Clinical trial NCT02312258
Conditions: Multiple Myeloma
Keywords: Drug Therapy
Sponsor: Takeda
Start date: 2015-04-09; Completion date: 2022-08-26
Enrollment: 706 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine the effect of ixazomib maintenance therapy on progression free survival (PFS) compared with placebo, in participants with NDMM who have had a major response (complete response \[CR\], very good partial response \[VGPR\], or partial response \[PR\]) to initial therapy and who have not undergone SCT.

Detailed description:
The drug being tested in this study is called ixazomib citrate. Ixazomib citrate is being tested to slow progressive disease (PD) and improve overall survival in people who have NDMM who have had a major positive response to initial therapy and have not undergone SCT. This study will look at the effect of ixazomib citrate has on the length of time that participants are free of PD and their overall survival.

The study will enrol approximately 700 participants. Participants will be randomly assigned (by chance, like flipping a coin) in 3:2 ratio to Ixazomib or matching placebo groups-which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need):

* Ixazomib citrate initiates at 3 mg which will be escalated to 4 mg with cycle 5 day 1
* 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. The treatment period will be approximately 24 months (equivalent to 26 cycles) or until patients experience PD or unacceptable toxicities, whichever occurs first.

This multi-center trial will be conducted worldwide. The overall time to participate in this study is approximately 78 to 106 months. Participants will make 28 visits to the clinic during the treatment period and will continue to make follow-up visits every 4 weeks until the next line of therapy begins. Participants will also be contacted by telephone every 12 weeks after last treatment visit for a follow-up assessment.

Arms: arm 1: Ixazomib placebo-matching capsule, orally, once on Days 1, 8, and 15 of each 28-day cycle from Cycles 1 through 26. arm 2: Ixazomib 3 mg, capsule, orally, once on Days 1, 8, and 15 of each 28-day cycle from Cycles 1 to 4 that may have been escalated to 4 mg thereafter up to Cycle 26.
Interventions: intervention 1: Placebo intervention 2: Ixazomib
Intervention descriptions: intervention 1: Ixazomib placebo-matching capsules. intervention 2: Ixazomib capsules.

Protocol documents:
Prot_002.pdf: 
CLINICAL STUDY PROTOCOL 
NCT Number: 
Study Title: 
Study Number: 
NCT02312258
A Phase 3, Randomized, Placebo-Controlled, Double-Blind Study 
of Oral Ixazomib Maintenance Therapy After Initial Therapy in 
Patients With Newly Diagnosed Multiple Myeloma Not Treated 
With Stem Cell Transplantation
C16021
Protocol Version and Date: 
Version 9.0: 18-November-2021




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Rationale for Amendment 09
This document describes the changes to the protocol incorporating Amendment 09. The primary 
reason for this amendment is to change the legal entity name of the sponsor. In addition, the 
China-specific Protocol Amendment 06 of the Global study has been subsumed into this Global 
protocol amendment so that the China-specific version of the Global protocol amendment will 
no longer be needed. This change is not reflected in the Purposes for Amendment 09 below 
because the patients in China currently in the Global study are in progression-free survival 2 
(PFS2) follow-up; therefore, the changes originally necessitating a China-specific amendment 
do not affect these patients any longer. Note that this Global Amendment 09 does not apply to 
the China Continuation Study, the current protocol for which is Protocol Amendment 08.
Minor grammatical, editorial, formatting, and administrative changes not affecting the conduct 
of the study are included for clarification and administrative purposes only. 
For specific examples of changes in text and where the changes are located, see Section 15.14.
Purposes for Amendment 09
The purposes of this amendment are to:
1. Change the legal entity name of the sponsor.
2. Clarify language regarding procedures for reporting product complaints or medication
errors.
3. Clarify language in study conduct regarding the coronavirus disease 2019 (COVID-19)
pandemic.
4. Clarify local laboratory assessment recordings.


