 
of the institution should contact and receive written approval from the sponsor before disposing of 
any such documents.
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13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
In general, summary tabulations will be presented by treatment arm and 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 
(KM) survival curves and 25th, 50th (median), and 75th percentiles will be provided along with 
their 95% CIs for time-to-event data.
Deviations from the statistical analyses outlined in this protocol will be indicated in the statistical 
analysis plan; any further modifications will be noted in the clinical study report.
Study C16029 is a phase 2 study with PFS as the primary endpoint. The preliminary data from the 
phase 2 study by 
 et al., an investigator-initiated study, demonstrated that greater clinical 
benefit (eg, ORR) may be achieved with the use of ixa+dex, with 4 mg and 5.5 mg doses of 
ixazomib, compared with pom+dex [7,8]. Therefore, this company-sponsored study is intended to 
provide further assessment on 1) the feasibility and safety of the dose escalation of 4 mg to 5.5 mg 
ixazomib after the first cycle, and 2) the efficacy of ixa+dex.
13.1.1 Analysis Sets
The populations used for analysis will include the following:
!
Safety population: The safety population is defined as all patients who receive at least 1 dose 
of any study therapy. Patients will be analyzed according to the treatment actually received. 
That is, those patients who are randomized to the active arm but receive the regimen in the 
control arm will be included in the control arm; those patients who are randomized to the 
control arm but receive the regimen in the active arm will be included in the active arm for 
safety analyses.
!
ITT population: The ITT population is defined as all patients who are randomized. Patients 
will be analyzed according to the treatment they are randomized to receive, regardless of any 
errors of dosing.
13.1.2 Analysis of Demographics and Other Baseline Disease 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, weight, baseline disease characteristics, 
and other parameters, as appropriate.
13.1.3 Efficacy Analysis
All available efficacy 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. In general, missing data will be treated as missing, and no data imputation 
will be applied, unless otherwise specified. 
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Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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13.1.3.1 Analyses for Primary Efficacy Endpoint
The analysis of the primary endpoint, PFS, will be based on the ITT population using 
investigator-assessed PD data. PFS is defined as the time from randomization to the first 
occurrence of confirmed PD or death from any cause, whichever occurs first. Patients without 
documentation of PD will be censored at the date of the last response assessment that is SD or 
better.
PFS will be analyzed after approximately 81 PFS events have been observed. Unstratified analyses 
of PFS will be conducted. 
A 2-sided, unstratified log-rank test will be used to compare the treatment groups with respect to 
PFS at a 2-sided alpha level of 0.20. In addition, an unadjusted unstratified Cox model will be used 
to estimate the HR and its 80% and 95% CIs for the treatment effect. The KM survival curves and 
KM medians (if estimable), along with their 2-sided 95% CIs, will also be provided for each 
treatment group. 
Sensitivity analyses for PFS will include:

PFS assessed by stratified analyses in the ITT population.
Subgroup analyses will be performed for PFS relative to baseline stratification factors and 
demographic data such as sex, race or ethnic group, and age, as appropriate. 
13.1.3.2 Analyses of Secondary Efficacy
The primary endpoint of PFS will be supported by prespecified evidence of clinical benefit as 
measured by other secondary endpoints. Other secondary efficacy parameters are OS, ORR, 
duration of response, time to response, and TTP. Disease responserelated endpoints will be 
analyzed using investigator-assessed response rate for the ITT population.
OS will be analyzed on the basis of the ITT population and is defined as the time from 
randomization to death from any cause. Patients without documentation of death at the time of 
analysis will be censored at the date last known to be alive. A 2-sided, unstratified log-rank test 
will be used to compare the treatment and control groups with respect to OS. In addition, an 
unadjusted unstratified Cox model will be used to estimate the HR and its 80% and 95% CIs for the 
treatment effect. OS will be also tested at 2-sided alpha=0.2. The KM survival curves and KM 
medians (if estimable), along with their 95% CIs, will also be provided for each study group.
ORR is defined as the rates of PR, VGPR, or CR, as evaluated by an investigator on the basis of 
central laboratory results according to IMWG criteria [55]. The percentage of each response 
category (CR, VGPR, and PR) and of the combination CR + VGPR will be determined. 
Duration of response is defined as the time from the first documentation of PR or better to the first 
documentation of PD. Responders without documentation of PD will be censored at the date of the 
last assessed response of PR or better. Duration of CR will be summarized descriptively using the 
KM method.
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Time to response is defined as the time from randomization to the first documentation of PR or 
better. Time to response will be summarized descriptively.
TTP is defined as the time from randomization to the date of first documented PD. Patients without 
documentation of PD at the time of analysis will be censored at the date of the last response 
assessment. TTP will be analyzed on the basis of the ITT population using methods similar to 
those used for PFS.
13.1.4 PK Analysis
PK data collected in this study may contribute to population PK and exposure/response (safety and 
efficacy) analyses. These analyses may include data from other ixazomib clinical studies and will 
be separately developed and reported.
13.1.5 QOL and HU Analyses
Analyses of patient-reported QOL outcomes will be performed for patients with data at baseline 
and at least 1 postbaseline measurement. Analyses of HU will be performed for the ITT 
population. 
The QOL analyses will be completed for all subscales, but particular emphasis will be placed on 
the Physical Functioning subscale. The main health-related QOL endpoint is time to maintained 
deterioration of Physical Functioning domain scores from the EORTC QLQ-C30, based on a 
minimally important difference of 10 (primary analysis) [63-65] and 5 (sensitivity analysis) [66]. 
The summary and subscale scores of EORTC QLQ-C30 and subscale scores of QLQ-MY20 will 
also be analyzed. Specifically, the actual value and change from baseline scores will be 
summarized using descriptive statistics by treatment group over time. The change from baseline 
on summary and subscale scores may also be analyzed using linear mixed models by incorporating 
the measurements across different time points. Additionally, the number and percentages of 
patients showing a clinically meaningful change from baseline will be summarized by treatment 
group over time. Questionnaire compliance will also be summarized. 
Published manuals/guidance for these questionnaires will be used for scoring and handling of 
missing data. Sensitivity analyses may be conducted to study the impact of missing data.
EQ-5D-5L item scores and visual analogue scale (VAS) scores will be summarized using 
descriptive statistics by treatment group over time. 
HU as measured by hospitalizations, emergency room visits, non–protocol-directed outpatient 
visits, and missed days of work by patients and/or caregivers will be summarized using descriptive 
statistics by treatment group.
13.1.6 Safety Analysis
All available 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.
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Safety will be evaluated by the incidence of AEs, severity and type of AEs, and by changes from 
baseline in the patient’s vital signs, weight, and clinical laboratory results using 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.

Grade ≥2 peripheral neuropathy.

