Clinical trial NCT02181413
Conditions: Multiple Myeloma Autologous Stem Cell Transplant
Keywords: Drug therapy Ixazomib citrate
Sponsor: Takeda
Start date: 2014-07-16; Completion date: 2023-09-08
Enrollment: 656 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine the effect of ixazomib citrate maintenance therapy on progression-free survival (PFS), compared to placebo, in participants with newly diagnosed multiple myeloma (NDMM) who have had a response (complete response \[CR\], very good partial response \[VGPR\], or partial response \[PR\]) to induction therapy followed by high-dose therapy (HDT) and autologous stem cell transplant (ASCT).

Detailed description:
The investigational drug being tested in this study is called ixazomib citrate. Ixazomib citrate is being tested to slow disease progression and improve overall survival in people who have NDMM and who have had any type of positive response to induction therapy followed by HDT and ASCT. This study will look at the effect ixazomib citrate has on the length of time that participants are free of progressive disease (PD) and their overall survival (OS).

The study enrolled 656 participants. Participants were randomly assigned (by chance, like flipping a coin) to one of the two treatment groups-which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need, or if the disease has progressed and the information is required for planning the next treatment):

* Ixazomib citrate 3 mg for the first 4 cycles, then 4 mg for the remaining 22 cycles
* Placebo (dummy inactive pill) - this is a capsule that looks like the study drug but has no active ingredient.

All participants will be asked to take one capsule on Days 1, 8 and 15 of each 28-day cycle, for up to 26 cycles (approximately 24 months).

This multi-center trial will be conducted globally. The overall time to participate in this study is up to 107 months. Participants will make 28 visits to the clinic during the treatment period and will continue to make visits after treatment has ended. During this initial follow up period, participants will be assessed for disease status with follow up every 12 weeks. After the next line of therapy begins, follow-up will occur every 12 weeks until death or termination of the study.

Arms: arm 1: Ixazomib citrate placebo-matching capsules, orally, once on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 26 until PD, unacceptable toxicity, or discontinuation for alternate reasons. arm 2: Ixazomib citrate 3 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 4. Ixazomib citrate 4 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 5 through 26 until PD, unacceptable toxicity, or discontinuation for alternate reasons. Participants who have had any dose reductions due to adverse events (AEs) would not be dose escalated.
Interventions: intervention 1: Ixazomib Citrate intervention 2: Placebo
Intervention descriptions: intervention 1: Ixazomib citrate capsules intervention 2: Ixazomib citrate placebo-matching capsules

Protocol documents:
Prot_002.pdf: 
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Rationale for Amendment 04
This document describes the changes in reference to the protocol incorporating Amendment No. 
04. The primary reason for this amendment is to change the legal entity name from Millennium
to Takeda Development Center Americas and to clarify some study procedures.
Additionally, this amendment clarifies other elements of the study procedures.
Descriptions of how to manage study procedures during the coronavirus disease 2019 (COVID-
19) pandemic have been added. Finally, the Schedule of Events (SOE) has been streamlined to
show only the assessments needed now that all patients have completed study therapy and are in
follow-up (the original SOE is now in Section 15.10).
Changes in Amendment 04
1. Updated the legal entity name, address, and telephone of the sponsor.
2. Updated the email address for product complaints and medication errors.
3. Created Streamlined SOE to show only the assessments needed now that all patients are
in follow-up, replacing the original SOE.
4. Clarified that new primary malignancy (NPM) reporting must be done through the end
of the study.
5. Clarified timeframe for performing health care resource utilization, European
Organization for Research and Treatment of Cancer (EORTC) Quality of Life (QLQ)
Core 30-item (C30) Questionnaire, and EORTC QLQ Multiple Myeloma Module-20
(MY20) assessments.
6. Recorded a change in wording related to days of missed work that might affect the
statistical analysis.
7. Changed PFS and PD Follow-up visits to be 12 weeks (+/-1 week) since the last
completed Follow-up visit, rather than every 4 weeks.
8. Clarified that the collection of central laboratory assessments (except for investigator
assessment of PFS2) has stopped now that the primary endpoint has been met.
9. Removed investigator assessment of disease response/status.
10. Added information about alternative monitoring approaches in the event a monitor
cannot visit the site in a timely manner due to the COVID-19 pandemic.
11. Added language regarding alternative methods for administering study
procedures/assessments when it is not possible for the patient to come to the study site
due to the COVID-19 pandemic.
12. Clarified that when a patient experiences disease progression, the investigator is
encouraged to unblind the patient and take this information into account in planning the
next line of therapy.
13. Added death as a reason for a patient’s withdrawal from the study.
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14. Updated signatories for the study.
15. Clarified how health care resource data are collected from patients.
16. Clarified the monitoring of adverse events.
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PROTOCOL SUMMARY
Study Title: A Phase 3, Randomized, Placebo-Controlled, Double-Blind Study of Oral Ixazomib 
Citrate (MLN9708) Maintenance Therapy in Patients With Multiple Myeloma Following 
Autologous Stem Cell Transplant 
Number of Patients: Approximately 652 patients with newly diagnosed multiple myeloma 
(NDMM) following induction therapy and autologous stem cell transplant (ASCT)
Study Objectives
Primary:

To determine the effect of ixazomib maintenance therapy on progression-free survival 
(PFS), compared to placebo, in patients with NDMM who have had a response (complete 
response [CR], very good partial response [VGPR], or partial response [PR]) to induction 
therapy followed by high-dose therapy (HDT) and ASCT. 
Key Secondary: 

To determine the effect of ixazomib maintenance therapy on overall survival (OS) compared 
to placebo. 
Other Secondary:

To determine the effect of ixazomib maintenance therapy on improving best response for 
patients who enroll in the study at PR or VGPR, as well as maintaining best overall response 
for patients who enroll in the study at CR. 

To determine the effect of ixazomib maintenance therapy on time to progression (TTP). 

To determine the effect of ixazomib maintenance therapy on progression-free survival 2 
(PFS2), defined as time from the date of randomization to the date of objective disease 
progression on next-line treatment or death from any cause, whichever occurs first. 

To determine the effect of ixazomib maintenance therapy on time to start of the next line of 
treatment, defined as the time from the date of randomization to the date of the first dose of 
the next line of antineoplastic therapy for any reason.

To determine the effect of ixazomib maintenance therapy on time to end of the next line of 
treatment, defined as the time from the date of randomization to the date of the last dose of 
the next line of antineoplastic therapy for any reason.

To determine the effect of ixazomib maintenance therapy on duration of the next line of 
antineoplastic therapy.

To assess the incidence of new primary malignancies in patients receiving ixazomib 
maintenance therapy compared with placebo following ASCT. 

To evaluate the frequency of conversion from minimal residual disease (MRD) positive to 
MRD negative, or the maintenance of MRD negativity, after 1 and 2 years of therapy in 
patients treated with ixazomib compared to placebo, using bone marrow aspirates and 8-
color flow cytometry or next-generation sequencing.

To assess the correlation between MRD status (assessed by 8-color flow cytometry and next-
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generation sequencing) and PFS and OS, using bone marrow aspirates. 

To determine the effects of ixazomib maintenance therapy on PFS and OS in high-risk 
cytogenetic patient groups characterized by individual or multiple cytogenetic abnormalities 
such as del17, t(4;14), t(14;16), ampl 1q, del13, and del1p

To determine the long-term safety and tolerability of ixazomib administration to multiple 
myeloma patients following ASCT. 

To assess overall health-related quality of life (HRQL), as measured by the global health 
domain of European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire (EORTC QLQ-C30). 

To collect pharmacokinetic (PK) data to contribute to population PK and exposure response 
(safety/efficacy) analysis.

To evaluate the resolution and improvement of peripheral neuropathy (PN), if it occurs, by 
grading at each subsequent monthly visit until 1) resolution of PN, 2) the start of an 
alternative antineoplastic treatment, or 3) 6 months after progression has occurred, 
whichever occurs first.
Overview of Study Design: This is a randomized, placebo-controlled, double-blind, phase 3 study 
in patients with NDMM who have undergone induction therapy according to regional standard of 
care (SoC), followed by a conditioning regimen containing high-dose melphalan (200 mg/m2) and 
ASCT. Induction therapy must include proteasome inhibitor (PI) and/or immunomodulatory drug 
(IMiD)-based regimens. Vincristine, Adriamycin (doxorubicin), and dexamethasone is not an 
acceptable induction therapy for this trial. 
Patients who have achieved clinical and hematologic recovery following induction, HDT, and ASCT 
will initiate screening for study eligibility no earlier than 75 days after transplant, complete screening 
within 15 days, and be randomized no later than 115 days after transplant. Eligible patients (those 
whose CR, VGPR, or PR has been documented during screening and who have met all 
inclusion/exclusion criteria) will be enrolled and randomized in a 3:2 ratio to ixazomib or placebo. 
Stratification is based on induction regimen (PI without an IMiD vs IMiD without a PI vs PI and 
IMiD); pre-induction International Staging System (ISS) (stage 1 vs stage 2 or 3); and response after 
transplantation, defined as the response following induction, HDT, and ASCT measured during 
screening (CR or VGPR vs PR) on the basis of the International Myeloma Working Group (IMWG) 
uniform response criteria, version 2011. 
Patients will receive blinded study drug (ixazomib capsules or matching placebo capsules) orally on 
Days 1, 8, and 15 of every 28-day cycle, for a maximum duration of approximately 24 months (to the 
nearest complete cycle [if there are no treatment delays, this would be 26 cycles]), or until 
documented disease progression (on the basis of the IMWG uniform response criteria, version 2011) 
or intolerable toxicities, whichever occurs first. The initial dose of study drug will be 3 mg of 
ixazomib or matching placebo, which will be increased to 4 mg on Cycle 5 Day 1 if tolerated during 
the first 4 cycles. Clinical, laboratory, disease response, and HRQL with an emphasis on tolerability 
and symptom burden, as well as MRD assessments will be made. Following documented disease 
progression, subsequent therapy will be determined by the investigator/treating physician. 
The primary endpoint of PFS will be supported by prespecified evidence of clinical benefit as 
measured by the key and other secondary endpoints. There are 5 planned interim analyses (IAs) and 
1 final analysis (FA) in the study. The first IA will be the primary analysis (and the only analysis) for 
PFS for statistical testing purposes. If PFS is significant at the first IA, then OS will be tested at this 
first IA and at subsequent analyses.
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Study Population: Patients with NDMM who have had a response (defined as CR, VGPR, or PR) to 
SoC induction therapy, high-dose melphalan (200 mg/m2), and single ASCT will be eligible for this 
study. Patients must receive no further myeloma consolidation therapy after ASCT.
Duration of Study: Patients will be treated for a maximum duration of approximately 24 months (to 
the nearest complete cycle [if there are no treatment delays, this would be 26 cycles]), or until 
documented disease progression or intolerable toxicity, whichever occurs first.
Subsequent to the 24 month active treatment period, or removal from study therapy due to disease 
progression or toxicity, patients will be followed in 4 follow-up periodsPFS, Progressive Disease, 
PFS2, and OSfor disease status, subsequent therapies, HRQL, new primary malignancies, and 
survival.
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Study Overview Diagram
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Abbreviations: ASCT=autologous stem cell transplant; IMiD=immunomodulatory drug; OS=overall survival; 
PD=progressive disease; PD2=second PD (on next-line therapy); PFS=progression-free survival, defined as time 
from randomization to PD or death from any cause; PFS2=time from the date of randomization to the date of 
objective disease progression on next-line treatment or death from any cause, whichever occurs first; 
PI=proteasome inhibitor; SOC=standard of care; VAD=vincristine, Adriamycin (doxorubicin), and 
dexamethasone.
* After the first 4 cycles of treatment, eligible patients will have their dose of ixazomib (or matching placebo) 
escalated from 3 mg to 4 mg. See Section 6.5, Criteria for Dose Escalation at Cycle 5, for more information about 
eligibility criteria.
**If a physician chooses to start next-line therapy before PD, the patient will skip the PD Follow-up period and will 
enter directly into the PFS2 Follow-up period.
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Study Periods and Corresponding Endpoints Diagram
Abbreviations: EOT=End of Treatment (visit); OS=overall survival; PD=progressive disease (disease progression); PD2=second PD (on next-line therapy); 
PFS=progression-free survival, defined as time from randomization to PD or death from any cause; PFS2=time from the date of randomization to objective 
disease progression on next-line treatment or death from any cause, whichever occurs first.
PFS is the primary endpoint; OS, the key secondary endpoint; and PFS2, time to next-line therapy, and duration of next-line therapy, other secondary and 
exploratory endpoints. 
* Duration=duration of next-line therapy. This duration starts with the onset of next-line therapy and ends when PD2 occurs or whenever the therapy is stopped 
for any other reason, whichever occurs first.
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Abbreviations: C=study cycle; COVID-19=coronavirus disease 2019; CR=complete response; D=study day; ECG=electrocardiogram; ECOG=Eastern 
Cooperative Oncology Group; EORTC=European Organization for Research and Treatment of Cancer; EOT=End of Treatment (visit); EQ-
5D=EuroQol 5-Dimensional Health Questionnaire; HU=healthcare resource utilization; Ig=immunoglobulin; MRD=minimal residual disease; 
OS=overall survival; PD=progressive disease; PFS=progression-free survival; PFS2=time from the date of randomization to the date of objective 
disease progression on next-line treatment or death from any cause, whichever occurs first; PN=peripheral neuropathy; QLQ-C30=Quality of Life 
Core 30-item Questionnaire; QLQ-MY20=Quality of Life Multiple Myeloma Module 20; SPEP=serum protein electrophoresis; UPEP=urine 
protein electrophoresis.
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 Takeda project clinician or designee. If the study 
schedule is shifted, assessments must be shifted to ensure that collection of assessments is completed before dosing. This 2-day window also is 
permissible for study days not specified in this Schedule of Events, including Cycle 2 Day 15 and Day 8 and Day 15 of Cycle 3 and beyond.
a Includes evaluation for PN.
b Patient-reported outcomes and HU assessments (ie, medical encounters) should be completed before any other study procedures are performed or study drug is 
administered. During the PFS2 Follow-up period only, EORTC QLQ-C30, EORTC QLQ-MY20, and HU assessments should be done ideally at the first 2 
visits (or at least within the first 4 visits). Patient-reported outcome questionnaires are preferred to be completed by patients in the clinic, but if needed (eg, due 
to the COVID-19 pandemic), the EORTC QLQ-C30 and EORTC QLQ-MY20 questionnaires may be completed at the patient’s home using paper versions of 
the questionnaires; as a last resort, these patient-reported outcomes can be collected via telephone using EORTC telephone interview administration scripts. At 
time points when a clinic visit is not required, or if needed due to the COVID-19 pandemic, the EQ-5D questionnaire may be administered over the telephone. 
HU data may be obtained over the telephone and/or via patient medical records, as needed.
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TABLE OF CONTENTS
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS .................................................17
1.0
BACKGROUND AND STUDY RATIONALE.............................................................20
1.1
Scientific Background..............................................................................................20
1.1.1
Disease Under Treatment.................................................................................20
1.1.2
Ixazomib, Takeda’s Next-Generation Proteasome Inhibitor .............................20
1.2
Nonclinical Experience............................................................................................21
1.3
Clinical Experience..................................................................................................21
1.3.1
Pharmacokinetics and Drug Metabolism..........................................................22
1.4
Study Rationale .......................................................................................................23
1.4.1
Rationale for Ixazomib Schedule and Dose......................................................26
1.4.2
Rationale for Minimal Residual Disease Assessment .......................................28
1.4.3
Rationale for Mutational Analyses...................................................................29
1.4.4
Rationale for Blood-Based Biomarkers............................................................30
1.5
Potential Risks and Benefits.....................................................................................30
2.0
STUDY OBJECTIVES .................................................................................................31
2.1
Primary Objective....................................................................................................31
2.2
Key Secondary Objective.........................................................................................31
2.3
Other Secondary Objectives.....................................................................................31
2.4
Exploratory Objectives ............................................................................................32
3.0
STUDY ENDPOINTS...................................................................................................33
3.1
Primary Endpoint.....................................................................................................33
3.2
Key Secondary Endpoint .........................................................................................33
3.3
Other Secondary Endpoints......................................................................................33
3.4
Exploratory Endpoints .............................................................................................34
4.0
STUDY DESIGN..........................................................................................................34
4.1
Overview of Study Design.......................................................................................34
4.2
Number of Patients ..................................................................................................37
4.3
Duration of Study ....................................................................................................37
5.0
STUDY POPULATION................................................................................................37
5.1
Inclusion Criteria .....................................................................................................37
5.2
Exclusion Criteria ....................................................................................................39
6.0
STUDY DRUG .............................................................................................................40
6.1
Study Drug Administration......................................................................................40
6.2
Test Article (Ixazomib Capsules and Matching Placebo Capsules)...........................40
6.3
Dose-Modification Guidelines .................................................................................41
6.4
Criteria for Dose Modification (Delays, Reductions, and Discontinuations) .............41
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6.4.1
Dose Adjustment .............................................................................................41
6.4.2
Criteria for Toxicity Recovery Before Beginning the Next Treatment Cycle....41
6.4.3
Study Drug Dose Modification for Hematologic Toxicities..............................42
6.4.4
Study Drug Dose Modification for Nonhematologic Toxicities........................43
6.5
Criteria for Dose Escalation at Cycle 5.....................................................................44
6.6
Excluded Concomitant Medications and Procedures ................................................44
6.7
Permitted Concomitant Medications and Procedures................................................45
6.8
Precautions and Restrictions ....................................................................................45
6.9
Management of Clinical Events ...............................................................................46
6.10
Blinding and Unblinding..........................................................................................49
6.11
Description of Investigational Agents ......................................................................49
6.12
Preparation, Reconstitution, and Dispensation..........................................................49
6.13
Packaging and Labeling...........................................................................................49
6.14
Storage, Handling, and Accountability.....................................................................49
6.15
Other Protocol-Specified Materials ..........................................................................50
7.0
STUDY CONDUCT......................................................................................................51
7.1
Study Personnel and Organizations..........................................................................51
7.2
Arrangements for Recruitment of Patients................................................................51
7.3
Treatment Group Assignments.................................................................................51
7.4
Study Procedures.....................................................................................................51
7.4.1
Informed Consent ............................................................................................52
7.4.2
Patient Demographics......................................................................................52
7.4.3
Medical History...............................................................................................52
7.4.4
Physical Examination ......................................................................................53
7.4.5
Vital Signs, Body Weight, and Height .............................................................53
7.4.6
Eastern Cooperative Oncology Group Performance Status...............................53
7.4.7
Pregnancy Test ................................................................................................53
7.4.8
Concomitant Medications and Procedures........................................................53
7.4.9
Adverse Events................................................................................................53
7.4.10
Enrollment.......................................................................................................54
7.4.11
Electrocardiogram ...........................................................................................54
7.4.12
Clinical Laboratory Evaluations.......................................................................54
7.4.13
Health Care Resource Utilization Data Collection............................................55
7.4.14
Quality of Life Assessment (European Organization for Research and 
Treatment of Cancer).......................................................................................56
7.4.15
Utility Measurement ........................................................................................56
7.4.16
Bone Marrow Aspiration .................................................................................57
7.4.17
Blood-Based Biomarker Analyses....................................................................58
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7.4.18
Imaging Disease Assessments..........................................................................59
7.4.19
2-Microglobulin .............................................................................................59
7.4.20
Quantification of M-Protein.............................................................................59
7.4.21
Quantification of Immunoglobulins .................................................................59
7.4.22
Serum Free Light Chain Assay ........................................................................59
7.4.23
Immunofixation of Serum and Urine................................................................59
7.4.24
Skeletal Survey................................................................................................59
7.4.25
Disease Response Assessment .........................................................................60
7.4.26
Pharmacokinetic Measurements.......................................................................60
7.4.27
Follow-up Assessments for PFS, PD, PFS2, and OS ........................................61
7.5
Unscheduled Visits ..................................................................................................62
7.6
Study Compliance....................................................................................................62
7.7
Completion of Treatment .........................................................................................62
7.8
Completion of Study................................................................................................63
7.9
Discontinuation of Treatment With Study Drug, and Patient Replacement ...............63
7.10
Withdrawal of Patients From Study .........................................................................63
8.0
STATISTICAL AND QUANTITATIVE ANALYSES..................................................63
8.1
Statistical Methods...................................................................................................63
8.1.1
Determination of Sample Size..........................................................................64
8.1.2
Randomization and Stratification.....................................................................65
8.1.3
Populations for Analysis ..................................................................................65
8.1.4
Procedures for Handling Missing, Unused, and Spurious Data.........................65
8.1.5
Demographic and Baseline Characteristics.......................................................66
8.1.6
Efficacy Analysis.............................................................................................66
8.1.7
Analyses of Patient-Reported Outcomes and Health Economics ......................68
8.1.8
PK/Pharmacodynamics/Biomarkers.................................................................70
8.1.9
Safety Analysis................................................................................................70
8.1.10
Interim Analysis ..............................................................................................72
9.0
STUDY COMMITTEES...............................................................................................73
9.1
Steering Committee .................................................................................................73
9.2
Independent Review Committee ..............................................................................73
9.3
Independent Data Monitoring Committee ................................................................73
10.0
ADVERSE EVENTS ....................................................................................................74
10.1
Definitions...............................................................................................................74
10.1.1
Pretreatment Event Definition..........................................................................74
10.1.2
AE Definition ..................................................................................................74
10.1.3
SAE Definition................................................................................................74
10.2
Procedures for Recording and Reporting AEs and SAEs..........................................75
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10.3
Monitoring of AEs and Period of Observation .........................................................76
10.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events.........77
11.0
ADMINISTRATIVE REQUIREMENTS ......................................................................77
11.1
Good Clinical Practice .............................................................................................77
11.2
Data Quality Assurance ...........................................................................................77
11.3
eCRF Completion....................................................................................................77
11.4
Study Monitoring.....................................................................................................78
11.5
Ethical Considerations .............................................................................................78
11.6
Patient Information and Informed Consent...............................................................78
11.7
Patient Confidentiality .............................................................................................79
11.8
Investigator Compliance ..........................................................................................79
11.9
On-site Audits/Inspection.........................................................................................79
11.10 Investigator and Site Responsibility for Drug Accountability...................................79
11.11 Product Complaints and Medication Errors (Including Overdose)............................79
11.12 Closure of the Study ................................................................................................80
11.13 Record Retention .....................................................................................................80
12.0
USE OF INFORMATION.............................................................................................81
13.0
INVESTIGATOR AGREEMENT.................................................................................82
14.0
REFERENCES..............................................................................................................83
15.0
APPENDICES...............................................................................................................89
15.1
Eastern Cooperative Oncology Group (ECOG) Scale for Performance Status ..........89
15.2
Multiple Myeloma Diagnostic Criteria.....................................................................89
15.3
Cockcroft-Gault Equation........................................................................................90
15.4
ISS Staging Criteria .................................................................................................90
15.5
Steroid Equivalent Doses.........................................................................................90
15.6
EQ-5D.....................................................................................................................91
15.7
European Organization for Research and Treatment of Cancer (EORTC) Multiple 
Myeloma Module (QLQ-MY20)..............................................................................94
15.8
European Organization for Research and Treatment of Cancer (EORTC QLQ C30 
Version 3)................................................................................................................96
15.9
Response Criteria.....................................................................................................98
15.10 Previous, Full Schedule of Events and PK Sampling Schedule (Schedules Before 
Implementation of Amendment 4)............................................................................99
15.11 Amendment 04 Detailed Summary of Changes ......................................................107
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LIST OF TABLES
Table 6-1
Study Drug Dose Adjustments ...........................................................................41
Table 6-2
Study Drug Dose Modification for Hematologic Toxicities ................................42
Table 6-3
Study Drug Dose Modification for Nonhematologic Toxicities ..........................43
Table 6-4
Criteria for Study Drug Retreatment and Cycle Delays Subsequent to 
Hematologic and Nonhematologic Toxicities .....................................................44
Table 6-5
Ixazomib Capsule Size and Color.......................................................................49
Table 7-1
Response Assessment.........................................................................................60
LIST OF FIGURES 
Figure 1-1
Relationship Between Response (Stable Disease) to Single-Agent Ixazomib 
and Adverse Events (Grade 2) and AUC (N=44) in Patients With Relapsed 
and/or Refractory Multiple Myeloma .................................................................27
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LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS 
Abbreviation
Term
AE
adverse event
AL
light-chain
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ampl
amplification
ASCO
American Society of Clinical Oncology
ASCT
autologous stem cell transplant
AST
aspartate aminotransferase
AUC
area under the plasma concentration versus time curve
BCRP
breast cancer resistance protein
BM
bone marrow
BMA
bone marrow aspirate
BSA
body surface area
BUN
blood urea nitrogen
CBC
complete blood count
CHMP
Committee for Medicinal Products for Human Use
CL
clearance, IV dosing
CR
complete response 
CT
computed tomography
CYP
cytochrome P450
del
deletion
DDI
drug-drug interaction
DLT
dose-limiting toxicity
DOR
duration of response
DVT
deep vein thrombosis
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EORTC-QLQ-C30
European Organization for Research and Treatment of Cancer (EORTC) Quality of 
Life (QLQ) Core 30-item (C30) Questionnaire
EOT
End of Treatment (visit)
EQ-5D
EuroQol 5-Dimensional Health Questionnaire
EQ VAS
EQ visual analogue scale
ESMO
European Society for Medical Oncology
EU
European Union
FA
final analysis
FDA
United States Food and Drug Administration
FISH
fluorescence in situ hybridization
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Abbreviation
Term
GCP
Good Clinical Practice
GI
gastrointestinal
HDT
high-dose therapy
HRQL
health-related quality of life
HU
health care resource utilization
IA
interim analysis
IB
Investigator’s Brochure
ICF
informed consent form
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
IRC
independent review committee
ISS
International Staging System
ITT
intent-to-treat
IV
intravenous; intravenously
IXRS
interactive web/voice response system
LenDex
lenalidomide+dexamethasone
MCL
mantle cell lymphoma
MedDRA
Medical Dictionary for Regulatory Activities
MM
multiple myeloma
MP
melphalan prednisone 
MRD
minimal residual disease
MRI
magnetic resonance imaging
MRP2
multidrug resistance associated protein
MTD
maximum tolerated dose
MY20
Multiple Myeloma Module-20
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NDMM
newly diagnosed multiple myeloma
NEC
not elsewhere classified
NFKB
nuclear factor kappa-light-chain-enhancer of activated B cells
NPM
new primary malignancy
OS
overall survival
PAD
bortezomib, Adriamycin (doxorubicin), and dexamethasone 
PD
progressive disease 
PE
pulmonary embolism
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Abbreviation
Term
PFS
progression-free survival
PFS1
progression-free survival on study therapy or before the next line of therapy if 
discontinued before progression
PFS2
time from the date of randomization to the date of objective disease progression on 
next-line treatment or death from any cause, whichever occurs first
PI
proteasome inhibitor 
PK
pharmacokinetic(s)
PN
peripheral neuropathy
PO
per os; by mouth (orally)
PR
partial response 
PSMB1
proteasome (prosome, macropain) subunit, beta type, 1
QOL
quality of life
RP2D
recommended phase 2 dose
RRMM
relapsed and/or refractory multiple myeloma
SAE
serious adverse event
sCR
stringent complete response
SCT
stem cell transplant/therapy
SD
stable disease
SMA
Safety Management Attachment (to the Investigator’s Brochure)
SNP
single-nucleotide polymorphism
SoC
standard of care
SPEP
serum protein electrophoresis
SPM
second primary malignancies
t1/2
terminal disposition half-life
TEAE
treatment-emergent adverse event
TMA
thrombotic microangiopathy
Tmax
first time of occurrence of maximum (peak) concentration
TRAF-3
TNF receptor-associated factor 3
TTP
time-to-progression
Tx
treatment
ULN
upper limit of the normal range
UPEP
urine protein electrophoresis
US
United States
VAD
vincristine, Adriamycin (doxorubicin), and dexamethasone 
VGPR
very good partial response
WHO
World Health Organization
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1.0
BACKGROUND AND STUDY RATIONALE
1.1
Scientific Background
1.1.1
Disease Under Treatment
Multiple myeloma (MM), a B-cell tumor of malignant plasma cells within the bone marrow, 
remains incurable despite advances in novel therapies with proteasome inhibitors (PIs), 
immunomodulatory drugs (IMiDs), and stem cell transplant (SCT) therapy. Multiple myeloma is 
characterized by the accumulation of plasma cells in the bone marrow (and other organs) and can 
result in bone marrow failure, bone destruction, hypercalcemia, and renal failure. It constitutes 
approximately 1% of all reported neoplasms and approximately 13% of hematologic cancers 
worldwide.[1] In the Americas, Canada, and Western European countries, approximately 5 to 7 
new cases of MM are diagnosed per 100,000 people each year.[1-3] Although less common in 
Asian countries, incidences of MM have increased almost 4-fold in the past 25 years and are 
characterized by younger age of onset, more invasive disease, and a less favorable prognosis.[4,5]
Multiple myeloma is sensitive to many cytotoxic drugs including alkylating agents, 
anthracyclines, and corticosteroids for both initial treatment and relapsed disease. Over the past 
decade, significant achievements have been made in expanding treatment options for MM with 
novel therapies such as thalidomide, bortezomib, and lenalidomide. These regimens have 
extended PFS and/or time-to-progression (TTP).[6-10] The introduction of novel therapies and 
the increased use of high-dose therapy (HDT) significantly improved OS in patients with newly 
diagnosed myeloma (NDMM) who were eligible for autologous stem cell transplant 
(ASCT).[11-13]
Despite more therapeutic options, MM remains incurable, and there is a need for new and better 
agents. When patients relapse after their initial therapy, they demonstrate variable responses to 
subsequent treatments with decreasing likelihood and duration of response (DOR). Patients 
become refractory to approved therapies and ultimately are left with no alternative treatment 
options. In an effort to expand the therapeutic armamentarium against MM with agents that 
target the proteasome, Takeda has developed ixazomib, a small molecule 20S proteasome 
inhibitor.
1.1.2
Ixazomib, Takeda’s Next-Generation Proteasome Inhibitor
The proteasome was validated as an effective oncology target with the clinical success of 
intravenous and subcutaneous bortezomib (VELCADE), the first-in-class, small molecule 
proteasome inhibitor (PI) developed by Takeda. Building on the efficacy seen with bortezomib in 
MM and other hematologic malignancies, Takeda has subsequently developed oral ixazomib 
citrate to improve the pharmacology of the agent and provide a more convenient mode of drug 
administration.
Like VELCADE, ixazomib citrate is a modified peptide boronic acid. Ixazomib citrate is the 
citrate ester of ixazomib, the biologically active form that potently, reversibly, and selectively 
inhibits the proteasome. Ixazomib citrate was formulated to improve the chemical properties of 
ixazomib for clinical delivery. Ixazomib citrate rapidly hydrolyzes to ixazomib upon contact 
with either plasma or aqueous solutions. In contrast to bortezomib, ixazomib demonstrates a 
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faster dissociation rate from the proteasome, possibly resulting in enhanced tumor penetration, 
exhibits antitumor activity in a broader range of tumor xenografts, and has more prolonged tissue 
penetration.
Ixazomib preferentially binds the 5 site of the 20S proteasome with a concentration producing 
50% inhibition (IC50) of 3.4 nM. At higher concentrations, it also inhibits the activity of the 1 
and 2 sites. Ixazomib was selective for the proteasome when tested against a panel of proteases 
(IC50 values between 20 and 100 M), kinases (IC50 values > 10 M), and receptors (IC50 values > 
10 M). Ixazomib and bortezomib have different 5 proteasome dissociation half-lives (t1/2), 
reflecting differences in their on-off binding kinetics (the 5 proteasome dissociation [t1/2] for 
ixazomib citrate and bortezomib is 18 and 110 minutes, respectively). On the basis of these 
favorable characteristics, ixazomib citrate (henceforth called simply “ixazomib”) is anticipated to 
be effective against MM.
1.2
Nonclinical Experience
Detailed information regarding the nonclinical pharmacology, absorption, distribution, 
metabolism, excretion, pharmacokinetics (PK) and toxicology of ixazomib may be found in the 
Investigator’s Brochure (IB).
1.3
Clinical Experience
Ixazomib has been evaluated as an oral single agent in phase 1 studies that have included patients 
with advanced solid tumors, lymphoma, relapsed/refractory MM (RRMM), and relapsed or 
refractory light-chain (AL) amyloidosis and demonstrated early signs of activity. Ongoing 
studies continue to investigate both single-agent ixazomib and ixazomib in combination with 
standard treatments. On the basis of encouraging preliminary data observed in patients with MM 
requiring systemic treatment, 2 phase 3 trials in patient populations with NDMM (C16014) and 
RRMM (C16010) are currently evaluating ixazomib in combination with lenalidomide and 
dexamethasone (LenDex) versus placebo/LenDex. Both trials are combining ixazomib at a 
weekly dose of 4 mg (as ixazomib) on Days 1, 8, and 15 in a 28-day cycle to a standard dose of 
lenalidomide with a weekly dexamethasone dose of 40 mg. In addition, a recently concluded 
clinical pharmacology study evaluated drug-drug interactions (DDIs) with ketoconazole, 
rifampin, and clarithromycin, effect of food, and relative bioavailability.[14] Studies evaluating 
the safety and PK of ixazomib alone (in Japanese patients) and in combination with lenalidomide 
and dexamethasone in Asian adult patients (including Japanese patients) with a diagnosis of 
RRMM are ongoing.
As of 27 March 2013, preliminary clinical data are available for a total of 653 patients across 13 
studies. The emerging safety profile indicates that ixazomib is generally well tolerated. The 
adverse events (AEs) are consistent with the class-based effects of proteasome inhibition and are 
similar to what has been previously reported with VELCADE though the severity of some, for 
example peripheral neuropathy (PN), is less. While some of these potential toxicities may be 
severe, they can be managed by clinical monitoring and standard medical intervention, or, as 
needed, dose modification or discontinuation. 
Fatigue was the most common AE reported among 384 patients treated in the oral (PO) studies 
(47%). Other common AEs reported in the pooled intravenous (IV) and PO safety populations 
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include nausea, thrombocytopenia, diarrhea, and vomiting. Rash is also a commonly reported 
TEAE; however, there is some variety in its characterization and causality, resulting in different 
preferred terms to describe it. A high-level term outline of rash events includes rashes, eruptions 
and exanthems not elsewhere classified (NEC); pruritus NEC; erythemas; papulosquamous 
conditions; and exfoliative conditions. The dose escalation phases of most trials reported in the 
IB have now completed enrollment, and gastrointestinal (GI) symptoms were the common dose-
limiting toxicities (DLTs) when the use of prophylactic anti-emetics was not permitted per 
protocol. In the expansion cohorts or phase 2 cohorts (as per each study), the incidence and 
severity of GI symptoms was mitigated by the use of the lower maximum tolerated dose 
(MTD)/recommended phase 2 dose (RP2D) (as per each study) and standard clinical usage of 
anti-emetics and/or antidiarrheal medications as deemed appropriate. Prophylactic use of anti-
emetics has not been required as with other agents but (as outlined in Section 6.9) has been used 
according to standard practice and is effective.
The most frequent (at least 20%) treatment-emergent adverse events (TEAEs) reported with the 
PO formulation pooled from single-agent studies (n=201) irrespective of causality to ixazomib 
citrate, include nausea (53%), fatigue (51%), diarrhea (44%), thrombocytopenia (34%), vomiting 
(38%), decreased appetite (32%), fever (21%), and anemia (21%). The most frequent (at least 
20%) TEAEs reported with the PO formulation pooled from combination trials, irrespective of 
the combination or causality to ixazomib (n=173), include diarrhea (47%), fatigue (44%), 
nausea (38%), peripheral edema (35%), constipation (33%), insomnia (29%), thrombocytopenia 
(28%), anemia (26%), vomiting (26%), neutropenia (25%), back pain (24%), pyrexia (23%), 
cough (20%), hypokalemia (20%), and upper respiratory tract infection (20%). Overall, rash of 
all grades is reported in approximately 50% of patients in combination trials and is more 
common when ixazomib is given in combination with lenalidomide, where rash is an 
overlapping toxicity. 
Additional detailed information regarding the clinical experience of ixazomib may be found in 
the IB, including information on the IV formulation.
1.3.1
Pharmacokinetics and Drug Metabolism
Clinical IV and PO PK data show that ixazomib (measured as the biologically active boronic 
acid form of ixazomib) has multi-exponential disposition with a rapid initial phase that is largely 
over by 4 hours. Oral ixazomib is rapidly absorbed with a median single-dose first time of 
occurrence of maximum (peak) ixazomib concentration (Tmax) of approximately 0.5 to 2.0 hours 
and a terminal disposition half-life (t1/2) after multiple dosing of approximately 5 to 7 days.[15]
Results of a population PK analysis (N=137) show that there is no relationship between body 
surface area (BSA) or body weight and clearance (CL). Also, on the basis of stochastic 
simulations for fixed dose, exposures are independent of the individual patient’s BSA.[16] On 
the basis of these data, a recommendation was made for fixed dosing in clinical trials. Also, an 
absolute bioavailability of 67% was determined for ixazomib using the population PK analysis. 
Please refer to the current IB and Safety Management Attachment (SMA) for information on the 
PK for IV doses of ixazomib. 
Metabolism appears to be the major route of elimination for ixazomib, and urinary excretion of 
the parent drug is negligible (<5% of dose). In vitro studies indicate that ixazomib is metabolized 
by multiple cytochrome P450s (CYPs) and non-CYP enzymes/proteins. At clinically relevant 
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concentrations of ixazomib, in vitro studies using human cDNA-expressed CYP isozymes 
showed that no specific CYP isozyme predominantly contributes to ixazomib clearance. At 
concentrations exceeding those observed clinically (10 µM), ixazomib was metabolized by 
multiple CYP isoforms with estimated relative contributions of 3A4 (42.3%), 1A2 (26.1%), 2B6 
(16.0%), 2C8 (6.0%), 2D6 (4.8%), 2C19 (4.8%) and 2C9 (<1%). In contrast, at 0.1 µM and 0.5 
µM substrate concentrations, which are closer to clinical concentrations of ixazomib following 
oral administration of 4 mg ixazomib, non-CYP mediated clearance was observed and seemed to 
play a major role in ixazomib clearance in vitro. These data indicate that at clinically relevant 
concentrations of ixazomib, minimal CYP-mediated DDIs with a selective CYP inhibitor would 
be expected. In addition, ixazomib is neither a reversible nor a time-dependent inhibitor of CYPs 
1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4/5. 
In a phase 1 DDI study, the PK of ixazomib (Cmax and AUC0-last) was similar with and without 
co-administration of clarithromycin, a strong CYP3A inhibitor (Study C16009, Arm 5) [14]; 
hence, no dose adjustment is necessary when ixazomib is administered with strong CYP3A 
inhibitors. These findings are explained by the in vitro metabolism data indicating the lack of a 
discernible contribution of CYP-mediated metabolism at clinically relevant ixazomib 
concentrations. As discussed earlier, no CYP isoforms have been identified to contribute 
meaningfully to ixazomib metabolism at clinically relevant concentrations and CYP3A
contribution to total metabolism was highest across all CYP isoforms when characterized at a 
supratherapeutic concentration of 10 µM. Therefore, based on the totality of information from 
the clinical clarithromycin DDI study and the in vitro CYP phenotyping data, it can be concluded 
that ixazomib PK is not likely to be altered upon co-administration with any CYP isoform-
selective inhibitor, including strong CYP1A2 inhibitors. Consistently in the population PK 
analysis, co-administration of strong CYP1A2 inhibitors did not affect ixazomib clearance. 
Therefore, no dose adjustment is required for patients receiving strong inhibitors of CYP1A2. 
Ixazomib may be a weak affinity substrate of P-gp but not of breast cancer resistance protein 
(BCRP) or multidrug resistance associated protein (MRP2) efflux pump transporters. Ixazomib is 
not an inhibitor of P-gp, BCRP, or MRP2. The potential for DDIs with substrates or inhibitors of 
P-gp, BCRP, and MRP2 is, therefore, inferred to be low.
In a DDI study, co-administration of ixazomib with rifampin decreased ixazomib Cmax by 54% 
and AUC by 74% (Study C16009, Arm 4).[14] Accordingly, concomitant administration of 
ixazomib with strong CYP3A inducers should be avoided. 
Additional details on the PK and drug metabolism of ixazomib are provided in the IB.
1.4
Study Rationale
Multiple myeloma is generally considered an incurable disease. However, high-dose 
chemotherapy incorporating ASCT has been found to prolong PFS and OS in patients who are 
sufficiently fit to undergo the procedure. In addition, the introduction of modern agents, 
including IMiDs and PIs, has improved the survival of both transplant patients and those who are 
transplant ineligible. 
Maintenance therapy is a long-duration, low-intensity therapy intended to prolong the duration of 
a patient’s response to primary antineoplastic treatment. Requirements for a successful 
maintenance therapy include good long-term tolerability and adherence (low discontinuation 
rates due to toxicity and convenience of administration), demonstration of clinical benefit either 
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in prolonging survival or improving quality of life (QOL) without shortening survival, and a 
favorable benefit:risk ratio. Although there is emerging evidence for the clinical benefit of 
maintenance therapy following SCT, a positive benefit:risk balance is yet to be established in 
existing therapies, no therapy has been approved for this indication, and a true standard of care 
(SoC) has not been adopted.[17] A recent review regarding the European perspective on Multiple 
Myeloma Treatment Strategies reveals that “although recent trials have provided important 
results regarding the utility and benefit of consolidation and maintenance in the post-ASCT 
setting, further studies are needed to provide answers to questions, such as duration of treatment, 
the impact on subsequent therapies, and who should receive post-ASCT treatment.[18] In 
addition, the measurement of QOL data in the maintenance setting is of importance to 
thoroughly assess the benefit of long-term therapy.”
The role of maintenance therapy in both the posttransplant and nontransplant settings has been 
extensively explored. A detailed review of the history of the clinical trials of maintenance 
therapy was published in 2012 by the International Myeloma Working Group (IMWG).[17]
Initially, trials of maintenance therapy consisted of continuation of chemotherapy with 
melphalan and prednisone (MP) following successful remission induction (1975-1988). 
Although remission periods were prolonged, there was no survival benefit observed in these 
studies, and maintenance with MP was not pursued further. Maintenance using interferon (1980-
2000) demonstrated an improved duration of remission and OS by approximately 6 months each; 
however, the highly toxic therapy was not pursued after the development of modern therapies 
due to the unfavorable safety profile. The immunomodulatory agent thalidomide has been 
extensively studied as a single agent or in combination maintenance therapy in both 
posttransplant and transplant-ineligible settings. Progression-free survival benefit was generally 
observed across studies. Overall survival benefits were observed in some studies,[19] whereas a 
decrement in OS was observed in others.[20] High rates of discontinuation were observed in all 
studies due to toxicity. In addition, patients with high-risk cytogenetics had no incremental 
benefit with thalidomide maintenance therapy,[21,22] and in 1 study patients experienced a 
decrement in benefit.[22]
Newer agents have demonstrated a more favorable safety profile while achieving depth of 
response in the maintenance setting (eg, the number of patients who improved their response 
from what was achieved during induction). Several studies with bortezomib have been conducted, 
both as part of a combination maintenance regimen and in direct comparison with 
thalidomide.[23-25] In the GIMEMA trial, maintenance with bortezomib and thalidomide 
showed a PFS benefit over no maintenance therapy.[23]
The phase 3 HOVON/GMMG study investigated induction therapy leading to ASCT and 
subsequent maintenance therapy in patients with MM.[24] Induction therapy with the regimen of 
bortezomib, Adriamycin (doxorubicin), and dexamethasone (PAD), followed by bortezomib 
maintenance was evaluated and compared with induction therapy using vincristine, doxorubicin, 
and dexamethasone (VAD) followed by thalidomide maintenance. Improvement was observed in 
responses in the PAD + bortezomib arm during the maintenance period. In addition, an 
incremental benefit was observed in high-risk cytogenetic patients with del(17)p13. However, 
the induction regimens in the 2 arms were different such that only the bortezomib maintenance 
arm received bortezomib during induction therapy, and thus the benefit of bortezomib as 
maintenance alone could not be not independently assessed.
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Additionally, lenalidomide has been assessed as maintenance therapy in 3 placebo controlled 
trials.[26-28] While all studies demonstrated a significant PFS advantage with lenalidomide 
maintenance therapy, only the CALGB trial showed a possible OS benefit, and data regarding 
the impact of lenalidomide maintenance on DOR to subsequent therapy were limited.[27] In 
addition, offsetting the potential clinical benefit of lenalidomide maintenance was the increased 
incidence of secondary primary malignancies (SPMs). Therefore, positive risk:benefit could not 
be established during the Committee for Medicinal Products for Human Use (CHMP) review to 
date.[29] To understand whether ixazomib maintenance therapy impacts the incidence of SPMs, 
as was observed in the lenalidomide trials, a secondary endpoint assessing the incidence of new 
primary malignancies is incorporated in the proposed trial.
There is currently limited use of maintenance and no universal standard of care (SoC) regarding 
maintenance therapy post ASCT. This is likely due to the lack of an evidence-based positive 
benefit:risk profile for drugs in the maintenance setting. The most recent European Society for 
Medical Oncology (ESMO) guidelines for the treatment of MM point out that thalidomide 
maintenance increases complete response (CR) rate and prolongs PFS and OS on the basis of 3 
randomized studies, “but the optimal duration of treatment and the respective impact of short 
consolidation versus prolonged maintenance is not yet known.”[30] The guidelines also point out 
that the role of other novel agents in this setting is currently under evaluation. In Western Europe, 
only about 37% of patients with MM receive maintenance therapy following ASCT, with 
approximately equal usage of lenalidomide, VELCADEand thalidomide, and older agents 
such as interferon less frequently used.[31] The 2012 IMWG “Consensus on Maintenance 
Therapy in Multiple Myeloma” notes that in their considerations for clinical practice, a wait-and-
see strategy remains a “valuable alternative” to maintenance therapy.[17] This position was 
reinforced in the 2013 “International Myeloma Working Group Recommendations for Global 
Myeloma Care,” which stated, “Still, at the current time, the panel does not recommend the 
routine use of maintenance therapy.”[32] In the US, current National Comprehensive Cancer 
Network (NCCN) guidelines (Version 2.2013) support the use of bortezomib, lenalidomide, and 
thalidomide maintenance therapies, while pointing out concerns regarding cumulative toxicity 
with thalidomide and increased incidence of secondary primary malignancies with lenalidomide; 
bortezomib maintenance was considered to be well tolerated. Although lenalidomide is approved 
by the United States Food and Drug Administration (FDA) for treatment of patients with RRMM, 
the drug is currently prescribed off-label as maintenance therapy for about 50% of patients after 
ASCT. 
In conclusion, maintenance therapy has not yet been proven to be a superior treatment strategy 
compared to the current paradigm of a post-ASCT treatment-free interval followed by salvage 
therapy at relapse. Together with the lack of a universal maintenance SoC and an evidence-based 
comparator with a demonstrated survival benefit for maintenance therapy post-ASCT, a strong 
justification is provided to conclude that a phase 3, placebo-controlled trial is an appropriate 
approach for determining the efficacy of single-agent ixazomib maintenance therapy.
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1.4.1
Rationale for Ixazomib Schedule and Dose 
1.4.1.1
Schedule Rationale
The balance of benefit versus risk is paramount in this phase 3 maintenance study. The study will 
administer ixazomib on a weekly dosing schedule, which is consistent with the other ixazomib 
pivotal trials. 
The 24-month duration of therapy was chosen on the basis of the favorable results from the 
HOVON-65/GMMG-HD4 trial.[24] In that study, 1 of the 2 study arms included a 2-year 
maintenance therapy period with VELCADE following induction therapy that contained 
VELCADE, and ASCT. Significant PFS and OS advantages were seen in this arm compared to 
the alternative arm, which included 2 years of thalidomide maintenance following a non-PI-
containing induction therapy and ASCT. Because ixazomib is a boron-based PI similar to 
VELCADE (having a similar site of action on the proteasome), the HOVON-65/GMMG-HD4 
study provides the basis for the sponsor’s position that 24 months of maintenance therapy is an 
acceptable duration for the ixazomib trial. 
In addition, in support of a fixed duration of therapy, it is possible that the incremental clinical 
benefit of prolonged maintenance therapy diminishes as the duration of maintenance continues. 
For example, in the HOVON-50 trial,[33] which studied the addition of thalidomide to induction 
in transplant-eligible MM patient followed by posttransplant thalidomide maintenance until 
progressive disease (PD) (compared to -interferon maintenance in the control arm), 
investigators found a significant PFS benefit for patients receiving thalidomide-containing 
induction therapy and thalidomide maintenance therapy. However, OS was not improved; 
survival following relapse was significantly shorter for patients receiving thalidomide. The 
investigators concluded that prolonged exposure to thalidomide may have been responsible for 
the decrement in survival after progression. They also concluded that a “limited duration of 
postinduction/intensification therapy until maximal response is preferable to avoid resistant 
relapse and to minimize the side effects of prolonged thalidomide exposure.”
It is also possible that prolonged therapy may negatively affect the duration of effectiveness of a 
subsequent therapy after progression due to the emergence of resistant disease while on 
continuous maintenance therapy—an important consideration for this newly diagnosed 
population that will inevitably experience relapse as part of the natural course of their disease.[34]
A finite treatment period of 24 months aims to reduce the risk of developing resistant disease. In 
addition, a secondary endpoint of PFS2 (time from the date from randomization to the date of 
objective disease progression on next-line treatment or death from any cause, whichever occurs 
first) will evaluate whether relapse following ixazomib maintenance is followed by a shorter 
response to the next line of antineoplastic therapy.
1.4.1.2
Dose Rationale
To determine an appropriate maintenance dose for this trial, safety and efficacy data from Study 
C16004 (a phase 1/2 study of single-agent ixazomib dosed weekly in RRMM patients) were used 
in a preliminary exposure/response (safety/efficacy) analysis. Data were available over a wide 
dose range (0.5-3.95 mg/m2; N=44), corresponding to a dose range of approximately 1 to 8.9 mg. 
The metric of exposure was AUC per day (derived from individual clearance values on the basis 
of population PK) for both the exposure/safety analysis and the exposure/efficacy analysis.
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For the safety analysis, 7 commonly occurring toxicities were evaluated: fatigue, rash, PN, 
diarrhea, anemia, thrombocytopenia, and neutropenia. The highest grade of toxicity over the 
treatment duration was used for each patient in the logistic regression analysis. The 
toxicity-graded data were then separated into 2 groups for the purposes of the analysis: Grade 2 
or higher versus Grade 1 or lower. The data were categorized in this way because patients on 
maintenance therapy will be receiving drug for a long duration and at a time when they are likely 
to be asymptomatic from their disease; therefore, an important component of a good maintenance 
treatment would be a tolerable adverse effect profile to contribute to an overall reasonable QOL. 
Under these conditions, even Grade 2 toxicities (particularly nonhematologic toxicities) may be a 
significant burden to the patient. Results from the logistic regression analysis indicated that of 
the 7 evaluated AEs, statistically significant relationships to exposure (p < 0.05) were observed 
for 5 AEs (fatigue, rash, diarrhea, thrombocytopenia, and neutropenia) as shown in Figure 1-1.
Primary logistic regression analysis was also performed for efficacy. For this analysis, efficacy 
data were separated into 2 groups: stable disease (SD) or higher versus PD. The data were 
categorized in this way because in the heavily treated RRMM population, clinical benefit rate 
including SD was considered to represent a meaningful indicator of treatment-related disease 
control. Results from the analysis showed a significant (p < 0.05) relationship between the 
probability of having disease control (eg, SD or higher) and AUC. The dose/response curves 
indicate that a favorable benefit:risk may be achieved at doses of 3 mg and 4 mg, below the 
MTD.
Figure 1-1
Relationship Between Response (Stable Disease) to Single-Agent Ixazomib 
and Adverse Events (Grade 2) and AUC (N=44) in Patients With Relapsed 
and/or Refractory Multiple Myeloma
Abbreviations: AE=adverse event; AUC=area under the curve; SD=stable disease; W=weekly.
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Currently, there are 2 ongoing phase 3 trials with ixazomib citrate, co-administered with 
lenalidomide and dexamethasone, in patients with MM (Study C16010 in patients with RRMM 
and Study C16014 in patients with NDMM). Takeda’s phase 3 dose in these 2 pivotal trials is 4 
mg weekly, which is 1 dose level below the ixazomib MTD of 5.5 mg, and was chosen to 
optimize benefit:risk on the basis of results from Study C16004.
As noted previously, the balance of benefit:risk is paramount in the proposed maintenance study. 
Patients entering Study C16019 will already have had a clinical response to HDT, will likely be 
symptom free from their disease, and at the time they start maintenance therapy will have not 
have been previously exposed to ixazomib citrate. Therefore, the approach in this study is to 
initiate ixazomib maintenance therapy at a once-weekly dose of 3 mg and, if tolerated well after 
4 cycles, increase the dose to 4 mg to provide maximum possible clinical benefit.
As shown in Figure 1-1, at the starting dose of 3 mg ixazomib weekly, which is 54% of the 5.5-
mg MTD, as a weekly single agent, the logistic regression analysis predicts that the probabilities 
of Grade 2 or higher AEs are reduced by approximately 10% to 20% compared to a dose of 4 mg. 
Further, the 3-mg dose is within the therapeutic range for ixazomib (Figure 1-1) and represents 
the Level -1 dose administered in the ongoing phase 3 trials in the RRMM or NDMM settings.
Nonetheless, to provide patients the opportunity to derive maximum clinical benefit, the starting 
dose of 3 mg will be increased to 4 mg at Cycle 5 Day 1, provided that during the most recent 2 
cycles (Cycle 3 and 4), there have been no nonhematologic AEs ≥Grade 2 related to study drug, 
no dose interruptions related to study drug toxicities, and no delays of greater than 1 week in 
starting a cycle due to study drug toxicities. Patients who have had any dose reduction will not 
dose escalate. The selection of the time point for dose escalation in patients tolerating ixazomib 
was based on the observation that subjects’ tolerance of study drug could be determined early. A 
review of aggregate data from 275 patients participating in 5 phase 1/2 ixazomib MM studies 
(data cutoff of 15 February 2013) found 31 patients who had discontinued participation due to 
AEs (11.6%). Of those who discontinued for AEs, 27 (87%) patients had done so by the end of 
Cycle 4.
1.4.2
Rationale for Minimal Residual Disease Assessment
The assessment of residual tumor cells persisting after therapy, or minimal residual disease 
(MRD), is a central component of accurate disease prognosis and monitoring in many 
hematologic malignancies. The prognostic value of MRD has been clearly established in the
chronic and acute leukemias and lymphomas.[35-42] As a result, molecular MRD analysis is 
currently used for risk stratification, as well as assessment of therapy-induced reduction in tumor 
burden and regrowth after chemotherapy in these indications.[43] Recent studies have suggested 
that MRD assessment may also play a role in the MM treatment paradigm. Numerous reports 
have shown that molecular MRD status is predictive of progression-free and OS in MM 
patients.[44-46] These studies have primarily assessed the bone marrow for the presence of 
MRD, and in this study the classical flow cytometry methodology will be employed for the 
assessment of normal/abnormal immunophenotype using bone marrow aspirates, as well as a 
novel sequencing-based approach, for the assessment of MRD present in the blood of MM 
patients.
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1.4.2.1
Timing and Methods of MRD Assessment 
MRD assessment will be conducted using bone marrow aspirate (BMA) and blood samples 
collected for all patients with a VGPR or CR at screening, at Cycle 13 and at EOT 
(approximately 24 months [to the nearest complete cycle; if there are no treatment delays, this 
would be 26 cycles]). In addition, patients whose response improves to CR during the trial will 
be requested to submit a BMA and a blood sample, and the BMA sample may be collected 
during the BMA procedure for CR confirmation. 
MRD assessment in BMA samples will be done at the central laboratory using an 
immunophenotype-based methodology. This flow cytometry assay will assess the presence or 
absence or expression levels of 8 markers that differ between normal plasma cells and tumor 
plasma cells. The assay results will establish whether the patient who has a CR is MRD positive 
or negative (on the basis of a prespecified cutoff). Leftover plasma cells from the BMA samples 
will be used for the assessment of MRD using next-generation sequencing. The sequencing-
based method identifies myeloma cells in peripheral blood or bone marrow samples on the basis 
of the cells’ unique immunoglobulin gene rearrangements.[47,48] The sequencing assay can 
detect residual disease at levels of 1 in 1 million leukocytes, which provides higher sensitivity than 
standard flow-cytometric methods.[49] This methodology will be used to assess MRD in blood 
samples as well.
1.4.2.2
MRD Analyses 
The quality of CRs, as defined by achievement of “depth of response (MRD negative),” and the 
maintenance of MRD-negative CRs will be evaluated in this study, along with the correlation 
between MRD status and long-term clinical benefits such as PFS and OS. This provides another 
way to identify and describe the value of maintenance therapy for patients with MM.
The correlation between the MRD status in bone marrow and in peripheral blood samples and 
their correlation with long-term clinical benefits, such as PFS and OS, could provide a clear 
practical advantage for the recurrent assessment of MRD during and after treatment.
1.4.3
Rationale for Mutational Analyses
The heterogeneity of clinical results with myeloma therapeutics is partly related to variation in 
the molecular subtypes of myeloma and the complex interaction of each tumor with the biology 
of the host. Several clinical studies have shown that tumor biology can be directly related to the 
clinical efficacy of either multidrug combinations in myeloma (a validated gene expression 
model of high-risk MM is defined by deregulated expression of genes mapping to chromosome 
1[50-52] or to outcome after single-agent VELCADE therapy).[53,54] A recent whole genome 
sequencing study of MM patients reported the presence of mutations in known cancer genes that 
had either not previously been reported in MM such as BRAF, or that were present at much 
higher frequency in MM than previously reported (KRAS, NRAS).[55] Similar studies with 
samples from VELCADE clinical trials highlighted the link between mutations in these pathways 
and response to proteasome inhibitor.[56] Mutational analysis of tumor samples from patients 
with RRMM highlights the prevalence of RAS/RAF pathway mutations and their potential 
impact on clinical outcomes.[56,57]
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In this clinical study, the link between clinical outcomes and the presence of specific gene 
mutations in key pathways, such as RAF/RAS, will be tested using archival tumor samples as 
well as a portion of bone marrow aspirates that are MRD positive (if available). These 
hypotheses will be tested in all patients. Additional analyses of tumor molecular characteristics 
may be done to identify biomarkers determined to be clinically meaningful in this study.
1.4.4
Rationale for Blood-Based Biomarkers
1.4.4.1
Circulating Proteasome Levels and Single-Nucleotide Polymorphism Analyses
Circulating proteasome levels have been demonstrated to be an independent prognostic factor in 
MM patients with increasing circulating proteasome levels correlating with advanced disease.[58]
Given that ixazomib directly targets the 20S proteasome, this leads to the possibility that 
pretreatment circulating proteasome levels may be relevant for prediction of patient response to 
therapy. Retrospective analysis of baseline serum proteasome levels from clinical trial samples 
for patients treated with bortezomib in combination with melphalan and prednisone 
demonstrated that circulating proteasome levels were associated with both OS and PFS only for 
bortezomib-containing therapy leading to the possibility that high-circulating proteasome levels 
could be both a poor prognostic and also a specific marker of poor outcome with bortezomib. 
These data point to the potential value of further exploring the relationship between predose 
circulating proteasome levels and response to ixazomib citrate. In this study, a blood sample will 
be collected at screening to test the levels of circulating proteasome and its association to 
ixazomib efficacy. Recent data identify host variation, specifically germline DNA variants in 
proteasome subunits, and the nuclear factor kappa-light chain enhancer of activated B-cells 
(NFKB) pathway, as factors that might contribute to VELCADE clinical activity. For example, 
in the retrospective analyses of 2 independent VELCADE MM studies (internal unpublished 
data), an increased long term clinical benefit in patients positive for P11A single-nucleotide 
polymorphism (SNP) in the proteasome (prosome, macropain) subunit, beta type, 1 (PSMB1) 
gene has been observed. In this study, a blood sample will be collected at baseline for the 
assessment of P11A SNP as well as other SNPs potentially associated to responsiveness or 
resistance to proteasome inhibition.
1.5
Potential Risks and Benefits
As of 27 March 2013, preliminary clinical data are available for a total of 653 patients across 13 
studies. Clinical safety data includes experience from patients who received multiple cycles 
followed by treatment-free periods and from patients who reduced or discontinued treatment. 
The emerging safety profile (as noted in the IB and SMA) indicates that the AEs reported with 
ixazomib are generally consistent with the class-based effects of proteasome inhibition and are 
similar to what has been previously reported with bortezomib, though the frequency may slightly 
differ. While some of these potential toxicities may be severe, they can be managed by clinical 
monitoring and standard medical intervention. It is possible that ixazomib will have toxicities 
that were not previously observed in or predicted from its evaluation in nonclinical studies or 
from ongoing and completed clinical studies. To mitigate the inherent risks in clinical studies of 
ixazomib citrate, patients are monitored closely for anticipated toxicities. Guidance for the 
management of AEs and procedures for modifying doses are provided in the protocols, and drug 
dosage can be modified by either reducing the dose administered or by interruption of the 
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scheduled treatment. The weekly oral schedule that will be evaluated in this trial has been 
evaluated and determined to be tolerable in other trials of oral ixazomib in MM or in the 
lymphoma trial of IV ixazomib at the corresponding oral doses after accounting for oral 
bioavailability.
Ixazomib shows early signs of antitumor activity as evidenced by at least a 50% reduction in 
disease burden in some patients and prolonged disease stabilization in others across all ongoing 
trials. VELCADE’s proven utility in the treatment of MM and mantle cell lymphoma (MCL) and 
ixazomib citrate’s increased tissue distribution and activity in several xenograft models against 
the same components of the ubiquitin proteasome system support the further clinical 
investigation of ixazomib citrate. 
This trial will be conducted in compliance with the protocol, Good Clinical Practice (GCP), 
applicable regulatory requirements, and International Conference on Harmonisation (ICH) 
guidelines.
2.0
STUDY OBJECTIVES
2.1
Primary Objective
The primary objective of this study is:

To determine the effect of ixazomib maintenance therapy on PFS, compared to placebo, 
in patients with NDMM who have had a response (CR, very good partial response 
[VGPR], or partial response [PR]) to induction therapy followed by HDT and ASCT.
2.2
Key Secondary Objective
The key secondary objective is:

To determine the effect of ixazomib maintenance therapy on OS compared to placebo. 
2.3
Other Secondary Objectives
The other secondary objectives are:

To determine the effect of ixazomib maintenance therapy on improving best response for 
patients who enroll in the study at PR or VGPR, as well as maintaining best overall 
response for patients who enroll in the study at CR.

To determine the effect of ixazomib maintenance therapy on TTP. 

To determine the effect of ixazomib maintenance therapy on progression-free survival 2 
(PFS2), defined as time from the date of randomization to the date of objective disease 
progression on next-line treatment or death from any cause, whichever occurs first. 

To determine the effect of ixazomib maintenance therapy on time to start of the next line 
of treatment, defined as the time from the date of randomization to the date of the first 
dose of the next line of antineoplastic therapy for any reason.

To determine the effect of ixazomib maintenance therapy on time to end of the next line 
of treatment, defined as the time from the date of randomization to the date of the last 
dose of the next line of antineoplastic therapy for any reason.
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
To determine the effect of ixazomib maintenance therapy on duration of the next line of 
antineoplastic therapy.

To assess the incidence of new primary malignancies in patients receiving ixazomib 
maintenance therapy compared with placebo following ASCT. 

To evaluate the frequency of conversion from MRD positive to MRD negative, or the 
maintenance of MRD negativity, after 1 and 2 years of therapy in patients treated with 
ixazomib compared to placebo, using bone marrow aspirates and 8-color flow cytometry 
or next-generation sequencing.

To assess the correlation between MRD status (assessed by 8-color flow cytometry and 
next-generation sequencing) and PFS and OS, using bone marrow aspirates.

To determine the effects of ixazomib maintenance therapy on PFS and OS in high-risk 
cytogenetic patient groups characterized by individual or multiple cytogenetic 
abnormalities, such as del17, t(4;14), t(14;16), ampl 1q, del13, or del1p. 

To determine the long-term safety and tolerability of ixazomib administration to multiple 
myeloma patients following ASCT. 

To assess overall health-related quality of life (HRQL), as measured by the global health
domain of the European Organization for Research and Treatment of Cancer Quality of 
Life Questionnaire (EORTC QLQ-C30). 

To collect PK data to contribute to population PK and exposure response (safety/efficacy) 
analysis.

To evaluate the resolution and improvement of PN, if it occurs, by grading at each 
subsequent monthly visit until 1) resolution of PN, 2) the start of an alternative 
antineoplastic treatment, or 3) 6 months after progression has occurred, whichever occurs 
first.
2.4
Exploratory Objectives

To measure the rate of increase in tumor burden, measured by M-protein level, after PD 
before the start of next-line therapy.

To determine the impact of mutations in the RAS/RAF pathway, and other key genes in 
MM, on the maintenance of response and on PFS and OS.

To determine the effects of ixazomib maintenance therapy on PFS and OS and response 
in patients with polymorphisms in proteasome and nuclear factor kappa-light chain 
enhancer of activated B-cells (NFB)–related genes, such as PSMB1 and TRAF3 or 
circulating proteasome levels.

To evaluate the correlation between MRD readouts, using sequencing, in bone marrow 
aspirates and blood samples.

To evaluate the correlation between MRD readouts in BMA samples using flow and 
MRD readouts in BMA samples using sequencing.
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
To evaluate potential mechanisms of treatment-emergent resistance, such as somatic 
mutations in proteasome subunits and in key signaling pathways, or change in pathways 
activity, in tumors that exhibit PD.

To assess HRQL in patients who receive ixazomib maintenance therapy as measured by 
function and symptom domains of the EORTC QLQ-C30 instrument and by the EORTC 
QLQ-MY20 instrument.

To evaluate health care resource utilization (HU) and calculate utility values using the 
EuroQol 5-Dimensional Health Questionnaire (EQ-5D).
3.0
STUDY ENDPOINTS
3.1
Primary Endpoint

PFS, defined as the time from the date of randomization to the date of first documentation 
of disease progression, as evaluated by an independent review committee (IRC), or death 
due to any cause, whichever occurs first.
3.2
Key Secondary Endpoint

OS, measured as the time from the date of randomization to the date of death.
3.3
Other Secondary Endpoints

Best response achieved or maintained (including PR, VGPR, and CR) prior to PD or 
subsequent therapy. 

TTP, measured as the time from randomization to the date of first documented progression.

PFS2, defined as time from the date from randomization to the date of objective disease 
progression on next-line treatment or death from any cause, whichever occurs first.

Time to start of the next line of therapy.

Time to end of the next line of therapy.

Duration of the next line of therapy.

Development of new primary malignancy.

The conversion rate from MRD positive to MRD negative, or the maintenance of MRD 
negativity, after 1 and 2 years of therapy in patients treated with ixazomib compared to 
placebo, using bone marrow aspirates and 8-color flow cytometry or next-generation 
sequencing. 

Correlation between MRD status (assessed by 8-color flow cytometry and next-generation 
sequencing) and PFS and OS, using bone marrow aspirates.

OS benefits in high-risk population, such as patients carrying del17, t(4;14), t(14;16), ampl 
1q, del13, or del1p.

PFS benefits in high-risk population, such as patients carrying del17, t(4;14), t(14;16), ampl 
1q, del13, or del1p.
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
Eastern Cooperative Oncology Group (ECOG) performance status.

AEs.

Serious adverse events (SAEs).

Assessments of clinical laboratory values. 

Collection of overall HRQL data from the Global Health Status/QOL subscale of the EORTC 
QLQ-C30. 

Ixazomib plasma concentration-time data.

Time to resolution and time to improvement of PN events.
3.4
Exploratory Endpoints

The rate of increase in tumor burden, measured by M-protein level, after PD before the start 
of next-line therapy. 

Association between mutations in key signaling pathways, such as RAS/RAF, and response, 
PFS, and OS, using archival materials.

Association between polymorphisms in proteasome and NFKB-related genes, such as 
PSMB1 and TRAF-3, or circulating proteasome levels, and response, TTP, PFS, and OS 
using blood samples.

Correlation between MRD readouts, using sequencing, in bone marrow aspirates and blood 
samples.

Correlation between MRD readouts in BMA samples using flow and MRD readouts in BMA 
samples using sequencing.

Detection of somatic mutations in proteasome subunits and in key signaling pathways, or 
change in pathways activity, in tumors that exhibit PD.

Collection of HRQL data from the function and symptom domains of the EORTC QLQ-C30 
and the MY20 module. 