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PROTOCOL SUMMARY
Study Title: A Phase 3, Randomized, Placebo-Controlled, Double-Blind Study of Oral Ixazomib 
Maintenance Therapy After Initial Therapy in Patients With Newly Diagnosed Multiple Myeloma 
Not Treated With Stem Cell Transplantation
Number of Patients: Approximately 700 patients with newly diagnosed multiple myeloma 
(NDMM) who had a major response to initial therapy and who have not undergone stem cell 
transplantation (SCT)
Study Objectives
Note, assessment of several study objectives was completed at the time of the first interim analysis
(IA). Upon implementation of Amendment 07, data collected after the first IA will be used to assess 
overall survival (OS), progression-free survival 2 (PFS2), patient reported outcomes, and safety only. 
The full list of study objectives is retained here for reference.
Primary

To determine the effect of ixazomib maintenance therapy on progression-free survival 
(PFS), defined as the time from randomization to progressive disease (PD) or death from 
any cause, compared with placebo, in patients with NDMM who have had a major 
responsedefined as complete response (CR), very good partial response (VGPR), or 
partial response (PR)to initial therapy and who have not undergone SCT
Key Secondary

To determine the effect of ixazomib maintenance therapy on OS compared with 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 and on 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

To determine the effect of ixazomib maintenance therapy on PFS2, defined as the time 
from randomization to objective disease progression on next-line treatment or death 
from any cause

To determine the effect of ixazomib maintenance therapy on the time to next-line 
therapy

To determine the effect of ixazomib maintenance therapy on the time to end of next-line 
therapy

To determine the effect of ixazomib maintenance therapy on duration of next-line 
therapy

To assess the incidence of new primary malignancy in patients receiving ixazomib 
maintenance therapy

To evaluate the frequency of conversion from minimal residual disease (MRD) positive 
to MRD negative, or the maintenance of MRD negativity, using 8-color flow cytometry 


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
To assess the correlation between MRD status (detected using 8-color flow cytometry) 
and PFS and OS, using bone marrow aspirates

To determine the effect of ixazomib maintenance therapy on PFS and OS in high-risk 
cytogenetic patient groups characterized by individual or multiple cytogenetic 
abnormalities including, but not limited to, del17, t(4;14), or t(14;16) 

To determine the long-term safety and tolerability of ixazomib maintenance therapy

To assess 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 Core 30 (EORTC QLQ-C30) in patients who receive ixazomib 
maintenance therapy 

To assess the correlation between frailty status and PFS and OS in patients receiving 
ixazomib maintenance therapy

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, if it occurs, in 
patients receiving ixazomib maintenance therapy
Overview of Study Design: This is a phase 3, randomized, double-blind, placebo-controlled, 
multicenter study in patients with NDMM who have not undergone SCT. Patients who have not 
undergone SCT may not have done so because of frailty due to advanced age (eg, 65 years) or 
comorbidity or because they decline SCT for other reasons.
Patients must have received initial therapy, for 6 to 12 months, according to standard of care before 
study enrollment and have been treated to achieve a major response category (PR or better) that is 
judged to be their best response by the investigator/treating physician. Partial response, VGPR, or 
CR must be documented at screening, and patients must have met all additional inclusion/exclusion 
criteria. Eligible and consenting patients are to be randomized no later than 60 days after the last 
dose of initial therapy. Randomization will occur in a 3:2 ratio of ixazomib or matching placebo. 
Approximately 700 patients are planned to be enrolled in this study at approximately 200 sites 
worldwide. 
There are 4 stratification factors: initial therapy (proteasome-inhibitor–containing or not); 
International Staging System stage before initial therapy (stage I or II vs stage III); age at time of 
randomization (<75 vs 75 years); and response to initial therapy, as measured during screening (CR 
or VGPR vs PR).
Patients will receive blinded ixazomib or matching placebo capsules (both hereafter referred to as 
“study drug”) orally on Days 1, 8, and 15 of every 28-day cycle. The starting dose will be 3 mg of 
study drug, which—if tolerated during the first 4 cycles—will be escalated to 4 mg beginning with 
Cycle 5 Day 1. The Treatment period will be approximately 24 months (equivalent to 26 cycles [if 
no cycle delays], to the nearest complete cycle) or until patients experience PD or unacceptable 
toxicity, whichever occurs first. 
Clinical, laboratory, disease response, and MRD assessments will be made, as will HRQL 
assessments with an emphasis on tolerability and symptom burden. After documented PD, 
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 