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.
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.
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.
All concomitant medications collected from the first dose of study therapy throughout the study 
period will be classified to preferred terms according to the World Health Organization drug 
dictionary.
Additional safety analyses may be performed to most clearly enumerate rates of toxicities and to 
further define the safety profile of ixazomib.
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13.1.6.1 New Primary Malignancy
Two types of incidence rates will be calculated for the safety population based on the new primary 
malignancy assessment:
!
Incidence proportions, defined as the percentage of patients reporting any new primary 
malignancy in the safety population with available information.
!
Incidence rates, defined as the number of patients reporting any new primary malignancy 
divided by the total duration of follow-up in the safety population with available information 
up to the onset of new primary malignancies.
For incidence proportions, the relative risks, defined as the ratio of incidence proportions between 
the 2 randomized treatment groups, will be provided along with their 95% CIs. For incidence rates, 
the relative risks, along with their 95% CIs, will be calculated using an exponential regression 
model for lifetime data (assuming constant hazards). 
Because of the distinct nature of hematologic and nonhematologic neoplasms, and the emerging 
signals of new primary malignancies for IMiDs, analyses of new primary malignancies may be 
performed separately for hematologic and nonhematologic malignancies.
13.1.7 Control of Overall Type I Error for the Primary Endpoint of PFS
Type I error is controlled by the primary endpoint, because only 1 test is planned for primary 
endpoint of PFS at a 2-sided level of 0.20.
13.2
Determination of Sample Size
Approximately 120 patients will be enrolled. The primary endpoint is PFS with assumption of an 
HR of 0.62 (median PFS, 7.3 months for ixa+dex vs 4.5 months for pom+dex). The analysis of 
PFS will be performed on the basis of approximately 81 PFS events in total (for 80% power at a 
2-sided 0.20 level of significance).
The PFS assumption for pom+dex is based on the PFS of 3.9 months (with a 95% CI of 3.5-4.6) for 
the subgroup of patients in the NIMBUS study with 2 prior lines who were lenalidomide refractory 
[45], with a higher value of 4.5 months chosen to be on the conservative side. The PFS assumption 
for ixa+dex is based on the PFS of 9.6 months in a similar population (2 prior lines, lenalidomide 
refractory), calculated on the basis of data from the 
 study as discussed above. Because this 
latter study had a smaller population and the PFS had a wider 95% CI (4.6-16.3) than the NIMBUS 
study, a more conservative value of 7.3 months was chosen.
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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. The CRO may also monitor the site remotely as described 
in the Monitoring Plan.
All aspects of the study and its documentation will be subject to review by the sponsor or designee, 
including but not limited to the Investigator’s Binder, study medication, subject medical records, 
informed consent documentation, documentation of subject authorization to use personal health 
information (if separate from the informed consent forms), 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 applicable local regulations and 
permitted by the IRB/IEC.
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 EC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the subject, or confound interpretation of primary study 
assessment. A Protocol Deviation Form or equivalent form should be completed by the site and 
signed by the sponsor or designee for any significant deviation from the protocol.
The procedure below applies to Japanese sites only. 
The investigator can deviate and change from the protocol for any medically unavoidable reason, 
for example, to eliminate an immediate hazard to study subjects, without a prior written agreement 
with the sponsor or a prior approval from IRB. In the event of a deviation or change, the principal 
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investigator should notify the sponsor and the head of the site of the deviation or change as well as 
its reason in a written form, and then retain a copy of the written form. When necessary, the 
principal investigator may consult and agree with the sponsor on a protocol amendment. If the 
protocol amendment is appropriate, the amendment proposal should be submitted to the head of 
the site as soon as possible and an approval from IRB should be obtained. The investigator should 
document all protocol deviations.
14.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the FDA, the United Kingdom Medicines and Healthcare 
products Regulatory Agency, the Pharmaceuticals and Medical Devices Agency of Japan). If the 
study site is contacted for an inspection by a regulatory body, the sponsor should be notified 
immediately. The investigator and institution guarantee access for quality assurance auditors to all 
study documents as described in Section 14.1.
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15.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, 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.
The rationale for the open-study design is primarily to reduce the treatment burden on study 
patients. A placebo control would require patients to ingest a large number of additional pills 
(23 additional placebo tablets per cycle for patients receiving pom+dex, and 41 additional placebo 
tablets per cycle for patients receiving ixa+dex). Furthermore, any QOL benefit attributed to 
taking oral medications during just 8 out of 28 days (ixa+dex arm) versus 22 out of 28 days 
(pom+dex arm) would be lost.
Pom+dex was selected as the control regimen for many reasons. Pom+dex is a US- and 
EU-approved treatment regimen for RRMM. Because the investigational regimen is an entirely 
oral therapy, the all-oral standard-of-care comparator of pom+dex provides a more balanced 
treatment burden between the 2 regimens than would a study where 1 regimen required periodic 
intravenous infusions. In addition, a comparison of ixa+dex to a single-agent comparator such as 
daratumumab would not allow for the characterization of the ixazomib contribution to the 
observed treatment effect, unlike the comparison of ixa+dex to pom+dex, in which the 
dexamethasone contribution would be similar in both treatment groups.
15.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable state and federal/local requirements 
of each participating region. The sponsor or designee will require documentation noting all names 
and titles of members who make up the respective IRB or IEC. If any member of the IRB or IEC 
has direct participation in this study, written notification regarding his or her abstinence from 
voting must also be obtained. Those American sites unwilling to provide names and titles of all 
members because of privacy and conflict of interest concerns should instead provide a 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 informed consent 
form, 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, informed consent form) reviewed; and state the approval date. In 
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addition, approval must be obtained from the Competent Regulatory Authority before 
commencement of the study and, in the case of a substantial amendment, before implementation of 
the amendment. The sponsor will ship drug/notify site once the sponsor has confirmed the 
adequacy of site regulatory documentation and, when applicable, the sponsor has received 
permission from competent authority to begin the trial. Until the site receives notification no 
protocol activities, including screening, may occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the informed consent 
form, 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 informed consent form, 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 informed consent form 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 informed consent form 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 
informed consent form and if applicable, the subject authorization form. The informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) must 
be approved by both the IRB or IEC and the sponsor before use.
The informed consent form, 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 informed consent 
form, 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 
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subject, or the subject’s legally acceptable representative, determines he or she will participate in 
the study, then the informed consent form and subject authorization form (if applicable) must be 
signed and dated by the subject, or the subject’s legally acceptable representative, at the time of 
consent and before the subject 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 informed consent 
form and subject authorization (if applicable) at the time of consent and before 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 informed consent form, 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 informed consent form, the signed subject authorization form 
(if applicable), and subject information sheet (if applicable) shall be given to the subject.
All revised informed consent forms 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 informed consent form.
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 [e]CRF).
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15.4
Publication, Disclosure, and Clinical Trial Registration Policy
15.4.1 Publication 
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
this section and the Clinical Study Site Agreement. In the event of any discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail.
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, Millennium 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 Millennium Policy/Standard. 
Millennium 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 Millennium and investigator/site contact information may be made public to support 
participant access to trials via registries. In certain situations/registries, Millennium 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 Millennium providing this information to callers must provide 
Millennium with a written notice requesting that their information not be listed on the registry site. 
15.4.3 Clinical Trial Results Disclosure
Millennium will post the results of clinical trials on ClinicalTrials.gov and 
www.clinicaltrialsregister.eu, as well as other publicly accessible websites (including the 
Millennium corporate site) and registries, as required by Millennium Policy/Standard, applicable 
laws, and/or regulations. 
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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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refractory multiple myeloma (MM-003): a randomised, open-label, phase 3 trial. Lancet Oncol 
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monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, 
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48. Lu J, Lu J, Chen W, Huo Y, Huang X, Hou J, et al. Clinical features and treatment outcome in 
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M, et al. Treatment of patients with relapsed/refractory multiple myeloma with lenalidomide 
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cytogenetic abnormalities and of previous therapies. Leukemia 2010;24(10):1769-78.
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52. Raab MS, Cavo M, Delforge M, Driessen C, Fink L, Flinois A, et al. Multiple myeloma: 
practice patterns across Europe. Br J Haematol 2016.
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53.DARZALEX (daratumumab) [prescribing information]. USPI. Horsham, PA: Janssen Biotech, 
Inc., November, 2015.
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59. Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. The European 
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60. Kvam AK, Wisloff F, Fayers PM. Minimal important differences and response shift in 
health-related quality of life; a longitudinal study in patients with multiple myeloma. Health & 
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61. Gimsing P, Carlson K, Turesson I, Fayers P, Waage A, Vangsted A, et al. Effect of 
pamidronate 30 mg versus 90 mg on physical function in patients with newly diagnosed 
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trial. Lancet Oncology 2010;11(10):973-82.
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health-related quality-of-life scores. Journal of Clinical Oncology 1998;16(1):139-44.
64. Kvam AK, Fayers PM, Wisloff F. Responsiveness and minimal important score differences in 
quality-of-life questionnaires: a comparison of the EORTC QLQ-C30 cancer-specific 
questionnaire to the generic utility questionnaires EQ-5D and 15D in patients with multiple 
myeloma. European Journal of Haematology 2011;87(4):330-7.
65. Cella D, Pickard AS, Duh MS, Guerin A, Mishagina N, Antra`s L, et al. Health-related quality 
of life in patients with advanced renal cell carcinoma receiving pazopanib or placebo in a 
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66. Stewart AK, Dimopoulos MA, Masszi T, Spicka I, Oriol A, Hajek R, et al. Health-Related 
Quality of Life Results From the Open-Label, Randomized, Phase III ASPIRE Trial 
Evaluating Carfilzomib, Lenalidomide, and Dexamethasone Versus Lenalidomide and 
Dexamethasone in Patients With Relapsed Multiple Myeloma. J Clin Oncol 2016.
67. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. American Journal of Clinical 
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68. Greipp PR, San Miguel J, Durie BG, Crowley JJ, Barlogie B, Blade J, et al. International 
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69. Rajkumar SV, Harousseau JL, Durie B, Anderson KC, Dimopoulos M, Kyle R, et al. 
Consensus recommendations for the uniform reporting of clinical trials: report of the 
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70. Durie BG, Harousseau JL, Miguel JS, Blade J, Barlogie B, Anderson K, et al. International 
uniform response criteria for multiple myeloma. Leukemia 2006;20(9):1467-73.
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assessment of multiple myeloma. Leukemia 2009;23(1):3-9.
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CONFIDENTIAL
Appendix A
Updated Schedule of Events 
The previous, full Schedule of Events in effect before Amendment 06 and the PK Sampling Schedule completed as of Amendment 06 
are no longer followed and have been moved to Appendix L for reference only.
Study Procedures
Treatment Period (a)
Cycle X and Beyond, Day 1
of Each 28-day Cycle
EOT
30 Days After Last Dose or Before 
Start of New Line of Treatment
Window, ± 1 week 
Window, + 1 week
Informed consent (reconsent)
X (b)
Complete physical examination, including for PN (c,d)
X
Symptom-directed physical examination, including for PN (c,d)
X
Pregnancy test, Arm A (e)
X
Pregnancy test, Arm B (e) (increased frequency required per 
pomalidomide PI)
X
X
Hematology laboratory tests, Arm A (d,f,g)
X
X
Hematology laboratory tests, Arm B (d,f,g) (increased frequency required 
per pomalidomide SmPC)
X
X
Chemistry laboratory tests (d,f,g)
X
X
Arm A: ixazomib
Single dose of 5.5 mg on Days 1, 8, 15 
(if Cycle 1 dose tolerated)
Arm A: dexamethasone 20 mg (10 mg if aged ≥75 yr)
Days 1, 2, 8, 9, 15, 16, 22, 23
Arm A: dexamethasone, if 4 mg dexamethasone is the only dosage 
available and patient is aged ≥75 yr
12 mg on Days 1, 8, 15, and 22; and 
8 mg on Days 2, 9, 16, and 23
Arm B: pomalidomide
Days 1-21
Arm B: dexamethasone 40 mg (20 mg if aged ≥75 yr)
Days 1, 8, 15, 22
AE reporting (h)
Recorded from the signing of informed consent form through 30 days after last dose of 
study therapy
SAEs and serious pretreatment events collected from the signing of informed 
consent form through 30 days after last dose of study therapy
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CONFIDENTIAL
Study Procedures
Treatment Period (a)
Cycle X and Beyond, Day 1
of Each 28-day Cycle
EOT
30 Days After Last Dose or Before 
Start of New Line of Treatment
Window, ± 1 week 
Window, + 1 week
Concomitant medications/procedures
Recorded from the signing of informed consent form through 30 days after last dose of 
study therapy
NPM assessment
Continuous from start of study therapy administration until death or termination of 
study by sponsor
NPM: new primary malignancy; PI: package insert.
Follow this Schedule of Events at the start of the next full treatment cycle upon implementation of Amendment 06. Patients who do not continue treatment must 
complete the End of Treatment assessments, which should occur 30 days (+1 week) after the last dose of study drug or prior to the initiation of subsequent
antineoplastic therapy, whichever comes first.
(a) Tests and procedures should be performed on schedule, within a 1-week window for Day 1 of each cycle. Unless otherwise specified, occasional changes are 
allowable within an additional 2-day window for holidays, vacations, and other administrative reasons. If a visit or procedure cannot be performed within the 
window, then the Millennium project clinician or designee should be consulted. If the study schedule is shifted, assessments should be shifted to be aligned with 
the new schedule. Note that, except for hematology and chemistry laboratory samples (see footnote f below), all required tests and procedures for a specific visit 
should be done on the same day as the study visit. 
(b) Before dosing on Day 1 of the next full treatment cycle upon implementation of Amendment 06, patients must 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) Patients should be assessed and treated according to local standard of care. Collect and record only clinically significant findings as AEs in the eCRF.
(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 
extenuating circumstances (eg, 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 any of the 
following study procedures/assessments is missed because a site visit is done remotely, the study procedure/assessment is waived: symptom-directed physical 
examination, hematology, clinical chemistry.
(e) In Arm A, 3 serum pregnancy tests must be performed for women of childbearing potential. The Cycle 1 Day 1 pregnancy test may be collected up to 3 days 
before dosing and results must be available and negative before dosing. In Arm B, for women of childbearing potential, 2 pregnancy tests (with 1 or both being 
a serum test) must be performed before starting pom+dex and results must be available and negative before dosing—the first within 10 to 14 days before dosing 
and the second within 24 hours before dosing. Then testing must be performed weekly during the first month and monthly thereafter in women with regular 
menstrual cycles, or every 2 weeks (at Day 15) in women with irregular menstrual cycles. In Arm B at the EOT visit, the test must be a serum pregnancy test. The 
results of each test must be available and negative before the study therapy is administered. Pregnancy tests may also be repeated during the study upon request 
by IECs/IRBs or if required by local regulations.
(f) Hematology and chemistry laboratory samples will be collected locally and may be collected up to 3 days before Day 1 of each cycle or prior to dosing on Day 
1. For Cycles 1 and 2 in both arms, the laboratory samples may be collected 24 hours prior to dosing on Day 15 or before dosing on Day 15. In addition, for Arm 
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CONFIDENTIAL
B (pom+dex) only, hematology samples will be collected at Cycle 1 and at Cycle 2 Days 8 and 22. Samples may be collected 24 hours before, or prior to dosing 
on, Days 8 and 22. Laboratory reports must be reviewed by the investigator prior to dosing for all cycle visits, and clinical significance must be indicated. In 
addition, the investigator must assess any AEs or concomitant medication changes prior to dosing. Local laboratory evaluations and evaluation of SPEP and 
UPEP for confirmation of PD may be done more frequently at the investigator’s discretion (ie, for acute management of TEAEs).
(g) All central laboratory assessments are discontinued. Patients should be assessed and treated according to local standard of care using local laboratory evaluations. 
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.
(h) Patients should be assessed and treated per local standard of care. All AEs/SAEs will be recorded in the eCRF according to the criteria outlined in Section 12.0. 
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.
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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 informed consent form 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 informed consent form 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
Millennium will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, United States, and Japan), including the following:

Millennium, its affiliates, and licensing partners.

Business partners assisting Millennium, 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 Millennium 
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 Millennium, 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 
Millennium and other parties for the purposes described above.
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Appendix D
Revised IMWG Diagnostic Criteria for MM
Source: Rajkumar et al 2014 [55].
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Appendix E
ECOG Scale for Performance Status
Grade
Description
0
Normal activity. Fully active, able to carry on all predisease performance without restriction.
1
Symptoms but ambulatory. Restricted in physically strenuous activity, but ambulatory and able to 
carry out work of a light or sedentary nature (eg, light housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, but unable to carry out any work 
activities. Up and about more than 50% of waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair.
5
Dead
Source: Oken et al 1982 [67].
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Appendix F
ISS Staging Criteria 
ISS
Stage
Criteria
Stage I
Serum 2-microglobulin <3.5 mg/L
Serum albumin ≥3.5 g/dL
Stage II
Neither stage I nor stage III (a)
Stage III
Serum 2-microglobulin ≥5.5 mg/L 
Source: Greipp et al 2005 [68].
(a) There are 2 categories for stage II: serum ß2-microglobulin <3.5 mg/L but serum albumin <3.5 g/dL; or serum 
2-microglobulin 3.5 to <5.5 mg/L irrespective of the serum albumin level.
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Appendix G
IMWG Uniform Response Criteria for MM
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Source: Rajkumar et al 2011 [69] (adapted from Durie et al [70] and Kyle et al [71] with permission).
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Appendix H
EORTC QLQ-C30 (version 3)
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Appendix I
EORTC QLQ-MY20
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Appendix J
EQ-5D-5L
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CONFIDENTIAL
Appendix K
Site HU Data Collection Form
CCI
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Te
on-Commercial Use Only and Subject to the Applica


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CCI
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Te
rcial Use Only and Subject to the Applicable T


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CCI
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Te
Non-Commercial Use Only and Subject to the Applicable T