Assessment of HU by collecting the number of medical encounters and assessment of health 
utility values per the EQ-5D questionnaire.
4.0
STUDY DESIGN
4.1
Overview of Study Design
This is a phase 3, randomized, double-blind, placebo-controlled, multicenter study in patients 
with NDMM. The purpose of the study is to evaluate the role of maintenance therapy with 
ixazomib (compared to matching placebo) in patients who have undergone induction therapy 
according to regional SoC, followed by a conditioning regimen containing high-dose melphalan 
(200 mg/m2) and a single ASCT. Induction therapy must include PI and/or IMiD-based regimens. 
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Vincristine, Adriamycin (doxorubicin), and dexamethasone (VAD) is not an acceptable 
induction therapy for this trial. 
Screening and Randomization
Patients who have achieved clinical and hematologic recovery following induction, HDT, and 
ASCT will initiate screening for study eligibility no earlier than 75 days after transplant, 
complete screening within 15 days, and be randomized no later than 115 days after transplant. 
Eligible patients (those who have a documented CR, VGPR, or PR during screening and who 
have met all additional inclusion/exclusion criteria) will be enrolled and randomized in a 3:2 
ratio to ixazomib or placebo. A Takeda project clinician or designee will confirm patient 
eligibility before randomization by the investigator. The stratification factors are induction 
regimen (PI without an IMiD vs IMiD without a PI vs PI and IMiD); pre-induction International 
Staging System (ISS) (stage 1 vs stage 2 or 3); and response after transplantation, defined as the 
response following induction, HDT, and ASCT measured during screening (CR or VGPR vs PR). 
Study Treatment
Patients will receive blinded study drug (ixazomib or matching placebo) orally on Days 1, 8, and 
15 of every 28-day cycle. Ixazomib capsules and matching placebo capsules will be subsequently 
referred to as study drug when detailing blinded study procedures. A starting dose of 3 mg of 
study drug will be used for all patients through Cycle 4. Upon evaluation of toxicities at the 
completion of Cycle 4, and on the basis of the dose escalation criteria detailed in Section 6.5, the 
study drug dose will be escalated to 4 mg beginning with Cycle 5 Day 1, and administered on the 
same schedule for the duration of the study, to provide maximum possible clinical benefit for 
patients who tolerated the first 4 cycles of treatment.
The treatment period of the study is defined as any time a patient is receiving study drug, and 
will comprise 28-day treatment cycles. Patients will have study assessments performed at regular 
treatment cycle intervals while they are participating in the study: weekly (Days 1, 8, and 15) for 
the first cycle, twice a treatment cycle during the second cycle (Days 1 and 8), and then once a 
treatment cycle for the remainder of their participation in the treatment period for a maximum 
duration of approximately 24 months (to the nearest complete cycle; if there are no treatment 
delays, this would be 26 cycles) or until they experience PD, unacceptable toxicity, or 
discontinue for alternate reasons, whichever occurs first. 
Patients will be assessed for disease response and PD every cycle during the treatment period by 
the treating physician/investigator, according to the IMWG uniform response criteria, version 
2011. In addition, an IRC will assess disease response and PD; the response evaluations are for 
endpoint determinations only and will not be shared with investigators. Dose-modification 
guidelines are given in Section 6.4. Unscheduled visits may occur between treatment cycles as 
required (see Section 7.5). For example, symptomatic pain progression should result in an 
interim unscheduled visit, as would ongoing Grade 3 or worse AEs.
Patients will receive study treatment for a maximum duration of approximately 24 months (to the 
nearest complete cycle; if there are no treatment delays, this would be 26 cycles) or until 
documented PD (on the basis of the IMWG uniform response criteria, version 2011) or 
intolerable toxicity, whichever occurs first. Patients who do not discontinue because of PD or 
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toxicities will complete the treatment cycle that is ongoing at 24 months (regardless of the cycle 
number) before discontinuing treatment.
Patients will attend an EOT visit 30 days (+1 week) after receiving their last dose of study drug.
Study Follow-up
At the EOT visit, patients will enter the follow-up phase (see the Study Overview Diagram). 
There are 4 Follow-up periods: PFS, PD, PFS2, and OS. 
Patients will be assessed for disease response and PD during the PFS Follow-up period by the 
treating physician/investigator, according to the IMWG uniform response criteria, version 2011, 
and by the IRC. After PD occurs, the date and characteristics of PD2, and disease status, will be 
assessed by the treating physician/investigator only.
Progression-Free Survival Follow-up and PD Follow-up
If a patient completes 24 months of study treatment (to the nearest complete cycle; if there are no 
treatment delays, this would be 26 cycles) before PD or discontinues the study drug before PD, 
the patient will enter the PFS Follow-up period of the study and undergo follow-up every 12 
weeks until PD occurs. After PD occurs, the patient enters the PD Follow-up period and 
continues to be followed every 12 weeks until initiation of the next line of therapy by the 
investigator/treating physician.
If a patient has PD while on study drug during the Treatment period, the patient will enter 
directly into the PD Follow-up period and will be followed every 12 weeks until initiation of the 
next line of therapy by the investigator/treating physician.
Progression-Free Survival 2 Follow-up and Overall Survival Follow-up
Patients who start the next line of therapy (regardless of when) will enter the PFS2 Follow-up 
period. During the PFS2 Follow-up period, follow-up will occur every 12 weeks until PD2 
occurs. 
After patients in the PFS2 Follow-up period have PD2 on next-line therapy, they enter the OS 
Follow-up period. During the OS Follow-up period, follow-up will occur every 12 weeks until 
death or termination of the study by the sponsor, whichever occurs first.
Study Endpoints and Other Details
The primary endpoint of PFS will be supported by prespecified evidence of clinical benefit as
measured by the key and other secondary endpoints. There will be 5 IAs and 1 FA in the study. 
The first IA will be the primary analysis (and the only analysis) for PFS for statistical testing 
purposes. If PFS is significant at the first IA, then OS will be tested at this first IA and at 
subsequent analyses.
An independent data monitoring committee (IDMC) will review safety and efficacy data at the 
IA and safety data at regularly scheduled meetings. An IRC will assess disease response and PD. 
See Section 9.3 for more information. 
If PFS is found to be significant at the first IA, then central efficacy laboratory data collection 
and investigator-assessed response for protocol purposes (along with IRC assessment of disease 
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response and PD) will cease and will not be recorded in the eCRF. Central laboratory samples 
are no longer collected since the primary endpoint was met. However, investigator assessment of 
response-based data may continue for the purpose of determining PFS2.
The original Schedule of Events (Section 15.10), Streamlined Schedule of Events, and the Study 
Periods and Corresponding Endpoints Diagram describe the study assessments and timing in 
detail. These include clinical, laboratory, and other response measures; HRQL evaluations 
through patient self-reported instruments; and MRD assessments.
For HRQL, the focus is on tolerability and symptom burden, but the instruments also elucidate 
the effects of disease on physical, social, psychological/emotional, and cognitive functioning. 
ECOG performance status and AEs will be assessed, and laboratory values, vital signs, and 
electrocardiograms (ECGs) will be obtained to evaluate the safety and tolerability of ixazomib. 
Toxicity will be evaluated according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE), version 4.03, effective date 14 June 2010.[59]
4.2
Number of Patients
Approximately 652 patients will be enrolled in this study from approximately 230 study centers 
in North America, Asia Pacific, Europe, and Latin America. Enrollment is defined as being 
randomized to treatment in the study.
4.3
Duration of Study
Patients will be treated until documented disease progression, intolerable toxicity, or for a 
maximum duration of approximately 24 months (to the nearest complete cycle), whichever 
occurs first. If there are no treatment delays, this would be 26 cycles. Subsequent to the 24-
month treatment period or removal from study therapy due to disease progression or toxicity, 
patients will be followed for disease status, subsequent therapies, HRQL, new primary 
malignancies, and survival.
5.0
STUDY POPULATION
Adult patients age 18 years or older with a confirmed diagnosis of MM who have had a response 
(CR, VGPR, or PR) to primary MM therapy consisting of SoC induction, a conditioning regimen 
containing high-dose melphalan (200 mg/m2), and single ASCT will be eligible for this study. 
5.1
Inclusion Criteria
Each patient must meet all of the following inclusion criteria to be randomized to treatment:
1. Adult male or female patients 18 years or older with a confirmed diagnosis of symptomatic 
multiple myeloma according to standard criteria (see Section 15.2).
2. Documented results available for cytogenetics/fluorescence in situ hybridization (FISH)
obtained at any time before transplant and for ISS staging at the time of diagnosis. 
3. Underwent SoC induction therapy (induction therapy must include PI and/or IMiD-based 
regimens as primary therapy for multiple myeloma), followed by a single ASCT with a high-
dose melphalan (200 mg/m2) conditioning regimen, within 12 months of diagnosis. 
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Vincristine, Adriamycin (doxorubicin), and dexamethasone (VAD) is not an acceptable 
induction therapy for this trial.
4. Started screening no earlier than 75 days after transplant, completed screening within 15 days, 
and randomized no later than 115 days after transplant.
5. Patient must have not received post-ASCT consolidation therapy.
6. Documented response to ASCT (PR, VGPR, CR/stringent complete response [sCR]) 
according to IMWG criteria (as defined in Section 15.9).
7. ECOG performance status of 0 to 2.
8. Female patients who: 

If they are of childbearing potential, agree to practice 2 effective methods of 
contraception, at the same time, from the time of signing the informed consent through 90 
days after the last dose of study drug, AND

Must also adhere to the guidelines of any treatment-specific pregnancy prevention 
program, if applicable, OR 

Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
postovulation methods] and withdrawal are not acceptable methods of contraception.)
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 drug, AND

Must also adhere to the guidelines of any treatment-specific pregnancy prevention 
program, if applicable, OR 

Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
postovulation methods for the female partner] and withdrawal are not acceptable methods 
of contraception.)
9. 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.
10. Suitable venous access for the study-required blood sampling.
11. Patient is willing and able to adhere to the study visit schedule and other protocol 
requirements.
12. Patients must meet the following clinical laboratory criteria at study entry:

Absolute neutrophil count (ANC) 1,000/mm3 and platelet count 75,000/mm3. Platelet 
transfusions to help patients meet eligibility criteria are not allowed within 3 days before 
randomization.

Total bilirubin 1.5 the upper limit of the normal range (ULN).
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
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 3 ULN.

Calculated creatinine clearance 30 mL/min.
5.2
Exclusion Criteria
Patients meeting any of the following exclusion criteria are not to be randomized to treatment:
1. Multiple myeloma that has relapsed following primary therapy or is not responsive to 
primary therapy. For this study, SD following ASCT will be considered nonresponsive to 
primary therapy.
2. Double (tandem) ASCT.
3. Radiotherapy within 14 days before the first dose of study drug.
4. Diagnosed or treated for another malignancy within 5 years before randomization or 
previously diagnosed with another malignancy with evidence of residual disease. Patients 
with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have 
undergone complete resection.
5. Female patients who are lactating and breastfeeding or have a positive serum pregnancy test 
during the Screening period. 
6. Major surgery within 14 days before randomization. 
7. Central nervous system involvement.
8. Infection requiring IV antibiotic therapy or other serious infection within 14 days before 
randomization.
9. Diagnosis of Waldenstrom’s macroglobulinemia, POEMS (polyneuropathy, organomegaly, 
endocrinopathy, monoclonal gammopathy, and skin changes) syndrome, plasma cell 
leukemia, primary amyloidosis, myelodysplastic syndrome, or myeloproliferative syndrome.
10. Evidence of current uncontrolled cardiovascular conditions, including uncontrolled 
hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, 
unstable angina, or myocardial infarction within the past 6 months.
11. Systemic treatment with strong CYP3A inducers (rifampin, rifapentine, rifabutin, 
carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John’s wort within 
14 days before randomization in the study.
12. Active hepatitis B or C virus infection, or known human immunodeficiency virus (HIV) 
positive. 
13. Comorbid systemic illnesses or other severe concurrent disease which, in the judgment of the 
investigator, would make the patient inappropriate for entry into this study or interfere 
significantly with the proper assessment of safety and toxicity of the prescribed regimens (eg, 
PN that is Grade 1 with pain or Grade 2 or higher of any cause). 
14. Psychiatric illness/social situation that would limit compliance with study requirements.
15. Known allergy to any of the study medications, their analogues, or excipients in the various 
formulations of any agent.
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16. Inability to swallow oral medication, inability or unwillingness to comply with the drug 
administration requirements, or GI procedure that could interfere with the oral absorption or 
tolerance of treatment.
17. Treatment with any investigational products within 60 days before the first dose of the study 
drug regimen.
6.0
STUDY DRUG
6.1
Study Drug Administration
All protocol-specific criteria for administration of study drug must be met and documented 
before drug administration. Study drug will be administered only to eligible patients under the 
supervision of the investigator or identified subinvestigator(s). Patients should be monitored for 
toxicity as necessary and doses of the appropriate study drug should be modified as needed to 
accommodate patient tolerance to treatment; this may include symptomatic treatment, dose 
interruptions, and adjustments of dose. 
All doses must be taken as outlined in the original Schedule of Events (Section 15.10). During 
the first cycle of treatment, all patients will receive doses of ixazomib or placebo capsules in the 
clinic. Subsequent to the Cycle 2 Day 8 assessment and dose, patients will take the study drug at 
home as directed for the remainder of Cycle 2. For subsequent cycles in which a predose PK is to 
be drawn on Day 1 (Cycles 3-10), the Day 1 dose should be taken in the clinic (see) particular 
note, the Cycle 5 Day 1 dose will be taken in the clinic following determination of whether the 
study drug dose should be escalated from 3 mg to 4 mg. All other doses may be taken at home. 
Refer to the study manuals for additional instructions regarding study drug administration.
6.2
Test Article (Ixazomib Capsules and Matching Placebo Capsules)
Ixazomib capsules and matching placebo capsules will be subsequently referred to as study drug 
when detailing blinded study procedures.
Ixazomib active capsules will be supplied as single capsules at 4 dose strengths, containing 0.5, 
2.3, 3.0, or 4.0 mg of ixazomib. Placebo capsules will be identical in shape, size, and color to the 
ixazomib capsules. Both the active and placebo capsules will be provided by the sponsor.
Study drug will be initially given as a single, oral dose of 3 mg weekly (Days 1, 8, and 15) for 3 
weeks, followed by 1 week without study drug in a 28-day cycle. Following the first 4 cycles of 
therapy, the dose will be increased to 4 mg on Cycle 5 Day 1 for patients tolerating the drug, 
according to the dose escalation criteria in Section 6.5.
Patients should be instructed to swallow the study drug capsules whole with water and not to 
break, chew, or open the capsules. Study drug should be taken on an empty stomach, at least 1 
hour before or no sooner than 2 hours after a meal. The capsule should be swallowed with water. 
A total of approximately 240 mL (8 oz) 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 never 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.
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6.3
Dose-Modification Guidelines
The patient will be evaluated for possible toxicities that may have occurred after the previous 
dose(s) according to the original Schedule of Events (Section 15.10). Toxicities are to be 
assessed according to the NCI CTCAE, version 4.03. Before beginning the next cycle of 
treatment, refer to the guidelines in Section 6.4. 
Further clarification can be obtained in consultation with the Takeda project clinician or designee. 
If multiple toxicities are noted, the dose adjustments and/or delays should be made according to 
the most severe toxicity guidelines. 
6.4
Criteria for Dose Modification (Delays, Reductions, and Discontinuations)
6.4.1
Dose Adjustment
Patients experiencing AEs attributed to study drug may continue in the study but may have doses 
of study drug held or reduced by at least 1 dose level as shown in Table 6-1. When a dose 
reduction of study drug is required due to toxicity, no dose re-escalation will be permitted.
Table 6-1
Study Drug Dose Adjustments 
Dose Level
Dose Reduction
Starting Dose
3 mga
4 mgb
-1
2.3 mg
3 mg
-2
1.5 mgc
2.3 mg
-3
Discontinue
1.5 mgc
-4
Discontinue
Discontinue
a Cycles 1-4, or for patients unable to dose escalate at Cycle 5.
b Patients who dose escalated at Cycle 5.
c This dose consists of 3 0.5-mg capsules taken together.
6.4.2
Criteria for Toxicity Recovery Before Beginning the Next Treatment Cycle
Treatment with study drug will be repeated every 28 days. The criteria for toxicity recovery 
before the patient can begin the next cycle of treatment are as follows:

Absolute neutrophil count (ANC) 1,000/mm3

Platelet count 75,000/mm3

All nonhematologic toxicity considered to be related to treatment with study drug 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 (eg, chronic anemia managed by
intermittent transfusions and/or erythropoietic growth factor).
If the patient fails to meet the previously cited criteria for retreatment, initiation of the next cycle 
of treatment should be delayed for 1 week. At the end of that time, the patient should be re-
evaluated to determine whether the criteria for re-treatment have been met. If the patient 
continues to fail to meet the previously cited criteria, delay therapy and continue to re-evaluate. 
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Should the start of the next cycle need to be delayed for ≥2 weeks because of incomplete 
recovery from treatment-related toxicity, the dose will be reduced by 1 dose level when therapy 
resumes. Should treatment need to be delayed for 4 weeks because of incomplete recovery from 
treatment-related toxicity, therapy with study drug 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.
6.4.3
Study Drug Dose Modification for Hematologic Toxicities
Please refer to Table 6-2 for dose delay and reduction recommendations for hematologic 
toxicities attributed to study drug. Dose level reductions should be made in accordance with 
those outlined in Table 6-1. 
Table 6-2
Study Drug 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 citrate/placebo dosing 
day (other than Day 1)
Study drug dose should be withheld. Complete blood 
count (CBC) 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, study drug may be reinitiated and reduced by 1 
dose level in accordance with reductions outlined in 
Table 6-1.
Dose Modifications for Subsequent 
Treatment Cycles 
Delay of 2 weeks at the start of a subsequent 
cycle due to lack of toxicity recovery as defined 
in Section 6.4.2: 

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 study drug until resolution per criteria.
Reduce study drug by 1 dose level as outlined in 
Table 6-1.
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 due to toxicity timing, ie, after Day 15 dosing 
thus a dose reduction was not required at that 
point in the cycle, reduce study drug 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.
Abbreviations: ANC=absolute neutrophil count; CBC=complete blood count.
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When a dose reduction of study drug is required, no re-escalation of dose will be permitted. 
Please refer to Table 6-4 for criteria for re-treatment and cycle delays.
6.4.4
Study Drug Dose Modification for Nonhematologic Toxicities
Please refer to Table 6-3 for dose delay and reduction recommendations for nonhematologic 
toxicities considered related to study drug. Dose level reductions should be made in accordance 
with those outlined in Table 6-1. 
Table 6-3
Study Drug Dose Modification for Nonhematologic Toxicities
Criteria
Action
Peripheral Neuropathy:
Grade 1 peripheral neuropathy 
No action
Grade 1 signs & 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 study drug until resolution 
to ≤ Grade 1 without pain or 
baseline
Grade 2 signs & symptoms: 
moderate symptoms, 
limiting instrumental 
activities of daily living 
(ADL)
New or worsening Grade 2 peripheral 
neuropathy with pain or Grade 3
Hold study drug until resolution 
to ≤ Grade 1 or baseline
Reduce study drug to next lower 
dose upon recovery as outlined in 
Table 6-1.
Grade 3 signs & symptoms: 
severe symptoms, limiting 
self care ADL, assistive 
device indicated
New or worsening Grade 4 peripheral 
neuropathy
Discontinue study drug
Grade 2 Rash
Symptomatic recommendations as per Section 6.9. The 
investigator and project clinician or designee may discuss 
considerations for dose modifications and symptom management.
All Other ≥ Grade 2 Nonhematologic 
Toxicities
Hold study drug until resolution to ≤Grade 1 or baseline.
Reduce study drug by 1 dose level as outlined in Table 6-1.
Note: A dose level reduction will be made either based on 
within-cycle criteria or for a subsequent cycle criteria, but not for 
both for a same cycle.
Grade 4 Nonhematologic Toxicities 
Consider permanently discontinuing study drug, except in the 
case where the investigator determines the patient is obtaining a 
clinical benefit and has discussed this with the project clinician or 
designee.
Abbreviations: ADL=activities of daily living.
Grade 4 nonhematologic toxicities will, in general, require that treatment with study drug be 
permanently discontinued. If, in the opinion of the investigator and the Takeda project clinician 
or designee, it is in the patient’s best interest to continue treatment with study drug, then the dose 
of study drug 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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When a dose reduction of study drug is required, no re-escalation of dose will be permitted.
Please refer to Table 6-4 for criteria for retreatment and cycle delays. Dose level reductions 
should be made in accordance with those outlined in Table 6-1.
Table 6-4
Criteria for Study Drug Retreatment and Cycle Delays Subsequent to 
Hematologic and Nonhematologic Toxicities
Criteria
Action
Both hematologic & nonhematologic 
event
Delay therapy 1 week.
Re-evaluate patient; if still not resolved, delay therapy 
1 additional week.
Hematologic & nonhematologic event 
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 6-1 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).
6.5
Criteria for Dose Escalation at Cycle 5
To provide patients the opportunity to derive maximum clinical benefit from study drug 
maintenance, the dose of 3 mg will be increased to 4 mg at Cycle 5 provided that, during the 
most recent 2 cycles (Cycle 3 and 4), there have been no nonhematologic AEs ≥Grade 2 related 
to study drug, no dose interruptions related to study drug toxicities, and no delays of greater than 
1 week in starting a cycle due to study drug toxicities. Patients who have had any dose reductions 
will not dose escalate. If dose escalation was inadvertently missed at Cycle 5, escalation may be 
performed with permission from the Takeda project clinician or designee.
6.6
Excluded Concomitant Medications and Procedures
The following medications and procedures are prohibited during the treatment period of the 
study. 
Systemic treatment with any of the following 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 DDI with an inducer, ixazomib exposure would be decreased.)

Strong CYP3A inducers: rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, and 
phenobarbital
The following medicinal products and procedures are prohibited during the active treatment 
period of the study:

St. John’s wort 

Any antineoplastic treatment with activity against MM, other than study drugs
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
Radiation therapy (note that, in general, the requirement for local radiation therapy indicates 
disease progression)

Platelet transfusions to help patients meet eligibility criteria are not allowed
6.7
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 first dose of the study 
drug regimen until 30 days after the final dose 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 [GM-CSF]) are permitted. Their use should follow the 
product label, published guidelines, and/or institutional practice; however, alternative usage 
may be reviewed with the Takeda project clinician or designee.

Erythropoietin will be allowed in this study.

Patients should be transfused with red cells and platelets as clinically indicated.

Patients who are receiving biphosphonates for previously identified lytic destruction of bone 
or with osteopenia may continue treatment according to the American Society of Clinical 
Oncology (ASCO) Clinical Practice Guidelines or institutional practice in accordance with 
the product label, unless specifically contraindicated. If bisphosphonate therapy was not 
started before the study start, initiation of treatment should be discussed with the project 
clinician. 

Institutional guidelines for deep vein thrombosis (DVT)/pulmonary embolism (PE) 
prophylaxis should be followed.

Supportive measures consistent with optimal patient care may be given throughout the study.
6.8
Precautions and Restrictions 
Fluid deficit should be corrected before initiation of treatment and during treatment.
Nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided in patients with impaired 
renal function, given reported NSAID-induced renal failure in patients with decreased renal 
function.
It is not known what effects ixazomib has on human pregnancy or development of the embryo or 
fetus. Therefore, female patients participating in this study should avoid becoming pregnant, and 
male patients should avoid impregnating a female partner. Nonsterilized female patients of 
reproductive age and male patients should use effective methods of contraception through 
defined periods during and after study treatment as specified below.
Female patients must meet 1 of the following: 

Postmenopausal for at least 1 year before the screening visit, or

Surgically sterile, or
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
If they are of childbearing potential, agree to practice 2 effective methods of contraception 
from the time of signing of the informed consent form (ICF) through 90 days after the last 
dose of study drug, or

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of 
the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods] and withdrawal are not acceptable methods of contraception.)
Male patients, even if surgically sterilized (ie, status postvasectomy) must agree to 1 of the 
following:

Practice effective barrier contraception during the entire study treatment period and through 
90 days after the last dose of study drug, or

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of 
the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods for the female partner] and withdrawal are not acceptable methods of contraception.)
6.9
Management of Clinical Events 
Prophylaxis Against Risk of Reactivation of Herpes Infection
Patients may be at an increased risk of infection including reactivation of herpes zoster and 
herpes simplex viruses. Unless there is a clinical contraindication, prophylactic antiviral therapy 
is required for every patient while receiving study treatment. Examples of acceptable antiviral 
therapy include acyclovir (eg, 400 mg given orally, 3 times a day), famcyclovir (eg, 125 mg 
given orally, twice a day), or valacyclovir (eg, 500 mg given orally, twice a day) or SoC/local 
practice. 
Pneumonia and Respiratory Tract Infections
Pneumonia, including serious infections, is a known risk in patients with multiple myeloma, 
especially following ASCT. Therefore, it is recommended that careful monitoring for serious 
respiratory tract infections and complications is followed with prompt introduction of antibiotics 
and supportive therapies, such as IV immunoglobulin, instituted as clinically indicated.
Nausea and/or Vomiting
Standard anti-emetics including 5-hydroxytryptamine 3 serotonin receptor antagonists are 
recommended for emesis if it occurs once treatment is initiated; prophylactic anti-emetics may 
also be considered at the physician’s discretion. Dexamethasone should not be administered as 
an anti-emetic. Fluid deficit should be corrected before initiation of study drug and during 
treatment.
Diarrhea
Prophylactic antidiarrheals will not be used in this protocol. However, 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. Fluid 
deficit should be corrected before initiation of treatment and during treatment. 
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Erythematous Rash With or Without Pruritus
Rash may range from limited erythematous areas, macular and/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 
predominately 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 
to 2 in severity. As in any other oncology trial, rash may occur in patients receiving placebo as 
well as in patients receiving ixazomib. 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 [see Section 
15.5]) is permitted. Management of a Grade 3 rash may require IV antihistamines or 
corticosteroids. Administration of study drug (and/or other causative agent if given in 
combination) should be modified per protocol and re-initiated 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, toxic epidermal necrolysis (TEN), drug reaction 
with eosinophilia and systemic symptoms (DRESS syndrome), and pemphigus vulgaris have 
been reported in oncology studies when ixazomib (or placebo) was given with concomitant 
medications that are known to cause rash (eg, Bactrim, lenalidomide, aspirin), and/or in the 
setting of confounding TEAEs. These severe, potentially life-threatening or deadly conditions 
may involve rash with skin peeling and mouth sores and should be clinically managed according 
to standard medical practice. Punch biopsies for histopathological analysis are encouraged at the 
discretion of the investigator. 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. Study drug 
administration should be modified as per dose modification recommendations in the protocol 
when thrombocytopenia occurs (see Section 6.4.3). Therapy can be reinitiated at a reduced level 
upon recovery of platelet counts. A rare risk is thrombotic thrombocytopenia 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.
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Neutropenia
Blood counts should be monitored regularly as outlined in the protocol with additional testing 
obtained 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. Study drug administration should be modified as per dose modification 
recommendations in the protocol when neutropenia occurs (see Section 6.4.3). Therapy can be 
reinitiated at a reduced level upon recovery of ANCs.
Fluid Deficit
Dehydration should be avoided since 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 GI toxicities and dehydration. 
Fluid deficit should be corrected before initiation of study drug and as needed during treatment 
to avoid dehydration (see Section 6.4.4).
Hypotension
Symptomatic hypotension and orthostatic hypotension with or without syncope have been 
reported with ixazomib. Blood pressure should be closely monitored 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 
and/or diuretics to manage their blood pressure (for either hypo- 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 initiation of study drug and as needed during treatment to avoid dehydration.
Posterior Reversible Encephalopathy Syndrome
One case of posterior reversible encephalopathy syndrome, which ultimately resolved, has been 
reported with ixazomib citrate. This condition is characterized by headache, seizures, and visual 
loss, as well as 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. 
Transverse Myelitis
One case of transverse myelitis has been reported with ixazomib. It is not known whether 
ixazomib causes transverse myelitis; however, because it 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 
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hospitalization for hemodynamic support. Gastric lavage may be considered if instituted within 1 
hour of ingestion of ixazomib overdose.
6.10
Blinding and Unblinding
To maintain the blind, all study personnel including the investigators, site personnel, study 
clinicians, and the sponsor will be blinded to the treatment assignments for the duration of the 
study. When a patient experiences disease progression, the investigator is encouraged to unblind 
the patient and take this information into account in planning the next line of therapy. 
Treatment assignments will be obtained through the interactive voice/web response system 
(IXRS) according to the procedures outlined in the study manuals. Information regarding the 
treatment assignments will be kept securely at Takeda or its designee, per its standard operating 
procedures. Emergency unblinding, if necessary, will be conducted via the IXRS.
6.11
Description of Investigational Agents
The ixazomib citrate drug product is provided in strengths of 4.0-, 3.0-, 2.3-, and 0.5-mg 
capsules as ixazomib (the active boronic acid). Matching placebo will be identical in size, shape, 
and color to the corresponding ixazomib capsule. The dose strengths are differentiated by both 
capsule size and color, as described in the Table 6-5. 
Table 6-5
Ixazomib Capsule Size and Color
Dose Strength (as Ixazomib)
Capsule Size
Capsule Color
4.0 mg
Size 3
Ivory
3.0 mg
Size 4
Light gray
2.3 mg
Size 4
Flesh
0.5 mg
Size 3
Dark green
For additional details, please see the IB and Pharmacy Manual.
6.12
Preparation, Reconstitution, and Dispensation
The study drug is dispensed in blisters in a child-resistant carton.
6.13
Packaging and Labeling
The study drug will be provided by Takeda. The study drug labels will fulfill all requirements 
specified by governing regulations. 
The capsules are individually packaged using cold form foil-foil blisters that are child resistant. 
There are 3 capsules per package. 
6.14
Storage, Handling, and Accountability
On receipt at the investigative site, study drug should remain in the blister and carton provided 
until use or dispensation. The container should be stored as directed by the label on the 
packaging. All excursions should be brought to the sponsor’s attention for assessment and 
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authorization for continued use. Ensure that the drug is used before the retest expiry date 
provided by Takeda. Expiry extensions will be communicated accordingly with updated 
documentation to support the extended shelf life.
Study drug dispensed to the patient for take-home dosing should remain in the blister packaging 
and carton and stored as directed by the label on the packaging as noted previously until the 
point of use. Comprehensive instructions should be provided to the patient to ensure compliance 
with dosing procedures. Patients who are receiving take-home medication should be given only 
1 cycle of medication at a time. Patients should be instructed to store the medication as directed 
by the label on the packaging for the duration of each cycle. Patients should be instructed to 
return their empty cartons to the investigative site, rather than discarding them, as permitted by 
site policy. Reconciliation will occur accordingly when the patient returns for their next cycle of 
take-home medication. Any excursions in temperature should be reported and dealt with on a 
case-by-case basis. 
Study drug dispensed to the patient for take-home dosing should remain in the blister packaging 
and carton and stored as directed by the label on the packaging as noted previously until the 
point of use. Comprehensive instructions should be provided to the patient to ensure compliance 
with dosing procedures. Patients who are receiving take-home medication should be given only 
1 cycle of medication at a time. Patients should be instructed to store the medication as directed 
by the label on the packaging for the duration of each cycle. Patients should be instructed to 
return their empty cartons to the investigative site, rather than discarding them, as permitted by 
site policy. Reconciliation will occur accordingly when the patient returns for their next cycle of 
take-home medication. 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 when handling the study drug. 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 study drug, 
including that study drug is to be taken as intact capsules.
Please refer to the Pharmacy Manual for additional instructions.
6.15
Other Protocol-Specified Materials 
No other drugs or ancillary material are supplied for use in this trial.
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7.0
STUDY CONDUCT
This trial will be conducted in compliance with the protocol, GCP, applicable regulatory 
requirements, and ICH guidelines.
7.1
Study Personnel and Organizations
The contact information for the Takeda project clinician or designee, the central laboratory, any 
additional clinical laboratories, or vendors participating in the study may be found in the study 
manuals. A full list of investigators is available in the sponsor’s investigator database.
7.2
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.
7.3
Treatment Group Assignments 
After written informed consent has been obtained, the patient will be assigned an enrollment 
code (country-, site-, and patient-specific) using IXRS.
Patient eligibility will be confirmed by a Takeda project clinician or designee before 
randomization by the investigator into the study. A centralized randomization using IXRS will be 
used. Patients will be randomized strictly sequentially at a center as they become eligible for 
randomization. If a patient discontinues from the study, that randomization code will not be 
reused, and the patient will not be allowed to re-enter the study.
7.4
Study Procedures
Patients will be evaluated at scheduled visits over 4 study periods: screening, treatment, EOT, 
and follow-up (PFS, PD, PFS2, and OS). 
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 Takeda project clinician or 
designee. If the study schedule is shifted, assessments must be shifted to ensure collection of 
assessments is completed before dosing. 
Refer to the original Schedule of Events (Section 15.10) and Streamlined Schedule of Events for 
timing of assessments. Additional details are provided as necessary in the sections that follow.
In acknowledgement of hospital, local, state, or national government restrictions, or other site-
related factors caused by the coronavirus disease 2019 (COVID-19) pandemic that may prevent 
investigators from conducting the study according to the Streamlined Schedule of Events at the 
clinical study site, investigators may continue patients in the study despite departure from the 
Streamlined 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 
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patients. For patients who are impacted by the COVID-19 pandemic, any procedures not 
conducted per the study protocol will be documented as a protocol deviation.
During contact with the patient, the study site physician or other qualified site staff should at 
minimum conduct AE collection. Other study assessments may be collected remotely as is 
feasible. 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.
7.4.1
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. 
7.4.2
Patient Demographics
The date of birth, race, ethnicity, and sex of the patient are to be recorded during screening.
7.4.3
Medical History
During the Screening period, a complete medical history will be compiled for each patient, 
including: 

Diagnosis (Section 15.2) and initial staging (Section 15.4) of MM, including biochemistry 
(serum protein electrophoresis [SPEP], urine protein electrophoresis [UPEP], serum/urine 
immunofixation, free light chains), bone marrow results, ISS stage (based on serum albumin 
and 2-microglobulin levels), and lactate dehydrogenase (LDH) levels. 

Cytogenetic evaluation should be performed before ASCT using FISH and/or conventional 
cytogenetics (karyotyping); if only 1 test is available, FISH is preferred. At a minimum, this 
should include testing for the presence or absence of at least 2 of the following 3 high-risk 
abnormalities, listed in order of preference: del(17p), t(4;14), and t(14;16). All cytogenetic 
evaluations will be performed locally by the site according to local standards. In selected 
regions where cytogenetic evaluation at the time of disease diagnosis is not routinely 
conducted, the sponsor may elect to make prescreening cytogenetic evaluation possible. For 
those regions, a prescreening ICF will be developed to permit cytogenetic evaluation on 
BMA samples.

MM-directed therapy including induction therapies and dates, transplant therapy including 
conditioning regimen and dates, along with clinically significant toxicities 

Disease response, including pre-and post-ASCT evaluation of disease status. 
NOTE: To minimize clinically redundant procedures, the investigator may choose to use the 
screening visit to serve as the clinical post-ASCT evaluation of disease status, as long as all 
requirements for screening are met. 