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measured by the key and other secondary endpoints. There will be 2 IAs and 1 final analysis (FA) in 
the study. The first IA will be the FA (and only analysis) for PFS for statistical testing purposes. If 
the test for PFS is significant at the first IA, then OS will be tested at this first IA and at the 
subsequent IA, and at the FA if needed. An independent data monitoring committee will review 
safety and efficacy data at the IAs and safety data at regularly scheduled meetings. An independent 
review committee (IRC) will assess disease response and PD.
The first IA has been conducted (data cutoff date 12 August 2019) and the primary endpoint of PFS 
based on IRC assessment was statistically significant. As such, upon implementation of Amendment 
07, all central laboratory efficacy measures of response/progression are discontinued. Bone marrow 
aspirates for confirmation of CR or MRD status are no longer required. No further IRC response or 
progression evaluations will be performed; investigators should continue to assess disease 
response/progression according to International Myeloma Working Group criteria (including use of 
local efficacy laboratory measures) for documentation of initial disease progression and PFS2. All 
central laboratory assessments of safety are also discontinued; patients should be assessed and 
treated according to standard of care using local laboratory evaluations.
All patients will continue to be followed in the study Follow-up periods. After the EOT visit, all 
patients will be followed every 3 months (12 weeks) for each of the Follow-up periods, depending on 
their disease status and subsequent therapies (see the Schedule of Events). Patients will be contacted 
every 12 weeks until death or termination of the study by the sponsor.
Study Population: Adult patients with NDMM who have had 6 to 12 months of initial therapy that 
is standard of care, during which the patient was treated to “best response” (in the investigator’s 
judgment), with documented major response (PR, VGPR, or CR, according to International 
Myeloma Working Group criteria) and who have not undergone SCT.
Duration of Study: Patients will be treated for a maximum duration of approximately 24 months 
(26 cycles [if there are no cycle delays], to the nearest complete cycle) or until documented PD or 
intolerable toxicity, whichever occurs first.
Subsequent to the 24-month active Treatment period or removal from study therapy because of PD 
or toxicity, patients will be followed in the PFS, PD, PFS2, and OS Follow-up periods for clinical 
status, disease status, subsequent therapies, HRQL, new primary malignancy, and survival.
It is anticipated that this study will last for approximately 78 to 106 months, including a 42-month 
Enrollment period, a 24-month Treatment period, and an additional 12- to 40-month Follow-up 
period from the time at which the last patient has the opportunity to complete study therapy, 
depending on the death events for the final OS analysis. 




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STUDY ENDPOINT AND FOLLOW-UP PERIOD 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 start and end of next-line therapy, 
and duration of next-line therapy are other secondary and exploratory endpoints. 
* Duration=duration of next-line therapy, defined as the date of onset of next-line therapy through the date of the 
last dose of next-line therapy.


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SCHEDULE OF EVENTS
As of Amendment 07, the first interim analysis has been conducted and the primary endpoint of progression-free survival based on 
independent review committee (IRC) assessment was statistically significant. As such, the majority of study objectives and endpoints 
have been assessed and study procedures are streamlined for patients still on study. Upon implementation of Amendment 07, all 
central laboratory efficacy measures of response/progression are discontinued. Bone marrow aspirates for confirmation of complete 
response or minimal residual disease status are no longer needed. No further IRC response or progression evaluations will be 
performed; investigators should continue to assess disease response/progression according to International Myeloma Working Group
criteria (using local efficacy laboratory measures) for documentation of initial disease progression and progression-free survival 2. All 
central laboratory assessments of safety are also discontinued; patients should be assessed and treated according to standard of care 
using local laboratory evaluations.
For ease of study conduct, the Schedule of Events now presented has been modified according to protocol requirements to apply to the 
remainder of the study. Beyond the assessments noted here, patients still on study should be treated by the investigator according to 
the local- or country-specific standard of care.
The full Schedule of Events before Amendment 07 has been moved to Section 15.13. The pharmacokinetic (PK) sampling schedule 
has also been moved to Section 15.13, as PK sample collection is no longer applicable because patients have completed at least 
10 cycles of treatment.
Study Proceduresa
Treatment Period
28-Day Cycles
End of 
Treatmentb
Follow-up
PFS
PD
PFS2
OS
Cycle
Cycle Xa and Beyond
Every 12 Wk 
Until PD
Every 12 Wk 
After PD Until 
Next-Line 
Therapy
Every 12 Wk 
Until PD2 on 
Next-Line 
Therapy
Every 12 Wk 
After PD on 
Next-Line 
Therapy
Day
1
Window
±1 Wk
+1 Wk
±1 Wk
±1 Wk
±1 Wk
±1 Wk
Informed Consent (Reconsent)
Xc
Complete Physical Examination, 
including for PNd
X
Symptom-Directed Physical 
Examination, including for PNd
X
X
X
Vital Signsd
X
X
X
X