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Appendix L
Previous, Full Schedule of Events and PK Sampling Schedule (Schedules Before Implementation of 
Amendment 06)
Previous Schedule of Events
Study Procedures
Screening
Treatment Period (a)
EOT (b)
Follow-up (c)
28-Day Cycles
PFS
OS
Cycle
C1
C2 (d)
C3
C4 and 
Beyond
30 days 
after last 
dose or 
before start 
of new line 
of 
treatment
Every 4 wk, 
Until PD or 
Subsequent 
Therapy
Every 12 
wk, After 
PD or 
Subseque
nt 
Therapy
Days
-28 to -1
1
8
15
22
1
8
15
22
1
1
Window
±2 days
+1 wk
±1 wk
±1 wk
Informed consent
X
Inclusion/exclusion criteria (e)
X
Demographics
X
Complete medical history and disease staging
X
Complete physical examination, including for 
PN
X
X
Symptom-directed physical examination, 
including for PN
X
X
X
X
X
ECOG performance status
X
X
X
X
X
X
Vital signs (f)
X
X
X
X
X
X
Height (cm)
X
Weight (kg)
X
X
X
X
X
X
12-Lead ECG 
X
Footnotes are on last table page.
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Previous Schedule of Events (continued)
Study Procedures
Screening
Treatment Period (a)
EOT (b)
Follow-up (c)
28-Day Cycles
PFS
OS
Cycle
C1
C2 (d)
C3
C4 and Beyond
30 days 
after last 
dose or 
before 
start of 
new line of 
treatment
Every 
4 wk, Until 
PD or 
Subsequen
t Therapy
Every 12 
wk, After 
PD or 
Subsequen
t Therapy
Days
-28 to -1
1
8
15
22
1
8
15
22
1
1
Window
± 2 days
+1 wk
± 1 wk
± 1 wk
EORTC QLQ-C30 (g)
X
X
X
X
X
X
X
EORTC QLQ-MY20 (g)
X
X
X
X
X
X
X
EQ-5D-5L (g)
X
X
X
X
X
X
X
X
HU assessment (g)
X
X
X
X
X
X
Imaging disease assessment
Bone (h)
X
Soft-tissue plasmacytoma (i)
X
X
X (& every 3 
cycles 
hereafter)
Investigator’s assessment of disease 
response/status 
X
X
X
X
X
X
Determination of dose escalation
X (d)
Footnotes are on last table page.
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Previous Schedule of Events (continued)
Study Procedures
Screening
Treatment Period (a)
EOT (b)
Follow-up (c)
28-Day Cycles
PFS
OS
Cycle
C1
C2 (d)
C3
C4 and Beyond
30 days 
after last 
dose or 
before 
start of 
new line of 
treatment
Every 
4 wk, Until 
PD or 
Subsequen
t Therapy
Every 12 
wk, After 
PD or 
Subsequen
t Therapy
Days
-28 to -1
1
8
15
22
1
8
15
22
1
1
Window
±2 days
+1 wk
±1 wk
±1 wk
Samples/Laboratory Assessments
Pregnancy test, Arm A (j)
X
X
X
Pregnancy test, Arm B (j) (increased frequency 
required per pom PI)
X
X
X
X
X
X
X
X
Hematology laboratory tests, Arm A (k)
X
X
X
X
X
X
X
X
X
Hematology laboratory tests, Arm B (k) 
(increased frequency required per pom SmPC)
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry laboratory tests (k)
X
X
X
X
X
X
X
LDH and β2-microglobulin
X
M-protein (SPEP)
X
X (l)
X
X
X
X
X
M-protein (UPEP [24-h urine])
X
X (l)
X
X
X
X
X
Serum free light chain assay
X
X (l)
X
X
X
X
X
Immunofixation: serum and urine (m)
X
X (l)
X
X
X
X
X
Quantification of immunoglobulins (n)
X
X (l)
X
X
X
X
X
BMA or biopsy for disease assessment (o)
X
Footnotes are on last table page.
CCI
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Property of Take
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C3
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15
15
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On
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U
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CONFIDENTIAL
Previous Schedule of Events (continued)
Study Procedures
Screening
Treatment Period (a)
EOT (b)
Follow-up (c)
28-Day Cycles
PFS
OS
Cycle
C1
C2 (d)
C3
C4 and Beyond
30 days 
after last 
dose or 
before start 
of new line 
of treatment
Every 
4 wk, Until 
PD or 
Subsequen
t Therapy
Every 12 
wk, After 
PD or 
Subsequen
t Therapy
Days
-28 to -1
1
8
15
22
1
8
15
22
1
1
Window
± 2 days
+1 wk
±1 wk
±1 wk
Study Therapy Administration
Arm A: ixazomib 
Single dose of 4 mg on 
Days 1, 8, 15
Single dose of 5.5 mg on Days 1, 8, 15 
(if Cycle 1 dose tolerated)
Arm A: dexamethasone 20 mg 
(10 mg if aged ≥75 yr) 
Days 1, 2, 8, 9, 15, 16, 22, 23 of each 28-day cycle
Arm A: dexamethasone, if 4 mg 
dexamethasone is the only dosage 
available and patient is aged ≥75 yr
12 mg dexamethasone on Days 1, 8, 15, and 22 of every 28-day cycle; 
and 
8 mg dexamethasone on Days 2, 9, 16, and 23 of every 28-day cycle
Arm B: pomalidomide 
Days 1-21 of each 28-day cycle
Arm B: dexamethasone 40 mg 
(20 mg if aged ≥75 yr) 
Days 1, 8, 15, 22 of each cycle
AE reporting (r)
Recorded from the signing of informed consent form through 30 days after last dose of study therapy
SAEs and serious pretreatment events collected from the signing of informed consent form through 30 days 
after last dose of study therapy
Concomitant medications/procedures
Recorded from the signing of informed consent form through 30 days after last dose of study therapy
NPM assessment
Continuous from start of study therapy administration until death or termination of study by sponsor
Survival
X
Subsequent therapy
X
Footnotes are on following page.
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BMA: bone marrow aspirate; C: study cycle; LDH: lactate dehydrogenase; NPM: new primary malignancy; PI: package insert; PN: peripheral neuropathy; SmPC: Summary of 
Product Characteristics.
(a) Tests and procedures should be performed on schedule, within a 2-day window for Day 1 of each cycle. Unless otherwise specified, occasional changes are allowable within an 
additional 2-day window for holidays, vacations, and other administrative reasons. If a visit or procedure cannot be performed within the window, then the Millennium project 
clinician or designee should be consulted. If the study schedule is shifted, assessments should be shifted to be aligned with the new schedule. Note that, except for hematology and 
chemistry laboratory samples (see footnote k below), all required tests and procedures for a specific visit should be done on the same day as the study visit.
(b) Before discontinuing a patient from treatment for PD, the Progressive Disease Review form must be completed as soon as possible, permitting pertinent data to be confirmed by 
a Millennium project clinician or designee. 
(c) Patients who have stopped treatment for any reason other than PD will first enter the PFS Follow-up period. Patients who have PD while on study therapy, during the Treatment 
period, will skip the PFS Follow-up period and will enter directly into the OS Follow-up period. Patients in the PFS Follow-up period who have PD or start subsequent anticancer 
therapy will end PFS Follow-up and will enter into the OS Follow-up period. See Figure 6.b for a detailed flow chart for both follow-up periods.
(d) All Arm A patients who tolerated the 4 mg dose of ixazomib in Cycle 1 (see Section 6.1.2) should dose escalate to 5.5 mg on Cycle 2 Day 1. If the patient qualified for escalation 
but escalation was inadvertently missed at Cycle 2 Day 1, escalation at a later cycle may be allowed after consultation with the Millennium project clinician or designee; in that case, 
the patient must have Day 15 hematology samples collected in addition to Day 1 hematology samples. Patients who dose escalate to 5.5 mg must receive the first cycle of the 5.5 mg 
dose in the clinic rather than taking it at home.
(e) Confirmation of patient eligibility by a Millennium project clinician or designee is required before randomization. Cycle 1 Day 1 should be no later than 7 days after the date of 
randomization. 
(f) Measurement of blood pressure and heart rate is to be performed at screening, along with temperature and respiratory rate. During the Treatment period, measurement of blood 
pressure and heart rate is to be performed; temperature and respiratory rate are collected only as clinically indicated.
(g) Patient-reported outcomes and HU assessment (eg, number of medical encounters) should be completed on the same day as the study visit, before any other study procedures are 
performed or study therapy is administered. At any time point when a clinic visit is not otherwise required (ie, during the OS Follow-up period), the EQ-5D-5L questionnaire may be 
administered over the telephone by trained site staff.
(h) Imaging to assess status of bone disease will be done at Screening (within 8 weeks before randomization) 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. 
(i) Imaging to assess extramedullary disease will be done at Screening (within 8 weeks before randomization) 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 1 Day 1 and every 3 cycles thereafter, unless the screening 
assessment is completed before 14 days prior to Cycle 1 Day 1; then the next assessment can be on Cycle 3 Day 1.
(j) In Arm A, 3 serum pregnancy tests must be performed for women of childbearing potential. The Cycle 1 Day 1 pregnancy test may be collected up to 3 days before dosing and 
results must be available and negative before dosing. In Arm B, for women of childbearing potential, 2 pregnancy tests (with 1 or both being a serum test) must be performed before 
starting pom+dex and results must be available and negative before dosing—the first within 10 to 14 days before dosing and the second within 24 hours before dosing. Then testing 
must be performed weekly during the first month and monthly thereafter in women with regular menstrual cycles, or every 2 weeks (at Day 15) in women with irregular menstrual 
cycles. In Arm B at the EOT visit, the test must be a serum pregnancy test. The results of each test must be available and negative before the study therapy is administered. Pregnancy 
tests may also be repeated during the study upon request by IECs/IRBs or if required by local regulations.
(k) Hematology and chemistry laboratory samples will be collected locally and may be collected up to 3 days before Day 1 of each cycle or prior to dosing on Day 1. For Cycles 1 and 
2 in both arms, the laboratory samples may be collected 24 hours prior to dosing on Day 15 or before dosing on Day 15. In addition, for Arm B (pom+dex) only, hematology samples 
will be collected at Cycle 1 and at Cycle 2 Days 8 and 22. Samples may be collected 24 hours before, or prior to dosing on, Days 8 and 22. Laboratory reports must be reviewed by the 
investigator prior to dosing for all cycle visits, and clinical significance must be indicated. In addition, the investigator must assess any AEs or concomitant medication changes prior 
to dosing. Local laboratory evaluations and evaluation of SPEP and UPEP for confirmation of PD may be done more frequently at the investigator’s discretion (ie, for acute 
management of TEAEs). Clinical laboratory evaluations for disease assessments (SPEP, UPEP, serum free light chain, immunofixation, and immunoglobulin) must be sent to the 
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central laboratory for evaluation until the data cutoff date for the study analysis has occurred. At that time, all central efficacy and investigator assessments for protocol purposes will 
be stopped and not recorded in the eCRF—namely, PK, SPEP, UPEP, serum free light chain, 
, serology, C-reactive protein, immunofixation, immunoglobulin, and 
LDH/albumin/β2-microglobulin at screening.
(l) If the screening test was performed more than 14 days before the first dose (Cycle 1 Day 1), the test will be repeated before dosing. The test closest to the first dose will be 
considered Baseline. Note that 24-hour urine collection is permitted before screening if it is part of standard clinical practice at the site.
(m) Note that Cycle 1 Day 1 dosing may proceed if MM isotype testing has been submitted to, but not yet analyzed at, the central laboratory. Immunofixation to also 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). 
Note that 24-hour urine collection is permitted before screening if it is part of standard clinical practice at the site.
(n) Blood samples for IgM, IgG, and IgA will be obtained at Screening and throughout the study at the time points specified. If the screening test was performed more than 14 days 
before the first dose (Cycle 1 Day1), the test will be repeated before dosing. The test closest to the first dose will be considered Baseline. Quantitative IgD and IgE will be done at 
Screening (and Baseline if needed) 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 for 
IgG and IgA. 
(o) To be performed at a local laboratory to assess disease status at Baseline and 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 bone marrow aspirate or biopsy drawn prior to consent is acceptable for the Baseline assessment provided 
that it is collected within 42 days before the first dose.
(p) 
(q) 
.
(r) When peripheral neuropathy occurs, each subsequent monthly evaluation will record the grade of peripheral neuropathy at that visit. (This is in contrast to other AEs where only 
increases in grade are recorded until the maximum grade is reached and then followed at that grade until complete resolution or return to Baseline.) Peripheral neuropathy will be 
followed monthly until: 1) resolution of peripheral neuropathy, 2) the start of a second-line alternative antineoplastic treatment, or 3) 6 months after PD has occurred, whichever 
occurs first.
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CONFIDENTIAL
Table A
Previous PK Sampling Schedule: Arm A (ixa+dex) Only (completed as of Amendment 06)
Cycle 1
Cycle 2
Cycles 3-4
Day 1
Day 15
Day 1
Day 15
Day 1
1 Hour Postdose 
(15 Minutes)
4 Hours Postdose 
(45 Minutes)
Any Time During 
Clinic Visit
Predose (a)
1 Hour Postdose 
(15 Minutes)
4 Hours Postdose 
(45 Minutes)
Any Time During 
Clinic Visit
Predose (a)
X
X
X
X
X
X
X
X
(a) All predose PK assessments should occur within 4 hours of dosing. If a predose sample is drawn from a patient and the patient does not receive a dose on that 
protocol visit day, a second predose sample does not need to be drawn on the subsequent visit where the dose is administered. All future visits should be done per the 
protocol. The exact date and time of each PK sample collection should be recorded in the source documents and eCRF.
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Appendix M Detailed Description of Amendments to Text
The primary sections of the protocol affected by the changes in Amendment 06 are indicated. The 
corresponding text has been revised throughout the protocol. 
Change 1: To note that the data cutoff date for the study analysis, which is the only planned formal 
analysis for this study, has now occurred.
The change occurs in Section 6.1.4 Statistical Analyses:
Initial 
wording:
Upon completion of this study, approximately 120 patients will have been enrolled 
globally. The PFS analysis will occur after approximately 81 PFS events have been 
observed (after approximately 28 months from first patient enrollment), for 80% 
power at a 2-sided 0.20 level of significance. Analysis of all secondary endpoints will 
occur at the same time as the PFS analysis; no further analyses are planned.
Amended 
or new 
wording:
Upon completion of this study, approximately 120 patients will have been enrolled 
globally. The PFSstudy analysis for PFS will occur after approximately 81 PFS 
events have been observed (after approximately 28 months from first patient 
enrollment), for 80% power at a 2-sided 0.20 level of significance. Analysis of all 
secondary endpoints will occur at the same time as the PFSthis study analysis, which 
is the only planned formal analysis for this study; no further formal analyses are 
planned. Long-term safety data collected after the data cutoff date for the study 
analysis will be summarized descriptively in a clinical study report addendum.
Rationale for Change: To clarify aspects of the study analysis.
Change 2: To note that, now that the data cutoff date for the study analysis has occurred, all 
central efficacy and investigator assessments of response for protocol purposes are now 
discontinued. 
The primary change occurs in Section 9.4.12 Disease Response Assessment by Investigator:
Initial 
wording:
Patients will be assessed for disease response according to the IMWG uniform 
response criteria, version 2011 (see Appendix G), until the PFS endpoint has been met 
for this study. At that time, all central efficacy and investigator assessments of disease 
response for protocol purposes will be stopped.
Amended 
or new 
wording:
After the primary endpoint ofdata cutoff date for the study analysis (including for
PFS) has been metoccurred, all central efficacy and investigator assessments of 
response for protocol purposes will be discontinued; patients will be followed for 
survival and the appropriate data collected..
Rationale for Change: To note that the data cutoff date for the study analysis has now occurred.
Section 2.0 STUDY SUMMARY also contains this change. 
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Change 3: To note that, now that the data cutoff date for the study analysis has occurred, the 
objective and endpoint of the study has changed to solely continue to collect long-term safety data.
The primary change occurs in Section 5.0 STUDY OBJECTIVES AND ENDPOINTS and Section 
6.1.3 Study Assessments:
Added 
text:
[Section 5.0]
As of Amendment 06, the objective and endpoint are to continue to collect 
long-term safety data from patients who are continuing on ixazomib and 
dexamethasone or pomalidomide and dexamethasone because of continuing 
clinical benefit. Data collection for all other study objectives and endpoints is
complete and no further formal analyses will be conducted. However, the 
original lists of objectives and endpoints are retained below for reference only.
Added 
text:
[Section 6.1.3]
Upon implementation of Amendment 06, data collection requirements will be 
limited to collection of AEs and SAEs. All other study assessments are no longer 
required. All central laboratory assessments are discontinued. Quality of life 
and HU assessments are discontinued. Patients will not be followed for the PFS 
or OS follow-up periods, because PFS and OS data are no longer being collected.
Rationale for Change: To clarify the study objective and endpoint at this point in the study.
The changes also occur in the following sections:

Section 2.0 STUDY SUMMARY
Change 4: To note that as of the current amendment, now that the data cutoff date for the study 
analysis has occurred, only patients who continue to demonstrate clinical benefit but have no 
access to study drugs other than staying in the study may stay in the study.
The primary change occurs in Section 6.1.3 Study Assessments, Section 9.8 Withdrawal of 
Patients From Study, and Section 9.9 Study Closure:
Added 
text:
[Section 6.1.3]
Only patients who continue to demonstrate clinical benefit but who do not have 
other means of access to the study drugs will continue on the study. As no 
further formal statistical analyses will be performed, only assessments 
contributing to long-term safety data are required. Most study assessments 
besides safety are discontinued to ease the burden of protocol-mandated 
assessments on patients.
Patients continuing their current study treatment may do so until such time as 
other means of accessing the study drugs are arranged. When possible, patients 
should complete an EOT visit and transition onto an alternative supply of (eg, 
commercially available) ixazomib or pomalidomide, as well as dexamethasone, 
or onto another standard of care treatment. Discontinued patients will be 
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treated by their physician per local standard of care.
Initial 
wording:
[Section 9.8]
The consequence of study withdrawal is that no new information will be collected 
from the withdrawn patient and added to the existing data or any database. However, 
every effort will be made to follow all patients for safety.
Amended 
or new 
wording:
[Section 9.8]
Upon implementation of Amendment 06, PFS and OS follow-up will no longer 
be performed. Patients will now complete the study immediately following the 
EOT visit. The consequence of study withdrawal is that no new information will be 
collected from the withdrawn patient and added to the existing data or any database.
However, every effort will be made to follow all patients for safety.
Deleted 
wording:
[Section 9.7 and Section 9.9]
Patients remaining on study drug at the time of study closure (whether after 
completion of the study analysis or any other reason) will be provided continued 
access to study drug by the sponsor as long as they are receiving clinical benefit, either 
through commercial drug supply or through continued treatment in another extension 
or rollover study.
[Section 9.7]
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 will remain in the study for 
posttreatment assessments as outlined in the Schedule of Events (Appendix A) until 
PD occurs.
Rationale for Change: To clarify which patients may remain on study at this point.
The following sections also contain this change:

Section 2.0 STUDY SUMMARY

Section 9.4.12 Disease Response Assessment by Investigator

Section 9.5 Completion of Study Treatment (for Individual Patients)

Section 9.7 Discontinuation of Treatment With Study Therapy

Section 9.9 Study Closure
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Change 5: To clarify that, as of the current amendment, the reason for a patient’s treatment 
discontinuation must be recorded in the eCRF but no approval by the sponsor is required to 
discontinue treatment.
The primary change occurs in Section 9.7 Discontinuation of Treatment With Study Therapy:
Initial 
wording:
Discontinuation of treatment with study therapy is to be reviewed and confirmed by 
the Millennium project clinician or designee.
Amended 
or new 
wording:
The reason for treatment discontinuation must be recorded in the eCRF but no 
approval is required.
Discontinuation of treatment with study therapy is to be reviewed and confirmed by 
the Millennium project clinician or designee. 
Rationale for Change: To clarify aspects of deciding to discontinue a patient’s treatment at this 
point in the study.
The following sections also contain this change:

Section 9.4.12 Disease Response Assessment by Investigator

Section 9.5 Completion of Study Treatment (for Individual Patients)
Change 6: To clarify that local laboratory evaluations are to be used henceforth.
The primary change occurs in Section 9.4.15.1 Clinical Chemistry and Hematology:
Added 
text:
Upon implementation of Amendment 06, centralized clinical laboratory 
evaluations are no longer required and local laboratories are to be used. Local 
laboratory evaluations should be entered into the eCRF only if required to 
understand 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. These 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.
Rationale for Change: To clarify that central laboratory assessments are discontinued at this 
point in the study.
Section 9.4.15.2 Clinical Laboratory Evaluations for Disease Assessments also contains this 
change.
Change 7: To simplify the Schedule of Events to reflect the other changes noted.
The change occurs in Appendix A Updated Schedule of Events:
Descripti
on of 
changes:
SOE changed to retain only the following rows:

Informed consent (reconsent).

Complete physical examination.
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
Symptom-directed physical examination.

Pregnancy tests.

Hematology and chemistry laboratory tests.

Study drug dosing.

AE reporting.

Concomitant medications/procedures reporting.

NPM assessment.
SOE changed to retain only the following columns:

Cycle X Day 1; window now changed from ± 2 days to ± 1 week.

EOT; window remains the same at +1 week.
Rationale for Change: To describe simplification of the Schedule of Events at this point in the 
study.
Change 8: To clarify that PK sample collection is now complete.
The change occurs in Section 9.4.18 PK Samples and Measurements:
Added 
text:
Upon implementation of Amendment 06, PK sample collection will be 
considered complete and no additional PK samples will be collected or 
quantified.
Rationale for Change: To clarify that PK sample collection is complete at this point in the study.
Change 9: To clarify that the previous, full Schedule of Events and the now-completed PK 
sampling schedule have been moved to a new appendix (Appendix L) for reference only.
The primary change occurs in a new Appendix L Previous, Full Schedule of Events and PK 
Sampling Schedule (Schedules Before Implementation of Amendment 06):
Added 
text:
[SOE and Table A in Appendix A now moved to a new Appendix L and labeled 
“Previous”]
Appendix L
Previous, Full Schedule of Events and PK Sampling Schedule 
(Schedules Before Implementation of Amendment 06)
…
Previous Schedule of Events
…
Table A
Previous PK Sampling Schedule: Arm A (ixa+dex) Only
(completed as of Amendment 06)
…
Rationale for Change: To retain previous study conduct information for reference.
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The following sections also contain this change:

Section 6.1.3 Study Assessments

Section 9.4 Study Procedures

Section 9.4.4 Physical Examinations

Section 9.4.6 ECOG Performance Status

Section 9.4.7 Vital Signs

Section 9.4.8 Height and Weight

Section 9.4.10 QOL and HU Assessments

Section 9.4.10.1 QOL

Section 9.4.10.2 HU

Section 9.4.15.1 Clinical Chemistry and Hematology

Section 9.4.15.2 Clinical Laboratory Evaluations for Disease Assessments

Section 9.4.18 PK Samples and Measurements
Change 10: Identify, as needed, text in the protocol that is no longer applicable as of the current 
amendment, now that the data cutoff date for the study analysis has occurred.
The primary change occurs in Section 6.1.3.1 Assessments During the Treatment Period and 
Section 6.1.3.2 Assessments During the Follow-up Periods: PFS and OS
Added 
text:
[Section 6.1.3.1]
Assessments Effective Only Before Amendment 06
…
Assessments Still in Effect as of Amendment 06
…
[Section 6.1.3.2]
The following section describes the study design before Amendment 06 was 
implemented and is no longer relevant after that time but is retained below for 
reference only.
…
Figure 6.a
Flow of Patients Through Follow-up Periods After the EOT Visit
(Only in Effect Before Amendment 06)
…
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Rationale for Change: To clarify protocol text that is no longer relevant at this point in the study.
The following sections also contain this change:
!
Section 9.4.6 ECOG Performance Status
!
Section 9.4.7 Vital Signs
!
Section 9.4.8 Height and Weight
!
Section 9.4.10 QOL and HU Assessments
!
Section 9.4.10.1 QOL
!
Section 9.4.10.2 HU
!
Section 9.4.11 Imaging Disease Assessment
!
Change 11: To add flexibility in study conduct in unavoidable circumstances (eg, the COVID-19 
pandemic).
The primary change occurs in Section 8.10.1.3 Storage, Handling, and Accountability, 9.4 Study 
Procedures, and 14.1 Study-Site Monitoring Visits:
Added 
text:
[Section 8.10.1.3]
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 study drug 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.
…
In case of extenuating circumstances that prevent a patient from attending the 
study site (eg, the COVID-19 pandemic), drug packs and dosing diaries 
should be returned at the next available on-site clinic visit.
…
[Section 9.4]
In acknowledgement of hospital, local, state, or national government 
restrictions, or other site-related factors caused by unavoidable circumstances 
(eg, 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 
CCI
Property of Takeda: For Non-Commercial Use On
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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.
If a patient misses an in-person study visit, the investigator/study team staff will 
speak directly with the patient by telephone or other medium (eg, a 
computer-based video communication) during each visit window to assess 
subject safety and overall clinical status. During this contact with the patient, the 
study site physician or other qualified site staff should at minimum conduct AE 
collection and an assessment of clinical symptoms. Other study assessments may 
be collected remotely as is feasible and may involve audio or video recording. 
Assessments/procedures that cannot be completed during the protocol-specified 
window because a site visit is done remotely (ie, symptom-directed physical 
examination, hematology, clinical chemistry) are waived.
…
[Section 14.1]
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 applicable local regulations and permitted by the 
IRB/IEC.
…
Rationale for Change: To account for unavoidable circumstances affecting study conduct.
This change also occurs in Appendix A Updated Schedule of Events.
Change 12: To indicate that, given the changes in the current amendment, patients remaining on 
study will need to be reconsented.
The change occurs in Section 9.4.1 Informed Consent:
Added 
text:
As of Amendment 06, 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.
Rationale for Change: To clarify the need for reconsenting.
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Change 13: Update language about management of clinical events in patients receiving ixazomib.
The change occurs in Section 8.8.1 Ixazomib:
Initial 
wording:
Erythematous Rash With or Without Pruritus
…
The rare risks of Stevens-Johnson syndrome, toxic epidermal necrolysis, drug 
reaction with eosinophilia and systemic symptoms (DRESS syndrome), and 
pemphigus vulgaris have been reported in oncology studies when ixazomib was given 
with concomitant medications that are known to cause rash (eg, Bactrim, 
lenalidomide, aspirin), and/or in the setting of confounding treatment-emergent 
adverse events (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. 
Additional information regarding these reactions can be found in the IB.
Thrombocytopenia
Blood counts should be monitored regularly 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 Section 8.4.3). Therapy can be reinitiated at a reduced 
level upon recovery of platelet counts. A rare risk is thrombotic thrombocytopenic
purpura, a rare blood disorder where blood clots form in small blood vessels
throughout the body characterized by thrombocytopenia, petechiae, fever, or possibly 
more serious signs and symptoms. Thrombotic thrombocytopenic purpura should be 
managed symptomatically according to standard medical practice.
…
Transverse Myelitis
One case of transverse myelitis has been reported in a patient receiving 
ixazomib+LenDex twice weekly, given for 16 cycles, followed by 4 complete cycles 
of ixazomib only in the maintenance phase (the patient received 2 additional doses 
beyond the 4 full cycles). During a break in therapy (Oct-Dec 2013) the patient 
experienced progressive neurologic deterioration. The event of transverse myelitis 
was diagnosed 1 day after the 22nd cycle of ixazomib maintenance was initiated. 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 contributed to the transverse myelitis cannot be excluded. Transverse myelitis 
should be managed according to standard medical practice.
…
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Amended 
or new 
wording:
Erythematous Rash With or Without Pruritus
…
The rare risks of Stevens-Johnson syndrome, toxic epidermal necrolysisTEN, 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 
treatment-emergent adverse events (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. 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 Section 8.4.3). Therapy can be reinitiated at a reduced 
level upon recovery of platelet counts. A rare risk isThrombotic microangiopathy 
(TMA), including thrombotic thrombocytopenicthrombocytopenia purpura (TTP), 
a and hemolytic uremic syndrome (HUS), are rare, serious blood disorder 
wheredisorders that cause low levels of platelets and red blood cells and result in
blood clots form in small blood vessels throughout the body characterized by 
thrombocytopenia, petechiae, fever, or possibly more serious signs and symptoms. 
Thrombotic thrombocytopenic purpura. 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 symptomatically according to standard medical practice.
…
Transverse Myelitis
One case of transverse myelitis has been reported in a patient receiving 
ixazomib+LenDex twice weekly, given for 16 cycles, followed by 4 complete cycles 
of ixazomib only in the maintenance phase (the patient received 2 additional doses 
beyond the 4 full cycles). During a break in therapy (Oct-Dec 2013) the patient 
experienced progressive neurologic deterioration. The event of transverse myelitis 
was diagnosed 1 day after the 22nd cycle of ixazomib maintenance was initiated
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 contributed to 
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the transverse myelitis cannot be excluded. Transverse myelitis should be managed 
according to standard medical practice.
…
Rationale for Change: To add information currently available around clinical events.
Change 14: To clarify details about ixazomib packaging, handling, and storage guidelines.
The primary change occurs in Section 8.1 Investigational Therapy: Ixazomib Administration (Arm 
A), Section 8.10.1.3 Storage, Handling, and Accountability, and Section 8.10.1.1 Preparation, 
Reconstitution, and Dispensation:
Added 
text:
[Section 8.1]
…
Refer to Section 8.10.1.3 and the Study Manual for additional instructions 
regarding study therapy administration.
…
Section 8.10.1.3
On receipt at the investigative site, ixazomib should remain in the blister pack 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 Millennium. Expiry extensions will be communicated 
accordingly with updated documentation to support the extended shelf life.
…
Initial 
wording:
[Section 8.10.1.1]
Ixazomib is dispensed in blisters in a child-resistant carton. For the 2.3, 3.0, 4.0, and 
5.5 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.
…
Amended 
or new 
wording:
[Section 8.10.1.1]
Ixazomib is dispensed in blistersa blister pack in a child-resistant carton. For the 2.3, 
3.0, 4.0, and 5.5 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 
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information.
…
Rationale for Change: To add clarification to this protocol.
Change 15: To clarify that PFS and OS data will be analyzed using unstratified tests, among 
others.
The change occurs in Section 13.1.3.1 Analyses for Primary Efficacy Endpoint and 13.1.3.2
Analyses of Secondary Efficacy:
Initial 
wording:
[Section 13.1.3.1]
…
A 2-sided, stratified log-rank test will be used to compare the treatment groups with 
respect to PFS at a 2-sided alpha level of 0.20. In addition, an unadjusted stratified
Cox model will be used to estimate the HR and its 80% and 95% CIs for the treatment 
effect. The KM survival curves and KM medians (if estimable), along with their 
2-sided 95% CIs, will also be provided for each treatment group. 
[Section 13.1.3.2]
OS will be analyzed on the basis of the ITT population and is defined as the time from 
randomization to death from any cause. Patients without documentation of death at 
the time of analysis will be censored at the date last known to be alive. A 2-sided, 
unstratified log-rank test will be used to compare the treatment and control groups 
with respect to OS. In addition, an unadjusted stratified Cox model will be used to 
estimate the HR and its 80% and 95% CIs for the treatment effect. OS will be also 
tested at 2-sided alpha=0.2. The KM survival curves and KM medians (if estimable), 
along with their 95% CIs, will also be provided for each study group.
…
Amended 
or new 
wording:
[Section 13.1.3.1]
…
A 2-sided, stratifiedunstratified log-rank test will be used to compare the treatment 
groups with respect to PFS at a 2-sided alpha level of 0.20. In addition, an unadjusted 
stratifiedunstratified Cox model will be used to estimate the HR and its 80% and 
95% CIs for the treatment effect. The KM survival curves and KM medians (if 
estimable), along with their 2-sided 95% CIs, will also be provided for each treatment 
group. 
[Section 13.1.3.2]
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OS will be analyzed on the basis of the ITT population and is defined as the time from 
randomization to death from any cause. Patients without documentation of death at 
the time of analysis will be censored at the date last known to be alive. A 2-sided, 
unstratified log-rank test will be used to compare the treatment and control groups 
with respect to OS. In addition, an unadjusted stratifiedunstratified Cox model will 
be used to estimate the HR and its 80% and 95% CIs for the treatment effect. OS will 
be also tested at 2-sided alpha=0.2. The KM survival curves and KM medians (if 
estimable), along with their 95% CIs, will also be provided for each study group.
Rationale for Change: To provide correct information about statistical testing for this study.
Change 16: To add information about submitting SAE reports.
The primary change occurs in Section 10.2 Procedures for Recording and Reporting AEs and 
SAEs:
Added 
text:
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.
Rationale for Change: To assist in timely submission of SAE reports.
Change 17: To correct a typographical error and clarify that there is only 1 study analysis planned 
(and as such, no interim analyses).
The change occurs in Section 9.9 Study Closure:
Initial 
wording:

Determination of efficacy based on IA.
Amended 
or new 
wording:

Determination of efficacy based on IAthe study analysis.
Rationale for Change: To correct a typographical error.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


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SAP_001.pdf: 


Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A Phase 2, Randomized, Open-Label Study Comparing Oral Ixazomib/Dexamethasone 
and Oral Pomalidomide/Dexamethasone in Relapsed and/or Refractory Multiple Myeloma
NCT Number: NCT03170882
SAP Approve Date: 11 November 2019
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable (PPD) information 
or company confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.