Review of all current medications, prior radiation (as permitted > 14 days before study 
therapy for symptomatic bone lesion or > 5 years before study therapy for another 
malignancy), and the patient’s current smoking status.
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Refer to the original Schedule of Events (Section 15.10) for specific time requirements and 
windows.
7.4.4
Physical Examination
A physical examination will be completed per SoC at the times specified in the original Schedule 
of Events (Section 15.10) and Streamlined Schedule of Events. Symptom-directed examinations 
should include examination of organ systems related to patient symptoms to document potential 
AEs, AE severity, AE resolutions, and verification of new primary malignancy 
(NPM). Assessment for PN will be conducted as part of all physical examinations.
7.4.5
Vital Signs, Body Weight, and Height 
Measurement of vital signs, including temperature, blood pressure, heart rate, respiratory rate (as 
clinically indicated), and body weight will be done at the time points specified in the original 
Schedule of Events (Section 15.10). Height will only be measured at the screening visit.
7.4.6
Eastern Cooperative Oncology Group Performance Status
Performance status will be assessed using the ECOG performance scale at the time points 
specified in the original Schedule of Events (Section 15.10) and Streamlined Schedule of Events. 
7.4.7
Pregnancy Test
A serum pregnancy test will be performed for women of childbearing potential at screening, 
within 3 days before dosing, and at EOT, or more frequently as required per local regulations. 
The results from these tests must be available and negative before the first dose of the study drug 
regimen is administered. 
The Cycle 1 Day 1 pregnancy test may be collected up to 3 days before dosing. The results must 
be available and negative before the first dose. If the Cycle 1 Day 1 serum pregnancy results are 
not available before dosing, a urine pregnancy test may be performed. 
Pregnancy tests may also be repeated during the study as per request of IEC/IRBs or if required 
by local regulations.
7.4.8
Concomitant Medications and Procedures
Concomitant medications and therapy will be recorded from the first dose of drug in the study 
drug regimen through 30 days after last dose of drug in the study drug regimen (see the original 
Schedule of Events [Section 15.10]). See Section 6.6 for a list of prohibited concomitant 
medications and therapies and Section 6.7 for a list of allowed concomitant medications and 
therapies. 
7.4.9
Adverse Events
Monitoring of AEs, serious and nonserious, will be conducted throughout the study as specified 
in the original Schedule of Events (Section 15.10) and Streamlined Schedule of Events. Refer to 
Section 10.0 for details regarding definitions, documentation, and reporting of pretreatment 
events, AEs, and SAEs. 
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7.4.10
Enrollment
A patient is considered to be enrolled in the study when he/she has been randomized to study 
treatment.
Procedures for completion of the enrollment information are described in the study manuals.
7.4.11
Electrocardiogram
A 12-lead ECG will be conducted at screening and at the times outlined in the original Schedule 
of Events (Section 15.10). 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.
7.4.12
Clinical Laboratory Evaluations
Clinical laboratory evaluations will be performed by a central laboratory until the primary 
endpoint of PFS is met. For dosing decisions, local hematology and chemistry laboratory results 
may be used; however, samples must also be sent to central labs. Hematology and chemistry 
panels may be collected up to 3 days before Day 1 dosing and (when required) 24 hours before 
Days 8 and 15 dosing.
The collection of samples by a central laboratory was stopped after the primary endpoint was 
met.
As the laboratory results may not be available at the initiation of the next cycle, it is not required 
that these measurements be reviewed before initiating the next treatment cycle unless either of 
the following applies:
1. The patient has an ongoing toxicity. If the patient has had a toxicity resulting in a dose 
hold, it is mandatory that safety labs (local or central) are collected AND reviewed 
before starting the next cycle of treatment.
2. It is required per your local practice to have safety labs reviewed prior to starting the 
next cycle of treatment.
Local laboratory evaluations may be done more frequently at the investigator’s discretion, such 
as for acute management of TEAEs. Local laboratory evaluations should be entered into the 
eCRF only if required to document an AE, dose modification, or other event, and the information 
entered should be limited to that required to understand the event (eg, for a dose hold for 
thrombocytopenia, enter the platelet count only). Handling and shipment of central clinical 
laboratory samples are outlined in the study manuals.
Clinical Chemistry, Hematology, and Urinalysis
Blood samples for analysis of the following clinical chemistry and hematological parameters and 
urine samples for urinalysis will be obtained as specified in the original Schedule of Events 
(Section 15.10).
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Hematology

Hemoglobin

Hematocrit

Platelet (count)

Leukocytes with differential

Neutrophils (ANC)
Serum Chemistry

Blood urea nitrogen 
(BUN)

Creatinine

Bilirubin (total)

Urate

Lactate dehydrogenase 
(LDH)

Gamma glutamyl 
transferase (GGT)

Phosphate

Albumin

Alkaline phosphatase 
(ALP)

Aspartate 
aminotransferase (AST)

Alanine 
aminotransferase (ALT)

Glucose 

Sodium

Potassium

Calcium

Chloride

Carbon dioxide 
(CO2)

Magnesium
Urinalysis

Turbidity and Color

pH

Specific gravity

Protein

Ketones

Bilirubin

Occult Blood

Nitrite

Urobilinogen

Glucose

Leukocytes

Microscopic 
analysis (only if 
macroscopic 
urinalysis 
parameters 
abnormal)
7.4.13
Health Care Resource Utilization Data Collection
During the treatment and the follow-up periods indicated in the original Schedule of Events 
(Section 15.10) and Streamlined Schedule of Events, all medical care encounters since the 
previous collection will be collected from patient charts and/or patients directly as needed,
regardless of the reason for the needed medical care encounter. Examples of data to be collected 
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are number and duration of medical care encounters, such as inpatient/outpatient admissions, 
visit type and reasons, and time of work loss. 
7.4.14
Quality of Life Assessment (European Organization for Research and Treatment 
of Cancer)
The HRQL assessments will be completed by the patient as specified in the original Schedule of 
Events (Section 15.10) and Streamlined Schedule of Events. The EORTC QLQ-C30 (30 items; 
see Section 15.8) incorporates 5 functional scales (physical functioning, role functioning, 
emotional functioning, cognitive functioning, and social functioning), 1 global health status/QOL 
scale, 3 symptom scales (fatigue, nausea and vomiting, and pain), and 6 single items (dyspnea, 
insomnia, appetite loss, constipation, diarrhea, and financial difficulties). 
The EORTC QLQ-MY20 multiple myeloma module (20 items; see Section 15.7) has 
4 independent subscales, 2 functional subscales (body image, future perspective), and 
2 symptoms scales (disease symptoms and side-effects of treatment). This will be administered 
subsequent to the EORTC QLQ-C30.
The time recall period for this instrument is 1 week (the week immediately preceding the 
assessment). These are reliable and valid measures of HRQL in patients with cancer and takes 
about 15 minutes to administer. The instruments consist of a total of 50 items and have been 
validated and used in many countries.
Patient-reported outcomes and HU assessments (ie, medical encounters) should be completed 
before any other study procedures are performed or study drug is administered. During the PFS2 
Follow-up period only, EORTC QLQ-C30, EORTC QLQ-MY20, and HU assessments should be 
done ideally at the first 2 visits (or at least within the first 4 visits). Patient-reported outcome 
questionnaires are preferred to be completed by patients in the clinic, but if necessary (eg, due to 
the COVID-19 pandemic), the EORTC QLQ-C30 and EORTC QLQ-MY20 questionnaires may 
be completed at the patient’s home using paper versions of the questionnaires; as a last resort, 
these patient-reported outcomes can be collected via telephone using EORTC telephone 
interview administration scripts. At time points when a clinic visit is not required, or if needed 
due to the COVID-19 pandemic, the EQ-5D questionnaire may be administered over the 
telephone. HU data may be obtained over the telephone and/or via patient medical records, as 
needed.
7.4.15
Utility Measurement
The EQ-5D (see Section 15.6) consists of 2 pages: the EQ-5D descriptive system and the EQ 
visual analogue scale (EQ VAS). The descriptive system comprises 5 dimensions (mobility, self 
care, usual activities, pain/discomfort, and anxiety/depression). 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). The EQ-5D will be administered 
as specified in the original Schedule of Events (Section 15.10) and Streamlined Schedule of 
Events; at time points when a clinic visit is not required, EQ-5D may be administered over the 
telephone and site staff may enter the data from the patient. 
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7.4.16
Bone Marrow Aspiration
7.4.16.1
Local Laboratory Evaluations
Disease Assessment
A bone marrow aspirate (BMA) will be obtained at screening for disease assessment and, at any 
time, a BMA sample will be obtained to assess CR or to investigate suspected PD. This 
evaluation will be performed locally. A standard BMA drawn before consent is acceptable for 
the screening sample, provided this is collected within 42 days of the first dose and unless VGPR 
or CR are suspected (in which case another BMA sample for MRD is needed for screening, as 
discussed below). 
Determination of the /λ ratio by immunohistochemistry or immunofluorescence should be 
performed to assess for sCR when a CR has been documented. A bone marrow biopsy can 
additionally be performed per local standards for disease assessments.
Cytogenetics/FISH
Cytogenetic evaluation should be performed before ASCT using FISH and/or conventional 
cytogenetics (karyotype). At a minimum, cytogenetic markers should include at least 2 of these 3 
high-risk abnormalities: del17, t(4;14) and t(14;16). Additional abnormalities (ampl 1q, del13, or 
del1p) may also be tested.
All cytogenetic evaluations will be performed locally by the site according to local standards. 
Prospective study patients at sites that do not routinely conduct cytogenetic evaluation at the time 
of disease diagnosis will be asked to sign a prescreening ICF to permit cytogenetic evaluation on 
bone marrow aspirate samples.
7.4.16.2
Central Laboratory Evaluations
Minimal Residual Disease
Bone marrow aspirate samples will be collected for MRD assessment at screening for all patients 
in CR and VGPR. A bone marrow aspirate sample for MRD will also be requested when a 
patient is having a bone marrow aspirate performed for confirmation of a suspected CR at any 
time on study. In addition, patients in VGPR or CR at Cycle 13 and at EOT (approximately 24 
months [to the nearest complete cycle]; if there are no treatment delays, this would be 26 cycles) 
will have BMA and blood samples collected for MRD at those 2 time points (unless already done 
within the most recent 2 cycles); BMA and blood samples will also be obtained in patients in CR 
or VGPR who stop therapy before Cycle 26. All samples will be used for the assessment of 
MRD using 8-color flow cytometry technology. These samples will be sent to a specialty 
laboratory.
A portion of the bone marrow aspirates, if available, will also be used for the assessment of 
MRD using a sequencing methodology. The concordance between flow and sequencing 
methodology readouts may also be assessed.
MRD will be also assessed in blood samples using a sequencing technology for all patients for 
whom tumor archival material is available (unstained slides, bone marrow aspirate as a formalin-
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fixed, paraffin-embedded block, or stained slides; biopsy samples will not be accepted). This 
material will be collected at screening and used for the identification of the MM tumor clone(s). 
The presence of the specific tumor clone(s) will then be assessed at screening, at Cycle 13, and at 
EOT (approximately 24 months [to the nearest complete cycle]; if there are no treatment delays, 
this would be 26 cycles). A blood sample will also be collected in patients suspected to have 
achieved CR at any time on study. These samples will be processed according to the Laboratory 
Manual, stored by the central laboratory, and analyzed in batches.
Molecular Analyses
Mutations in key signaling pathways in MM, such as RAS/RAF, and other tumor molecular 
characteristics determined to be clinically meaningful for this study, will be assessed in each 
patient using archival materials and/or tumor DNA from bone marrow aspirates, as available.
In addition, mechanisms of treatment-emergent resistance, such as somatic mutations in 
proteasome subunits and key signaling pathways or change in pathway activity, will be studied 
in tumors of patients who experience PD. For this purpose, an optional BMA sample will be 
collected at the time of PD. This sample may be collected at time of PD confirmation, at the EOT 
visit, or before starting a new therapy (as the second pull if a sample is collected for PD 
confirmation).
7.4.17
Blood-Based Biomarker Analyses
Two blood samples will be collected at screening for testing candidate biomarker relationship to 
response or resistance to ixazomib therapy. Polymorphisms in mechanism and pathway-related 
genes, including proteasome subunits and NFKB regulators, such as NFKB1, TRAF3, and IKB, 
will be assessed. Polymorphisms of NFKB family genes are associated with development of 
multiple myeloma and treatment outcome in patients receiving bortezomib-based regimens and 
may be relevant for the efficacy of proteasome inhibitors generally.[60] Relationship between 
response to ixazomib and circulating proteasome levels in serum will also be analyzed. 
Circulating proteasome levels have been demonstrated to be an independent prognostic factor in 
MM patients with increasing circulating proteasome levels correlating with advanced disease.[58]
Given that ixazomib directly targets the 20S proteasome, this leads to the possibility that 
pretreatment circulating proteasome levels may be relevant for prediction of patient response to 
therapy. Retrospective analysis of baseline serum proteasome levels from clinical trial samples 
for patients treated with bortezomib in combination with melphalan and prednisone 
demonstrated that circulating proteasome levels were associated with both OS and PFS only for 
bortezomib-containing therapy[60] leading to the possibility that high-circulating proteasome 
levels could be both a poor prognostic and also a specific marker of poor outcome with 
bortezomib. These data point to the potential value of further exploring the relationship between 
predose circulating proteasome levels and response to ixazomib citrate. These have been linked 
to the efficacy of bortezomib. Polymorphisms of NFKB family genes are associated with 
development of MM and treatment outcome in patients undergoing bortezomib-based regimens. 
Details regarding the preparation, handling, and shipping of samples are provided in the study 
manuals.
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7.4.18
Imaging Disease Assessments
For patients with documented extramedullary disease at the time of diagnosis, other assessments 
and scans, such as a CT, positron emission tomography-computed tomography (PET-CT), or 
MRI scan, may be required to better delineate the sites and measurements of extramedullary 
disease at the time of screening. Follow-up scans should be obtained at EOT. Additional 
assessments can be done at the discretion of the investigator (ie, for suspected new lesions or 
PD). The modality to be used is at the discretion of the investigator, and all follow-up scans 
should use the same imaging modality as was used at screening. 
Imaging assessments will be analyzed locally and reports maintained with the patient record for 
review during monitoring visits.
7.4.19
2-Microglobulin
A blood sample will be collected at screening for serum 2-microglobulin testing and analyzed 
by a central laboratory. A local laboratory may additionally be used at the discretion of the 
investigator. The stratification will be by pretreatment ISS stage 1 vs stage 2 or 3, using local 
results obtained before initiation of induction therapy. Local and central results will be used for 
analysis.
7.4.20
Quantification of M-Protein
A blood sample and urine sample will be obtained at screening and at the time points specified in 
the original Schedule of Events (Section 15.10) until PFS significance has been claimed in this 
study. 
7.4.21
Quantification of Immunoglobulins
A blood sample for quantification of immunoglobulins (IgM, IgG, IgA, IgD, and IgE) will be 
obtained at screening and at times outlined in the original Schedule of Events (Section 15.10). 
Quantitative IgD and IgE will be done at screening (and baseline if needed) only. For the rare 
patient with IgD or IgE MM, the quantitative test for that antibody will be followed at the same 
time points as quantitative Igs (in addition to IgM, IgG, and IgA).
7.4.22
Serum Free Light Chain Assay
A blood sample for serum free light chain assay will be obtained at screening and at the times 
outlined in the original Schedule of Events (Section 15.10).
7.4.23
Immunofixation of Serum and Urine
Serum and urine samples will be obtained for serum and urine immunofixation tests at screening 
and at the times outlined in the original Schedule of Events (Section 15.10). 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.
7.4.24
Skeletal Survey
A complete skeletal survey, using roentgenography, will be performed at screening (within 
8 weeks before randomization) and at EOT. If at any time the physician believes there are 
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symptoms or signs that suggest increased or new bone lesions, a repeat of the skeletal survey 
should be performed. For imaging of symptomatic sites, plain films may be obtained for 
additional clarity.
In certain circumstances and at the discretion of the investigator, a CT-scan, a PET-CT scan, or 
whole body MRI may be done at screening in place of a skeletal survey, provided that the same 
modality for assessment is used throughout the study. 
7.4.25
Disease Response Assessment
Patients will be assessed for disease response according to the IMWG uniform response criteria, 
version 2011 (see Section 15.9) [61]. Takeda or a designee will not be assessing responses in the 
PFS2 period. 
Response assessments should be made every 12 weeks during the PFS follow-up period until 
disease progression (see the Streamlined Schedule of Events). At this time, the primary endpoint 
has been met; therefore, central efficacy assessments for protocol purposes have been stopped; 
all investigator assessments of response should be based on local laboratories per local clinical
practice.
Response categories are as follows in Table 7-1:
Table 7-1
Response Assessment
Complete response
CR
Subcategory: stringent complete response
sCR
Partial response
PR
Subcategory: Very good partial response
VGPR
Stable disease
SD
Progressive disease
PD
CR must be confirmed with follow-up assessments of SPEP, UPEP, immunofixation of blood 
and urine, and serum free light chains as outlined in Section 15.9. One bone marrow assessment 
(locally evaluated) has to occur to document CR; no second bone marrow confirmation of CR is 
needed.
Please note that to determine a response of sCR, 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.
At any point during treatment, patients suspected of having PD will have response assessments 
repeated to confirm disease progression (ie, 2 sets of response assessments at least 1 week apart).
7.4.26
Pharmacokinetic Measurements
Plasma concentrations of the complete hydrolysis product of ixazomib citrate (ixazomib) will be 
measured using a validated LC/MS/MS assay. 
Details regarding the preparation, handling, and shipping of the pharmacokinetic samples are 
provided in the study manuals. Blood samples (3 mL) for the determination of plasma 
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concentrations of ixazomib (the complete hydrolysis product of ixazomib citrate) will be 
collected during Cycles 1 through 10. Samples are to be collected at the time points specified in 
the Ixazomib Pharmacokinetic Sampling Schedule
7.4.27
Follow-up Assessments for PFS, PD, PFS2, and OS
At EOT, patients will enter a Follow-up period for PFS, PD, or PFS2. See the Streamlined 
Schedule of Events for assessments during each period. See the Study Periods and
Corresponding Endpoints Diagram for information about the sequence of follow-up. Information 
about any new primary malignancies will be collected during the study, including during all 4 
Follow-up periods. PFS and PD Follow-up visit is scheduled to be 12 weeks (+/-1 week) since 
the last completed Follow-up visit. 
7.4.27.1
PFS Follow-up and PD Follow-up
Patients who complete 24 months (to the nearest complete cycle; if there are no treatment delays, 
this would be 26 cycles) of treatment or who have stopped treatment for any reason other than 
PD will first enter the PFS Follow-up period. During this period, follow-up will occur every 12 
weeks until the occurrence of PD. After PD occurs during the PFS Follow-up period, patients 
enter the PD Follow-up period. During this period, follow-up will occur every 12 weeks until 
next-line antineoplastic therapy is initiated by the investigator/treating physician. 
If a patient has PD while on study drug during the Treatment period, the patient will enter 
directly into the PD Follow-up period and will be followed every 12 weeks until initiation of the 
next line of therapy by the investigator/treating physician.
In both the PFS and PD Follow-up periods, the EORTC QLQ-C30 and MY20 questionnaires, the 
HU assessment, and the EQ-5D questionnaire will be administered every 12 weeks.
7.4.27.2
PFS2 Follow-up and OS Follow-up
All patients who underwent maintenance therapy and then receive subsequent anticancer therapy 
will be transitioned to PFS2 period.
Patients who start the next line of therapy (regardless of when) will enter the PFS2 Follow-up 
period. The next line of therapy will be recorded, including dates of initiation and termination 
(for progression or death), regardless of whether it is initiated before or after PD. Information 
about disease response/status should also be collected during the PFS2 Follow-up period. During 
the PFS2 Follow-up period, follow-up will occur every 12 weeks until PD2 occurs. 
During the PFS2 Follow-up period only, EORTC QLQ-C30, EORTC QLQ-MY20, and HU 
assessments should be administered ideally at the first 2 visits (or at least within the first 4 visits). 
The EQ-5D questionnaire should be administered every PFS2 visit. Patient-reported outcome 
questionnaires are preferred to be completed by patients in the clinic, but if needed (eg, due to 
the COVID-19 pandemic), the EORTC QLQ-C30 and EORTC QLQ-MY20 questionnaires may 
be completed at the patient’s home using paper versions of the questionnaires; as a last resort, 
these patient-reported outcomes can be collected via telephone using EORTC telephone 
interview administration scripts. At time points when a clinic visit is not required, or if needed 
due to the COVID-19 pandemic, the EQ-5D questionnaire may be administered over the 
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telephone. HU data may be obtained over the telephone and/or via patient medical records, as 
needed. 
After patients in the PFS2 Follow-up period have PD2 on next-line therapy, they enter into the 
OS Follow-up period. During the OS Follow-up period, follow-up will occur every 12 weeks 
until death or termination of the study by the sponsor, whichever occurs first. In the OS Follow-
up period, the EQ-5D questionnaire may be administered every visit, which occurs every 12 
weeks, via telephone. 
During the OS Follow-up period, assessments can be made over the telephone and do not require 
a clinic visit. Data may be collected by methods that include, but are not limited to, telephone, e-
mail, mail, and social security indexes. Both the patient and the current treating physician will be 
contacted during the OS Follow-up period to provide information about the patient’s disease 
status and current MM treatments (drug regimen, interval, dose, start/stop date). Should an NPM 
be reported, unscheduled visits should be considered to assess the patient and update the eCRF.
NOTE: Related SAEs must be reported to the Takeda Department of Pharmacovigilance or 
designee. This includes deaths that the investigator considers related to study drug that occur 
during the posttreatment follow-up. In addition, new primary malignancies that occur during the 
follow-up periods, irrespective of causality to study drug, must be reported to the Takeda 
Department of Pharmacovigilance or designee. 
Refer to Section 10.0 for details regarding definitions, documentation, and reporting of SAEs.
7.5
Unscheduled Visits
Unscheduled visits may occur between treatment cycles as required. At unscheduled visits, the 
HU data should be captured. Other assessments may be performed as clinically indicated at the 
discretion of the investigator.
7.6
Study Compliance
Study drug will be administered or dispensed only to eligible patients under the supervision of 
the investigator or identified subinvestigator(s). The appropriate study personnel will maintain 
records of study drug receipt and dispensing.
7.7
Completion of Treatment
Patients will be considered to have completed study treatment if they meet any of the following 
criteria:

Have received at least a maximum treatment duration of 24 months (to the nearest 
complete cycle). If there are no treatment delays, this would be 26 cycles.

PD/death after the completion of Cycle 1.
A Takeda project clinician or designee and the investigator will review PD before taking the 
patient off treatment for PD. Patients will attend an EOT visit 30 days (+1 week) after receiving 
their last dose of the study drug regimen, and will continue to be followed for other follow-up 
assessments specified in the Streamlined Schedule of Events. Refer to the original Schedule of 
Events (Section 15.10) for EOT visit assessments.
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7.8
Completion of Study
Patients will be considered to have completed the study if they are followed until death or until 
the sponsor terminates the study. 
7.9
Discontinuation of Treatment With Study Drug, and Patient Replacement
For patients who did not complete study treatment as defined in Section 7.7, treatment with study 
drug must be discontinued for pregnancy. Treatment with study drug may also be discontinued 
permanently for any of the following reasons: 

Adverse event (including SAE)

Protocol violation

Study terminated by sponsor

Withdrawal by subject

Lost to follow-up

Other
Once study drug has been discontinued, all study procedures outlined for the EOT visit will be 
completed as specified in the original Schedule of Events (Section 15.10). The primary reason 
for study drug discontinuation will be recorded on the eCRF.
7.10
Withdrawal of Patients From Study
A patient may be withdrawn from the study for any of the following reasons:

Study terminated by sponsor

Withdrawal by patient

Death

Lost to follow-up

Other
The consequence of study withdrawal is that no new information will be collected from the 
withdrawn patient and added to the existing data or any database. However, every effort will be 
made to follow all patients for safety.
8.0
STATISTICAL AND QUANTITATIVE ANALYSES
8.1
Statistical Methods
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 percent per category for categorical data. The Kaplan-Meier 
survival curves and 25th, 50th (median), and 75th percentiles will be provided along with their 2-
sided 95% confidence intervals (CIs) for time-to-event data. 
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Details for the FA will be provided in the SAP. The SAP will be written by Takeda and will be 
finalized before the first formal IA for OS, which is also the FA for PFS. 
Deviations from the statistical analyses outlined in this protocol will be indicated in the SAP; any 
further modifications will be noted in the final clinical study report.
8.1.1
Determination of Sample Size
The primary objective of this study is to determine if ixazomib improves PFS compared with 
placebo. The study will not be stopped after the PFS analysis. However, even if a significant PFS 
is observed, the trial will continue to obtain an adequate statistical power for OS. 
The total sample size is calculated based on maintaining approximately 80% power to test the 
OS. The study is also adequately powered to test PFS. There are 5 planned IAs and 1 FA. The 
first IA will be the primary analysis (and the only analysis) for PFS for statistical testing 
purposes. If PFS is significant at the first IA, then OS will be tested at this IA and subsequent
analyses. 
The primary analysis of PFS, which is also the first IA of OS, will be performed 25 months after 
the last patient has been enrolled or approximately 328 PFS events have been observed, 
whichever occurs later. With projected 328 PFS events, it will have 95% power to detect a 
hazard ratio of 0.67 (ie, median PFS of 26 months for control versus 39 months for treatment) 
using a 2-sided log-rank test at a 2-sided alpha level of 0.05 and assuming approximately 15% 
dropout rate at month 30. This IA is expected to occur at 45 months after the first patient is 
enrolled, including a 20-month enrollment period and an additional 25-month follow-up after the 
last patient enrolled. This will be the FA for PFS for statistical testing purposes, with the 
opportunity to claim PFS benefit. With a projected 328 PFS events, an observed hazard ratio of 
0.802 or better (ie, median PFS of 26 months for control versus 32.4 months for treatment, 25% 
improvement) will likely lead to statistical significance for PFS at this analysis. If the test for 
PFS is not statistically significant, the study will be claimed as unsuccessful and no further 
formal testing will be conducted. 
If the test for PFS is significant, OS will be tested.
The total event size calculation for OS is based on the adaptive sample size reassessment 
approach [62], which, in this study’s setting, is an adaptive event size reassessment approach. 
The minimum event size of 260 death events is based on an optimistic assumption of a hazard 
ratio of 0.70 (ie, median OS of 70 months for control vs 100 months for treatment, 43% 
improvement) with approximately 80% power at a 2-sided level of significance. The O’Brien-
Fleming alpha spending function (the Lan-Demets method) is used to calculate the significance 
boundary based on the observed number of death events in each IA with a total of 260 OS events 
for the FA. 
The second IA will be performed when approximately 140 death events have been observed; the 
third IA will be performed at approximately 170 death events. The fourth IA for OS will be 
performed when approximately 200 death events have been observed. If OS significance is not 
claimed at the fourth IA, the conditional power based on OS will be calculated. If the conditional 
power falls in the promising zone, the event size will be determined according to a prespecified 
event size adaptation rule, with an event cap of approximately 350 death events. The fifth IA will 
be performed when approximately 230 death events have been observed. If the OS results are 
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statistically significant at any of the IAs (the first through fifth IAs), the study can be stopped 
early, and this analysis on OS will be the FA for formal hypothesis testing on OS. No futility 
analysis will be performed in the study. 
The event size adaptation rule is a prespecified stepwise function to avoid the back calculation 
problem resulting from 1 event size corresponding to either barely promising or highly 
promising interim results. The event size adaptation rule will be designed by the sponsor’s 
independent design statistician and approved by the sponsor’s head of biostatistics. Neither the 
independent design statistician nor the head of biostatistics is involved in the study conduct. 
The adaptation rules will be outlined in a separate document and will not be accessible to the 
sponsor’s study team until completion of the study. The rules will be available only to the 
sponsor’s independent design statistician, the sponsor’s head of biostatistics, the IDMC, and the 
statistics representative on the sponsor’s executive committee (if different from the sponsor’s 
head of biostatistics). 
8.1.2
Randomization and Stratification
The randomization scheme will be generated by an independent statistician at Takeda who is not 
on the study team. Before dosing, a randomization number will be assigned to each patient. The 
randomization assignment will be implemented by an IXRS. 
Eligible patients will be randomized in a 3:2 ratio to ixazomib or placebo treatment arms, 
stratified by: induction therapy of PI without an IMiD vs IMiD without a PI vs PI and IMiD; pre-
induction ISS (stage 1 vs stage 2 or 3); and response after transplantation, defined as the 
response to induction/ASCT measured during screening (CR or VGPR vs PR). 
8.1.3
Populations for Analysis
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 
study drug. Patients will be analyzed according to the treatment they actually received.
Intent-to-Treat (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. 
Per-Protocol (PP) population: The PP population is a subset of the ITT population. The PP 
population consists of all patients who do not have major protocol violations, as determined by 
the study clinician, who is blinded to study drug assignment. All decisions to exclude patients 
from the PP population will be made before the unblinding of the study.
8.1.4
Procedures for Handling Missing, Unused, and Spurious Data
All available efficacy and 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.
In general, missing data will be treated as missing and no data imputation will be applied, unless 
otherwise specified. For patient-reported outcomes data, primarily missing data imputation will 
be based on published instrument specific methods. Other missing data imputation method such 
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as Last Observation Carry Forward (LOCF) and multiple imputation method may be explored as 
sensitivity analyses for patient-reported outcomes data.
If there are missing values between visits for an individual AUC calculation for HRQL, a linear 
interpretation will be implemented to impute missing values. 
For AUC calculations based on a prespecified time period, if the HRQL data are not collected 
before the end of the prespecified time period, the score 0 will be imputed from the last available 
visit to the end of the prespecified time period.
8.1.5
Demographic and Baseline Characteristics
The demographic and baseline characteristics will be summarized in a descriptive fashion. Data 
to be evaluated will include age, gender, race, weight, baseline disease characteristics, and other 
parameters, as appropriate.
8.1.6
Efficacy Analysis
A closed sequential testing procedure will be used to test the primary endpoint of PFS and the 
key secondary endpoint of OS with the following order: (1) PFS (primary endpoint) at the 1st IA. 
(2) OS (first key secondary endpoint) at the IAs or FA. PFS will be tested at a 2-sided alpha level 
of 0.05. OS will be tested at the IAs or FA at the significance level determined by the O'Brien-
Fleming alpha spending function (the Lan-DeMets method). Because of the closed sequential 
testing property, the family-wise type I error is strongly controlled for both the primary endpoint 
and the key secondary endpoint. 
All other efficacy endpoints will be tested at a 2-sided alpha level of 0.05. 
8.1.6.1
Analyses for Primary Efficacy Endpoints
The analysis of primary endpoint, PFS, will be based on the ITT population using IRC-assessed 
progression data. PFS is defined as the time from the date of randomization to the date of first 
documentation of PD or death due to any cause, whichever occurs first. Patients without 
documentation of PD will be censored at the date of last response assessment that is SD or better. 
PFS will be analyzed 25 months after the last patient has been enrolled or when approximately 
328 PFS events have occurred, whichever occurs later. 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 0.05. In 
addition, an unadjusted stratified Cox model will be used to estimate the hazard ratio and its 95% 
CIs for the treatment effect using the stratification factors. 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. 
Sensitivity analyses for PFS include:
1. PFS assessed by the investigator will be analyzed in the ITT population.
2. PFS assessed by the IRC will be analyzed in the per protocol population.
PFS assessed by the IRC using different censoring mechanisms will be analyzed in the ITT 
population, for example, not censoring for patients who discontinue treatment and go on 
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alternative antineoplastic therapy. Details of different censoring approaches will be included in 
the SAP.
Subgroup analyses will be performed for PFS relative to baseline stratification factors, 
demographic data such as gender, race, and age. In addition, a stepwise Cox model will be 
implemented to identify potential predictive factors using relevant demographic or diagnostic 
covariates, with the entry level fixed at 0.25 and a stay level fixed at 0.10. 
8.1.6.2
Analyses of Key Secondary Efficacy
The primary endpoint of PFS will be supported by prespecified evidence of clinical benefit as 
measured by the key secondary endpoint, OS. Overall survival will be analyzed based on the ITT 
population and is defined as the time from the date of randomization to the date of death. Patients 
without documentation of death at the time of analysis will be censored at the date last known to 
be alive. 
A 2-sided, stratified log-rank test will be used to compare the treatment groups with respect to 
OS. In addition, an unadjusted stratified Cox model will be used to estimate the hazard ratio and 
its 95% CIs for the treatment effect using the stratification factors. The 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.
Subgroup analyses will be performed for OS relative to baseline stratification factors, 
demographic data such as sex, race, and age. Also, a stepwise Cox model will be implemented to 
identify potential predictive factors using relevant demographic or diagnostic covariates, with the 
entry level fixed at 0.25 and a stay level fixed at 0.10.
8.1.6.3
Analyses of Other Secondary Efficacy Endpoints
The primary endpoint of PFS will be supported by prespecified evidence of clinical benefit as 
measured by other secondary endpoints. Other secondary efficacy parameters include the best 
response during maintenance, duration of CR, time to progression (TTP), PFS2, time to end of 
the next line of therapy, and duration of the next line of therapy. 
Disease response-related endpoints will be analyzed using IRC-assessed response rate.
Best Response During Maintenance
The percentage of each response category (CR, VGPR, PR) and CR + VGPR will be determined. 
A chi-square test will be used to compare the best response during maintenance between those 2 
arms. 
Duration of CR
Duration of CR is defined as the time from the date of randomization for those who are CR at 
randomization or the date of CR for those who converted to CR during maintenance to the date 
of first documentation of PD. Responders without documentation of PD will be censored at the 
date of last response assessment that is CR. Duration of CR will be summarized descriptively 
using the Kaplan-Meier method.
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TTP
TTP 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 analysis will be censored at the date of 
last response assessment. TTP will be analyzed based on the ITT population using the similar 
method as PFS.
Progression-Free Survival 2 
Progression-free survival 2 (PFS2) is defined as time from the date of randomization to the date 
of objective disease progression on next-line treatment or death from any cause, whichever 
occurs first. The second PD should occur during or after the second line of antineoplastic therapy 
but before the third line of therapy. Patients who do not have documented PD will be censored at 
the date of last response assessment which is SD or better. PFS2 will be analyzed by the treating 
physician/investigator based on the ITT population using the similar method as PFS.
Time to End of the Next Line of Therapy
Time to end of the next line of therapy is defined as the time from the date of randomization to 
the date of last dose of the next antineoplastic therapy or death due to any cause, whichever 
occurs first. Time to end of the next line of therapy will be analyzed based on the ITT population 
using the similar method as PFS. Patients who are still on treatment on the next line of therapy 
will be censored at the date of last response assessment that is SD or better. 
Duration of the Next Line of Therapy
Duration of the next line of therapy is defined as the time from the date of the first dose of the 
next line of therapy to the date of the last dose of the next antineoplastic therapy or death due to 
any cause, whichever occurs first. Duration of the next line of therapy will be analyzed on those 
patients who actually received the next line of therapy following the study treatment using the 
ITT principle. Patients who are still on treatment on the next line of therapy will be censored at 
last visit. Duration of the next line of therapy will be summarized using the K-M method.
8.1.7
Analyses of Patient-Reported Outcomes and Health Economics 
Analyses of patient-reported outcomes and health economics will be performed using the ITT 
population.
8.1.7.1
Patient-Reported Outcomes Analysis
The actual value and change from baseline of the subscale scores for EORTC QLQ-C30 and 
MY20 will be summarized using descriptive statistics and plotted by treatment group over time.
The number and percentage of patients with a meaningful change from baseline in subscale 
scores will be summarized by treatment group over time. The published minimal important 
difference (MID) will be used to define such meaningful change from baseline. Specific interest 
will be on global health status, but data on all other subscales will also be analyzed.
The change from baseline in subscale scores will be presented using cumulative distribution 
function (CDF) figures. The subscale scores will also be analyzed using mixed models by 
incorporating the measurements across all available time points.
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8.1.7.2
Average HRQL Score Based on Scores From the EORTC QLQ-C30 Global Quality 
of Life Domain 
For each patient, an average HRQL score will be calculated from baseline to last measurement 
before disease progression. 
Once the average score is measured at the individual level, a 2-sample t-test will be used to 
assess whether the mean average score in the ixazomib group is noninferior to that in the placebo 
group. The noninferiority margin is 12.
Analyses of the global QOL during the PD Follow-up period (following progression until start of 
next-line therapy) and the PFS2 Follow-up period (from the start of next-line therapy until PD2) 
may be conducted—such as descriptive statistics, linear regression, t-test, or linear mixed models. 
Comparisons of the average global QOL during the treatment period or follow-up periods may 
be also considered.
In addition, the AUC approach as a sensitivity analysis will be used to examine the differential 
effect of treatment throughout the study. The AUC approach aggregates the cumulative absolute 
HRQL score over time: the y axis represents the absolute EORTC QLQ-C30 global QOL score 
(range: 0-100); the x axis represents the time horizon. 
For each individual patient, an AUC will be calculated from baseline to a prespecified time 
period, such as 24 months for the first IA, 36 months for the fourth IA, and 48 months for the FA. 
Missing data will be imputed using a linear mixed model. Once the AUC is measured at the 
individual level, a 2-sample t-test will be used to assess whether the mean AUC in the ixazomib 
arm is noninferior to that in the placebo arm. The noninferiority margin is set to be 12 × the time 
period for the AUC analysis. This is consistent with the average score approach, as the time 
period is fixed. 
Additionally, the distribution of individual AUCs in the 2 treatment groups may be described by 
summary statistics, such as means, standard deviations, median, etc. 
If the noninferiority test is statistically significant, then the superiority test will be performed to 
further examine the benefit of the differential effect of treatment.
The average score and AUC analyses described above will also apply to other scales of EORTC 
QLQ-C30 and MY20.
8.1.7.3
Health Economics Analysis Using Health Care Resource Utilization and Health 
Utility
EQ-5D scores will be summarized in descriptive statistics for treatment arms. 
HU data will be summarized in descriptive statistics of medical encounters (length of stay, 
inpatient, outpatient, and reason), or other activities for treatment arms.
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8.1.8
PK/Pharmacodynamics/Biomarkers
8.1.8.1
PK Analysis
PK data collected in this study will 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. 
8.1.8.2
MRD Analysis
MRD negativity is defined as absence of MRD and MRD positivity is defined as presence of 
MRD. The conversion rate from MRD positive to MRD negative as well as the maintenance of 
MRD negativity will be assessed and reported in both arms. MRD negativity will also be 
reported in all patients who achieve a CR, regardless of whether they receive ixazomib or 
placebo during the study. The MRD assessment will be performed using BMA samples and flow 
cytometry, and sequencing may also be performed on BMA and/or blood samples from the 
patients. Degree of correlation between these 2 methodologies will be assessed as well. 
Association between MRD status with PFS and OS will be evaluated independently from the 
methodology used for the assessment. The association between MRD status and PFS and OS will 
be evaluated in both study arms, and concordance between flow cytometry and sequencing 
readouts will be assessed.
8.1.8.3
Biomarker Analysis
PFS, OS, and disease response will be evaluated in the patients defined by mutations in key 
signaling pathways, such as RAS/RAF; polymorphisms in proteasome genes, such as 
polymorphism P11A in PSMB1 or polymorphisms in NFKB regulatory genes, such as NFKB1, 
TRAF3, and IKB. PFS, OS; and response will also be examined in patients defined by different 
levels of circulating proteasome. 
OS and PFS in High-Risk Population 
OS and PFS in a high-risk population, defined as patients carrying cytogenetic abnormalities, 
such as del17, t(4;14), t(14;16), ampl 1q, del13, or del1p, will be analyzed using the similar 
method as PFS and OS in the ITT population. Cytogenetic characteristics will be documented by 
the site at the time of disease diagnosis and will not be reassessed during the course of the study.
8.1.9
Safety Analysis
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 drug and reasons for discontinuation will be tabulated.
Treatment-emergent AEs that occur after administration of the first dose of study drug and 
through 30 days after the last dose of study drug will be tabulated. 
Adverse events will be tabulated according to the Medical Dictionary for Regulatory Activities 
(MedDRA) and will include the following categories: 