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Study Proceduresa
Treatment Period
28-Day Cycles
End of 
Treatmentb
Follow-up
PFS
PD
PFS2
OS
Cycle
Cycle Xa and Beyond
Every 12 Wk 
Until PD
Every 12 Wk 
After PD Until 
Next-Line 
Therapy
Every 12 Wk 
Until PD2 on 
Next-Line 
Therapy
Every 12 Wk 
After PD on 
Next-Line 
Therapy
Day
1
Window
±1 Wk
+1 Wk
±1 Wk
±1 Wk
±1 Wk
±1 Wk
Weightd
X
X
ECOG Performance Statusd
X
X
X
X
EORTC QLQ-C30e
X
X
X
X
X (twice only)
EORTC QLQ-MY20e
X (C7, 10, 13, 16, 19, 
22, 25)
X
X
X
X (twice only)
EQ-5D-5Le
X (C7, 10, 13, 16, 19, 
22, 25)
X
X
X
X
X
HU assessmente
X
X
X
X
X (twice only)
Investigator assessment of disease 
response/status (using local 
laboratory data)d
X
X
X
Xf
Ixazomib or placebo
Single dose on Days 1, 
8, and 15 of each cycle
Adverse event/serious adverse event 
reportingg
Recorded from the first dose of study 
drug through 30 days after last dose of 
study drugs
Concomitant 
medications/procedures
Recorded from the first dose of study 
drug through 30 days after last dose of 
study drug




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Tests and procedures should be performed on schedule, but unless otherwise specified, occasional changes are allowable within a 7-day window for holidays, 
vacations, and other administrative reasons or a longer window after discussion with the Takeda Development Center Americas, Inc (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. 
a
Follow this Schedule of Events at the start of the next full treatment cycle upon implementation of Amendment 07.
b
When a study patient has documented disease progression, the investigator should unblind the patient to determine the study treatment assignment and take 
this information into account in planning the patient’s second-line therapy. See Section 6.10 for more information.
c
Before dosing on Day 1 of the next full treatment cycle upon implementation of Amendment 07, patients must be reconsented. Patients who are in one of the 
Follow-up periods must also be reconsented. Consenting/reconsenting should be done in person. Remote consenting/reconsenting is permitted as long as the 
process adheres to site, IRB/IEC, and GCP standards and local regulations. 
d
Alternative methods for administering study procedures/assessments may be considered when it is not possible for the patient to come to the study site due to 
the COVID-19 pandemic. Alternative methods should be considered for performing the assessments by other means than the patient presenting to the clinic 
(eg, remote assessment, having laboratory assessment performed at a facility closer to the patient’s home). If any of the following study 
procedures/assessments is missed because a site visit is done remotely, the study procedure/assessment is waived: complete physical examination, symptom-
directed physical examination, weight, ECOG performance status, HU. Patients should otherwise be assessed by the investigator, with data recorded, 
according to standard of care. 
e
Patient-reported outcomes and HU assessment (eg, 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, the EORTC QLQ-C30, EORTC QLQ-MY20, and HU assessments should be done 
twice—ideally once approximately 12 weeks after the start of next-line therapy and again 12 weeks later. Patient-reported outcome questionnaires are 
preferred to be completed by patients in the clinic, but if needed due to 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-5L questionnaire may be administered over the telephone. HU data may be obtained over the telephone and/or via 
patient medical records, as needed.
f
Information about disease response/status should be collected during the PFS2 Follow-up period, until PD2 has occurred during next-line therapy.
g
When PN occurs, each subsequent monthly evaluation will record the grade of PN at that visit. (This is in contrast to other adverse events 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 the PN, 2) the start of a second-line alternative antineoplastic treatment, or 3) 6 months after PD 
has occurred, whichever occurs first.
h
A serum pregnancy test will be performed for women of childbearing potential at the End of Treatment visit, or more frequently as required per local 
regulations.
i
As of Amendment 07, all central laboratory efficacy measures of response/progression are discontinued. Investigators should continue to assess disease 
response/ progression according to International Myeloma Working Group criteria, using local efficacy laboratory measures, for documentation of initial 
disease progression, and PFS2 (see Section 7.4.13 and the Laboratory Manual). All central laboratory assessments of safety are also discontinued; patients 
should be assessed and treated according to standard of care using local laboratory evaluations. Local laboratory assessments are not recorded in the electronic 
data capture (EDC).
j
Blood samples (using local laboratory assessment) for serology will be used to measure antibody levels against measles, varicella-zoster virus, and tetanus 
and to quantify B cells, T cells, and natural killer cells.
k
Immunofixation is also to be done by the local laboratory to confirm CR (if the M-protein level is undetectable by protein electrophoresis in both serum and 
urine, the local laboratory will perform immunofixation testing in both serum and urine).