1.0
TITLE PAGE
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: C16029
A Phase 2, Randomized, Open-Label Study Comparing Oral Ixazomib/Dexamethasone and 
Oral Pomalidomide/Dexamethasone in Relapsed and/or Refractory Multiple Myeloma
PHASE 2
Version: Final 1.0
Date: 11 November 2019
Prepared by:
Based on:
Protocol Version: Amendment 5
Protocol Date: 16 September 2019
PPD
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xazomib
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1.1
Approval Signatures
Electronic signatures can be found on the last page of this document.
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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..........................................................................................5
4.0
OBJECTIVES .................................................................................................................7
4.1
Primary Objective......................................................................................................7
4.2
Secondary Objectives.................................................................................................7
4.3
Safety Objective ........................................................................................................7
4.4
Exploratory Objective................................................................................................7
4.5
Study Design .............................................................................................................7
5.0
ANALYSIS ENDPOINTS...............................................................................................9
5.1
Primary Endpoint.......................................................................................................9
5.2
Secondary Endpoints .................................................................................................9
5.3
Safety Endpoint .........................................................................................................9
5.4
Exploratory Endpoint.................................................................................................9
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................10
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................11
7.1
General Principles....................................................................................................11
7.1.1
Study Definitions ...............................................................................................11
7.1.2
Definition of Study Days....................................................................................11
7.1.3
Definition of Study Visit Windows ....................................................................11
7.1.4
Conventions for Missing Adverse Event Dates...................................................11
7.1.5
Conventions for Missing Concomitant Medication Dates...................................12
7.2
Analysis Sets ...........................................................................................................13
7.2.1
Intent-to-Treat Population ..................................................................................13
7.2.2
Safety Population...............................................................................................13
7.3
Disposition of Subjects ............................................................................................14
7.4
Demographic and Other Baseline Characteristics.....................................................14
7.5
Medical History and Concurrent Medical Conditions...............................................15
7.6
Medication History and Concomitant Medications...................................................15
7.7
Study Drug Exposure and Compliance.....................................................................16
7.8
Efficacy Analysis.....................................................................................................16
7.8.1
Primary Efficacy Analysis..................................................................................17
7.8.2
Secondary Efficacy Analysis..............................................................................18
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Statistical Analysis Plan
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7.9
Pharmacokinetic/Pharmacodynamic Analysis/Biomarker Analysis ..........................19
7.9.1
Pharmacokinetic Analysis ..................................................................................19
7.9.2
Biomarker analysis.............................................................................................19
7.10
Other Outcomes Analyses of Patient-Reported Outcomes and Health Economics ....20
7.10.1 Patient Reported Outcomes (PROs)....................................................................20
7.10.2 Health Economics Analysis Using Medical Resource Utilization and Utility......23
7.11
Safety Analysis........................................................................................................23
7.11.1 Adverse Events ..................................................................................................23
7.11.2 Clinical Laboratory Evaluations .........................................................................25
7.11.3 Vital Signs .........................................................................................................26
7.11.4 12-Lead ECGs ...................................................................................................26
7.11.5 Other Observations Related to Safety.................................................................26
7.12
Changes in the Statistical Analysis Plan...................................................................27
8.0
REFERENCES..............................................................................................................28
LIST OF IN-TEXT TABLES
Table 7.a
Handling of Missing Assessment and Censoring for PFS Primary Analysis 
Based on FDA Guidance....................................................................................17
Table 7.b
Handling of missing assessment and censoring for PFS Sensitivity Analysis 
based on EMA guidance ....................................................................................18
Table 7.c
List of subgroups ...............................................................................................18
Table 7.d
Definition of Subscale Scores of EORTC QLQ-C30 ..........................................21
Table 7.e
Definition of Subscale Scores of EORTC QLQ-MY20.......................................21
LIST OF IN-TEXT FIGURES
Figure 4.a
Study Schema, from Randomization Through End of Therapy.............................8
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3.0
LIST OF ABBREVIATIONS
AE
adverse event
ANC
absolute neutrophil count
CI
confidence interval
CMH
Cochran-Mantel-Haenszel
CR
complete response 
Del
deletion
DOR
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EOT
End of Treatment (visit)
EQ-5D
EuroQol 5-Dimensional Health Questionnaire
FA
final analysis
FDA
United States Food and Drug Administration
GCP
Good Clinical Practice
HR
Hazard Ratio
HU
health utilization
IA
interim analysis
IDMC
independent data monitoring committee
IMiD
immunomodulatory drug
IMWG
International Myeloma Working Group
ITT
intent-to-treat
ixa+dex
ixazomib+dexamethasone (investigational study therapy, given in Arm A)
K-M
Kaplan-Meier
MedDRA
Medical Dictionary for Regulatory Activities
MID
minimally important difference
NCI
National Cancer Institute
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
ORR
overall response rate
OS
overall survival
PD
progressive disease (disease progression)
PFS
progression-free survival
PK
pharmacokinetic(s)
PN
peripheral neuropathy
pom+dex
pomalidomide+dexamethasone (control study therapy; given in Arm B)
PR
partial response 
PRO
patient-reported outcome
PSMB1
Proteasome subunit beta type-1
QLQ
Quality of Life Questionnaire (EORTC)
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Statistical Analysis Plan
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QOL
quality of life
QTc
rate-corrected QT interval (millisec) of electrocardiograph
RRMM
relapsed and/or refractory multiple myeloma
SAE
serious adverse event
SAP
statistical analysis plan
sCR
stringent complete response
SD
stable disease
T
translocation
TTP
time to progression
VGPR
very good partial response
WHO
World Health Organization
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4.0
OBJECTIVES
4.1
Primary Objective
The primary objective is to compare the effect of ixazomib+dexamethasone (ixa+dex) versus 
pomalidomide+dexamethasone (pom+dex) on progression-free survival (PFS) in Relapsed 
and/or Refractory Multiple Myeloma (RRMM) patients who have received at least 2 prior lines 
of therapy, including lenalidomide and a proteasome inhibitor, and are refractory to lenalidomide 
but not refractory to proteasome inhibitors.
4.2
Secondary Objectives
Secondary objectives are: 
!
To compare overall survival (OS) in patients treated with ixa+dex versus pom+dex.
!
To compare duration of response, overall response rate (ORR), time to response, and time to 
progression with ixa+dex versus pom+dex.
!
To obtain health-related quality of life (QoL) data related to physical functioning of patients 
treated with ixa+dex versus pom+dex. 
!
To assess health-related QoL by additional function and symptom domains of the European 
Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire 
(QLQ) Core 30 (C30) instrument and by the EORTC QLQ multiple myeloma module 
(MY20) and EuroQol 5-Dimensional Health Questionnaire (EQ-5D-5L) instruments in 
patients receiving ixa+dex versus those receiving pom+dex.
!
To evaluate health utilization (HU) by patients receiving ixa+dex versus those receiving 
pom+dex.
!
To collect plasma concentration-time data for ixazomib to contribute to population 
pharmacokinetic (PK) characterization of ixazomib and to conduct exposure-response 
analyses for patients receiving ixa+dex.
4.3
Safety Objective
The safety objective is to compare the safety/tolerability of ixa+dex to that of pom+dex.
4.4
Exploratory Objective
4.5
Study Design
This is a prospective open-label, randomized, 2-arm, multicenter phase 2 study of patients with 
RRMM who have received at least 2 prior lines of therapy. The 3 stratification factors are 
International Staging System stage (I or II vs III at study entry), prior lines of therapy (2 vs 3 or 
more), and age (<65 vs ≥65 years). Patients will be randomized to receive ixa+dex (Arm A) or 
CCI
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
s 
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Statistical Analysis Plan
11 November 2019
pom+dex (Arm B) in a 3:2 ratio until first confirmed progressive disease (PD) or unacceptable 
toxicities.
The study design is illustrated in Figure 4.a.
Figure 4.a
Study Schema, from Randomization Through End of Therapy
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Statistical Analysis Plan
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5.0
ANALYSIS ENDPOINTS
5.1
Primary Endpoint
The primary endpoint is PFS, defined as the time from randomization to the first occurrence of 
confirmed PD, as evaluated by the investigator, according to International Myeloma Working 
Group (IMWG) criteria, or death from any cause, whichever occurs first.
5.2
Secondary Endpoints
Secondary endpoints are:
!
OS, measured as the time from randomization to death from any cause.
!
ORR, defined as partial response (PR), very good PR (VGPR), or complete response (CR), as 
evaluated by an investigator according to IMWG criteria.
!
Duration of response, defined as the time from the first documentation of PR or better to first 
documentation of PD.
!
Time to response, defined as the time from randomization to the first documentation of PR or 
better. 
!
Time to progression (TTP), defined as the time from randomization to first documentation of 
PD.
!
Health-related QOL as measured by the physical domain of the EORTC QLQ-C30.
!
Health-related QOL as measured by other domains of the EORTC QLQ-C30, by the EORTC 
QLQ-MY20, and by the 5-level classification system of the EQ-5D-5L.
!
HU as measured by the number and duration of medical encounters.
5.3
Safety Endpoint
The safety endpoint is the safety/tolerability of ixa+dex versus pom+dex.
5.4
Exploratory Endpoint
CCI
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Statistical Analysis Plan
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6.0
DETERMINATION OF SAMPLE SIZE
Approximately 120 patients will be enrolled. The primary endpoint is PFS with assumption of an 
HR of 0.62 (median PFS, 7.3 months for ixa+dex vs 4.5 months for pom+dex). The analysis of 
PFS will be performed on the basis of approximately 81 PFS events in total (for 80% power at a 
2-sided 0.20 level of significance).
The PFS assumption for pom+dex is based on the PFS of 3.9 months (with a 95% CI of 3.5-4.6) 
for the subgroup of patients in the NIMBUS study with 2 prior lines who were lenalidomide 
refractory, with a higher value of 4.5 months chosen to be on the conservative side. The PFS 
assumption for ixa+dex is based on the PFS of 9.6 months in a similar population (2 prior lines, 
lenalidomide refractory), calculated on the basis of data from the 
 study as discussed in 
the protocol, Because this latter study had a smaller population and the PFS had a wider 95% CI 
(4.6-16.3) than the NIMBUS study, a more conservative value of 7.3 months was chosen.
CCI
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Statistical Analysis Plan
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7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
General Principles 
All statistical analyses will be conducted using SAS® Version 9.2, or higher.
Where appropriate, variables will be summarized descriptively by study visit. For the categorical 
variables, the count and proportions of each possible value will be tabulated by treatment group. 
The denominator for the proportion will be based on the number of subjects who provided non-
missing responses to the categorical variable. For continuous variables, the number of subjects 
with non-missing values, mean, median, SD, minimum, and maximum values will be presented 
by treatment. The Kaplan-Meier survival curves and 25th, 50th (median), and 75th percentiles 
will be provided along with their 95% CIs for time-to-event data.
Means and medians will be presented to 1 more decimal place than the recorded data. The 
standard deviations (SDs) will be presented to 2 more decimal places than the recorded data. 
Confidence intervals about a parameter estimate will be presented using the same number of 
decimal places as the parameter estimate.
All confidence intervals, statistical tests, and resulting P-values will be reported as 2-sided and 
will be assessed at α=0.05 significance level unless otherwise stated. P-values will be rounded to 
3 decimal places prior to assessment of statistical significance.
Baseline values are defined as the last observed value before the first dose of study medication. 
7.1.1
Study Definitions
7.1.2
Definition of Study Days
Study Day 1 is defined as the date on which a subject is administered their first 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 on the basis of the scheduled visit at which they are collected. These 
visit designators are predefined values that appear as part of the visit tab in the electronic case 
report form (eCRF). 
7.1.4
Conventions for Missing Adverse Event Dates
Adverse events with start dates that are completely or partially missing will be imputed as 
follows:

If month and year are known but day is missing.
–
If month and year are the same as month and year of first dose date, then impute to first 
dose date.
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Statistical Analysis Plan
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–
If month and year are different than month and year of first dose date, then impute to first 
date of the month.

If year is known but day and month are missing.
–
If year is same as year of 1st dose date, then 1st dose date will be used instead.
–
If year is different than year of 1st dose date, then 1st of January of the year will be 
imputed. 
–
If all is missing, then it is imputed with 1st dose date.
Imputing missing AE start date is mandatory. After the imputation, all imputed dates are checked 
against the stop dates to ensure the start date does not occur after stop date. If the imputed start date 
occurs after stop date, then keep the imputed date same as the stop date. Adverse events with stop 
dates that are partially missing will be imputed as follows:

If month and year are known but day is missing, the last day of the month will be imputed 

If year is known, but day and month are missing,
–
If YYYY < year of last dose, then 31st of December will be imputed.
–
If YYYY = year of last dose, then 31st of December will be imputed.
–
If YYYY > year of last dose, then 1st of January will be imputed.
Imputing missing AE stop date is not mandatory if AE is regarded as ongoing. However if it is to 
be done, the rules are outlined above. If subject dies, then use death date for AE stop date. 
After the imputation, all imputed dates are checked against the start dates to ensure the stop date 
does not occur before start date. If the imputed stop date occurs prior to start date, then keep the 
imputed date the same as the start date. 
7.1.5
Conventions for Missing Concomitant Medication Dates
Concomitant therapies with start dates that are completely or partially missing will be analyzed as 
follows:

If month and year are known, but day is missing, then impute day to first of the month.
–
If year is known, but day and month are missing, then 1st of January of the year will be 
imputed.

If all is missing, then impute date to Date of Birth (DOB).
–
If DOB is not available but age is available, then estimate DOB by using screening date 
and age (age = screening date – DOB).
Concomitant therapies with stop dates that are completely or partially missing will be analyzed as 
follows:

If “ongoing” is checked, no imputation is necessary.
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Statistical Analysis Plan
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
If month and year are known but day is missing, the last day of the month will be imputed.

If year is known, but day and month are missing, 
–
If YYYY < year of last dose, then 31st of December will be imputed.
–
If YYYY = year of last dose, then 31st of December will be imputed.
–
If YYYY > year of last dose, then 1st of January will be imputed.

If all is missing, then impute date to 31st of December in the year of last dose.
Imputing missing concomitant therapies is optional. However if it is to be done, the rules are 
outlined above. If subject dies, then use death date for concomitant therapies stop date. After the 
imputation, all imputed dates are checked against the start dates to ensure stop date does not occur 
before start date. If the imputed stop dates occurs prior to start date, then keep the imputed date 
same as the start date.
The imputation rules for missing/partial start dates of subsequent therapies are as follows:

When month and year are present and the day of the month is missing,
–
If the month and year of the start date are the same as the month and year of treatment 
termination, the day of treatment termination is imputed, whichever is earliest.
–
If the start month and year are not the same as the month and year of treatment 
termination, the first day of the month is imputed.

When only a year is present, or no components of the start date are present, the date will not 
be imputed.
7.2
Analysis Sets
7.2.1
Intent-to-Treat Population
The Intent-to-Treat (ITT) population is defined as all patients who are randomized. Patients will 
be analyzed according to the treatment they were randomized to receive, regardless of any errors 
of dosing.
The ITT population will be used for the primary, secondary efficacy analyses, and resource 
utilization and patient reported outcome analysis. 
7.2.2
Safety Population 
The safety population is defined as all patients who receive at least 1 dose of any study drug. 
Patients will be analyzed according to the treatment they received. That is, those patients who are 
randomized to the ixazomib arm but receive the regimen in the control arm will be included in 
the control arm; those patients who are randomized to the control arm but receive the regimen in 
the ixazomib arm will be included in the active arm for safety analyses. More specifically, 
patients who received any dose of Ixazomib will be included in the Ixazomib arm, and patients 
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Statistical Analysis Plan
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who did not receive any dose of Ixazomib will be included in the control arm, regardless of their 
randomized treatment.
Safety population will be used for all safety related analyses such as adverse events (AEs), 
concomitant medication, laboratory tests, and vital signs.
7.3
Disposition of Subjects
Patient disposition includes the number and percentage of patients for the following categories: 
patients in each of the study populations, patients discontinued from the treatment, primary 
reason to discontinue from the treatment, patients on-going on treatment, patients participated in 
PFS follow-up/OS follow-up, patients discontinued from the study, and primary reason to 
discontinue from the study. All percentages will be based on the number of patients in the ITT 
population. 
A listing will present data concerning patient disposition.
7.4
Demographic and Other Baseline Characteristics
The ITT population will be used for the summaries by treatment groups in a descriptive fashion. 
Demographics
Demographic data at study entry to be evaluated will include age, sex, race, ethnicity, height, 
weight, and body surface area. Patient enrollment by region and country will also be summarized 
by treatment group and control group.
Disease Specific History
Characteristics include type of myeloma, Durie-Salmon stage, ISS, evidence of lytic bone and 
extramedullary disease will be summarized. 
Prior therapies will be summarized including the numbers and percentages of patients who had 
prior systemic therapy, prior transplant, prior surgery, and prior radiation therapy. This table will 
also include regimens and the number of lines of prior systemic therapies, best hematologic 
responses to prior systemic therapy, relapsed and/or refractory status to prior systemic therapy,
and months since progression from last prior systemic therapy and months since diagnosis. A by-
patient listing will also be presented for prior systemic therapy.
Months from diagnosis to the randomization date for each treatment is calculated by
randomization date - date of diagnosis 
365.25/12
Baseline disease characteristics
Baseline characteristics includes, but are not limited to, Eastern Cooperative Oncology Group 
(ECOG) performance status, type of myeloma, serum M-protein, urine M-protein, serum 
involved FLC and its ratio,
- microglobulin by category (i.e, <3.5, ≥3.5 and < 5.5, ≥5.5 
mg/L), serum creatinine and its category (≤2, >2 mg/dL), international staging system, creatinine 
2