Treatment-emergent AEs
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
Drug-related treatment-emergent AEs

Grade 3 or higher treatment-emergent AEs

Grade 3 or higher drug-related treatment-emergent AEs

The most commonly reported treatment-emergent AEs (ie, those events reported by 10% of 
all patients)

SAEs
A listing of treatment-emergent AEs resulting in study drug discontinuation will be provided.
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 based on 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 first dose of study drug through the study period will 
be classified to generic terms according to the World Health Organization (WHO) drug 
dictionary.
Additional safety analyses may be performed to most clearly enumerate rates of toxicities and to 
further define the safety profile of ixazomib citrate.
8.1.9.1
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 the subjects reporting any new primary 
malignancy in the safety population with available information; and

Incidence rates, defined by the number of the subjects 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, 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 IMiDs, analyses of new primary malignancies 
may be performed separately for hematologic and nonhematologic malignancies.
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8.1.9.2
Time to Resolution and Improvement of PN Events
PN is defined as the treatment-emergent adverse event in the high-level term of peripheral 
neuropathies NEC according to MedDRA. 
A PN event is considered as resolved if its final outcome is resolved with no subsequent PN 
event of the same preferred term occurring on the resolution date or the day before and after. A 
PN event is considered as improved if the event improves from the maximum grade. That is, all 
the grades recorded after the maximum grade is less than the maximum grade.
Time to resolution and time to improvement are to be defined for each PN event. Time to 
resolution is defined as the time from the initial onset date (inclusive) to the resolution date for 
resolved events. Time to improvement is defined as the time from the initial onset date (inclusive) 
of the maximum grade to the first onset date that the toxicity grade is below the maximum grade 
with no higher grade thereafter, or the resolution date, whichever occurs first.
Time to improvement and time to resolution of PN events will be summarized by outcome 
(improvement or resolution) using the K-M method. The K-M survival curve and K-M medians 
(if estimable), along with their 2-sided 95% CIs, will be presented. This analysis is based on 
event, thus 1 subject could contribute multiple observations if the subject has more than 1 PN 
event.
The analysis may be conducted for patients with any PN events or those with ≥2 PN events or 
those ≥3 PN events, respectively, if data permits.
8.1.10
Interim Analysis
There are 5 planned IAs. The first IA will be performed when approximately 328 PFS events 
have occurred or 25 months after the last patient has been enrolled, whichever occurs later. The 
first IA will be the primary analysis and the only analysis for the primary endpoint of PFS for 
statistical testing purposes. After PFS is tested at the first IA, central efficacy and investigator 
assessments of disease response for protocol purposes will be discontinued (except for 
investigator assessment of PFS2). The second, third, fourth, and fifth IAs will be conducted for 
OS when approximately 140, 170, 200, and 230 death events have occurred, respectively. 
The test significance for the IAs of OS will be determined using O’Brien-Fleming boundaries 
(the Lan-DeMets method) with a total of 260 death events. 
On the basis of OS results in the fourth IA, the planned number of OS events may be increased to 
up to 350 death events if the observed treatment effect is promising but not large enough to yield 
the likely conclusion of statistical significance at the end of the study using the original planned 
number of OS events. It is also possible for the entire study design to remain unchanged as a 
result of the IAs. The Cui-Hung-Wang test statistic [63] will be used in the FA of OS to protect 
the type I error. 
The IAs will be conducted by the independent statistical center and presented for review to the 
IDMC. During the closed session of the IDMC meeting at the fourth IA, the IDMC will compare 
the conditional power for OS based on the interim results with the prespecified event size and 
primary endpoint adaptation rules and recommend to the sponsor executive committee the final 
adaptation decision. This recommendation will be documented in the IDMC closed meeting 
minutes. 
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9.0
STUDY COMMITTEES 
9.1
Steering Committee
A steering committee that includes a subset of investigators in this study and representatives 
from Takeda will be formed to provide advice on the conduct of the study and publications.
9.2
Independent Review Committee
An IRC, blinded to treatment arm assignments, will review all disease evaluation data between 
screening and PD (including PFS Follow-up period; does not apply to PFS2 assessment) from 
the study and determine disease status (response and progression). Data from the IRC will not be 
provided back to the investigator during the conduct of the study.
9.3
Independent Data Monitoring Committee 
An IDMC supported by an independent statistician will review safety and efficacy data at 
the planned IAs. The IDMC will provide a recommendation regarding study continuation based 
on the safety and efficacy parameters. In the event that the study is terminated early based on the 
IDMC recommendation, Takeda will notify the appropriate regulatory authorities. In addition, 
the IDMC will periodically review safety data at regularly scheduled meetings prespecified in 
the IDMC charter. 
The first formal safety review will occur after approximately 60 subjects have been randomized 
and undergone at least 1 cycle of study treatment. Subsequently, periodic safety reviews will also 
occur as prespecified in the IDMC charter.
Study accrual will not be interrupted due to 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 
serious AEs, treatment-related AEs, serious treatment-related events, and events requiring the 
discontinuation of study drug) 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 due to 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 Takeda. Further details will be provided in the 
IDMC charter.
At the fourthIA, if OS significance is not claimed, the conditional power based on OS will be 
calculated. During the closed session of the IDMC meeting at the fourth IA, the IDMC will 
compare the conditional power for OS based on the interim results with the prespecified effect 
size adaptation rules and recommend to the sponsor executive committee the final adaptation 
decision. This recommendation will be documented in the IDMC closed meeting minutes. 
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10.0
ADVERSE EVENTS
10.1
Definitions
10.1.1
Pretreatment Event Definition
A pretreatment event is any untoward medical occurrence in a patient or subject who has signed 
informed consent to participate in a study but before administration of any study medication; it 
does not necessarily have to have a causal relationship with study participation.
10.1.2
AE Definition
An AE refers to any untoward medical occurrence in a patient or subject administered a 
pharmaceutical product; the untoward medical occurrence does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product whether or not it is related to the medicinal product. 
This includes any newly occurring event, or a previous condition that has increased in severity or 
frequency since the administration of study drug.
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is 
considered by the investigator to be a clinically significant change from baseline. 
10.1.3
SAE Definition
An SAE refers to 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 below on planned hospitalizations).

Results in persistent or significant disability or incapacity. (Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions).

Is a congenital anomaly/birth defect.

Is a medically important event. This refers to an AE that may not result in death, be 
immediately life threatening, or require hospitalization, but may be considered serious when, 
based on appropriate medical judgment, may jeopardize the patient, require medical or 
surgical intervention to prevent 1 of the outcomes listed above, or involves suspected 
transmission via a medicinal product of an infectious agent. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse; any organism, virus, or infectious particle 
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(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.[59] Clarification should be 
made between a serious AE (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 Takeda 
Department of Pharmacovigilance or designee (contact information provided below). This 
should be done by faxing the SAE Form within 24 hours after becoming aware of the event. The 
SAE Form, created specifically by Takeda, will be provided to each clinical study site. A sample 
of the SAE Form may be found in the study manuals. Follow-up information on the SAE or 
serious pretreatment event may be requested by Takeda SAE report information must be 
consistent with the data provided on the eCRF.
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SAE Reporting Contact Information
Cognizant
US and Canada
Toll-Free Fax #: 1-800-963-6290
E-mail: takedaoncocases@cognizant.com
All Other Countries (Rest of World)
Fax #: 1-202-315-3560
E-mail: takedaoncocases@cognizant.com
Planned hospital admissions or surgical procedures for an illness or disease that existed before 
the patient was enrolled in the trial are not to be considered AEs unless the condition deteriorated 
in an unexpected manner during the trial (eg, surgery was performed earlier or later than 
planned).
For both serious and nonserious AEs, the investigator must determine both the intensity of the 
event and the relationship of the event to study drug administration. For serious pretreatment 
events, the investigator must determine both the intensity of the event and the relationship of the 
event to study procedures.
Intensity for each AE, including any laboratory abnormality, will be determined using the 
NCI CTCAE, Version 4.03, effective date 14 June 2010.[59] The criteria are provided in the 
study manuals.
Relationship to study drug administration will be determined by the investigator responding yes 
or no to this question: Is there a reasonable possibility that the AE is associated with the study 
drug?
10.3
Monitoring of AEs and Period of Observation
AEs, both nonserious and serious, will be monitored throughout the study as follows: 

AEs will be reported from the first dose of study drug through 30 days after administration of 
the last dose of study drug and recorded in the eCRFs. 

Serious pretreatment events will be reported to the Takeda Department of Pharmacovigilance 
or designee from the time of the signing of the ICF up to first dose of study drug but will not 
be recorded in the eCRF.

Related and unrelated SAEs will be reported to the Takeda Department of Pharmacovigilance 
or designee from the first dose of study drug through 30 days after administration of the last 
dose of study drug and recorded in the eCRF. After this period, only related SAEs must be 
reported to the Takeda Department of Pharmacovigilance or designee. SAEs should be 
monitored until they are resolved or are clearly determined to be due to a patient’s stable or 
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chronic condition or intercurrent illness(es). In addition, NPMs that occur during the follow-
up periods must be reported, irrespective of causality to the study drug, from the first dose of 
study drug through death or termination of the study by the sponsor.
10.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or 
disease state) of a female patient occurring while the patient is on study drug, or within 90 days 
of the patient’s last dose of study drug, are considered immediately reportable events. Study drug 
is to be discontinued immediately. The sponsor must also be contacted immediately by faxing a
completed Pregnancy Form to the Takeda Department of Pharmacovigilance or designee (see 
Section 10.2). The pregnancy must be followed for the final pregnancy outcome. 
If a female partner of a male patient becomes pregnant during the male patient’s participation in 
this study, the sponsor must also be contacted immediately by faxing a completed Pregnancy 
Form to the Takeda Department of Pharmacovigilance or designee. Every effort should be made 
to follow the pregnancy for the final pregnancy outcome.
11.0
ADMINISTRATIVE REQUIREMENTS
11.1
Good Clinical Practice
The study will be conducted in accordance with the ICH-GCP and the appropriate regulatory 
requirement(s). The investigator will be thoroughly familiar with the appropriate use of the study 
drug as described in the protocol and the IB.
11.2
Data Quality Assurance
The investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each study patient. 
Study data will be entered into an eCRF by site personnel using a secure, validated, web-based 
electronic data capture (EDC) application. Takeda will have access to all data upon entry in the 
EDC application. 
Study monitors will discuss instances of missing or uninterpretable data with the investigator for 
resolution. Any changes to study data will be made to the eCRF and documented via an 
electronic audit trail associated with the affected eCRF.
11.3
eCRF Completion 
Takeda, or its designee, will provide the study sites with secure access to and training on the 
EDC application, sufficient to permit site personnel to enter or correct information in the eCRFs 
for the patients for whom they are responsible.
eCRFs will be completed for each study patient. It is the investigator’s responsibility to ensure 
the accuracy, completeness, clarity, and timeliness of the data reported in the patient’s eCRF.
The investigator, or designated representative, should complete the eCRF as soon as possible 
after information is collected.
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The investigator must provide through the EDC application formal approval of all the 
information in the eCRFs and changes to the eCRFs to endorse the final submitted data for the 
patients for which he or she is responsible. The audit trail entry will show the user’s 
identification information and the date and time of the correction.
Takeda, or its designee, will retain the eCRF data and corresponding audit trails. A copy of the 
final archival eCRF in the form of a compact disk (CD) or other electronic media will be placed 
in the investigator’s study file.
11.4
Study Monitoring
Monitoring and auditing procedures developed or approved by Takeda will be followed to 
comply with GCP guidelines.
All information recorded on the eCRFs for this study must be consistent with the patient’s source 
documentation. During the course of the study, the study monitor will make study site visits to 
review protocol compliance, verify eCRFs against source documentation, assess drug 
accountability, and ensure that the study is being conducted according to pertinent regulatory 
requirements. The review of medical records will be performed in a manner that ensures that 
patient confidentiality is maintained. In the event a monitor cannot visit the site in a timely 
manner due to the COVID-19 pandemic, alternative monitoring approaches, such as telephone 
contact, may be used to ensure data quality and integrity and maintain patient safety. Alternative 
monitoring approaches should be used only where allowed by the local health authority and 
permitted by the IRB/IEC. Remote monitoring and site staff interviews for consistency check of 
data can be used.
11.5
Ethical Considerations
The study will be conducted in accordance with applicable regulatory requirement(s) and will 
adhere to GCP standards. The IRB/IEC will review all appropriate study documentation to 
safeguard the rights, safety, and well-being of the patients. The study will be conducted only at 
sites where IRB/IEC approval has been obtained. The protocol, IB, ICF, advertisements (if 
applicable), written information given to the patients (including diary cards), safety updates, 
annual progress reports, and any revisions to these documents will be provided to the IRB/IEC 
by the investigator or the sponsor, as allowed by local regulations.
11.6
Patient Information and Informed Consent
After the study has been fully explained, written informed consent will be obtained from the 
patient or his/her legal representative before study participation. The method of obtaining and 
documenting the informed consent and the contents of the consent must comply with the ICH-
GCP and all applicable regulatory requirements. 
Patients in the PFS and PD Follow-up periods may need to be reconsented upon implementation 
of Amendment 4, according to IRB/IEC standards. Reconsenting should be done in person, 
where possible. Remote reconsenting is permitted as long as the process adheres to site, IRB/IEC, 
and GCP standards and local regulations.
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11.7
Patient Confidentiality
To maintain patient privacy, all eCRFs, study drug accountability records, study reports, and 
communications will identify the patient by initials where permitted and/or by the assigned 
patient number. The patient’s confidentiality will be maintained and will not be made publicly 
available to the extent permitted by the applicable laws and regulations.
11.8
Investigator Compliance
The investigator will conduct the trial in compliance with the protocol provided by Takeda and 
given approval/favorable opinion by the IRB/IEC and the appropriate regulatory authority(ies). 
Modifications to the protocol are not to be made without agreement of both the investigator and 
Takeda. Changes to the protocol will require written IRB/IEC approval/favorable opinion before 
implementation, except when the modification is needed to eliminate an immediate hazard or 
hazards to patients. Takeda, or its designee, will submit all protocol modifications to the 
appropriate regulatory authority(ies) in accordance with the governing regulations.
When immediate deviation from the protocol is required to eliminate an immediate hazard or 
hazards to patients, the investigator will contact Takeda, or its designee, if circumstances permit, 
to discuss the planned course of action. Any departures from the protocol must be documented.
11.9
On-site Audits/Inspection
Regulatory authorities, the IEC/IRB, and/or Takeda may request access to all source documents, 
eCRFs, and other study documentation for on-site audit or inspection. Direct access to these
documents must be guaranteed by the investigator, who must provide support at all times for 
these activities.
11.10
Investigator and Site Responsibility for Drug Accountability
Accountability for the study drug at the trial site is the responsibility of the investigator. Drug 
accountability records indicating the drug’s delivery date to the site, inventory at the site, use by 
each patient, and amount returned to Takeda, or its designee (or disposal of the drug, if approved 
by Takeda), will be maintained by the clinical site. Takeda or its designee will review drug 
accountability at the site on an ongoing basis.
All material containing study drug will be treated and disposed of in accordance with governing 
regulations.
11.11
Product Complaints and Medication Errors (Including Overdose)
A product complaint is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product. Individuals who 
identify a potential product complaint situation should immediately report the event to 
ctmcomplaint@takeda.com.
Product complaints or medication errors in and of themselves are not AEs. If a product complaint 
results in an SAE, an SAE Form should be completed and sent to Cognizant (refer to Section 
10.2).
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A medication error is a preventable event that involves an identifiable patient and that leads to 
inappropriate medication use, which may result in patient harm. Whereas overdoses constitute 
medication errors, doses missed inadvertently by a patient do not. Investigators must record all 
medication errors (including overdose) on the appropriate eCRF. Individuals who identify a 
potential medication error situation should immediately report this to ctmcomplaint@takeda.com.
11.12
Closure of the Study
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 of the end of the study, a summary of the clinical trial results will be submitted to 
the competent authorities and IECs in all member states involved in the study.
Study participation by individual sites or the entire study may be prematurely terminated if, in 
the opinion of the investigator or Takeda, there is sufficient reasonable cause. Written 
notification documenting the reason for study termination will be provided to the investigator or 
Takeda by the terminating party.
Circumstances that may warrant termination include, but are not limited to:

Determination of unexpected, significant, or unacceptable risk to patients

Failure to enter patients at an acceptable rate

Insufficient adherence to protocol requirements

Insufficient, incomplete, and/or unevaluable data

Determination of efficacy based on IA

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 EDC 
application, will not have a right to use the EDC application, and will cease using the password 
or access materials once their participation in the study has concluded. In the event that any 
access devices for the EDC application have been provided, these will be returned to Takeda 
once the site’s participation in the study has concluded.
Within 15 days of premature closure, Takeda must notify the competent authorities and IECs of 
any member state where the study is being conducted, providing the reasons for study closure. 
11.13
Record Retention
The investigator will maintain all study records according to the ICH-GCP and applicable 
regulatory requirement(s). Records will be retained for at least 2 years after the last marketing 
application approval or 2 years after formal discontinuation of the clinical development of the 
investigational product or according to applicable regulatory requirement(s). If the investigator 
withdraws from the responsibility of keeping the study records, custody must be transferred to a 
person willing to accept the responsibility and Takeda notified. 
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12.0
USE OF INFORMATION
All information regarding ixazomib supplied byTakeda to the investigator is privileged and 
confidential information. The investigator agrees to use this information to accomplish the study 
and will not use it for other purposes without consent from Takeda. It is understood that there is 
an obligation to provide Takeda with complete data obtained during the study. The information 
obtained from the clinical study will be used toward the development of ixazomib and may be 
disclosed to regulatory authority(ies), other investigators, corporate partners, or consultants as 
required.
Upon completion of the clinical study and evaluation of results by Takeda, the hospital or 
institution and/or investigator may publish or disclose the clinical trial results pursuant to the 
terms contained in the applicable Clinical Trial Agreement.
A Steering Committee that includes a subset of investigators in this study and representatives 
from Takeda will be formed to advise on the conduct of the study and development of 
publications and presentations. This policy may be changed with the agreement of both the 
investigators and Takeda.
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13.0
INVESTIGATOR AGREEMENT
I have read Protocol C16019 Amendment 04: A Phase 3, Randomized, Placebo-Controlled, 
Double-Blind Study of Oral Ixazomib Citrate (MLN9708) Maintenance Therapy in Patients 
With Multiple Myeloma Following Autologous Stem Cell Transplant 
I agree to conduct the study as detailed herein and in compliance with International Conference 
on Harmonisation Guidelines for Good Clinical Practice and applicable regulatory requirements 
and to inform all who assist me in the conduct of this study of their responsibilities and 
obligations.
Principal investigator printed name
Principal investigator signature
Date
Investigational site or name of institution and 
location (printed)
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14.0
REFERENCES
1. Palumbo A, Anderson K. Multiple myeloma. N Engl J Med 2011;364(11):1046-60.
2. Landgren O, Weiss BM. Patterns of monoclonal gammopathy of undetermined significance 
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15. Gupta N, Liu G, Berg D, Kalebic T, Gomez-Navarro J. Clinical Pharmacokinetics of 
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16. Gupta N, Saleh M, Venkatakrishnan K. Flat-Dosing Versus BSA-Based Dosing for 
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23. Palumbo A, Bringhen S, Rossi D, Cavalli M, Larocca A, Ria R, et al. Bortezomib-
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compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: 
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24. Sonneveld P, Schmidt-Wolf IG, van der Holt B, El Jarari L, Bertsch U, Salwender H, et al. 
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25. Mateos M-V, Oriol A, Teruel A-I, Bengoechea E, Pérez M, López J, et al. Maintenance 
Therapy with Bortezomib Plus Thalidomide (VT) or Bortezomib Plus Prednisone (VP) In 
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26. Attal M, Lauwers-Cances V, Marit G, Caillot D, Moreau P, Facon T, et al. Lenalidomide 
maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med 
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27. McCarthy PL, Owzar K, Hofmeister CC, Hurd DD, Hassoun H, Richardson PG, et al. 
Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med 
2012;366(19):1770-81.
28. Palumbo A, Hajek R, Delforge M, Kropff M, Petrucci MT, Catalano J, et al. Continuous 
lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med 
2012;366(19):1759-69.
29. Revlimid (Lenalidomide) European Public Assessment Report. European Medicines Agency 
Committee for Medicinal Products for Human Use. 21 June 2012. Publication No. 
EMA/432817/2012.
30. Harousseau JL, Dreyling M. Multiple myeloma: ESMO Clinical Practice Guidelines for 
diagnosis, treatment and follow-up. Ann Oncol 2010;21 Suppl 5:v155-7.
31. Kantar Health. Treatment Architecture: Western Europe Multiple Myeloma. CancerMPact® 
Western Europe 2012.
32. Ludwig H, Miguel JS, Dimopoulos MA, Palumbo A, Garcia Sanz R, Powles R, et al. 
International Myeloma Working Group recommendations for global myeloma care. 
Leukemia 2013.
33. Lokhorst HM, van der Holt B, Zweegman S, Vellenga E, Croockewit S, van Oers MH, et al. 
A randomized phase 3 study on the effect of thalidomide combined with adriamycin, 
dexamethasone, and high-dose melphalan, followed by thalidomide maintenance in patients 
with multiple myeloma. Blood 2010;115(6):1113-20.
34. Badros AZ. Lenalidomide in myeloma--a high-maintenance friend. N Engl J Med 
2012;366(19):1836-8.
35. Bruggemann M, Pott C, Ritgen M, Kneba M. Significance of minimal residual disease in 
lymphoid malignancies. Acta Haematol 2004;112(1-2):111-9.
36. Foroni L, Coyle LA, Papaioannou M, Yaxley JC, Sinclair MF, Chim JS, et al. Molecular 
detection of minimal residual disease in adult and childhood acute lymphoblastic leukaemia 
reveals differences in treatment response. Leukemia 1997;11(10):1732-41.
37. Moreton P, Kennedy B, Lucas G, Leach M, Rassam SM, Haynes A, et al. Eradication of 
minimal residual disease in B-cell chronic lymphocytic leukemia after alemtuzumab therapy 
is associated with prolonged survival. J Clin Oncol 2005;23(13):2971-9.
38. Mortuza FY, Papaioannou M, Moreira IM, Coyle LA, Gameiro P, Gandini D, et al. Minimal 
residual disease tests provide an independent predictor of clinical outcome in adult acute 
lymphoblastic leukemia. J Clin Oncol 2002;20(4):1094-104.
39. Pott C, Hoster E, Delfau-Larue MH, Beldjord K, Bottcher S, Asnafi V, et al. Molecular 
remission is an independent predictor of clinical outcome in patients with mantle cell 
lymphoma after combined immunochemotherapy: a European MCL intergroup study. Blood 
2010;115(16):3215-23.
40. Liu H, Johnson JL, Koval G, Malnassy G, Sher D, Damon LE, et al. Detection of minimal 
residual disease following induction immunochemotherapy predicts progression free survival 
in mantle cell lymphoma: final results of CALGB 59909. Haematologica 2012;97(4):579-85.
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41. Andersen NS, Pedersen LB, Laurell A, Elonen E, Kolstad A, Boesen AM, et al. Pre-emptive 
treatment with rituximab of molecular relapse after autologous stem cell transplantation in 
mantle cell lymphoma. J Clin Oncol 2009;27(26):4365-70.
42. Geisler CH, Kolstad A, Laurell A, Andersen NS, Pedersen LB, Jerkeman M, et al. Long-term 
progression-free survival of mantle cell lymphoma after intensive front-line 
immunochemotherapy with in vivo-purged stem cell rescue: a nonrandomized phase 2 
multicenter study by the Nordic Lymphoma Group. Blood 2008;112(7):2687-93.
43. Pott C. Minimal residual disease detection in mantle cell lymphoma: technical aspects and 
clinical relevance. Semin Hematol 2011;48(3):172-84.
44. Paiva B, Vidriales MB, Cervero J, Mateo G, Perez JJ, Montalban MA, et al. Multiparameter 
flow cytometric remission is the most relevant prognostic factor for multiple myeloma 
patients who undergo autologous stem cell transplantation. Blood 2008;112(10):4017-23.
45. Sarasquete ME, Garcia-Sanz R, Gonzalez D, Martinez J, Mateo G, Martinez P, et al. 
Minimal residual disease monitoring in multiple myeloma: a comparison between allelic-
specific oligonucleotide real-time quantitative polymerase chain reaction and flow cytometry. 
Haematologica 2005;90(10):1365-72.
46. Martinez-Sanchez P, Montejano L, Sarasquete ME, Garcia-Sanz R, Fernandez-Redondo E, 
Ayala R, et al. Evaluation of minimal residual disease in multiple myeloma patients by 
fluorescent-polymerase chain reaction: the prognostic impact of achieving molecular 
response. Br J Haematol 2008;142(5):766-74.
47. Faham M, Zheng J, Moorhead M, Carlton VE, Stow P, Coustan-Smith E, et al. Deep-
sequencing approach for minimal residual disease detection in acute lymphoblastic leukemia. 
Blood 2012;120(26):5173-80.
48. Gawad C, Pepin F, Carlton VE, Klinger M, Logan AC, Miklos DB, et al. Massive evolution 
of the immunoglobulin heavy chain locus in children with B precursor acute lymphoblastic 
leukemia. Blood 2012;120(22):4407-17.
49. Rawstron AC, Orfao A, Beksac M, Bezdickova L, Brooimans RA, Bumbea H, et al. Report 
of the European Myeloma Network on multiparametric flow cytometry in multiple myeloma 
and related disorders. Haematologica 2008;93(3):431-8.
50. Shaughnessy JD, Jr., Zhan F, Burington BE, Huang Y, Colla S, Hanamura I, et al. A 
validated gene expression model of high-risk multiple myeloma is defined by deregulated 
expression of genes mapping to chromosome 1. Blood 2007;109(6):2276-84.
51. Nair B, van Rhee F, Shaughnessy JD, Jr., Anaissie E, Szymonifka J, Hoering A, et al. 
Superior results of Total Therapy 3 (2003-33) in gene expression profiling-defined low-risk 
multiple myeloma confirmed in subsequent trial 2006-66 with VRD maintenance. Blood 
2010;115(21):4168-73.
52. Broyl A, Hose D, Lokhorst H, de Knegt Y, Peeters J, Jauch A, et al. Gene expression 
profiling for molecular classification of multiple myeloma in newly diagnosed patients. 
Blood 2010;116(14):2543-53.
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53. Mulligan G, Mitsiades C, Bryant B, Zhan F, Chng WJ, Roels S, et al. Gene expression 
profiling and correlation with outcome in clinical trials of the proteasome inhibitor 
bortezomib. Blood 2007;109(8):3177-88.
54. Keats JJ, Fonseca R, Chesi M, Schop R, Baker A, Chng WJ, et al. Promiscuous mutations 
activate the noncanonical NF-kappaB pathway in multiple myeloma. Cancer Cell 
2007;12(2):131-44.
55. Chapman MA, Lawrence MS, Keats JJ, Cibulskis K, Sougnez C, Schinzel AC, et al. Initial 
genome sequencing and analysis of multiple myeloma. Nature 2011;471(7339):467-72.
56. Mulligan G, Lichter D, Di Bacco A, Blakemore S, Berger A, Koenig E, et al. Mutational 
Analysis of Tumor Samples From Patients with Relapsed or Refractory Multiple Myeloma 
(MM) Highlights the Prevalence of RAS/RAF Pathway Activation and Demonstrates 
Previously Unreported Mutations in Known Cancer Genes. Blood (ASH Annual Meeting 
Abstracts) 2011;118(21):abstr 1377.
57. Mulligan G, Lichter DI, Di Bacco A, Blakemore SJ, Berger A, Koenig E, et al. Mutation of 
NRAS but not KRAS significantly reduces myeloma sensitivity to single-agent bortezomib 
therapy. Blood 2014;123(5):632-9.
58. Jakob C, Egerer K, Liebisch P, Turkmen S, Zavrski I, Kuckelkorn U, et al. Circulating 
proteasome levels are an independent prognostic factor for survival in multiple myeloma. 
Blood 2007;109(5):2100-5.
59. Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03. U.S. 
Department of Health and Human Services National Cancer Institute. 14 June 2010.
60. Du J, Huo J, Shi J, Yuan Z, Zhang C, Fu W, et al. Polymorphisms of nuclear factor-
{kappa}B family genes are associated with development of multiple myeloma and treatment 
outcome in patients receiving bortezomib-based regimens. Haematologica 2011;96(5):729-37.
61. 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.
62. Mehta CR, Pocock SJ. Adaptive increase in sample size when interim results are promising: 
a practical guide with examples. Stat Med 2011;30(28):3267-84.
63. Cui L, Hung HM, Wang SJ. Modification of sample size in group sequential clinical trials. 
Biometrics 1999;55(3):853-7.
64. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 
1982;5(6):649-55.
65. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16(1):31-41.
66. Durie BG, Salmon SE. A clinical staging system for multiple myeloma. Correlation of 
measured myeloma cell mass with presenting clinical features, response to treatment, and 
survival. Cancer 1975;36(3):842-54.
67. Knoben J, Anderson P. Handbook of Clinical Drug Data, 6th ed.: Drug Intelligence Pub, Inc.; 
1988.
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68. Rajkumar SV, Harousseau JL, Durie B, Anderson KC, Dimopoulos M, Kyle R, et al. 
Consensus recommendations for the uniform reporting of clinical trials: report of the 
International Myeloma Workshop Consensus Panel 1. Blood 2011;117(18):4691-5.
69. Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and response 
assessment of multiple myeloma. Leukemia 2009;23(1):3-9.
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15.0
APPENDICES
15.1
Eastern Cooperative Oncology Group (ECOG) Scale for Performance Status
Grade
Description
0
Normal activity. Fully active, able to carry on all predisease performance without restriction
1
Symptoms but ambulatory. Restricted in physically strenuous activity, but ambulatory and 
able to carry out work of a light or sedentary nature (eg, light housework, office work)
2
In bed < 50% of the time. Ambulatory and capable of all self-care, but unable to carry out 
any work activities. Up and about more than 50% of waking hours.
3
In bed > 50% of the time. Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to 
bed or chair
5
Dead
Source: Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5 (6):649-55. [64]
15.2
Multiple Myeloma Diagnostic Criteria
IMWG Criteria for the Diagnosis of Myeloma
Diagnosis
Diagnostic Criteria: All Three Required
Symptomatic multiple myelomaa

Monoclonal plasma cells in the bone marrow 10% and/or 
presence of a biopsy-proven plasmacytoma