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TABLE OF CONTENTS
LIST OF TABLES....................................................................................................................16
LIST OF FIGURES...................................................................................................................16
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
Ongoing Studies of Ixazomib .............................................................................21
1.3.2
Overall Clinical Experience................................................................................23
1.3.3
Pharmacokinetics and Drug Metabolism ............................................................25
1.4
Study Rationale........................................................................................................26
1.4.1
Rationale for Investigating Maintenance Therapy in Multiple Myeloma.............26
1.4.2
Rationale for Placebo Control ............................................................................29
1.4.3
Rationale for Ixazomib Schedule and Dose ........................................................29
1.4.4
Rationale for Minimal Residual Disease Assessment..........................................32
1.4.5
Rationale for Blood-Based Biomarkers and Antibody Titers ..............................34
1.5
Potential Risks and Benefits.....................................................................................34
2.0
STUDY OBJECTIVES..................................................................................................36
2.1
Primary Objective....................................................................................................36
2.2
Key Secondary Objective.........................................................................................36
2.3
Other Secondary Objectives.....................................................................................36
2.4
Exploratory Objectives ............................................................................................37
3.0
STUDY ENDPOINTS...................................................................................................39
3.1
Primary Endpoint.....................................................................................................39
3.2
Key Secondary Endpoint..........................................................................................39
3.3
Other Secondary Endpoints......................................................................................39
3.4
Exploratory Endpoints .............................................................................................40
4.0
STUDY DESIGN..........................................................................................................41
4.1
Overview of Study Design.......................................................................................41
4.2
Number of Patients ..................................................................................................44
4.3
Duration of Study ....................................................................................................44
5.0
STUDY POPULATION................................................................................................45
5.1
Inclusion Criteria .....................................................................................................45
5.2
Exclusion Criteria ....................................................................................................46


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6.0
STUDY DRUG .............................................................................................................48
6.1
Study Drug Administration ......................................................................................48
6.2
Test Article (Ixazomib Capsules and Matching Placebo Capsules)...........................48
6.3
Dose-Modification Guidelines .................................................................................49
6.4
Criteria for Dose Modification (Delays, Reductions, and Discontinuations) .............49
6.4.1
Dose Adjustment................................................................................................49
6.4.2
Criteria for Toxicity Recovery Before Beginning the Next Treatment 
Cycle .................................................................................................................49
6.4.3
Study Drug Dose Modification for Hematologic Toxicities ................................50
6.4.4
Study Drug Dose Modification for Nonhematologic Toxicities ..........................51
6.5
Criteria for Dose Escalation at Cycle 5.....................................................................52
6.6
Excluded Concomitant Medications and Procedures ................................................52
6.7
Permitted Concomitant Medications and Procedures................................................53
6.8
Precautions and Restrictions ....................................................................................53
6.9
Management of Clinical Events ...............................................................................54
6.10
Blinding and Unblinding..........................................................................................56
6.11
Description of Investigational Agents ......................................................................57
6.12
Preparation, Reconstitution, and Dispensation..........................................................57
6.13
Packaging and Labeling ...........................................................................................58
6.14
Storage, Handling, and Accountability.....................................................................58
6.15
Other Protocol-Specified Materials ..........................................................................59
7.0
STUDY CONDUCT......................................................................................................60
7.1
Study Personnel and Organizations ..........................................................................60
7.2
Arrangements for Recruitment of Patients................................................................60
7.3
Treatment Group Assignments.................................................................................60
7.4
Study Procedures .....................................................................................................60
7.4.1
Informed Consent...............................................................................................61
7.4.2
Patient Demographics ........................................................................................61
7.4.3
Medical History .................................................................................................61
7.4.4
Physical Examination.........................................................................................62
7.4.5
Vital Signs, Body Weight, and Height................................................................62
7.4.6
Eastern Cooperative Oncology Group Performance Status .................................62
7.4.7
Frailty Status......................................................................................................63
7.4.8
Pregnancy Test...................................................................................................63
7.4.9
Concomitant Medications and Procedures..........................................................63
7.4.10 Adverse Events ..................................................................................................63
7.4.11 Enrollment .........................................................................................................63
7.4.12 Electrocardiogram..............................................................................................64