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Statistical Analysis Plan
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clearance by category (ie, <30, ≥30 and <60, ≥60 and <90, ≥90 mL/min), lactate dehydrogenase, 
serum albumin by category (ie, <35, ≥35 g/L), corrected calcium, hemoglobin will be 
summarized. 
A patient’s type of myeloma is determined by heavy chain type (IgG, IgA, IgM, IgD, IgE, 
biclonal, other and unknown) and light chain type (kappa, lambda, and biclonal). In descriptive 
summaries, Myeloma type will be summarized separately for the heavy chain patients (according 
to IgG, IgA, IgM, IgD, IgE, biclonal, other) and for the light chain patients (according to kappa 
or lambda or biclonal). 
Creatinine clearance is to be calculated using the Cockcroft-Gault formulas as follows:
For male patients: 
For female patients:
Distribution of stratification factors will also be summarized.
Bone marrow evaluation and Extramedullary Disease Assessment at study entry 
The following categories of extent of disease at study entry will be summarized: bone marrow 
aspirate and bone marrow biopsy (number of patients, % plasma cells, marrow cellularity, 
Kappa/Lambda ratio), combined % plasma cells in bone marrow aspiration and biopsy (the 
higher value will be used if both available), skeletal survey results, number and percentage of 
lytic bone lesions present, number of extramedullary plasmacytoma present, and type of 
extramedullary plasmacytoma. 
7.5
Medical History and Concurrent Medical Conditions
General medical history such as cardiac risk, peripheral neuropathy at study entry will be 
summarized by treatment groups.
7.6
Medication History and Concomitant Medications
The prior medications will be listed for all patients by treatment groups. Prior regimens will be 
summarized by PI containing, IMiD containing, corticosteroids containing, cyclophosphamide 
containing, liposomal doxorubicin containing, platinum containing, akaylator containing, 
monoclonal containing, busulfan containing, and others.
The concomitant medications will be coded by preferred term using the World Health 
Organization (WHO) Drug Dictionary. The number and percentage of patients taking 
concomitant medications from the first dose through 30 days after the last dose of study 
medication will be tabulated by Anatomical Therapeutic Chemical (ATC) classification
[mg/dL])
creatinine
(serum
72
weight[kg]
)
Age[years]
(140
clearance
creatinine




[mg/dL])
creatinine
(serum
72
weight[kg]
)
Age[years]
(140
85
.0
clearance
creatinine





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pharmacological subgroup and WHO drug generic term for each treatment group in the safety 
population. Concomitant medication of antibacterials by indication, concomitant medication of 
antimetics, and prophylaxis in relation to herpes zoster will be summarized. By-patient listing 
will also be presented for concomitant medications.
Concomitant procedures will not be coded.
7.7
Study Drug Exposure and Compliance
A summary of drug exposure to Ixazomib/Pomalidomide will be characterized by number of 
treated cycles, numbers and percentages of patients who had ≥1, ≥2, …, and ≥18 treated cycles,
total amount of dose taken, total number of dose taken, extend pf exposure (days), relative dose 
intensity (%), by each treatment group in the safety population. Summary of numbers and 
percentages of patients using aggregate treated cycles, such as 1 to 3, 4 to 6, 7 to 9, 10 to 12, 13 
to 18, and ≥19 treated cycles, will also be presented in the same table. 
Exposure to dexamethasone will be characterized similar to exposure to Ixazomib/Pomalidomide 
by treatment group. 
Extent of exposure (days) is calculated as (last dose date of study drug – first dose date of study 
drug + 1).
A treated cycle is defined as a cycle in which the patient received any amount of any study drug
regimen. 
Relative dose intensity (%) is defined as 100 * (Total amount of dose taken) / (Total prescribed 
dose of treated cycles). Total prescribed dose of treated cycles for Ixazomib is calculated as: for 
all patients after C2D1, it equals number of prescribed doses per cycles * dose prescribed at 
enrollment (4 mg) * 1 cycle + dose prescribed at C2D1 (5.5 mg) * number of prescribed doses 
per cycle * (number of treated cycles - 1).
Relative dose intensity will be displayed as <50%, 50% - <= 80%, 80% - <100%, = 100%, and 
>100% by treatment group and for all patients. 
The duration of treatment at 5.5 mg Ixazomib will be also calculated from the first date when 
subjects were dosed with 4 mg till either the last dosing date or the first time they had dose 
reduced, whichever comes earlier.
Dosing data will also be presented in a by-patient listing.
7.8
Efficacy Analysis
All available efficacy data will be included in data listings and tabulations. Data that are 
potentially spurious or erroneous will be examined according to standard data management 
operating procedures. In general, missing data will be treated as missing, and no data imputation 
will be applied, unless otherwise specified. 
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7.8.1
Primary Efficacy Analysis
The analysis of the primary endpoint, PFS, will be based on the ITT population using 
investigator-assessed confirmed PD data using unstratified analysis. PFS is defined as the time 
from randomization to the first occurrence of confirmed PD or death from any cause, whichever 
occurs first. Patients without documentation of PD will be censored at the date of the last 
response assessment that is SD or better. Per IMWG criteria, 2 consecutive response assessments 
are required to document PD.
The null and alternative hypotheses for PFS are:
H0: PFS in ixa+dex Arm = PFS in pom+dex Arm
Ha: PFS in ixa+dex Arm > PFS in pom+dex Arm
A 2-sided, unstratified log-rank test will be used to compare the treatment groups with respect to 
PFS at a 2-sided alpha level of 0.05. In addition, an unadjusted unstratified Cox model will be 
used to estimate the HR and its 95% CIs for the treatment effect. The Kaplan-Meier (K-M) 
survival curves and K-M medians (if estimable), along with their 2-sided 95% CIs, will also be 
provided for each treatment group. 
The details regarding the handling of missing assessment and censoring for PFS analysis are 
presented in Table 7.a.
Table 7.a
Handling of Missing Assessment and Censoring for PFS Primary 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 documented disease progression 
Event
No documented death or disease progression 
Date of last adequate assessment*
Censored
Lost to follow-up, withdraw consent before any 
documented death or disease progression 
Date of last adequate assessment*
Censored 
Death or progression after more than one missed 
visit 
Date of last adequate assessment*
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
Event
Death between adequate assessment visits
Date of death
Event
*Adequate disease assessment is defined as there is sufficient data to evaluate a patient’s disease status.
Sensitivity analyses for PFS will include:

PFS assessed by stratified analyses in the ITT population.
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Subgroup analyses will be performed for PFS relative to baseline stratification factors and 
demographic data such as sex, race or ethnic group, and age, as appropriate.
Table 7.b
Handling of missing assessment and censoring for PFS Sensitivity Analysis 
based on EMA guidance 
Situation
Date of Progression or Censoring
Outcome
Alternate antineoplastic started prior to disease progression 
Date of documented disease progression 
Event
Death or disease progression after more than one missed 
visit
Date of death or disease progression 
Event 
The plan of subgroups for PFS is presented in the Table 7.c below:
Table 7.c
List of subgroups
Subgroup
Definition of Group
Age
<65 vs ≥65
Sex
male vs female
Race
white, black-African American, Asian, other
ISS stage 
I or II vs. III
Region
Europe vs other region
Lines of prior therapies
2 vs 3 or more
Prior Velcade therapy
Exposed vs naïve
Refractory to last line of prior therapy
yes vs no
Relapsed and/or refractory
Refractory vs Relapse and refractory
Renal function based on baseline creatinine clearance
<60 mL/min, and ≥60 mL/min
Liver Function based on baseline ALT or AST
≥1.5ULN vs. <1.5 ULN
ECOG performance status
0 or 1 vs 2
Additional exploratory analyses may be performed if deemed necessary.
7.8.2
Secondary Efficacy Analysis
The primary endpoint of PFS will be supported by prespecified evidence of clinical benefit as 
measured by other secondary endpoints. Other secondary efficacy parameters are OS, ORR, 
duration of response, time to response, and TTP. Disease responserelated endpoints will be 
analyzed using investigator-assessed response rate for the ITT population. Unstratified analyses 
will be conducted. 
Overall Survival
The OS will be analyzed on the basis of the ITT population and is defined as the time from 
randomization to death from any cause. Patients without documentation of death at the time of 
analysis will be censored at the date last known to be alive. A 2-sided, unstratified log-rank test 
will be used to compare the treatment and control groups with respect to OS. In addition, an 
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unadjusted unstratified Cox model will be used to estimate the HR and its 80% and 95% CIs for 
the treatment effect. OS will be also tested at 2-sided alpha=0.2. The KM survival curves and 
KM medians (if estimable), along with their 95% CIs, will also be provided for each study 
group.
Overall Response Rate
The ORR is defined as the proportion of patients who achieved PR or better relative to the ITT 
population. A logistic regression model will be used to estimate the treatment effect in terms of 
odds ratio. The odds ratio and its associated 95% CIs will be presented.
Time to Response
Time to response is defined as the time from randomization to the first documentation of PR or 
better. Time to response will be compared in the ITT population and summarized descriptively 
for the responders.
Duration of Response
Duration of response is defined as the time from the date of first documentation of a PR or better 
to the date of first documentation of PD for responders. Responders without documentation of 
PD will be censored at the date of their last response assessment that is SD or better. Duration of 
response will be summarized descriptively using the K-M method. 
Time to Progression
Time to progression is defined as the time from the date of randomization to the date of first 
documentation of PD. Patients without documentation of PD at the time of the analysis will be 
censored at the date of their last response assessment that is SD or better. Time to progression
will be analyzed in the ITT population using a similar method as PFS.
7.9
Pharmacokinetic/Pharmacodynamic Analysis/Biomarker Analysis
7.9.1
Pharmacokinetic Analysis
Ixazomib plasma concentration-time data will be presented in listings and summarized by time 
point. 
PK data collected in this study may contribute to population PK and exposure/response (safety 
and efficacy) analyses. These analyses may include data from other ixazomib clinical studies. 
The analysis plan for the population PK and exposure/response analyses will be separately 
defined and the results of these analyses will be reported separately.
7.9.2
Biomarker analysis 
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7.10
Other Outcomes Analyses of Patient-Reported Outcomes and Health Economics
7.10.1 Patient Reported Outcomes (PROs)
Health-related QOL will be assessed using the cancer-specific EORTC QLQ-C30 (Table 7-4), 
which contains 30 items across 5 functional scales, 9 symptom scales and a global health
status/QOL scale. Items 1-28 have 4 response levels (not at all, a little, quite a bit, and very 
much) and items 29 and 30 rely on a 7-point numeric rating scale. A summary score of EORTC 
QLQ-C30 will be calculated from the mean of 13 of the 15 EORTC QLQ-C30 subscales (the 
Global health status/Quality of Life scale and the Financial Difficulties scale are not included).
The EORTC QLQ-MY20 (Table 7-5) has 20 items across 2 functional subscales and 2 symptoms 
scales.
Raw scores are converted into scale scores ranging from 0 to 100. For the functional subscales 
and the global health status/QOL subscale, higher scores represent better QOL; for the symptom 
subscales, lower scores represent better QOL.
Descriptive Analyses
Patient-reported outcome (PRO) assessments using the EORTC QLQ-C30 and EORTC QLQ-
MY-20 will be analyzed using patients with PRO measurements at baseline and at least one post 
baseline measurement in the ITT population. 
The descriptive statistics of actual value and change from baseline for the subscale scores and 
summary score of EORTC QLQ-C30 and subscale scores of EORTC QLQ-MY20 will be 
summarized by treatment group over time. Particular emphasis will be placed on the Physical 
Functioning subscale of EORTC QLQ-C30.
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Table 7.d
Definition of Subscale Scores of EORTC QLQ-C30
Subscale
Individual Items
Global health status/
Quality of life
29-30
Functional scales
Physical functioning
1-5
Role functioning
6-7
Emotional functioning
21-24
Cognitive functioning
20, 25
Social functioning
26-27
Symptom scales/items
Fatigue
10, 12, 18
Nausea and vomiting
14-15
Pain
9, 19
Dyspnea
8
Insomnia
11
Appetite loss
13
Constipation
16
Diarrhea
17
Financial difficulties
28
Table 7.e
Definition of Subscale Scores of EORTC QLQ-MY20
Subscale
Individual Items
Functional scales/items
Future perspective
18-20
Body image
17
Symptom scales
Disease symptoms
1-6
Side effects of treatment
7-16
Analysis based on minimally important difference (MID)
For the summary score and each subscale score of EORTC QLQ-C30 as well as each subscale 
score of EORTC QLQ-MY20, the number and percentage of patients with an improvement in 
score from baseline based on minimally important differences (MIDs) of 10 (primary 
analyses)1,2,3 and 5 (sensitivity analyses)4 will be summarized by treatment group over time. 
                                               