Monoclonal protein present in the serum and/or urineb

Myeloma-related organ dysfunction (1)c
[C] Calcium elevation in the blood (serum calcium 
> 10.5 mg/dL or upper limit of normal)
[R] Renal insufficiency (serum creatinine > 2 mg per 100 
ml)
[A] Anemia (hemoglobin < 10 g per 100 ml or 2 g < 
normal)
[B] Lytic bone lesions or osteoporosisd
Source: International Myeloma Foundation, myeloma.org. Accessed 16 January 2012.
a These criteria identify Stage IB and Stages II and III A/B myeloma by Durie/Salmon stage. Stage IA 
becomes smoldering or indolent myeloma.
b If no monoclonal protein is detected (nonsecretory disease), then 30% monoclonal bone marrow plasma 
cells and/or a biopsy-proven plasmacytoma required.
c A variety of other types of end-organ dysfunctions can occasionally occur and lead to a need for therapy. 
Such dysfunction is sufficient to support classification as myeloma if proven to be myeloma related.
d If a solitary (biopsy-proven) plasmacytoma or osteoporosis alone (without fractures) is the sole defining 
criteria, then 30% plasma cells are required in the bone marrow.
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15.3
Cockcroft-Gault Equation
For males: 
Creatinine Clearance=(140-age[years]) weight [kg] OR (140–age[years]) weight [kg]
        72 (serum creatinine[mg/dL])
   0.81 (serum creatinine[mol/L])
For females: 
Creatinine Clearance=0.85 ((140-age[years]) weight [kg]) OR 0.85 (140-age[years] weight [kg])
    72 (serum creatinine[mg/dL])
0.81 (serum creatinine[mol/L])
Source: Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16(1):31-41.[65]
15.4
ISS Staging Criteria 
International Staging System
Stage
Criteria
Stage I
Serum 2-microglobulin <3.5 mg/L
Serum albumin 3.5 g/dL
Stage II
Neither Stage I or Stage IIIa
Stage III
Serum 2-microglobulin 5.5 mg/L 
Source: Durie BG, Salmon SE. A clinical staging system for multiple myeloma. Correlation of measured 
myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer 
1975;36(3):842-54.[66]
Abbreviations: ISS=International Staging System.
a There are two categories for stage II: serum 2-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.
15.5
Steroid Equivalent Doses
Approximate equivalent doses:
Steroid
Glucocorticoid
Anti-inflammatory
(mg)
Mineralicorticoid
(mg)
Half-life
(hours)
Cortisone
100
100
812
Hydrocortisone
80
80
812
Prednisone
20
100
1236
Prednisolone
20
100
1236
Methylprednisolone
16
no effect
1236
Dexamethasone
2
no effect
3672
Source: Knoben JE, Anderson PO. Handbook of Clinical Drug Data, 6th ed. Drug Intelligence Pub, Inc. 
1988.[67]
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15.6
EQ-5D
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15.7
European Organization for Research and Treatment of Cancer (EORTC) Multiple 
Myeloma Module (QLQ-MY20)
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15.8
European Organization for Research and Treatment of Cancer (EORTC QLQ 
C30 Version 3)
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15.9
Response Criteria
Source: Rajkumar SV, et al. 2011.[68] (adapted from Durie et al.[61] and Kyle et al.[69] with permission).
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15.10
Previous, Full Schedule of Events and PK Sampling Schedule (Schedules Before Implementation of Amendment 4) 
Study Procedures
Screening
Treatment Period
EOTa
Follow-upb
28-Day Cyclesb
PFS
PD
PFS2
OS 
Cycle
C1
C2
C3
C4-C5
C6-C26
Before 
PD, 
Every 
4 wk
After PD 
but Before 
Next-Line 
Therapy, 
Every 4 wk
After Next-Line 
Therapy but 
Before PD on Next-
Line Therapy, 
Every 12 wk
After PD on 
Next-Line 
Therapy, 
Every 
12 wk
Days
-15 to -1
1
8
15
1
8
1
1
1
Window
±2 days
1 wk
±1 wk
Informed consent
X
Inclusion/exclusion 
criteriac
X
Demographics
X
Complete medical 
history and disease 
staging
X
Complete physical 
examinationd
X
X
Symptom-directed 
physical 
examinationd
X
X
X
X
X
X
X
ECOG performance 
status
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
Height (cm)
X
Weight (kg)
X
X
X
X
X
X
X
Pregnancy test 
(serum)e
X
X
X
12-lead ECG 
X
X
Hematology 
laboratoryf
X
X
X
X
X
X
X
X
X
X
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Study Procedures
Screening
Treatment Period
EOTa
Follow-upb
28-Day Cyclesb
PFS
PD
PFS2
OS 
Cycle
C1
C2
C3
C4-C5
C6-C26
Before 
PD, 
Every 
4 wk
After PD 
but Before 
Next-Line 
Therapy, 
Every 4 wk
After Next-Line 
Therapy but 
Before PD on Next-
Line Therapy, 
Every 12 wk
After PD on 
Next-Line 
Therapy, 
Every 
12 wk
Days
-15 to -1
1
8
15
1
8
1
1
1
Window
±2 days
1 wk
±1 wk
Chemistry 
laboratoryf
X
X
X
X
X
X
X
Urinalysis
X
EORTC QLQ-C30g
X
X
X
X
X
X
X
X
X
X (twice only)
EORTC QLQ-
MY20g 
X
X
X (C4)
X (C7, 10, 
13,16, 19, 
22, 25)
X
X
X
X (twice only)
EQ-5Dg
X
X
X (C4)
X (C7, 10, 
13,16, 19, 
22, 25)
X
X 
(every 3 
months)
X (every 3 
months)
X
X
HU assessment (also 
for unscheduled 
visits)g
X
X
X
X
X
X
X
X
X (twice only)
Skeletal surveyh
X
X
Imaging disease 
assessmenti
X
X
Investigator 
assessment of 
disease 
response/status
X
X
X
X
X
X
X
2-microglobulin
X
M-protein 
measurements 
(SPEP)
Xj
Xj
X
X
X
X
X
X
X
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CONFIDENTIAL
Study Procedures
Screening
Treatment Period
EOTa
Follow-upb
28-Day Cyclesb
PFS
PD
PFS2
OS 
Cycle
C1
C2
C3
C4-C5
C6-C26
Before 
PD, 
Every 
4 wk
After PD 
but Before 
Next-Line 
Therapy, 
Every 4 wk
After Next-Line 
Therapy but 
Before PD on Next-
Line Therapy, 
Every 12 wk
After PD on 
Next-Line 
Therapy, 
Every 
12 wk
Days
-15 to -1
1
8
15
1
8
1
1
1
Window
±2 days
1 wk
±1 wk
M-protein 
measurements 
(UPEP [24 hour 
Urine collection])
Xj
Xj
X
X
X
X
X
X
X
Serum free light 
chain assay
Xj
Xj
X
X
X
X
X
X
X
Immunofixation -
serum and urinek
Xj
Xj
X
X
X
X
X
X
X
Quantification of Igl
Xj
Xj
X
X
X
X
X
X
X
Bone marrow 
aspiration (BMA)
Disease 
assessment 
BMAm
X
MRD BMA—
scheduledn
X
X (C13)
X
MRD BMA—
unscheduled
Additional MRD BMA specimen requested at the time of 
first CR (may be collected during the BMA procedure for 
CR confirmation)
Archival tumor 
sample
Xo
PD BMAp
X
X
Blood samples for 
biomarker analysis
MRD Peripheral 
blood specimenn
X
X (C13)
X
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Protocol Incorporating Amendment No. 04
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CONFIDENTIAL
Study Procedures
Screening
Treatment Period
EOTa
Follow-upb
28-Day Cyclesb
PFS
PD
PFS2
OS 
Cycle
C1
C2
C3
C4-C5
C6-C26
Before 
PD, 
Every 
4 wk
After PD 
but Before 
Next-Line 
Therapy, 
Every 4 wk
After Next-Line 
Therapy but 
Before PD on Next-
Line Therapy, 
Every 12 wk
After PD on 
Next-Line 
Therapy, 
Every 
12 wk
Days
-15 to -1
1
8
15
1
8
1
1
1
Window
±2 days
1 wk
±1 wk
MRD Peripheral 
blood 
specimen—
unscheduled
Additional MRD peripheral blood specimen requested at the 
time of first CR (may be collected during the BMA 
procedure for CR confirmation)
Plasma 
biomarker 
(proteasome 
level)
X
Blood sample 
for germline 
DNA 
X
Adverse event 
reporting
Recorded from the first dose of drug in the study drug 
regimen through 30 days after last dose of drug in the study 
drug regimenq
Serious adverse events and serious pretreatment events will be 
collected from signing of the informed consent form through 30 days after 
the last dose of drug in the study drug regimen
Concomitant 
medications/ 
procedures
Recorded from the first dose of drug in the study drug 
regimen through 30 days after last dose of drug in the study 
drug regimen
New primary 
malignancy 
assessment
Continuous from the start of study drug regimen administration until death or termination of the study by the sponsor
Herpes zoster 
prophylaxis
Required, unless medically contraindicated, 
throughout treatment period
Survival
X
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Study No. C16019
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Protocol Incorporating Amendment No. 04
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CONFIDENTIAL
Study Procedures
Screening
Treatment Period
EOTa
Follow-upb
28-Day Cyclesb
PFS
PD
PFS2
OS 
Cycle
C1
C2
C3
C4-C5
C6-C26
Before 
PD, 
Every 
4 wk
After PD 
but Before 
Next-Line 
Therapy, 
Every 4 wk
After Next-Line 
Therapy but 
Before PD on Next-
Line Therapy, 
Every 12 wk
After PD on 
Next-Line 
Therapy, 
Every 
12 wk
Days
-15 to -1
1
8
15
1
8
1
1
1
Window
±2 days
1 wk
±1 wk
f
Clinical laboratory evaluations will be performed by a central laboratory. For dosing decisions, local hematology and chemistry laboratory results may 
be used; however, samples must still be sent to the central laboratory as well. Hematology and chemistry panels may be collected up to 3 days before 
Day 1 dosing and 24 hours before Days 8 and 15 dosing, where required. Local laboratory evaluations may be done more frequently at the 
investigator’s discretion (ie, for acute management of treatment-emergent adverse events). 
g Patient-reported outcomes and HU assessment (ie, number of medical encounters) should be completed before any other study procedures are 
performed or study drug is administered. During the PFS2 Follow-up period only, assessments should be done twice—ideally once approximately 8-
12 weeks after the start of next-line therapy and again 8-12 weeks later—and are preferred to be administered in the clinic, but if needed, the QLQ-C30 
and QLQ-MY20 questionnaires may be completed at home. At time points when a clinic visit is not required, the EQ-5D questionnaire may be 
administered over the telephone.
h Skeletal survey will be performed at screening (within 8 weeks before randomization) and at EOT for all patients. Additional assessments can be done 
at the discretion of the investigator (ie, for suspected increased or new bone lesions). In certain circumstances and at the discretion of the investigator, 
a computed tomography (CT) scan, a positron emission tomography (PET)-CT scan, or whole body magnetic resonance imaging (MRI) may be done 
at screening in place of a skeletal survey, provided that the same modality for assessment is used throughout the study. 
i
Patients with documented extramedullary disease at diagnosis should have imaging disease assessment by CT, PET-CT, or MRI performed at 
screening and at EOT. Additional assessments can be done at the discretion of the investigator (ie, for suspected new lesions or progressive disease). 
The modality is at the discretion of the investigator, but should be kept consistent throughout.
j
If the screening test was performed more than 14 days before the first dose, the test will be repeated at baseline.
k
Immunofixation to be done to confirm CR (if the M-protein level is undetectable by protein electrophoresis in both serum and urine, the central 
laboratory will perform immunofixation testing in both serum and urine).
l
Blood samples for quantification of Ig (IgM, IgG, IgA) will be obtained throughout the study at the time points specified. Quantitative IgD and IgE 
will be done at screening (and baseline if needed) only, except for the rare patient with IgD or IgE multiple myeloma, for whom the quantitative test 
for that antibody will be done at the same time points as, and in addition to, IgM, IgG, and IgA measurements.
m To be evaluated at a local laboratory to assess disease status at screening. To be repeated if the patient is considered to possibly have CR (eg, 
resolution of serum and urine M-protein), or to investigate suspected PD if applicable.
n For all patients in CR or very good partial response (VGPR) at screening, an additional bone marrow aspirate aliquot and a peripheral blood specimen 
will be collected and sent to the central laboratory for MRD. For patients achieving suspected CR during study therapy, a portion of the bone marrow 
aspirate obtained to document the CR should be sent to the central laboratory for MRD. In addition, patients in VGPR or CR at Cycle 13 and at EOT 
(approximately 24 months [to the nearest complete cycle; if there are no treatment delays, this would be 26 cycles]) will have BMA and blood samples 
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Study No. C16019
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CONFIDENTIAL
Study Procedures
Screening
Treatment Period
EOTa
Follow-upb
28-Day Cyclesb
PFS
PD
PFS2
OS 
Cycle
C1
C2
C3
C4-C5
C6-C26
Before 
PD, 
Every 
4 wk
After PD 
but Before 
Next-Line 
Therapy, 
Every 4 wk
After Next-Line 
Therapy but 
Before PD on Next-
Line Therapy, 
Every 12 wk
After PD on 
Next-Line 
Therapy, 
Every 
12 wk
Days
-15 to -1
1
8
15
1
8
1
1
1
Window
±2 days
1 wk
±1 wk
collected for MRD at those 2 time points (unless already done within the most recent 2 cycles); BMA and blood samples will also be obtained in 
patients in CR or VGPR who stop therapy before Cycle 26. All bone marrow analyses for disease status are evaluated locally, with an aliquot of the 
bone marrow sent to the central laboratory for MRD analyses. Blood samples for MRD (processed accordingly to the laboratory manual) will be sent 
to the central laboratory for storage.
o Archival tumor material from the time of diagnosis and any available other prestudy time points (eg, postinduction response assessment) is to be used as a 
calibration sample for MRD assessment. The material should consist of (in order of preference) unstained slides; bone marrow aspirate as a FFPE ; or stained 
slides. Bone marrow biopsy samples will not be accepted. 
p A BMA for patients who have PD is optional but highly recommended. This may be a second pull of the sampling already done at this time point to investigate 
suspected PD.
q 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 progression has occurred, whichever occurs first.
r
Patients will receive blinded study drug (ixazomib or matching placebo) orally on Days 1, 8, and 15 of every 28-day cycle. A starting dose of 3 mg of 
ixazomib (or matching placebo) will be given to all patients through Cycle 4. Upon evaluation of toxicities at Cycle 4, and on the basis of the dose 
escalation criteria detailed in Section 6.5, the dose will be escalated to 4 mg (or matching placebo) on Cycle 5 Day 1, and administered on the same 
schedule for the duration of the study, to provide maximum possible clinical benefit for patients who tolerated the first 4 cycles of treatment. If dose 
escalation was inadvertently missed at Cycle 5, escalation may be performed with permission from the Takeda project clinician or designee.
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CONFIDENTIAL
Ixazomib Pharmacokinetic Sampling Schedule
Cycle 1
Cycle 2
Cycles 3-10
Day 1
Day 8
Day 15
Day 1
Day 8
Day 1
1 hour 
postdose
(0.25 
hr)
4 hours 
postdose
(0.75 
hr)
Predosea
Predosea
Predoseb
Predosea
Predoseb
X
X
X
X
X
X
X
Note: 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 as per the protocol.
a If pharmacokinetics (PK) sample is taken on a dosing day (due to allowable 2-day window of visits), PK sample must be taken within 4 hours before 
dose of study drug. If PK sample is taken on a nondosing day, ie, sample on Day 14 and dose on Day 15, PK sample can be taken at any time during 
the visit. 
b Day 1 predose PK assessments should occur within 4 hours of dosing.
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15.11
Amendment 04 Detailed Summary of Changes
The primary sections of the protocol affected by the changes in Amendment 04 are indicated. 
The corresponding text has been revised throughout the protocol.
Change 1: Updated the legal entity name, address, and telephone of the sponsor.
The primary change occurs on the cover page:
Initial wording:
Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of 
Takeda Pharmaceutical Company Limited
40 Landsdome Street
Cambridge, MA USA 02139
Telephone: +1 (617) 679-7000
Please note: Millennium Pharmaceuticals, Inc., a wholly owned 
subsidiary of Takeda Pharmaceutical Company Limited, may be 
referred to in this protocol as “Millennium,” “Sponsor,” or 
“Takeda”.
Amended or new 
wording:
Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of 
Takeda Pharmaceutical Company LimitedTakeda Development 
Center Americas, Inc.
40 Landsdome Street95 Hayden Avenue
Cambridge, Lexington, MA USA 0213902421 USA
Telephone: +1 (617) 679-7000
Please note: Millennium Pharmaceuticals, Inc., a wholly owned 
subsidiary of Takeda Pharmaceutical Company Limited, may be 
referred to in this protocol as “Millennium,” “Sponsor,” or 
“Takeda”.
Rationale for Change:
To reflect the new legal entity name of the sponsor of Takeda Development Center 
Americas rather than Millennium.
The following sections also contain this change: 
Section 1.1.1 Disease Under Treatment
Section 1.1.2 Ixazomib, Takeda’s Next-Generation Proteasome Inhibitor
Section 1.4.1.2 Dose Rationale
Section 4.1 Overview of Study Design
Section 6.3 Dose-Modification Guidelines
Section 6.4.4 Study Drug Dose Modification for Nonhematologic Toxicities
Section 6.5 Criteria for Dose Escalation at Cycle 5
Section 6.7 Permitted Concomitant Medications and Procedures
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CONFIDENTIAL
Section 6.10 Blinding and Unblinding
Section 6.13 Packaging and Labeling
Section 6.14 Storage, Handling, and Accountability
Section 7.1 Study Personnel and Organizations
Section 7.3 Treatment Group Assignments
Section 7.4.25 Disease Response Assessment
Section 7.4.27.2 PFS2 Follow-up and OS Follow-up
Section 7.7 Completion of Treatment
Section 8.1 Statistical Methods
Section 8.1.2 Randomization and Stratification
Section 9.1 Steering Committee
Section 9.3 Independent Data Monitoring Committee
Section 10.2 Procedures for Recording and Reporting AEs and SAEs
Section 10.3 Monitoring of AEs and Period of Observation
Section 10.4 Procedures for Reporting Drug Exposure During Pregnancy and Birth Events
Section 11.2 Data Quality Assurance
Section 11.3 eCRF Completion
Section 11.4 Study Monitoring
Section 11.8 Investigator Compliance
Section 11.9 On-site Audits/Inspection
Section 11.10 Investigator and Site Responsibility for Drug Accountability
Section 11.11 Product Complaints and Medication Errors (Including Overdose)
Section 11.12 Closure of the Study
Section 11.13 Record Retention
Section 12.0 USE OF INFORMATION
Section 15.10 Previous, Full Schedule of Events and PK Sampling Schedule (Schedules 
Before Implementation of Amendment 4)
Change 2: Updated the email address for product complaints and medication errors.
The primary change occurs in Section 11.11 Product Complaints and Medication Errors 
(Including Overdose).
Initial wording:
A product complaint is a verbal, written, or electronic expression 
that implies dissatisfaction regarding the identity, strength, purity, 
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CONFIDENTIAL
quality, or stability of a drug product. Individuals who identify a 
potential product complaint situation should immediately contact 
Dohmen Life Sciences (see below) and report the event. Whenever 
possible, the associated product should be maintained in accordance 
with the label instructions pending further guidance from a 
Millennium Quality representative.
A medication error is a preventable event that involves an 
identifiable patient and that leads to inappropriate medication use, 
which may result in patient harm. Whereas overdoses constitute 
medication errors, doses missed inadvertently by a patient do not. 
Investigators must record all medication errors (including overdose) 
on the appropriate eCRF. Individuals who identify a potential 
medication error situation should immediately report this via the 
phone number or email address provided below.
For Product Complaints or Medication Errors (Including 
Overdose) for Ixazomib
Contact Dohmen Life Sciences Services at
1-844-N1-POINT (1-844-617-6468)
Fax at 1-800-881-6092
Email: GlobalOncologyMedinfo@takeda.com
Product complaints or medication errors in and of themselves are not 
AEs and may or may not be associated with an AE. If a product 
complaint or a medication error results in an AE or SAE, an 
additional report describing the AE or SAE should also be 
completed and sent to Cognizant (refer to Section 10.2).
Amended or new 
wording:
A product complaint is a verbal, written, or electronic expression 
that implies dissatisfaction regarding the identity, strength, purity, 
quality, or stability of a drug product. Individuals who identify a 
potential product complaint situation should immediately contact 
Dohmen Life Sciences (see below) and report the event. Whenever 
possible, the associated product should be maintained in accordance 
with the label instructions pending further guidance from a 
Millennium Quality representative.to ctmcomplaint@takeda.com.
Product complaints in and of themselves are not AEs. If a 
product complaint is associated with an SAE, an SAE Form 
should be completed and sent to Cognizant (refer to Section
10.2).
A medication error is a preventable event that involves an 
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CONFIDENTIAL
identifiable patient and that leads to inappropriate medication use, 
which may result in patient harm. Whereas overdoses constitute 
medication errors, doses missed inadvertently by a patient do not. 
Investigators must record all medication errors (including overdose) 
on the appropriate eCRF. Individuals who identify a potential 
medication error situation should immediately report this via the 
phone number or email address provided belowto 
ctmcomplaint@takeda.com.
For Product Complaints or Medication Errors (Including 
Overdose) for Ixazomib
Contact Dohmen Life Sciences Services at
1-844-N1-POINT (1-844-617-6468)
Fax at 1 800 881 6092
Email: GlobalOncologyMedinfo@takeda.com
Product complaints or medication errors in and of themselves are not 
AEs and may or may not be associated with an AE. If a product 
complaint or a medication error results in an AE or SAE, an 
additional report describing the AE or SAE should also be 
completed and sent to Cognizant (refer to Section 10.2).
Rationale for Change:
The email address for product complaints changed. 
Change 3: Created Streamlined Schedule of Events to show only the assessments needed 
now that all patients are in follow-up, essentially replacing the original Schedule of 
Events. 
Initial version:
See Section 15.10 Previous, Full Schedule of Events and PK 
Sampling Schedule (Schedules Before Implementation of 
Amendment 4)
Amended version:
See Streamlined Schedule of Events.
Deleted central laboratory collection of samples. Removed 
investigator assessment of disease response/status through MBA 
rows for PFS Follow-up period but kept for PFS2. Removed 
footnotes c and d. Added missing abbreviations. Changed follow-up
to 12 weeks from 4 weeks for PFS and PD. Removed empty rows. 
Changed to 1st 2 visits from twice only for PFS2 and OS. 
Initial SOE 
footnotes
Patient-reported outcomes and HU assessment (ie, number of medical encounters) 
should be completed before any other study procedures are performed or study 
drug is administered. During the PFS2 Follow-up period only, EORTC QLQ-
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C30, EORTC QLQ-MY20 and HU assessments should be done ideally at the 
first 2 visits (or at least within the first 4 visits). Patient-reported outcome 
questionnaires are preferred to be completed by patients in the clinic, but if 
needed e.g.due to the COVID-19 pandemic), the EORTC QLQ-C30 and 
EORTC QLQ-MY20 questionnaires may be completed at the patient’s home 
using mailed paper versions of the questionnaires; as the last resort, these PROs 
can be collected via telephone using EORTC telephone interview 
administration scripts. At time points when a clinic visit is not required, or if 
needed due to the COVID-19 pandemic, the EQ-5D questionnaire may be 
administered over the telephone. HU data may be obtained over the telephone 
and/or via patient medical records, as needed.
Amended SOE 
footnotes
Patient-reported outcomes and HU assessment assessments (ie, number of
medical encounters) should be completed before any other study procedures are 
performed or study drug is administered. During the PFS2 Follow-up period 
only, EORTC QLQ-C30, EORTC QLQ MY20 QLQ-MY20, and HU 
assessments should be done ideally at the first 2 visits (or at least within the 
first 4 visits). Patient-reported outcome questionnaires are preferred to be 
completed by patients in the clinic, but if needed e.g(eg, due to the COVID-19 
pandemic), the EORTC QLQ-C30 and EORTC QLQ-MY20 questionnaires 
may be completed at the patient’s home using mailedpaper versions of the 
questionnaires; as thea last resort, these PROspatient-reported outcomes can 
be collected via telephone using EORTC telephone interview administration 
scripts. At time points when a clinic visit is not required, or if needed due to the 
COVID-19 pandemic, the EQ-5D questionnaire may be administered over the 
telephone. HU data may be obtained over the telephone and/or via patient 
medical records, as needed.
Rationale for Change:
To reflect the current phase of study.
Change 4: Clarified the timelines for new primary malignancy reporting in Section 10.3
of the protocol.
The primary change occurs in Section 10.3.
Initial wording:
In addition, new primary malignancies that occur during the follow-
up periods must be reported, irrespective of causality to the study 
drug, from the first dose of study drug through death, termination of 
the study by the sponsor, or for a minimum of 3 years after the last 
dose of the investigational product, whichever occurs first. 
Amended or new 
wording:
In addition, new primary malignancies NPMs that occur during the 
follow-up periods must be reported, irrespective of causality to the 
study drug, from the first dose of study drug through death, or 
termination of the study by the sponsor. or for a minimum of 3 years 
after the last dose of the investigational product, whichever occurs 
first. 
Rationale for Change:
To reflect the current phase of study.
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Change 5: Clarified timeframes for performing HU and EORTC assessments. 
The primary change occurs in Sections 7.4.14 Quality of Life Assessment (European 
Organization for Research and Treatment of Cancer), 7.4.27.2 PFS2 Follow-up and OS 
Follow-up, and 15.10 Previous, Full Schedule of Events and PK Sampling Schedule 
(Schedules Before Implementation of Amendment 4).
Initial wording in 
Section 7.4.14:
Patient-reported outcomes and HU assessment (ie, number of 
medical encounters) should be completed before any other study 
procedures are performed or study drug is administered. Patient-
reported outcome questionnaires are preferred to be completed by 
patients in the clinic, but if needed due to the COVID-19 pandemic), 
the EORTC QLQ-C30 and EORTC QLQ-MY20 questionnaires may 
be completed at the patient’s home using mailed paper versions of 
the questionnaires; At time points when a clinic visit is not required, 
or if needed due to the COVID-19 pandemic, the EQ-5D 
questionnaire may be administered over the telephone. HU data may 
be obtained over the telephone and/or via patient medical records, as
needed
Amended wording 
in 7.4.14:
Patient-reported outcomes and HU assessments (ie, number of
medical encounters) should be completed before any other study 
procedures are performed or study drug is administered. During the 
PFS2 Follow-up period only, EORTC QLQ-C30, EORTC QLQ-
MY20, and HU assessments should be done ideally at the first 2 
visits (or at least within the first 4 visits). Patient-reported 
outcome questionnaires are preferred to be completed by patients in 
the clinic, but if necessary (eg, due to the COVID-19 pandemic 
restrictions pandemic), the EORTC QLQ-C30 and EORTC QLQ-
MY20 questionnaires may be completed at the patient’s home using 
paper versions of the questionnaires; as a last resort, these patient-
reported outcomes can be collected via telephone using EORTC 
telephone interview administration scripts. At time points when a 
clinic visit is not required, or if needed due to the COVID-19 
pandemic, the EQ-5D questionnaire may be administered over the 
telephone. HU data may be obtained over the telephone and/or via 
patient medical records, as needed.
Initial wording in 
Section 7.4.27.2
In the PFS2 Follow-up period, the EORTC QLQ-C30 and MY20 
questionnaires, the EQ-5D questionnaire, and the HU assessment 
should be administered twice, ideally once approximately 8 to 12 
weeks after the start of next-line therapy and again 8 to 12 weeks 
later. After patients in the PFS2 Follow-up period have PD2 on next-
line therapy, they enter into the OS Follow-up period. During the OS 
Follow-up period, follow-up will occur every 12 weeks until death 
or termination of the study by the sponsor, whichever occurs first. In 
the OS follow-up period, the EQ-5D questionnaire will be 
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administered every 3 months.
Amended wording 
in 7.4.27.2
In During the PFS2 Follow-up period only, the EORTC QLO and
EORTC QLQ-C30, EORTC QLQ-MY20 questionnaires, and the 
HU assessments should be administered ideally at the first 2
PFS2visits (or at least within the first 4 visitsvisits). The EQ-5D 
questionnaire should be administered every PFS2 visit. Only, but 
the EQ-5D questionnaire assessment should be done every PFS2 
visit. Patient-reported outcome questionnaires are preferred to 
be completed by patients in the clinic, but if needed (e.g.(eg, due 
to the COVID-19 pandemic), the EORTC QLQ-C30 and 
EORTC QLQ-MY20 questionnaires may be completed at the 
patient’s home using paper versions of the questionnaires; as
thea last resort, these patient-reported outcomes can be collected 
via telephone using EORTC telephone interview administration 
scripts. Time points when a clinic visit is not required, or if 
needed due to the COVID-19 pandemic, the EQ-5D 
questionnaire may be administered over the telephone. HU data 
may be obtained over the telephone and/or via patient medical 
records, as needed. Paper questionnaire completion (MY20/C30) 
can be done at home also in PFS and PD Follow up.
After patients in the PFS2 Follow-up period have PD2 on next-line 
therapy, they enter into the OS Follow-up period. During the OS 
Follow-up period, follow-up will occur every 12 weeks until death 
or termination of the study by the sponsor, whichever occurs first. In 
the OS follow-up period, the EQ-5D questionnaire will may be 
administered every visit, which occurs every 12 weeks, via 
telephone.
Rationale for change: To clarify EORTC and HU assessments.
Change 6: Recorded a change in wording related to days of missed work that might affect 
the statistical analysis.
The primary change occurs in Section 8.1.7.3 Health Economics Analysis Using Health
Care Resource Utilization and Health Utility.
Initial wording:
EQ-5D scores will be summarized in descriptive statistics for 
treatment arms. 
HU data will be summarized in descriptive statistics of medical 
encounters (length of stay, inpatient, outpatient, and reason), number 
of missing days from work or other activities by patient and care-
giver for treatment arms.
Amended or new 
wording:
EQ-5D scores will be summarized in descriptive statistics for 
treatment arms. 
HU data will be summarized in descriptive statistics of medical 
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encounters (length of stay, inpatient, outpatient, and reason), number 
of missing days from work or other activities by patient and care 
giver for treatment arms.
Rationale for Change:
To account for the deletion of “number of missing days from work” and “by patient and 
care giver,” affecting the statistical analysis. 
Change 7: Clarified calculation of follow-up visits. 
The primary change occurs in Section 7.4.27 Follow-up Assessments for PFS, PD, PFS2, 
and OS.
Initial wording:
At EOT, patients will enter a Follow-up period for PFS, PD, or 
PFS2. See the Schedule of Events for assessments during each 
period. See the Study Periods and Corresponding Endpoints 
Diagram for information about the sequence of follow-up. 
Information about any new primary malignancies will be collected 
during the study, including during all 4 Follow-up periods. 
Calculation of Follow-up visits to be 12 weeks (+/-1 week) since the 
last completed Follow-up visit from visit, rather than every 4 weeks.
Amended or new 
wording:
At EOT, patients will enter a Follow-up period for PFS, PD, or 
PFS2. See the Streamlined Schedule of Events for assessments 
during each period. See the Study Periods and Corresponding 
Endpoints Diagram for information about the sequence of follow-up. 
Information about any new primary malignancies will be collected 
during the study, including during all 4 Follow-up periods. 
Calculation of Follow-up visits to be 12 weeks (+/-1 week) since the 
last completed Follow-up visit from visit, rather than every 4 weeks. 
PFS and PD Follow-up visit is scheduled to be 12 weeks (+/-1 
week) since the last completed Follow-up visit.
The following section also contains this change: 
15.10 Previous, Full Schedule of Events and PK Sampling Schedule (Schedules Before 
Implementation of Amendment 4).
Rationale for Change:
Changed PFS and PD Follow-up visits to be 12 weeks (+/-1 week) since the last 
completed Follow-up visit, rather than every week. 
Change 8: Central laboratory is no longer collecting samples.
The primary change occurs in Section 7.4.12 Clinical Laboratory Evaluations.
Initial wording:
7.4.12 Clinical Laboratory Evaluations
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Clinical laboratory evaluations will be performed by a central 
laboratory. For dosing decisions, local hematology and chemistry 
laboratory results may be used; however, samples must also be sent 
to central labs. Hematology and chemistry panels may be collected 
up to 3 days before Day 1 dosing and (when required) 24 hours 
before Days 8 and 15 dosing. 
Amended or new 
wording:
Clinical laboratory evaluations will be performed by a central 
laboratory. until the primary endpoint of PFS is met. For dosing 
decisions, local hematology and chemistry laboratory results may be 
used; however, samples must also be sent to central labs. 
Hematology and chemistry panels may be collected up to 3 days 
before Day 1 dosing and (when required) 24 hours before Days 8 
and 15 dosing.
The collection of samples by a central laboratory was stopped 
after the primary endpoint was met.
Rationale for Change: To clarify study procedures now that the primary endpoint has 
been met.
Change 9: Remove investigator assessment of disease response/status.
The primary change occurs in Section 7.4.25 Disease Response Assessment.
Initial wording:
… this study. At that time, central efficacy and investigator 
assessments for protocol purposes will be stopped except for 
investigator assessment of PFS2. The Millennium project clinician 
or designee and investigator will review the assessment of PD before 
taking the patient off treatment. After PD, and during the PFS2 
follow-up period; response assessments are made by the investigator 
(or treating physician) on the basis of local laboratory data.
Amended 
wording:
… At this study.At that time, the primary endpoint has been met; 
therefore, central efficacy and investigator assessments for protocol 
purposes will behave been stopped except for investigator 
assessment of PFS2. The Millennium project clinician or designee 
and investigator will review the assessment of PD before taking the 
patient off treatment. After PD, and during the PFS2 follow up 
period,; all investigator assessments of response assessments are 
made by the investigator (or treating physician) on the basis 
ofshould be based on local laboratory data laboratories per local 
clinical practice.
The following section also contains this change: 
Streamlined Schedule of Events
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Rationale for Change:
Clarify study procedures now that the primary endpoint has been met.
Change 10: Added information about alternative monitoring approaches in the event a 
monitor cannot visit the site in a timely manner due to the COVID-19 pandemic. 
The primary change occurs in Section 11.4 Study Site Monitoring visits.
Initial wording:
Monitoring and auditing procedures developed or approved by 
Millennium will be followed to comply with GCP guidelines.
All information recorded on the eCRFs for this study must be 
consistent with the patient’s source documentation. During the 
course of the study, the study monitor will make study site visits to 
review protocol compliance, verify eCRFs against source 
documentation, assess drug accountability, and ensure that the study 
is being conducted according to pertinent regulatory requirements. 
The review of medical records will be performed in a manner that 
ensures that patient confidentiality is maintained. 
Modified text:
Monitoring and auditing procedures developed or approved by 
Millennium Takeda will be followed to comply with GCP 
guidelines.
All information recorded on the eCRFs for this study must be 
consistent with the patient’s source documentation. During the 
course of the study, the study monitor will make study site visits to 
review protocol compliance, verify eCRFs against source 
documentation, assess drug accountability, and ensure that the study 
is being conducted according to pertinent regulatory requirements. 
The review of medical records will be performed in a manner that 
ensures that patient confidentiality is maintained. In the event a 
monitor cannot visit the site in a timely manner due to the 
COVID-19 pandemic, alternative monitoring approaches, such 
as telephone contact, may be used to ensure data quality and 
integrity and maintain patient safety. Alternative monitoring 
approaches should be used only where allowed by the local Hhealth 
Aauthority and permitted by the IRB/IEC. Remote monitoring and 
site staff interviews for consistency check of data can be used.
Rationale for Change: Provides for alternative means of monitoring during the COVID-
19 pandemic to account for unavoidable circumstances affecting study conduct.
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Change 11: Added language regarding alternative methods for administering study 
procedures/assessments when it is not possible for the patient to come to the study site due 
to the COVID-19 pandemic.
The primary change occurs in Section 7.4 Study Procedures.
Initial wording 
Patients will be evaluated at scheduled visits over 4 study periods: 
screening, treatment, EOT, and follow-up (PFS, PD, PFS2, and OS). 
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 
Pharmaceuticals Inc. (Millennium) project clinician or designee. If 
the study schedule is shifted, assessments must be shifted to ensure 
collection of assessments is completed before dosing. 
Refer to the Schedule of Events for timing of assessments. 
Additional details are provided as necessary in the sections that 
follow.
Added new text:
Patients will be evaluated at scheduled visits over 4 study periods: 
screening, treatment, EOT, and follow-up (PFS, PD, PFS2, and OS). 
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 
Pharmaceuticals Inc. (Millennium) Takeda project clinician or 
designee. If the study schedule is shifted, assessments must be 
shifted to ensure collection of assessments is completed before 
dosing. 
Refer to the original Schedule of Events (Section 15.10) and 
Streamlined Schedule of Events for timing of assessments. 
Additional details are provided as necessary in the sections that 
follow.
In acknowledgement of hospital, local, state or national 
government restrictions, or other site-related factors caused by 
the coronavirus disease 2019 (COVID-19) pandemic that may 
prevent investigators from conducting the study according to the 
Streamlined Schedule of Events at the clinical study site, 
investigators may continue patients in the study despite 
departure from the Streamlined 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 
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patients. For patients who are impacted by the COVID-19 
pandemic, any procedures not conducted per the study protocol 
will be documented as a protocol deviation.
During contact with the patient, the study site physician or other 
qualified site staff should at minimum conduct AE collection. 
Other study assessments may be collected remotely as is feasible. 
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.
Rationale for Change:
To account for the COVID-19 pandemic affecting study conduct. 
Change 12: Updated language regarding unblinding in patients experiencing disease 
progression.
The primary change occurs in Section 6.10 Blinding and Unblinding.
Initial wording
To maintain the blind, all study personnel including the 
investigators, site personnel, study clinicians, and the sponsor will 
be blinded to the treatment assignments for the duration of the study. 
When a patient is discontinued from the study, the investigator may 
request unblinding if it is necessary for determination of the 
patient’s subsequent anticancer treatment. 
Treatment assignments will be obtained through the interactive 
voice/web response system (IXRS) according to the procedures 
outlined in the study manuals. Information regarding the treatment 
assignments will be kept securely at Millennium or its designee, per 
its standard operating procedures. Emergency unblinding, if 
necessary, will be conducted via the IXRS.
Records of the patient number, the date each drug in the study drug 
regimen was dispensed, and the treatment assignment will be 
maintained by the study site. If the treatment assignment must be 
revealed for the safety of the patient, to treat an AE, or to inform 
decisions for subsequent therapy, the investigator will contact the 
Millennium project clinician or designee (contact information is in 
the study manuals). A decision to break the blind must be reached by 
the Millennium project clinician or designee and the investigator. 
The investigator, or designee, may break the blind through the IXRS 
independent of the Millennium project clinician or designee only if 
it is considered to be an emergency by the investigator that requires 
specific knowledge of the blinded study treatment to properly treat 
the AE/safety issue. If the treatment of the AE/safety issue is the 
same regardless of the study drug assignment, the blind should not 
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be broken. In addition, the patient will be discontinued from further 
study drug administration in this study.
Amended or new 
wording:
To maintain the blind, all study personnel including the 
investigators, site personnel, study clinicians, and the sponsor will 
be blinded to the treatment assignments for the duration of the study. 
When a patient experiences disease progression, the investigator 
is encouraged to unblind the patient and take this information 
into account in planning the next line of therapy. is discontinued 
from the study, the investigator may request unblinding if it is 
necessary for determination of the patient’s subsequent anticancer 
treatment.
Treatment assignments will be obtained through the interactive 
voice/web response system (IXRS) according to the procedures 
outlined in the study manuals. Information regarding the treatment 
assignments will be kept securely at Millennium Takeda or its 
designee, per its standard operating procedures. Emergency 
unblinding, if necessary, will be conducted via the IXRS.
Records of the patient number, the date each drug in the study drug 
regimen was dispensed, and the treatment assignment will be 
maintained by the study site. If the treatment assignment must be 
revealed for the safety of the patient, to treat an AE, or to inform 
decisions for subsequent therapy, the investigator will contact the 
Millennium project clinician or designee (contact information is in 
the study manuals). A decision to break the blind must be reached by 
the Millennium project clinician or designee and the investigator. 
The investigator, or designee, may break the blind through the IXRS 
independent of the Millennium project clinician or designee only if 
it is considered to be an emergency by the investigator that requires 
specific knowledge of the blinded study treatment to properly treat 
the AE/safety issue. If the treatment of the AE/safety issue is the 
same regardless of the study drug assignment, the blind should not 
be broken. In addition, the patient will be discontinued from further 
study drug administration in this study.
Rationale for Change: 
Enables investigator to unblind a patient experiencing disease progression to plan next 
line of therapy. 
Change 13: Added death as a reason for a patient’s withdrawal from the study.
The primary change occurs in Section 7.10 Withdrawal of Patients From Study
Initial wording:
7.10 Withdrawal of Patients From Study
A patient may be withdrawn from the study for any of the following 
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Amended or new 
wording:
Health cCare Resource Utilization Data Collection
During the treatment and the follow-up periods indicated in the 
original Schedule of Events (Section 15.10) and Streamlined 
Schedule of Events, all medical care encounters since the previous 
collection will be collected from all patient charts and/or patients
directly as needed, regardless of the reason for the needed medical 
care encounter. Examples of data to be collected are number and 
duration of medical care encounters, such as inpatient/outpatient 
admissions, homecare, visit type and reasons, and time of work 
loss. 
Rationale for Change:
To clarify how data are collected for health care resource utilization.
Change 16: Clarified the monitoring of AEs
The primary change occurs in Section 10.3 Monitoring of AEs and Period of Observation.
Initial wording:
AEs, both nonserious and serious, will be monitored throughout the 
study as follows: 

AEs will be reported from the first dose of study drug through 30 
days after administration of the last dose of study drug and 
recorded in the eCRFs. 
1. Serious pretreatment events will be reported to the 
Millennium Department of Pharmacovigilance or designee 
from the time of the signing of the ICF up to first dose of 
study drug, but will not be recorded in the eCRF.
2. Related and unrelated SAEs will be reported to the 
Millennium Department of Pharmacovigilance or designee 
from the first dose of study drug through 30 days after 
administration of the last dose of study drug and recorded in 
the eCRF. After this period, only related SAEs must be 
reported to the Millennium Department of 
Pharmacovigilance or designee. SAEs should be monitored 
until they are resolved or are clearly determined to be due to 
a patient’s stable or chronic condition or intercurrent 
illness(es). In addition, new primary malignancies that occur 
during the follow-up periods must be reported, irrespective 
of causality to the study drug, from the first dose of study 
drug through death, termination of the study by the sponsor, 
or for a minimum of 3 years after the last dose of the 
investigational product, whichever occurs first. 
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Amended or new 
wording:
AEs, both nonserious and serious, will be monitored throughout the 
study as follows: 

AEs will be reported from the first dose of study drug through 30 
days after administration of the last dose of study drug and 
recorded in the eCRFs. 