1 Osoba D, Rodrigues G, Myles J, Zee B, Pater J. Interpreting the significance of changes in health-related quality-
of-life scores. J Clin Oncol 1998;16:139–44.
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Specifically, patients with a change from baseline for the better of ≥MID will be classified as 
“improved”.
Analysis of time to maintained quality of life deterioration
For the summary score and each subscale score of EORTC QLQ-C30 as well as each subscale 
score of EORTC QLQ-MY20, deterioration will be defined as a worsening in score from study 
entry ≥10 (primary analyses) and ≥5 (sensitivity analyses). Maintained deterioration will be 
defined as two consecutive scores that meet the definition of deterioration. Time to maintained 
QoL deterioration will be defined as the time from the date of randomization to the date of the 
second of the two consecutive scores that meet the definition for deterioration. Patients without 
any QoL deterioration or with only one score that meets the definition of deterioration will be 
censored at the date of last QoL measurement. 
A 2-sided stratified log-rank test will be used to compare the treatment groups with respect to 
time to maintained QoL deterioration. In addition, an unadjusted, stratified Cox model will be 
used to estimate the hazard ratio and its 95% CI. The Kaplan-Meier survival curves will also be 
provided for each treatment group. 
Analysis based on linear mixed effects models
For the summary score and each subscale score of EORTC QLQ-C30 as well as each subscale 
score of EORTC QLQ-MY20, the change from baseline score to each scheduled treatment cycle 
visit will be analyzed using linear mixed models. These models will include the following 
covariates: treatment group, baseline score, stratification factors (International Staging System 
stage, prior lines of therapy, and age), visits, and interactions between treatment group and visits. 
The interaction term between baseline score and visit may also be considered as a covariate. The 
estimated mean change from baseline score with 95% CIs for each treatment group will be 
provided at each treatment cycle visit. In addition, the mean difference in the changes from
baseline between the treatment groups with 95% CIs and p-values will be provided at each 
treatment cycle visit.
Missing data
Details of scoring and initial handling of missing data are included in the EORTC QLQ-C30 and 
EORTC QLQ-MY20 scoring guidelines.
                                                                                                                                                      
2 Cella D, Pickard AS, Duh MS, et al. Health-related quality of life in patients with advanced renal cell carcinoma 
receiving pazopanib or placebo in a randomized phase III trial. Eur J Cancer. 2012 Feb;48(3):311-23.
3 Kvam AK, Fayers PM, Wisloff F. Responsiveness and minimal important score differences in quality-of-life 
questionnaires: a comparison of the EORTC QLQ-C30 cancer-specific questionnaire to the generic utility 
questionnaires EQ-5D and 15D in patients with multiple myeloma. Eur J Haematol. 2011;87(4):330-337
4 Stewart AK, Dimopoulos MA, Masszi T, et al. Health-Related Quality-of-Life Results From the Open-Label, 
Randomized, Phase III ASPIRE Trial Evaluating Carfilzomib, Lenalidomide, and Dexamethasone Versus 
Lenalidomide and Dexamethasone in Patients With Relapsed Multiple Myeloma. J Clin Oncol. 2016 Nov 
10;34(32):3921-3930. 
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Sensitivity analyses may be conducted to study the impact of missing data.
Compliance for EORTC QLQ-C30 and EORTC QLQ-MY20 will also be summarized by 
number expected and number and percentage received by treatment group over time.
7.10.2 Health Economics Analysis Using Medical Resource Utilization and Utility
The EQ-5D-5L consists of 5 dimensions (mobility, self-care, usual activities, pain/discomfort, 
and anxiety/depression) each rated on 5 levels. The visual analogue scale (VAS) ranges from 0 
(worst imaginable health state) to 100 (best imaginable health state). 
EQ-5D-5L item scores and VAS scores will be summarized in descriptive statistics for treatment 
arms over time. 
Compliance of EQ-5D-5L will also be summarized by treatment group over time. 
HU data will be summarized in descriptive statistics of medical encounters (length of stay, 
inpatient, outpatient, and reason), number of missing days from work (by patient and care-giver)
for treatment arms.
7.11
Safety Analysis
7.11.1 Adverse Events
Adverse events
Adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA).
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 the MedDRA by system organ class, high level terms and 
preferred terms and will include the following categories: 

Treatment-emergent AEs.

Drug-related treatment-emergent AEs.

Grade 3 or higher treatment-emergent AEs (also report Grade 3 and 4 separately).

Grade 3 or higher drug-related treatment-emergent AEs (also report Grade 3 and 4 
separately).

The most commonly reported treatment-emergent AEs (i.e., those events reported by 10% 
of patients in either treatment group).

Serious AEs (SAEs).

Drug related SAEs.

AEs that prevented dose escalation at C2.
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Patients with the same AE more than once will have that event counted only once within each 
body system, once within each high level term, and once within each preferred term.
Drug-related treatment-emergent AEs will also be summarized by the National Cancer Institute 
Common Toxicity Criteria (NCI CTCAE) version 4.03. Patients with the same AE more than 
once will have the maximum intensity of that event counted within each body system, once 
within each high level term, and once within each preferred term. 
The most commonly reported treatment-emergent AEs (ie, those events reported by 10% of any 
treatment arm) will be tabulated by preferred term. Patients with the same AE more than once 
will have that event counted only once within each preferred term.
An overall summary AE table will include numbers and percentages of patients who had at least 
one AE, drug-related AE, grade 3 or higher AE (also grade 3 and 4 AE respectively), grade 3 or 
higher drug-related AE (also grade 3 and 4 drug-related AE respectively), SAEs, drug-related 
SAE, AE resulting in discontinuation, and on-study deaths. On-study death is defined as the 
death that occurs between the first dose of any study drug and within 30 days of the last dose of 
any study drug.
All concomitant medications collected from screening through the study period will be classified 
to preferred terms according to the World Health Organization (WHO) drug dictionary.
Additionally, by-patient listings and summary tables of the AE of special interest (AESI) and 
AEs of clinical importance (AECI) will be presented including New primary malignancy,
Peripheral neuropathy, Rash, Encephalopathy, Liver impairment, Hypotension, Heart failure, 
Arrhythmias, Myocardial infarction, Thrombocytopenia, Neutropenia, Gastrointestinal, and 
Renal impairment. 
Incidence of New Primary Malignancies (NPM)
Two types of incidence rates 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.

Incidence rates, defined by the number of the subjects reporting any new primary malignancy 
divided by the total duration of follow-up (patient-years = pt-yrs) in the safety population 
with available information up to the onset of new primary malignancies. 
For incidence proportions, the relative risks, defined as the ratio of incidence proportions
between the 2 randomized treatment groups, were provided along with their 95% CIs. For
incidence rates, the relative risks, along with their 95% CIs, will be calculated using an
exponential regression model for lifetime data (assuming constant hazards).
Due to the distinct nature of hematologic and nonhematologic neoplasms, as well as the 
emerging signals of new primary malignancies for immunomodulating agents, analyses of new 
primary malignancies may be performed separately for hematologic and nonhematologic
malignancies.
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Serious Adverse Events
The number and percentage of patients experiencing at least one treatment-emergent SAE will be 
summarized by MedDRA primary system organ class, high level term, and preferred term. Drug-
related SAEs will be summarized similarly.
In addition, a by-patient listing of the SAEs will be presented (the patient listing will contain all 
SAEs regardless of treatment-emergent AE status).
Deaths
A by-patient listing of the deaths will be presented. All deaths occurring on-study will be 
displayed (regardless of treatment-emergent AE status). 
Adverse Events Resulting in Discontinuation of Study Drug
A by-patient listing of treatment-emergent AEs resulting in discontinuation of study drug will be 
presented.
7.11.2 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 (eg, less 
than (<) a certain value, or greater than (>) a certain value), the given numeric value will be used 
in the summary statistics, ignoring the non-numeric qualifier. However, for the bone marrow 
plasma cell percentage, the convention as (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.
Laboratory test results will be summarized according to the scheduled sample collection time 
point. Change from baseline will also be presented. Unscheduled laboratory test results will be 
listed and included in laboratory shift tables. The parameters to be analyzed are as follows:

Hematology: hemoglobin, neutrophils (ANC), platelets counts, and leukocytes with 
differential.

Serum chemistry: blood urea nitrogen (BUN), creatinine, total bilirubin, urate, lactate 
dehydrogenase (LDH), albumin, alkaline phosphatase (ALP), aspartate aminotransferase 
(AST), alanine aminotransferase (ALT), β2-microglobulin, calcium, potassium, C-reactive 
protein, magnesium, and gamma glutamyl transferase (GCT).
Shift tables will be constructed for laboratory parameters to tabulate changes in NCI CTCAE for 
toxicity (version 4.03) from study entry to post study entry worst CTC grade. Parameters to be 
tabulated will include:

Hematology: ANC, hemoglobin, platelets, 
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
Serum chemistry: ALT, AST, ALP, creatinine, total bilirubin, calcium, magnesium, 
potassium.
Summary statistics will also be presented for shift from urinalysis values at study entry.

Urinalysis: Turbidity and color, pH, specific gravity, protein, ketones, bilirubin, occult blood, 
nitrite, urobilinogen, glucose, leukocytes, microscopic analysis.
Mean laboratory values and box plots over time for key lab parameters will be produced, 
including but not limited to ANC, platelets, and liver function tests (ALT/SGPT, AST/SGOT, 
alkaline phosphatase, and total bilirubin).
By-patient listings to be presented include hematology, serum chemistry, urinalysis, urine total 
protein, and urine creatinine.
7.11.3 Vital Signs
The actual values of vital sign parameters including temperature, blood pressure, heart rate, and 
body weight, will be summarized over time for each treatment arm. Change from baseline will 
also be presented.
A by-patient listing will also be presented.
7.11.4 12-Lead ECGs
Descriptive statistics for the actual values and changes from baseline in ECGs will be listed by 
time point.
Rate-corrected QT interval (millisec) of electrocardiograph (QTc) interval will be calculated 
using Bazett’s correction and Fridericia’s correction, if necessary. The formulas are:
QTc (Bazett) = QT / (RR0.5)
QTc (Fridericia) = QT / (RR0.33)
where RR = 60 / heart rate (bpm)
In addition, a categorical analysis of QTc intervals will be performed for each time point. The 
number and percentage of patients in each QTc interval (< 450 msec, 450-480 msec, > 480-
<500 msec, and ≥ 500msec) will be summarized at baseline and each of the subsequent time 
points. Categories of changes from baseline (≥ 30 msec and ≥ 60 msec) will be summarized as 
well. Maximum QTc intervals and maximum changes from baseline will also be summarized 
similarly in a separate display.
ECG abnormalities will be presented in a data listing.
7.11.5 Other Observations Related to Safety
Eastern Cooperative Oncology Group performance status and shifts from baseline to post-
baseline assessment over time, and ECOG score frequency table over time will be summarized. 
Shifts from baseline to the worst post-baseline score will be tabulated by treatment arm.
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Pregnancy testing results will be presented in a by-patient listing.
Additional safety analyses may be performed to most clearly enumerate rates of toxicities and to 
further define the safety profile of Ixazomib, e.g. analyses of TEAEs of clinical importance.
Type I Error Control
Type I error is controlled by the primary endpoint, because only 1 test is planned for primary 
endpoint of PFS at a 2-sided level of 0.20.
7.12
Changes in the Statistical Analysis Plan 
In protocol amendment 05, even though it was specified that the unstratified analysis will be 
implemented for PFS and OS, in the description, it mentioned that unadjusted stratified Cox 
model will be used to estimate the HR. It is clarified in the SAP that unstratified log-rank test as 
well as unadjusted unstratified Cox model will be used for both PFS and OS analyses.
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8.0
REFERENCES
1. Durie BG, Harousseau JL, Miguel JS, Blade J, Barlogie B, Anderson K, et al. International 
uniform response criteria for multiple myeloma. Leukemia 2006; 20(9): 1467-73. 
2. Robins JM and Finkelstein DM. Correcting for Noncompliance and Dependent Censoring in 
an AIDS Clinical Trial with Inverse Probability of Censoring Weighted (IPCW) Log-Rank 
Tests. Biometrics 2000; 56: 779-788. 
3. Robins JM, Tsiatis AA. Correcting for non-compliance in randomized trials using rank 
preserving structural failure time models. Communications in Statistics – Theory and 
Methods 1991; 20: 2609–2631. 
4. D’Agostino R.B., Lee M.L., Belanger A.J., Cupples L.A., Anderson K., and Kannel W.B. 
Relation of pooled logistic regression to time dependent Cox regression analysis: the 
Framingham Heart Study. Statistics in Medicine, 9(12): 1501–1515, 1990.
5. Xie J. and Liu C. (2005). Adjusted Kaplan-Meier Estimator and Log-Rank Test with Inverse 
Probability of Treatment Weighting for Survival Data. Statistics in Medicine,
10;26(10):2276, 2007.
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