Serious pretreatment events will be reported to the Millenium
Takeda Department of Pharmacovigilance or designee from the 
time of the signing of the ICF up to first dose of study drug, but 
will not be recorded in the eCRF.

Related and unrelated SAEs will be reported to the Millennium
Takeda Department of Pharmacovigilance or designee from the 
first dose of study drug through 30 days after administration of 
the last dose of study drug and recorded in the eCRF. After this 
period, only related SAEs must be reported to the Millennium
Takeda Department of Pharmacovigilance or designee. SAEs 
should be monitored until they are resolved or are clearly 
determined to be due to a patient’s stable or chronic condition or 
intercurrent illness(es). In addition, NPMsnew primary 
malignancies that occur during the follow-up periods must be 
reported, irrespective of causality to the study drug, from the 
first dose of study drug through death, or termination of the 
study by the sponsor. or for a minimum of 3 years after the last 
dose of the investigational product, whichever occurs first.
Rationale for Change: Deleted the reporting of NPMs for a minimum of 3 years after 
last dose of investigational product, whichever occurs first.
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SAP_000.pdf: 
This may include, but is not limited to, redaction of the following: 


• 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 3, Randomized, Placebo-Controlled, Double-Blind Study of Oral Ixazomib 
Citrate (MLN9708) Maintenance Therapy in Patients With Multiple Myeloma Following 
Autologous Stem Cell Transplant
NCT Number: NCT02181413
SAP Approve Date: 31May2018
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 information or company confidential information. 
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.


Ixazomib Citrate (MLN9708)
Statistical Analysis Plan, Study C16019
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STATISTICAL ANALYSIS PLAN
A Phase 3, Randomized, Placebo-Controlled, Double-Blind Study of Oral Ixazomib 
Citrate (MLN9708) Maintenance Therapy in Patients With Multiple Myeloma 
Following Autologous Stem Cell Transplant
Protocol #:  C16019
SAP Version:
Date of Statistical Analysis Plan:
Version 1.0
    31May2018
Approval Signatures
Protected Personal Data


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Statistical Analysis Plan, Study C16019
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TABLE OF CONTENTS
LIST OF TABLES...............................................................................................................3
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS ............................................4
1. INTRODUCTION............................................................................................................7
1.1 Study Design..............................................................................................................7
1.2 Study Objectives ........................................................................................................8
2. POPULATIONS FOR ANALYSIS................................................................................11
2.1 Intent-to-Treat Population.........................................................................................11
2.2 Safety Population .....................................................................................................11
2.3 Per-Protocol (PP) population ....................................................................................11
3. HYPOTHESES AND DECISION RULES.....................................................................11
3.1 Statistical Hypotheses...............................................................................................11
3.2 Statistical Decision Rules .........................................................................................12
4. INTERIM ANALYSIS...................................................................................................12
4.1 Interim Analysis .......................................................................................................12
4.2 Independent Data Monitoring Committee (IDMC)....................................................13
4.3 Independent Review Committee (IRC).....................................................................14
5. STATISTICAL METHODOLOGY ...............................................................................14
5.1 Sample Size Justification..........................................................................................14
5.2 Randomization and Stratification..............................................................................16
5.3 Blinding and Unblinding ..........................................................................................16
5.4 Data Handling ..........................................................................................................16
5.4.1 Methods for Handling Missing Data...................................................................16
5.4.2 Definition of Reference Values..........................................................................20
5.4.3 Windowing of Visits..........................................................................................20
5.4.4 Justification of Pooling ......................................................................................20
5.4.5 Withdrawals, Dropouts, Loss to Follow-up ........................................................20
5.5 Patient Disposition ...................................................................................................20
5.6 Demographics and Disease Characteristics at Study Entry........................................21
5.6.1 Demographics....................................................................................................21
5.6.2 Medical History.................................................................................................21
5.6.3 Disease Status at Initial Diagnosis......................................................................21
5.6.4 Disease Status at Study Entry.............................................................................22
5.6.5 Bone marrow cytogenetic at initial diagnosis .....................................................23
5.7 Treatments and Medications .....................................................................................23
5.7.1 Concomitant Medications ..................................................................................23
5.7.2 Study Treatments...............................................................................................23
5.8 Efficacy Analyses.....................................................................................................25
5.8.1 Primary Efficacy Endpoint.................................................................................25
5.8.2 Key Secondary Efficacy Endpoint......................................................................28
5.8.3 Other Secondary Efficacy Endpoints and Analyses ............................................30
5.9 Pharmacokinetic and Biomarker Analysis.................................................................33
5.9.1 Pharmacokinetic Analyses .................................................................................33
5.9.2 Biomarker Analysis ...........................................................................................34


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5.9.3 Minimal Residual Disease Analysis ...................................................................34
5.10 Analyses of Patient-Reported Outcomes and Health Economics .............................35
5.10.1 Patient Reported Outcomes (PROs)..................................................................35
5.10.2 Health Economics Analysis Using Medical Resource Utilization and Utility....39
5.11 Safety Analyses ......................................................................................................39
5.11.1 Adverse Events................................................................................................40
5.11.2 Laboratory Data...............................................................................................43
5.11.3 Electrocardiograms ..........................................................................................44
5.11.4 Vital Signs .......................................................................................................44
5.11.5 Eastern Cooperative Oncology Group (ECOG) Performance Status .................45
5.11.6 Other Safety Assessments ................................................................................45
6. CHANGES TO PLANNED ANALYSES FROM PROTOCOL .....................................45
7. PROGRAMMING CONSIDERATIONS .......................................................................45
7.1 Statistical Software...................................................................................................45
7.2 Rules and Definitions ...............................................................................................45
8. REFERENCES...............................................................................................................45
LIST OF TABLES
Table 5-1   
Censoring Rules for PFS Primary Analysis Based on FDA Guidance..........26
Table 5-2   
Handling of missing assessment and censoring for PFS Sensitivity 
Analysis based on EMA guidance ...............................................................27
Table 5-3        List of subgroup...........................................................................................28
Table 5-4        Censoring for PFS2 For Those Who have Received Second line Therapy 
following Study Treatment..........................................................................32
Table 5-5        Censoring for PFS2 for Those Who have not received Second Line of 
Therapy.......................................................................................................32
Table 5-6        Definition of Subscale Scores of EORTC QLQ-C30....................................36
Table 5-7        Definition of Subscale Scores of EORTC QLQ-MY20 ................................36


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LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS
Abbreviation
Term
AE
adverse event
AL
light-chain
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ampl
amplification
ASCO
American Society of Clinical Oncology
ASCT
autologous stem cell transplant
AST
aspartate aminotransferase
AUC
area under the curve
BCRP
breast cancer resistance protein
BM
bone marrow
BMA
bone marrow aspirate
BSA
body surface area
BUN
blood urea nitrogen
CBC
complete blood count
CHMP
committee for Medicinal Products for Human Use
CL
clearance
CR
complete response 
CT
computed tomography
CYP
cytochrome P450s
del
deletion
DDI
drug-drug interaction
DLT
dose-limiting toxicity
DOR
duration of response
DVT
deep vein thrombosis
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EORTC
European Organization for Research and Treatment of Cancer 
EOT
End of Treatment (visit)
EQ-5D
EuroQol 5-Dimensional Health Questionnaire
EQ VAS
EQ visual analogue scale
ESMO
European Society for Medical Oncology
EU
European Union
FA
final analysis
FDA
United States Food and Drug Administration
FFPE
formalin-fixed, paraffin-embedded
FISH
fluorescence in situ hybridization


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Abbreviation
Term
GCP
Good Clinical Practice
GI
gastrointestinal
HDT
high-dose therapy
HRQL
health related quality of life
HU
health utilization
IA
interim analysis
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
IDMC
independent data monitoring committee
IEC
independent ethics committee
IMiD
immunomodulating drugs
IMWG
international Myeloma Working Group
IR
immunophenotype
IRB
institutional review board
IRC
independent review committee
ISC
independent statistical center
ISS
international Staging System
ITT
intent-to-treat
IV
intravenous; intravenously
IXRS
interactive web/voice response system
LenDex
lenalidomide + dexamethasone
MCL
mantle cell lymphoma
MedDRA
Medical Dictionary for Regulatory Activities
Millennium
Millennium Pharmaceuticals, Inc., and its affiliates
MM
multiple myeloma
MP
melphalan prednisone 
MRD
minimal residual disease
MRI
magnetic resonance imaging
MRP2
multidrug resistance associated protein
MTD
maximum tolerated dose
QLQ-MY20
Multiple Myeloma Module
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NDMM
newly diagnosed multiple myeloma
NEC
not elsewhere classified
NFKB
nuclear factor kappa-light-chain-enhancer of activated B cells
OS
overall survival
PAD
bortezomib, Adriamycin® (doxorubicin), and dexamethasone 


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Abbreviation
Term
PD
progressive disease 
PE
pulmonary embolism
PFS
progression-free survival
PI
proteasome inhibitor 
PK
pharmacokinetic(s)
PN
peripheral neuropathy
PO
per os; by mouth (orally)
PR
partial response 
PSMB1
proteasome (prosome, macropain) subunit, beta type, 1
QLQ-C30
Quality of Life Questionnaire
QOL
quality of life
RISS
revised international staging system stage
RP2D
recommended phase 2 dose
RRMM
relapsed and/or refractory multiple myeloma
SAE
serious adverse event
sCR
stringent complete response
SCT
stem cell transplant/ therapy
SD
stable disease
SMA
Safety Management Attachment (to the Investigator’s Brochure)
SNP
single-nucleotide polymorphism
SoC
standard of care
SPEP
serum protein electrophoresis
SPM
second primary malignancies
t1/2
terminal disposition phase half-life
TEAE
treatment-emergent adverse event
Tmax
first time of occurrence of maximum (peak) concentration
TTP
time-to-progression
Tx
treatment
ULN
upper limit of the normal range
UPEP
urine protein electrophoresis
US
United States
VAD
vincristine, doxorubicin, and dexamethasone 
VGPR
very good partial response
vs
versus
WHO
World Health Organization
Company Confidential Information


Ixazomib Citrate (MLN9708)
Statistical Analysis Plan, Study C16019
Confidential
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1.   
INTRODUCTION
In general, the purpose of the Statistical Analysis Plan (SAP) is to provide a framework that 
addresses the protocol objectives in a statistically rigorous fashion, with minimized bias or 
analytical deficiencies. Specifically, this plan has the following purpose:
To prospectively outline the types of analyses and data presentations that will address the 
study objectives outlined in the protocol, and to explain in detail how the data will be 
handled and analyzed, adhering to commonly accepted standards and practices of 
biostatistical analysis in the pharmaceutical industry.
1.1   
Study Design
This is a randomized, placebo-controlled, double-blind, phase 3 study in patients with newly 
diagnosed multiple myeloma (NDMM) who have undergone induction therapy according to 
regional standard of care (SoC), followed by a conditioning regimen containing high-dose 
melphalan (200 mg/m2) and Autologous Stem Cell Transplant (ASCT).  Induction therapy 
must include proteasome inhibitor (PI) and/or immunomodulating drug (IMiD)-based 
regimens. Vincristine, Adriamycin (doxorubicin), and Dexamethasone (VAD) are not an 
acceptable induction therapy for this trial.  
Patients who have achieved clinical and hematologic recovery following induction, high-
dose therapy (HDT), and ASCT will initiate screening for study eligibility no earlier than 75 
days after transplant, complete screening within 15 days, and be randomized no later than 
115 days after transplant.  Eligible patients (those whose complete response [CR], very good 
partial response [VGPR] or partial response [PR] have been documented during screening 
and who have met all inclusion/exclusion criteria) will be enrolled and randomized in a 3:2 
ratio to ixazomib citrate or placebo.  Stratification is based on:  induction regimen (PI 
without an IMiD vs IMiD without a PI vs PI and IMiD); pre-induction International Staging 
System (ISS) (stage I vs stage II or III); and response after transplantation, defined as the 
response following induction, HDT, and ASCT measured during screening (CR or VGPR vs 
PR) on the basis of the International Myeloma Working Group (IMWG) criteria.
Patients will receive blinded study drug (ixazomib citrate capsules or matching placebo 
capsules) orally on Days 1, 8, and 15 of every 28-day cycle, for a maximum duration of 
approximately 24 months (26 cycles, to the nearest complete cycle), or until documented 
disease progression (on the basis of the IMWG criteria) or intolerable toxicities, whichever 
comes first.  To provide patients the opportunity to derive maximum clinical benefit from 


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study drug maintenance, the dose of 3 mg will be increased to 4 mg at Cycle 5 provided that 
during the most recent 2 cycles (Cycle 3 and 4), there have been no nonhematologic AEs 
≥Grade 2 related to study drug, no dose interruptions related to study drug toxicities, and no 
delays of greater than 1 week in starting a cycle due to study drug toxicities. Patients who 
have had any dose reductions will not dose escalate. If dose escalation was inadvertently 
missed at Cycle 5, escalation may be performed with permission from the Millennium 
project clinician or designee.
Clinical, laboratory, disease response, and health related quality of life (HRQL) with an 
emphasis on tolerability and symptom burden, as well as minimal residual disease (MRD)
assessments will be made.  Following documented disease progression, subsequent therapy 
will be determined by the investigator/ treating physician.  
The primary endpoint of PFS will be supported by prespecified evidence of clinical benefit 
as measured by the key and other secondary endpoints.  There will be 2 interim analyses 
(IAs) and 1 final analysis (FA) in the study.  The first IA will be the FA for PFS for 
statistical testing purposes.
1.2   
Study Objectives
The primary objective is:

To determine the effect of ixazomib citrate maintenance therapy on PFS, compared 
to placebo, in patients with NDMM who have had a response (CR, VGPR, or PR) to
induction therapy followed by HDT and ASCT 
The key secondary objective is:

To determine the effect of ixazomib citrate maintenance therapy on overall survival 
(OS) compared to placebo 
Other secondary objectives are:

To determine the effect of ixazomib citrate maintenance therapy on improving best 
response for patients who enroll in the study at PR or VGPR, as well as maintaining 
best overall response for patients who enroll in the study at CR.  

To determine the effect of ixazomib maintenance therapy on time to progression 
(TTP) 


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
To determine the effect of ixazomib maintenance therapy on progression-free 
survival 2 (PFS2), defined as time from the date of randomization to the date of 
objective disease progression on next-line treatment or death from any cause, 
whichever comes first.

To determine the effect of ixazomib maintenance therapy on time to start of the next 
line of treatment, defined as the time from the date of randomization to the date of 
the first dose of the next line of antineoplastic therapy for any reason.

To determine the effect of ixazomib maintenance therapy on time to end of the next 
line of treatment, defined as the time from the date of randomization to the date of 
the last dose of the next line of antineoplastic therapy for any reason

To determine the effect of ixazomib maintenance therapy on duration of the next line 
of antineoplastic therapy 

To assess the incidence of new primary malignancies in patients receiving ixazomib 
maintenance therapy compared with placebo following ASCT

To evaluate the frequency of conversion from MRD positive to MRD negative, or 
the maintenance of MRD negativity, after 1 and 2 years of therapy in patients treated 
with ixazomib citrate compared to placebo, using bone marrow aspirates and 8-color 
flow cytometry or next-generation sequencing.

To assess the correlation between MRD status (assessed by 8-color flow cytometry 
and next-generation sequencing) and PFS and OS, using bone marrow aspirates.

To determine the effects of ixazomib maintenance therapy on PFS and OS in high-
risk cytogenetic patient groups characterized by individual or multiple cytogenetic 
abnormalities, such as del17, t(4:14), t(14:16), ampl 1q, del13, or del1p.

To determine the long-term safety and tolerability of ixazomib administration to 
multiple myeloma patients following ASCT. 

To assess overall HRQL, as measured by global health domain of European 
Organization for Research and Treatment of Cancer Quality of Life Questionnaire 
(EORTC QLQ-C30).


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!
To collect pharmacokinetic (PK) data to contribute to population PK and exposure 
response (safety/ efficacy) analysis.
!
To evaluate the resolution and improvement of peripheral neuropathy (PN), if it 
occurs, by grading at each subsequent monthly visit until 1) resolution of PN, 2) the 
start of an alternative antineoplastic treatment, or 3) 6 months after progression has 
occurred, whichever comes first.
Exploratory objectives are:
Company Confidential Information


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2.   
POPULATIONS FOR ANALYSIS
2.1   
Intent-to-Treat Population
The Intent-to-Treat (ITT) population is defined as all patients who are randomized and post 
randomization data are available. Patients will be analyzed according to the treatment they 
were randomized to receive, regardless of any errors of dosing. Patients who are regarded as 
screen failure and lack any data post randomization will be excluded from ITT population. 
The ITT population will be used for the primary, secondary efficacy analyses, and resource 
utilization and patient reported outcome analysis.
2.2   
Safety Population
The safety population is defined as all patients who receive at least 1 dose of ixzaomib or 
placebo. Patients will be analyzed according to the treatment they actually received. Patients 
who received any dose of ixazomib will be included in the ixazomib arm, and patients who 
received only placebo will be included in the placebo arm, regardless of their randomized 
treatment.
The safety population will be used for all safety related analyses such as adverse events 
(AE), concomitant medication, laboratory tests, and vital signs.
2.3   
Per-Protocol (PP) population
The PP population consists of all ITT patients who do not violate the terms of the protocol in 
a way that would impact the study outcome significantly. All decisions to exclude patients 
from the PP population will be made by the Takeda Project Clinician or designee prior to 
unblinding the study for IAs or FA purpose.  
The PP population will be used as a sensitivity analysis of the ITT population for the 
primary efficacy endpoint PFS if more than 5% patients are excluded from this analysis.
3.   
HYPOTHESES AND DECISION RULES
3.1   
Statistical Hypotheses
There is one primary endpoint in this study.
The null and alternative hypotheses for PFS are:
H0: PFS in Ixazomib Arm = PFS in Placebo Arm


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Ha: PFS in Ixazomib Arm > PFS in Placebo Arm
There is one key secondary efficacy endpoint in this study.
The null and alternative hypotheses for OS are:
H0: OS in Ixazomib Arm = OS in Placebo Arm
Ha: OS in Ixazomib Arm > OS in Placebo Arm
3.2   
Statistical Decision Rules
A closed sequential testing procedure will be used to test the primary endpoint of PFS and
the key secondary endpoint of OS. First PFS will be tested at the first IA at a 2-sided alpha 
level of 0.05 at the IA. If 2-sided, stratified log-rank test p value for PFS is ≥ 0.05, the study 
will be deemed unsuccessful and no further formal hypothesis testing will be conducted. 
Otherwise, the null hypothesis for PFS will be rejected and the test for PFS is claimed to be 
statistically significant. In this case, OS will be tested according to the group sequential test 
method at this IA and subsequent analyses, in which the significance level will be 
determined by the O'Brien-Fleming alpha spending function (the Lan-DeMets method). Due 
to the closed sequential testing property, the family-wise type I error is strongly controlled 
for both PFS and OS.
All other efficacy endpoints will be tested at a 2-sided alpha level of 0.05 unless otherwise 
specified.
4.   
INTERIM ANALYSIS
4.1   
Interim Analysis
There are two planned interim analyses. The first IA will be performed when approximately 
328 PFS events have occurred or 25 months after the last patient has been enrolled, 
whichever occurs later. The first IA will be the only analysis for PFS for formal statistical 
testing purpose. After PFS is tested at the first IA, central efficacy and investigator 
assessments of disease response for protocol purposes will be discontinued (except for 
investigator assessment of PFS2). The second IA will be conducted for OS when 
approximately 200 death events have occurred. 
The test significance for the IAs of OS will be determined using O’Brien-Fleming 
boundaries (the Lan-DeMets method) with a total of 260 death events. 


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Based on OS results in the second IA, the planned number of OS events needed to trigger 
the FA may be increased if the observed treatment effect is promising, but not large enough 
to yield the likely conclusion of statistical significance at the end of the study using the 
originally planned number of OS events. It is also possible for the entire study design to 
remain unchanged as a result of the IAs. The Cui-Hung-Wang test statistic will be used in 
the FA of OS to protect the type I error. 
4.2   
Independent Data Monitoring Committee (IDMC)
An IDMC supported by an independent statistician from independent statistical center (ISC) 
will review safety and efficacy data at planned interim analyses. The IDMC will provide a 
recommendation regarding study continuation based on the safety and efficacy parameters. 
In the event that the study is terminated early based on the IDMC recommendation, the 
Sponsor will notify the appropriate regulatory authorities. 
In addition, the IDMC will periodically review safety data at regularly scheduled meetings 
pre-specified in the IDMC charter. The first formal safety review will occur after 
approximately 60 subjects (36 in the ixazomib citrate arm and 24 in the placebo arm) have 
been randomized and received at least 1 cycle of study treatment. Subsequently, periodic 
safety reviews will also occur as pre-specified in the IDMC charter.
Study accrual will not be interrupted due to the scheduled safety reviews. The IDMC or 
ixazomib citrate 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 serious AEs, treatment-related AEs, serious treatment-related 
events, and events resulting in discontinuation of study drug) will be tabulated. Listings 
and/or narratives of “on-study” deaths and other serious and significant AEs, including any 
early withdrawals due to AEs, will be provided. Records of all meetings will be archived. 
The IDMC will communicate major concerns and recommendations regarding study 
modification or termination to the sponsor. Further details will be provided in the IDMC 
charter.
At the 2nd IA if OS significance is not claimed, the conditional power based on OS will be 
calculated. During the closed session of the IDMC meeting at the 2nd IA, the IDMC will 
compare the conditional power for OS based on the interim results with the prespecified 
effect size adaptation rules, and recommend to the sponsor executive committee the final 


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adaptation decision. This recommendation will be documented in the IDMC closed meeting 
minutes.
4.3   
Independent Review Committee (IRC)
An independent review committee (IRC), blinded to treatment arm assignments and 
investigator determination of response, will review all disease evaluation data (including 
PFS follow-up period; does not apply to PFS2 assessments) from the study and determine 
disease status (response and progression), according to IMWG criteria as specified in the 
IRC charter. Data from the IRC will not be provided back to the investigator during the 
conduct of the study.
5.   
STATISTICAL METHODOLOGY
In general, summary tabulations will be presented by treatment arm and control arm, and 
will be displayed by the number of observations, mean, standard deviation, median, 
minimum, and maximum for continuous variables, and the number and percent per category 
for categorical data. The Kaplan-Meier survival curves and 25th, 50th (median), and 75th 
percentiles will be provided along with their 2-sided 95% CIs for time-to-event data.
5.1   
Sample Size Justification
The primary objective of this study is to determine if ixazomib improves PFS compared 
with placebo in patients with NDMM post HDT and ASCT. The study will not be stopped 
after the PFS analysis, even if a significant PFS is observed, so that an adequate statistical 
power for OS can be obtained.  
The total sample size is calculated based on maintaining 80% power to test the OS. The 
study is also adequately powered to test PFS. There are 2 planned IAs and 1 FA. The first IA 
will be the only analysis for PFS for formal statistical testing purposes. If PFS is significant 
at the first IA, then OS will be tested at this IA and subsequent analyses.
The FA of PFS, which is also the first IA of OS, will be performed 25 months after the last 
patient has been enrolled or when approximately 328 PFS events have been observed, 
whichever occurs later. With projected 328 PFS events, it will have 95% power to detect a 
hazard ratio of 0.67 (ie, median PFS of 26 months for control versus 39 months for 
treatment) using a 2-sided log-rank test at a 2-sided alpha level of 0.05 and assuming 
approximately 15% dropout rate at month 30. This will be the FA for PFS for formal 
statistical testing purposes, with the opportunity to claim PFS benefit. With projected 328 


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PFS events, an observed hazard ratio of 0.802 or better (ie, median PFS of 26 months for 
control versus 32.4 months for treatment, 25% improvement) will likely to lead to statistical 
significance for PFS at this analysis. If the test for PFS is not statistically significant, the 
study will be claimed as unsuccessful and no further formal hypothesis testing will be 
conducted. 
If the test for PFS is statistically significant, OS will be tested. If the OS results are 
statistically significant at either interim analysis 1 (IA1) or interim analysis 2 (IA2), the 
study can be stopped early, and this analysis on OS will be the FA for formal hypothesis 
testing on OS. Otherwise, determination of the number of OS events at FA will occur at IA2. 
The total event size calculation for OS is based on the adaptive sample size reassessment 
approach, which in this study’s setting, it is an adaptive event size reassessment approach. 
The minimum event size of 260 death events is based on an optimistic assumption of a 
hazard ratio of 0.70 (ie, median OS of 70 months for control versus 100 months for 
treatment) with 80% power at a 2-sided level of significance. The O’Brien-Fleming alpha 
spending function (the Lan-Demets method) is used to calculate the significance boundary 
based on observed number of death events in each IA with a total of 260 OS events for the 
FA. 
The second IA for OS will be performed when approximately 200 death events have been 
observed, which is expected to occur approximately 60 months after the first patient is 
enrolled. If OS significance is not claimed, the conditional power based on OS will be 
calculated. If the conditional power falls in the promising zone, the event size will be 
determined according to a prespecified event size adaptation rule, with an event cap of 
approximately 350 death events. No futility analysis will be performed in the study. 
The event size adaptation rule is a pre-specified stepwise function to avoid the back 
calculation problem resulting from one sample size corresponding to either barely promising 
or highly promising interim results. The event size adaptation rule will be designed by the 
sponsor’s independent design statistician and approved by the sponsor’s head of 
biostatistics. Neither the independent design statistician nor the head of biostatistics is 
involved in the study conduct. 
The adaptation rule will be outlined in a separate document and will not be accessible to the 
sponsor’s study team until completion of the study. The rules will be available only to the 
sponsor’s independent design statistician, the sponsor’s head of biostatistics, the IDMC, and 


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the statistics' representative on the sponsor’s executive committee (if different from the 
sponsor’s head of biostatistics). 
5.2   
Randomization and Stratification 
Randomization scheme will be generated by an independent statistician who is not on the 
study team. Prior to dosing, a randomization number will be assigned to each patient. The 
randomization assignment will be implemented by an interactive voice/ web response 
system (IXRS).
Eligible patients will be randomized in a 3:2 ratio to receive ixazomib arm or placebo arm, 
stratified by induction regimen (PI without an IMiD vs IMiD without a PI vs PI and IMiD); 
pre-induction International Staging System (ISS) (stage I vs stage II or III); and response 
(CR or VGPR vs PR) after transplantation, defined as the response following induction, 
HDT, and ASCT as assessed by the investigators. 
5.3   
Blinding and Unblinding
This is a double-blind study: all study personnel including the investigators, site personnel, 
study clinicians, and the sponsor will be blinded to the treatment assignments. Only the ISC 
and IDMC will have access to unblinded individual patient level data in the electronic data 
capture system.  The periodic safety analyses will be generated for IDMC by an ISC. The
formal IA analyses will also be conducted by ISC for the IDMC. An unblinded submission 
working group will be formed to prepare submission package and/or work with Agencies for 
submission purpose at IA. 
Refer to section 4.2 for the roles and responsibilities of IDMC.
5.4   
Data Handling
5.4.1   
Methods for Handling Missing Data
All available efficacy and 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.
In general, missing data will be treated as missing and no data imputation will be applied,
unless otherwise specified. For patient reported outcomes data, primarily missing data
imputation will be based on published instrument specific methods. Other missing data
imputation method such as Last Observation Carry Forward (LOCF) and multiple


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imputation method may be explored as sensitivity analyses for patient reported outcomes
data.
5.4.1.1   Missing/Partial Dates in Screening Visit
The following rules apply to dates recorded in the screening visits. 

If only the day-component is missing, the first day of the month will be used if the year 
and the month are the same as those for the first dose of study drug.  Otherwise, the 15th 
will be used. 

If only a year is present, and it is the same as the year of the first dose of study drug, the 
15th of January will be used unless it is later than the first dose, in which case the date of 
the first of January will be used, unless other data indicates that the date is earlier. 

If only a year is present, and it is not the same as the year of the first dose of study drug, 
the 15th of June will be used, unless other data indicate that the date is earlier.  
5.4.1.2   Missing/Partial Dates in Adverse Events/Concomitant Therapies/Subsequent 
Therapies
5.4.1.2.1 Missing/Partial Dates in Adverse Events
Adverse events with start dates that are completely or partially missing will be imputed as 
follows:

If month and year are known but day is missing 
oIf month and year are the same as month and year of first dose date, then impute to
   first dose date 
oIf 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 
oIf  year is same as year of 1st dose date, then 1st dose date will be used instead
oIf year is different than year of 1st dose date, then 1st of January of the year will be 
   imputed. 

If all is missing, then it is imputed with 1st dose date.


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Imputing missing AE start date is mandatory. After the imputation, all imputed dates are 
checked against the start dates to ensure the stop date does not occur before start date. If the
imputed stop date occurs prior to start date, then keep the imputed date same as the start date. 
Adverse events with stop dates that are completely or partially missing will be imputed as 
follows:

If “ongoing” is checked, no imputation is necessary.

If month and year are known but day is missing, the last day of the month will be imputed 

If year is known, but day and month are missing,
o
If YYYY < year of last dose,  then 31st of December will be imputed
o
If YYYY = year of last dose,  then 31st of December will be imputed 
o
If YYYY > year of last dose,  then 1st of January will be imputed 

If all are missing, then impute date to 31st of December, in the year of last dose.
Imputing missing AE stop date is not mandatory if AE is regarded as ongoing. However if it 
is to be done, the rules are outlined above. If 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. 
5.4.1.2.2 Missing/Partial Dates in Concomitant Therapies
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
o
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) 
o
If DOB is not available but age is available, then estimate DOB by using screening 
date and age (age = screening date – DOB) 


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Concomitant therapies with stop dates that are completely or partially missing will be analyzed 
as follows:

If “ongoing” is checked, no imputation is necessary.
   If month and year are known but day is missing, the last day of the month will be imputed 

If year is known, but day and month are missing, 
o
If YYYY < year of last dose,  then 31st of December will be imputed 
o
If YYYY = year of last dose,  then 31st of December will be imputed 
o
If YYYY > year of last dose,  then 1st of January will be imputed 

If all 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 the death date will be used 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
the imputed date will be kept the same as the start date.
5.4.1.2.3 Missing/partial dates in subsequent therapies
Subsequent therapies with start dates that are completely or partially missing will be 
analyzed as follows:

When month and year are present and the day of the month is missing, 
o
If the onset month and year are the same as the month and year of last dose with 
study drug, the day of last dose + 1 will be imputed.  
o
If the onset month and year are not the same as the month and year of last dose 
with study drug, the first day of the month is imputed. 

When only a year is present, 
o
If the onset year is the same as the year of last dose with study drug, the date of 
last dose + 1 will be imputed.  


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o
If the onset year is not the same as the year of last dose with study drug, the first 
day of the year is imputed. 

If no components of the onset date are present the date of last dose + 1 will be 
imputed.
5.4.2   
Definition of Reference Values
Unless otherwise specified, the reference for assessment during this study will be based on 
the value collected at the time closest to, but before, the start of study drug administration.
The  reference for response assessment during this study will be based on the value collected 
at the time of initial diagnosis. For the purpose of assessming PD, the disease nadir will be 
considered as study entry (or sometime later as appriopirate). 
5.4.3
Windowing of Visits
All data will be categorized based on the scheduled visit at which it was collected.  These 
visit designators are predefined values that appear as part of the visit tab in the eCRF.  
5.4.4   
Justification of Pooling
All data from all sites will be pooled.  Study center or treatment-by-center interaction will 
not be included in any statistical analysis.
5.4.5   
Withdrawals, Dropouts, Loss to Follow-up
Time to event parameters will be censored if patients withdraw, drop out, or are lost to 
follow-up before documentation of the events (progressive disease/death).  Rules for 
censoring are detailed in section 5.8.
5.5   
Patient Disposition
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 for discontinuation from the treatment, patients on-going on 
treatment, patients participating in any follow-up, patients with dose escalation at C5D1, 


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patients discontinued from the study, and primary reason for discontinuation 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.
5.6   
Demographics and Disease Characteristics at Study Entry
5.6.1   
Demographics
Demographics will be summarized by treatment groups in a descriptive fashion in the ITT 
population. Demographic data at study entry to be evaluated will include age, sex, race, 
ethnicity, height, weight, and body surface area. Patient enrollment by region and country 
will also be summarized by treatment groups.
5.6.2   
Medical History
General medical history and prior medications will be listed for all patients by treatment 
groups. Prior induction regimens will be summarized by PI containing, IMiD containing, 
corticosteroids containing, cyclophosphamide containing, liposomal doxorubicin containing, 
platinum containing, akaylator containing, monoclonal antibody containing, busulfan 
containing, and others. 
ASCT procedure will be displayed including type of condition regimen, recovery of ANC > 
500 cells/mm3, day of recovery to ANC, recovery of platelet count > 20,000 cells/mm3, and 
days of recovery to platelet count.  Peripheral blood stem cell mobilization regimen, best 
response by investigators prior ASCT and post ASCT will also be detailed in summaries. 
5.6.3   
Disease Status at Initial Diagnosis 
Efficacy data including serum M-protein, urine M-protein, and serum involved FLC, serum 
FLC ratio will be summarized for ITT population. Other characteristics include type of 
myeloma,
-microglobulin, albumin, Durie-Salmon stage, lactate dehydrogenase (LDH), 
cytogenetics, international staging system stage (ISS), revised international staging system 
stage (RISS), lytic bone, and extramedullary disease. Time from initial diagnosis to first 
dose of study treatment, from initial diagnosis to ASCT, and from ASCT to first dose of 
study treatment will be summarized for all patients. 
2
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5.6.4   
Disease Status at Study Entry
Disease characteristics at study entry includes, but are not limited to, Eastern Cooperative 
Oncology Group (ECOG) performance status, 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), creatinine 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, lytic bone 
lesions, and extramedullary disease will be summarized for all patients. 
A patient’s type of myeloma is determined by heavy chain type (IgG, IgA, IgM, IgD, IgE, 
and other) 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:
Months from diagnosis to the randomization date for each treatment is calculated by 
randomization date - date of diagnosis  
365.25/12
Distribution of stratification factors will also be summarized.
5.6.4.1   
Extent of disease at study entry
The following categories of extent of disease at study entry will be summarized: bone 
marrow aspirate (number of patients, % plasma cells), bone marrow biopsy (number of 
2

[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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patients, % plasma cells, marrow cellularity, Kappa/Lambda ratio), combined % plasma 
cells in bone marrow aspiration and biopsy, and plasmacytomas. 
5.6.5   
Bone marrow cytogenetic at initial diagnosis
High risk cytogenetic categories are defined as (1) del17 group: patients with del17 alone (2) 
cytogenetic high-risk group: patients with any of the following cytogenetic abnormalities: 
del17, t(4;14), t(14;16). The standard risk group corresponding to high risk group is defined 
as patients for whom the test del17, t(4;14), t(14;16) are normal. “Unclassifiable” is defined 
as patients who do not have cytogenetic data that can be categorized to high risk or standard 
risk corresponding to high risk group, either because of missing, unknown or indeterminate 
results. (3) cytogenetic expanded high-risk group: patients with any of the following 
abnormalities: del17, t(4;14), t(14;16), or ampl 1q. The standard risk group corresponding to 
expanded high risk group is defined as patients for whom del17, t(4;14) , t(14;16) and ampl
1q are normal. “Unclassifiable” is defined as patients who do not have cytogenetic data that 
can be categorized to expanded high risk or standard risk corresponding to expanded high 
risk group, either because of missing, unknown or indeterminate results. 
The percentage of each category will be summarized. 
5.7   
Treatments and Medications
5.7.1   
Concomitant Medications
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 the end of the on-treatment period will 
be tabulated by Anatomical Therapeutic Chemical (ATC) classification 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.
5.7.2   
Study Treatments
Following the Screening period, eligible patients will be randomized to receive ixazomib or 
placebo in a double-blind fashion with the randomization ratio of 3:2, respectively.


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Ixazomib Arm: Patients will receive ixazomib citrate on Days 1, 8, and 15 of a 28-day 
cycle.  
Placebo Arm: Patients will receive placebo capsule on Days 1, 8, and 15 of a 28-day cycle.  
In both arms, a starting dose of 3 mg ixazomib or matched placebo will be used for all 
patients through Cycle 4. Upon evaluation of toxicities at the completion of Cycle 4, if 
during the most recent 2 cycles (Cycle 3 and 4), there have been no nonhematologic AEs 
≥Grade 2 related to study drug, no dose interruptions related to study drug toxicities, and no 
delays of greater than 1 week in starting a cycle due to study drug toxicities, the dose may be 
escalated to 4 mg at Cycle 5 Day 1. Patients who have had any dose reductions will not get 
dose escalated. If dose escalation was inadvertently missed at Cycle 5, escalation may be 
performed with permission from the Millennium project clinician or designee.
Patients will receive study treatment for a maximum duration of approximately 24 months 
(26 cycles if no delays), or until documented disease progression or intolerable toxicities, 
whichever comes first.  
The number of patients who have been escalated at Cycle 5 Day 1 will be summarized. For 
those who didn’t escalate, their reasons of no escalation will be displayed. 
5.7.2.1   
Duration of Follow-up
The duration of OS follow-up is defined as time from the randomization date to the death or 
last visit of known alive. If a subject is alive, this patient is treated as an event in OS follow-
up and the duration equals to the date of a subject is last known to be alive – randomization 
date + 1. If a subject is dead, this patient is censored for OS follow-up and the duration 
equals to date of death - randomization date + 1. 
The Kaplan Meier (K-M) approach will be used to calculate the mediaon duration of follow 
up. 
5.7.2.2   Extent of Exposure
A summary of drug exposure to ixazomib/placebo will be characterized by number of 
treated cycles, numbers and percentages of patients who had ≥1, ≥2 , …, and = 26 treated 
cycles, total amount of dose taken, total number of dose taken, and relative dose intensity 
(%), by each treatment group in the safety population. Aggregate summary of numbers and 
percentages of patients who had 1-4, 5-8, 9-12, 13-16, 17-20, 21-24, 25-26 treated cycles 


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will also be presented in the same table. Extent of exposure (days), which is calculated as 
(last dose date of study drug – first dose date of study drug + 1), will also be presented.
A treated cycle is defined as a cycle in which the patient received any amount of any study 
drug. 
Relative dose intensity (%) is defined as 100 * (Total amount of dose taken) / (Total 
prescribed dose of treated cycles). Total prescribed dose of treated cycles is calculated as: 
for patients who were treated at or after C5D1, it equals number of prescribed doses per 
cycles * dose prescribed at enrollment (3mg) * 4 cycles + dose prescribed at C5D1 (4mg) * 
number of prescribed doses per cycle * (number of treated cycles - 4). For patients who were 
not treated more than 4 cycles, it equals dose prescribed at enrollment (3mg) * number of 
prescribed doses per cycle * number of treated cycles.
Relative dose intensity will also be displayed as <50%, 50% - <= 80%, >80% - < 100%, = 
100%,  and > 100%. The duration of treatment at 4 mg 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. In addition, relative dose intensity will be 
calculated for those escalated to 4 mg at cycle 5, counted only for doses starting from cycle 
5.
Dosing data will also be presented in a by-patient listing.
5.8   
Efficacy Analyses
All efficacy evaluations will be conducted using the ITT population unless otherwise 
specified.
5.8.1   
Primary Efficacy Endpoint
There is one primary endpoint, PFS, which is defined as the time from the date of 
randomization to the date of first documentation of PD or death due to any cause, whichever 
occurs first. Patients without documentation of PD will be censored at the date of last 
response assessment that is stable disease (SD) or better. The details regarding the handling
of missing assessment and censoring for PFS analysis are presented in Table 5-1.


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Table 5-1   
Censoring Rules for PFS Primary Analysis Based on FDA Guidance
Situation
Date of Progression or Censoring
Outcome
No randomization and/or no post 
randomization 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 visits 
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.
5.8.1.1   Primary Efficacy Analysis
PFS will be analysized at the first IA, when 25 months after the last patient has been 
enrolled or approximately 328 (approximately 50%) PFS events have been observed,
whichever occurs later. 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 0.05. In addition, an 
unadjusted stratified Cox model will be used to estimate the hazard ratio and its 95% CIs for 
the treatment effect using the stratification factors. The Kaplan Meier (K-M) survival curves 
and K-M median PFS (if estimable), along with their 2-sided 95% CIs, will be provided for 
each treatment group. PFS assessed by IRC in ITT population will be the primary analysis. 
Sensitivity analyses for PFS include:
1. PFS assessed by investigator will be analyzed in the ITT population.
2. PFS assessed by IRC will be analyzed in the PP population if more than 5% patients 
are excluded from this analysis.
3. PFS assessed by IRC using the missing assessment and censoring rules based on 
EMA guidance with two combined alterations from FDA guidance as presented in 
Table 5-2.


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Table 5-2   
Handling of missing assessment and censoring for PFS Sensitivity 
Analysis based on EMA guidance 
Situation
Date of Progression or Censoring
Outcome
Alternate antineoplastic therapy 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
PFS assessed by IRC evaluations to which different censoring mechanisms have been 
applied will be analyzed in the ITT population, for example, not censoring for patients who 
discontinue treatment and go on alternative antineoplastic therapy. Sensitivity analyses will 
be performed on the basis of one alteration at a time, not on combined alterations unless 
specified otherwise. Additional sensitivity analysis for PFS might be conducted on treating 
start date of alternate antineoplastic therapy as events.
In addition, a stepwise Cox model will be implemented to identify potential predictive 
factors using relevant demographic or diagnostic covariates, with the entry level fixed at 
0.25 and a stay level fixed at 0.05. Besides treatment and the stratification factors, the model 
may include the following significant covariates including, but not limited to, treatment arm, 
age, race (white, non-white), ECOG score at study entry (0 or 1, 2), cytogenetic test (high 
risk, other), and corrected calcium, ISS(I,  II or III), revised ISS (I or II, III), creatinine 
clearance, etc.
The plan of subgroups for PFS is presented in the Table 5-3 below with a few identifided 
key subgroups:


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Table 5-3        List of subgroup
Subgroup
Definition of Group
Age
< 60 years vs.  ≥ 60 and < 75 years  
Pre-induction ISS
I vs. II vs. III
Pre-induction ISS 
I vs. II or III as one stratification factor
Revised ISS stage at initial diagnosis
I vs. II vs. III
Sex
male vs. female
Race
white vs. black-African American vs. Asian vs. other
Region
APAC vs. EMEA vs. other 
Best response post transplant 
CR or VGPR vs. PR as one stratification factor
Response at study entry
CR vs. VGPR or less
Cytogenetic risk
high risk group vs. standard risk group corresponding to high risk 
group vs. unclassifiable group; 
expanded high risk group vs. standard risk group corresponding 
to expanded high risk group vs. unclassifiable group
Induction regimen
PI exposed vs. PI naive (IMiD only)
Induction regimen
PI and IMiD vs. PI only vs. IMiD only as one stratification factor
Subgroup testing will be conducted using the two-sided alpha of 0.05. In addition, five 
prespecified key subgroups (Age: < 60 years; Pre-induction ISS: II or III; Best response post 
transplant: CR or VGPR; Cytogeneic risk: high risk group and expanded high risk group) 
will be tested at a 2-sided alpha level of 0.05 with the Hochberg procedure for multiplicity 
correction. 
Additional exploratory analyses may be performed if deemed necessary.
5.8.2   
Key Secondary Efficacy Endpoint
There is one key secondary endpoint: OS.
Overall Survival
OS is defined as the time from the date of randomization to the date of death. Patients
without documentation of death at the time of analysis will be censored at the date last
known to be alive. OS will be analyzed based on the ITT population.


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5.8.2.1   Key Secondary Efficacy Analysis
Overall Survival
A 2-sided, stratified log-rank test will be used to compare the treatment groups with respect 
to OS. In addition, an unadjusted stratified Cox model will be used to estimate the hazard 
ratio and its 95% CIs for the treatment effect using the stratification factors. The 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.
In addition, a stepwise stratified Cox regression model will be used to further evaluate the 
treatment effects on OS after adjusting for some prognostic factors. Besides treatment and 
the stratification factors, the model may include, but is not limited to, the following 
prognostic factors simultaneously: age, race (white, non-white), ECOG score at study entry 
(0 or 1, 2), cytogenetic test (high risk, other), and corrected calcium, ISS(I,  II or III), revised 
ISS (I or II, III), creatinine clearance, etc.
To adjust for the potential effects of subsequent therapies after patients discontinued study 
treatment, the following two methods will be used:

Marginal Structural Models (MSM) by Robin and Finkelstein

Inverse Probability of Censoring Weighted (IPCW) method by Robins and 
Finkelstein 
In the MSM and IPCW analyses, in order to derive weights adjusting for the time-fixed and 
time-varying confounding effects due to taking alternative therapies, the covariates affecting
disease progression, post-progression treatment, and OS endpoint will be used. Potential 
time-fixed covariates at study entries are region(APAC, EMEA, other), age(<60, ≥60 and 
<75), race(white, non-white), ECOG score (0 or 1, 2), induction therapy(PI only, IMiD only, 
PI and IMiD), response at study entry (CR or VGPR, PR), percentage of plasma cells (≤30, 
> 30, missing), presence of extramedullary plasmacytomas (yes, no), presence of lytic bone 
lesions (yes, no), hemoglobin, platelets, creatinine clearance, albumin, and corrected 
calcium. Potential time-fixed covariates at initial diagnosis are type of myeloma (IgA,
other), ISS (I, II or III), RISS (I or II, III), cytogenetic abnormalities (high risk, others), 
LDH, 2 microglobulin. Time-varying covariates include duration of exposure, disease 
progression status at each study visit, hemoglobin value at each study visit and 
progression/relapse visit, platelets value at each study visit and progression/relapse, 


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M-protein value at each study visit and progression/relapse, type of subsequent therapy with 
proteasome inhibitor, types of subsequent therapy with IMIDs.
The final criteria for selected covariates would need to be statistically have a p-value of less 
than or equal to 0.1 in the multivariate logistic regression models for weight calculations. If 
there are more than 5% missing in the covariate, then this covariate will be dropped from the 
weighting calculation and final OS model. For both MSM and IPCW analyses, logistic 
regression models on repeated measurements will be used to approximate the Cox models in 
the weight derivations from which stabilized weights will be derived per subject per 
observation. Adjusted K-M curves will also be presented along with hazard ratios and 95% 
confidence intervals, and adjusted p-values based on MSM and IPCW approaches. SAS proc 
PHREG procedure with counting process type of data input, which takes multiple 
observations per subject, will be used as the final Cox model for OS for both MSM and 
IPCW approaches, where robust variance will be used to accommodate covariance 
introduced by correlated longitudinal observations within each subjects and other extra 
variabilities due to departure from model assumptions.
Subgroup analyses will be performed for OS following Table 5-3. 
5.8.3   
Other Secondary Efficacy Endpoints and Analyses
Other secondary efficacy parameters include best response achieved or maintained prior to 
PD or subsequent therapy, time to progression, PFS2, time to start of the next line of 
therapy, time to end of the next line of therapy, duration of the next line of therapy, OS and 
PFS in high-risk population. Conversion of MRD + to MRD-; maintenance of MRD-; 
correlation between MRD status and PFS and OS.
Disease response-related endpoints prior to PD will be analyzed using IRC-assessed
responses.
Best Response achieved or maintained prior to PD or subsequent therapy
The time frame for a response is determined from the start of the study treatment until 
confirmed PD or subsequent therapy, whichever comes earlier.  
The percentage of response (PR, VGPR, CR, or sCR) will be determined relative to the ITT 
population. 


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For patients who entered into study with PR response, the percentage of patients maintaining 
PR as best confirmed response, and converting to VGPR/CR as best confirmed response will 
be displayed. For patients who entered into study with VGPR response, the percentage of 
patients maintaining VGPR as best confirmed response, and converting to CR as best
confirmed response will be displayed. For patients who entered into study with CR response, 
the percentage of patients maintaining CR as best confirmed response will be displayed.
For patients entered into study with CR response, the percentage of patients maintaining CR 
at 12 and 24 months will be displayed; duration of CR will be summarized descriptively 
using the Kaplan-Meier method. 
The IRC-assessed response data will be used for the analysis.  Investigator-assessed 
response data will be used for the sensitivity analysis.
Time to Progression (TTP)
TTP 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 analysis will be censored at the 
date of last response assessment that is SD or better. Patients who take alternative anti-
neoplastic therapy prior to progression, or die during study treatment will also be censored at 
the date of last response assessment that is SD or better. TTP will be analyzed based on the 
ITT population using the similar method as PFS. The subgroup analysis of TTP will be 
analyzed following Table 5-3. 
Progression-free survival 2 (PFS2)
Progression-free survival 2 (PFS2) is defined as time from the date of randomization to the 
date of first documentation of PD (as assessed by investigator) on the next-line treatment
following study treatment or death from any cause, whichever occurs first. 
PFS2 will be analyzed based on the ITT population as assessed by investigator using the 
similar method as PFS. 
The details of the handling of missing assessment and censoring are presented in Table 5-4
and Table 5-5.


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Table 5-4        Censoring for PFS2 For Those Who have Received Second line 
Therapy following Study Treatment
Situation
Date of Progression or Censoring
Outcome
Documented death or disease progression 
during second line therapy 
Date of death/disease progression
Event
No documented death or disease progression 
during second line therapy
Date of last assessment
Censored
Lost to follow-up, withdraw consent before 
any documented death or disease progression 
during second line therapy   
Date of last assessment
Censored 
Start of third line therapy prior to the disease 
progression  during second line therapy
Date of last disease assessment prior to 
starting the third line therapy
Censored
If a patient has no response assessment during second line therapy, it will be censored at first dose of 
second line therapy.
Table 5-5        Censoring for PFS2 for Those Who have not received Second Line of 
Therapy
Situation
Date of Progression or Censoring
Outcome
No documented death
Date of last visit
Censored
Death 
Date of death
Event
In addition, one sensitivity analysis for PFS2 might be conducted on treating start date of 3rd
line therary as events if the patients have not experience PD on the second line yet.
Time to start of the next line of therapy
Time to start of the next line of therapy is defined as the time from the date of randomization 
to the date of the first dose of the next line of antineoplastic therapy, for any reason. 
Time to start of next line therapy will be analyzed based on the ITT population using the 
similar method as PFS. Patients who have not started the second line therapy will be 
censored at date of last known to be alive.


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Time to end of the next line therapy  
Time to end of next line therapy is defined as the time from the date of randomization to the 
date of last dose of next antineoplastic therapy following study treatment or death due to any 
cause, whichever occurs first.  
Time to end of next line therapy will be analyzed based on the ITT population using the 
similar method as PFS. Patients who have not completed the second line therapy will be 
censored at date of last known to be alive.
Duration of next line therapy  
Duration of next line therapy is defined as the time from the date of first dose of next line 
therapy to the date of the last dose of the next antineoplastic therapy or death due to any 
cause, whichever occurs first.  
Duration of next line therapy will be analyzed on those patients who actually received next 
line therapy following the study treatment using the ITT principal. Patients who are still on 
treatment on the next line of therapy will be censored at date of last known to be alive. 
Duration of next line therapy will be summarized using the Kaplan-Meier method.
PFS and OS in Cytogenetic Risk Populations
PFS and OS will be analyzed in high risk group using a similar method as those in the ITT 
population. 

Cytogenetic high risk group defined as patients carrying any of the following 
cytogenetic abnormalities: del17, t(4;14), or t(14;16)

Cytogenetic expanded high-risk group defined as patients carrying any of the 
following cytogenetic abnormalities: del17, t(4;14), t(14;16) or ampl 1q
In addition, PFS and OS analyses will be summarized by cytogenetics test del17, t(4;14), 
t(14;16) and ampl 1q if data permit. 
5.9   
Pharmacokinetic and Biomarker Analysis
5.9.1   
Pharmacokinetic Analyses
Plasma concentration-time data will be presented in listings and summarized by time point
in tables.


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PK data collected in this study will 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.
5.9.2   
Biomarker Analysis
5.9.3   
Minimal Residual Disease Analysis
Minimal Residual Disease (MRD) will be assessed at study entry, cycle 12/13 and at the end 
of treatment (2 years) in all the VGPR and CR patients independent from the arm of the 
study, unless already done within the most recent 2 cycles. If MRD status is missing or not-
evaluable, it will be assumed as MRD positive.
MRD status by response at study entry for each treatment arm and overall population will be 
summarized. MRD status by response at C12/13, EOT for VGPR and CR patients for each 
treatment arm and overall population will be summarized. PFS and OS by MRD subgroup 
analyses will be analyzed according to MRD subgroups listed below. 
!
For overall population: MRD+ vs. MRD- at study entry
!
For patients who were MRD- at study entry: treatment vs. control.
!
For patients who were MRD+ at study entry and converted to MRD – at anytime 
point post study entry: treatment vs. control.
!
For patients who were MRD+ at study entry and still maintain MRD+ at anytime 
point post study entry: treatment vs. control.
The rate of maintenaning MRD negativity at Cycle 12/13, EOT and any time point post 
study entry for patients who were MRD negative at study entry will be compared between 
Company Confidential Information


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treatment and control arms. The rate of maintenaning MRD negativity at Cycle 12/13, EOT 
and any time point post study entry for patients who were CR and MRD negative at study 
entry will be compared between treatment and control arms. The rate of maintenaning MRD
negativity at Cycle 12/13 and EOT for patients who were MRD negative at study entry may 
be compared between treatment and control arms in selected subgroups if data permit. 
The rate of converting to MRD negative by 3-month interval and any time point post study 
entry for patients who were MRD positive at study entry will be made between treatment 
and control arms. The rate of converting to MRD negative at any time point post study entry 
for patients who were CR and MRD positive at study entry will be made between treatment 
and control arms. The rate of converting to MRD negative at any time point post study entry 
for patients who were MRD positive at study entry may be made between treatment and 
control arms in selected subgroups if data permit.
Time from MRD negative to MRD positive, PD or death will be summarized using the 
Kaplan-Meier method. 
Time from MRD positive at study entry to first MRD negative post study entry will be 
summarized using the Kaplan-Meier method. 
Limit of Detection of MRD will be summarized for all MRD evaluable patients.
MRD analyisis on maintenance of MRD negativity, conversion to MRD negativity and 
correlation with PFS and OS based on different threshold (10-4, 10-5, 10-6) may be performed 
if data permit. 
5.10   Analyses of Patient-Reported Outcomes and Health Economics
5.10.1   Patient Reported Outcomes (PROs)
Descriptive Statistics 
Patient-reported outcome (PRO) assessments using the EORTC QLQ-C30 and the EORTC 
QLQ-MY20 will be analyzed using patients with PRO measurements at study entry and at 
least one post study entry measurement in the ITT population. 
The descriptive statistics of actual value and change from study entry 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. Specifically, two different groupings of 


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observations will be used: 1. based on cycle visit and 2. based on 4-week intervals from 
study entry. 
The subscales of EORTC QLQ-C30 and QLQ-MY20 are defined as shown in Table 5-6 and 
Table 5-7. The summary score of EORTC QLQ-C30 will be calculated from the mean of 13 
of the 15 QLQ-C30 scales (the Global Quality of Life scale and the Financial Impact scale 
are not included).
Table 5-6        Definition of Subscale Scores of EORTC QLQ-C30
Subscale
Individual Items
Physical functioning
1-5
Role functioning
6-7
Emotional functioning
21-24
Cognitive functioning
20, 25
Social functioning
26-27
Quality of life
29-30
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 5-7        Definition of Subscale Scores of EORTC QLQ-MY20
Subscale
Individual Items
Future perspective
18-20
Body image
17
Disease symptoms
1-6
Side effects of treatment
7-16


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Analysis based on minimally important difference (MID)  
The number and percentage of patients with either a stable score or an improvement  in 
score from study entry based on a minimally important difference (MID) of 10 will be 
summarized by treatment group over time. Specifically, patients with a change for the better 
of ≥MID will be classified as “improved”. Those with no change in score from study entry 
or a change in score within MID will be classified as “stable”. The number and percentage 
of patients with “improved” or “stable” subscale scores based on a MID of 5 will also be 
summarized by treatment group over time.
Analysis based on Linear mixed effects model by incorporating covariates   
1. For the summary score and each subscale score of EORTC QLQ-C30 as well as each 
subscale score of QLQ-MY20, the change in score from study entry to each 
scheduled treatment cycle visit will be analyzed using repeated measures linear 
mixed models. These models will include the following covariates: treatment group, 
score at study entry, stratification factors, visits, and interactions between treatment 
group and visits. The interaction term between score at study entry and visit may also 
be considered as a covariate. The estimated mean change in score from study entry 
with 95% CIs for each treatment group will be provided at each treatment cycle visit. 
In addition, the mean difference in the changes from study entry between the 
treatment groups with 95% CIs and p-values will be provided at each treatment cycle 
visit. 
2. For the summary score and each subscale score of EORTC QLQ-C30 as well as each 
subscale score of QLQ-MY20, the change in score from study entry to a pre-
specified time period (e.g., 24, 36, or 48 4-week intervals) will be analyzed using 
similar linear mixed models to the analyses based on scheduled treatment cycle visit 
above. Only time periods where at least 50% of patients have the potential to be 
included will be considered. These models will include the following covariates: 
treatment group, score at study entry, stratification factors, time from study entry, 
interactions between treatment group and time from study entry. The interaction term 
between score at study entry and time from study entry may also be considered as a 
covariate. The estimated mean change in score from study entry with 95% CIs for 
each treatment group as well as the mean difference in the changes from study entry 
between the treatment groups with 95% CIs and p-values will be provided at every 
three 4-week intervals post study entry. 


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Change from study entry scores using cumulative distribution function (CDF) figures  
The change in score from study entry to Cycle 26 (or last visit prior to Cycle 26) will be 
presented using cumulative distribution function (CDF) figures. The x-axis represents the 
changes in score (range: -100 to 100) and the y-axis represents the cumulative percentage of 
patients with a given change in score.
An Average Score from the EORTC QLQ-C30 Global Quality of Life domain 
For each patient, an average score will be calculated using all available scores from study 
entry to last measurement prior to PD.  For each group, an average score will be calculated 
from the patient averages. A 2-sample t-test will be used to assess whether the mean average 
score in the ixazomib arm is noninferior to that in the placebo arm. The noninferiority 
margin is 12.  
Analyses of the global quality of life during the PFS Follow-up period (following EOT until 
progression), the PD Follow-up period (following progression until start of next-line 
therapy), and the PFS2 Follow-up period (from the start of next-line therapy until PD2) may 
be conducted. Comparisons of the average global quality of life during the treatment period 
or follow-up periods may be also considered.
In addition, the area under the curve (AUC) approach will be used to examine the 
differential effect of treatment throughout the study as a sensitivity analysis.  The AUC 
approach aggregates the cumulative absolute HRQOL score over time: the y-axis represents 
the absolute EORTC QLQ-30 global quality of life score (range: 0-100); the x-axis 
represents the time horizon. 
For each individual patient, two AUCs will be calculated: 1. from study entry to last time 
on-treatment and 2. from study entry to a pre-specified time period (e.g., 24, 36, or 48 4-
week intervals). Only time periods where at least 50% of patients have the potential to be 
included will be considered. In order to calculate the AUCs for each individual, a linear 
relationship will be assumed between measurements and the worst possible value will be 
assumed after the last measurement. For each group, the average AUCs will be calculated 
from the patient averages. A 2-sample t-test will be used to assess whether the mean AUC in 
the ixazomib arm is noninferior to that in the placebo arm.  The noninferiority margin is set 
to be 12 * the time period for the AUC analysis.  This is consistent with the average score 
approach, as the time period is fixed. 


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Additionally, distribution of individual AUCs in the 2 treatment groups may be described by 
summary statistics, such as means, standard deviations, medians, etc.
If the noninferiority test is statistically significant, then the superiority test will be performed 
to further examine the benefit of the differential effect of treatment. 
The average score and AUC analyses described above will also apply to other scales of 
EORTC QLQ-C30 and QLQ-MY20.  
Missing data   
Details of scoring and initial handling of missing data are included in the EORTC QLQ-C30 
and QLQ-MY20 scoring guidelines.
Missing data patterns will be examined.  As a sensitivity analysis, different imputation 
methods for missing data including Last Observation Carry Forward (LOCF) and imputing 
death as worst possible score, and pattern mixture model may be performed if appropriate 
after examining missing data patterns.  
Compliance for EORTC QLQ-C30 and QLQ-MY20 will also be summarized by number of 
expected and number and percentage of received by treatment group over time and overall.
5.10.2
Health Economics Analysis Using Medical Resource Utilization and Utility
EQ-5D scores will be summarized in descriptive statistics for treatment arms over time. 
Compliance for EQ-5D will also be summarized by number of expected and number and 
percentage of received by treatment group over time and overall.
HU data will be summarized in descriptive statistics of medical encounters (length of 
hospital stay; number of inpatient, ICU, emergency department and outpatient encounters, 
and reason for each), number of missing days from work or other activities by patient and 
care-giver for treatment arms.
Further modeling will be performed separately in post hoc analyses.
5.11   Safety Analyses
Safety will be evaluated by the incidence of AEs, severity and type of AEs, and by changes 
from study entry in the patient’s vital signs, weight, and clinical laboratory results using the 


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safety population. Exposure to the study drug and reasons for discontinuation will be 
tabulated.
5.11.1   Adverse Events
5.11.1.1   Adverse Events
Adverse events will be coded using 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 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 (ie, those events reported by 
10% of patients in either treatment group) 

Serious AEs (SAEs)

Drug-related (SAEs)

AE resulting in discontinuation

AEs that prevented dose escalation at C5
Patients with the same AE more than once will have that event counted only once within 
each body system, once within each high level term, and once within each preferred term.
Treatment-emergent AEs will also be summarized by the National Cancer Institute Common 
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. 


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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, grade 3 or higher drug-related AE, 
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) of 
new primary malignancy and AEs of clinical importance (AECI) of peripheral neuropathy, 
rash, encephalopathy, liver impairment, hypotension, heart failure, arrhythmias, myocardial 
infarction, thrombocytopenia, neutropenia, gastrointestinal, and renal impairment will be 
presented.
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. 
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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Time to Resolution and Improvement of Peripheral Neuropathy (PN) Events
Peripheral neuropathy is defined as the treatment emergent adverse event in the high-level 
term of peripheral neuropathies NEC according to MedDRA.
A PN event is considered as resolved if its final outcome is resolved with no subsequent PN 
event of the same preferred term occurring on the resolution date or the day before and after. 
A PN event is considered as improved if the event improves from the maximum grade
(meaning that all the grades recorded after the maximum grade are less than the maximum 
grade).
Time to resolution and time to improvement are to be defined for each PN event. Time to 
resolution is defined as the time from the initial onset date (inclusive) to the resolution date 
for resolved events. Time to improvement is defined as the time from the initial onset date 
(inclusive) of the maximum grade to the first onset date that the toxicity grade is below the 
maximum grade with no higher grade thereafter, or the resolution date, whichever occurs 
first.
Time to improvement and time to resolution of PN events will be summarized by outcome 
(improvement or resolution) using the Kaplan-Meier method. The K-M survival curve and 
K-M medians (if estimable), along with their 2-sided 95% CIs, will be presented. This 
analysis is event based, thus 1 subject could contribute multiple observations if the subject 
has more than 1 PN event.
The analysis may be conducted for patients with any PN events or those with ≥ 2 PN events 
or those ≥ 3 PN events, respectively, if data permit.
5.11.1.2   Serious Adverse Events
The number and percentage of patients experiencing at least one treatment-emergent SAE 
will be summarized by MedDRA primary system organ class, high level term, and preferred 
term. Drug-related 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).
5.11.1.3   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). 


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5.11.1.4   Adverse Events Resulting in Discontinuation of Study Drug
A by-patient listing of treatment-emergent AEs resulting in discontinuation of study drug 
will be presented.
5.11.2   Laboratory Data
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 results at study entry 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: lymphocytes, hemoglobin, neutrophils (ANC), platelets counts and 
leukocytes.

Serum chemistry: blood urea nitrogen (BUN), creatinine, total bilirubin, urate, 
lactate dehydrogenase (LDH), albumin, alkaline phosphatase (ALP), aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), glucose, corrected 
calcium, sodium, potassium, chloride, carbon dioxide (CO2), magnesium, and 
phosphate.
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:


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
Hematology: ANC, hemoglobin, platelets counts, lymphocytes and leukocytes.

Serum chemistry: ALT, AST, ALP, creatinine, total bilirubin, corrected calcium, 
magnesium, potassium, sodium, and phosphate.
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.
5.11.3   Electrocardiograms
Descriptive statistics for the actual values and changes from values at study entry in ECGs 
will be listed by time point.
QTc interval will be calculated using Bazett’s correction and Fridericia’s correction, if 
necessary.  The formulas are:
QTc (Bazett) = QT / (RR0.5)
QTc (Fridericia) = QT / (RR0.33)
where RR = 60 / heart rate (bpm)
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 study entry and each of the 
subsequent time points.  Categories of changes from study entry (≥ 30 msec and ≥ 60 msec) 
will be summarized as well. Maximum QTc intervals and maximum changes from study 
entry will also be summarized similarly in a separate display.
ECG abnormalities will be presented in a data listing.
5.11.4   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 study 
entry will also be presented.  


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A by-patient listing will also be presented.
5.11.5
Eastern Cooperative Oncology Group (ECOG) Performance Status
Eastern Cooperative Oncology Group performance status and shifts from study entry to post
study entry assessment over time, and ECOG score frequency table over time will be 
summarized.  Shifts from study entry to the worst post study entry score will be tabulated by 
treatment arm.
5.11.6   Other Safety Assessments
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 MLN9708, e.g. analyses of TEAEs of clinical 
importance. Tables will be provided with a summary of the patient incidence of all TEAEs 
of clinical importance by PT, severity, and seriousness for each analysis set within each 
category of TEAEs of clinical importance.
6.   
CHANGES TO PLANNED ANALYSES FROM PROTOCOL
Reference materials for this statistical plan include Clinical Study Protocol C16019
Amendment 1 (Protocol Amendment dated 05April 2016), and Clinical Study Protocol 
C16019 Amendment 2 (Protocol Amendment dated 21April 2017).
7.   
PROGRAMMING CONSIDERATIONS
7.1   
Statistical Software 
SAS version 9.2 (or higher) will be used for all analyses.  
7.2   
Rules and Definitions
Patient populations are defined in Section 2.
Values at study entry are defined in Section 5.4.2.
8.   
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epidemiology. Epidemiology 2000; 11(5): 550-560.  
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Glimm E, Maurer W, Bretz F. Hierarchical testing of multiple endpoints in group 
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Huang Y, Hsu J; Hochberg's Step-Up Method: Cutting Corners Off Holm's Step-Down 
Method. Biometrika 2007; 94 (4): 965-975. doi: 10.1093/biomet/asm067