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7.4.13 Clinical Laboratory Evaluations .........................................................................64
7.4.14 Health Utilization Data Collection......................................................................66
7.4.15 Quality of Life Assessment (European Organization for Research and 
Treatment of Cancer) .........................................................................................66
7.4.16 Utility Measurement...........................................................................................67
7.4.17 Bone Marrow Aspiration....................................................................................67
7.4.18 Blood-Based Biomarker Analyses......................................................................68
7.4.19 Imaging Assessments.........................................................................................69
7.4.20 Quantification of M-Protein ...............................................................................69
7.4.21 Quantification of Immunoglobulins....................................................................69
7.4.22 Serum Free Light Chain Assay...........................................................................69
7.4.23 Immunofixation of Serum and Urine ..................................................................69
7.4.24 Disease Response Assessment............................................................................70
7.4.25 Pharmacokinetic Measurements .........................................................................71
7.4.26 Follow-up Assessment for Progression-Free Survival, Progressive 
Disease, Progression-Free Survival 2, and Overall Survival................................71
7.5
Unscheduled Visits ..................................................................................................72
7.6
Study Compliance....................................................................................................72
7.7
Completion of Treatment .........................................................................................72
7.8
Completion of Study................................................................................................72
7.9
Discontinuation of Treatment With Study Drug .......................................................73
7.10
Withdrawal of Patients from Study ..........................................................................73
8.0
STATISTICAL AND QUANTITATIVE ANALYSES..................................................74
8.1
Statistical Methods...................................................................................................74
8.1.1
Determination of Sample Size............................................................................74
8.1.2
Randomization and Stratification .......................................................................75
8.1.3
Populations for Analysis ....................................................................................76
8.1.4
Procedures for Handling Missing, Unused, and Spurious Data ...........................76
8.1.5
Demographic and Baseline Characteristics.........................................................76
8.1.6
Efficacy Analysis...............................................................................................76
8.1.7
Analyses of Patient-Reported Outcomes and Health Economics.........................79
8.1.8
Pharmacokinetics/Pharmacodynamics/Biomarkers.............................................80
8.1.9
Safety Analysis ..................................................................................................81
8.1.10 Interim Analyses................................................................................................82
9.0
STUDY COMMITTEES ...............................................................................................85
9.1
Steering Committee .................................................................................................85
9.2
Independent Review Committee ..............................................................................85
9.3
Independent Data Monitoring Committee ................................................................85


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10.0
ADVERSE EVENTS.....................................................................................................86
10.1
Definitions...............................................................................................................86
10.1.1 Pretreatment Event Definition ............................................................................86
10.1.2 Adverse Event Definition...................................................................................86
10.1.3 Serious Adverse Event Definition ......................................................................86
10.2
Procedures for Recording and Reporting Adverse Events and Serious 
Adverse Events........................................................................................................87
10.3
Monitoring of Adverse Events and Period of Observation........................................88
10.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events .........89
11.0
ADMINISTRATIVE REQUIREMENTS ......................................................................90
11.1
Good Clinical Practice .............................................................................................90
11.2
Data Quality Assurance ...........................................................................................90
11.3
Electronic Case Report Form Completion ................................................................90
11.4
Study Monitoring.....................................................................................................90
11.5
Ethical Considerations .............................................................................................91
11.6
Patient Information and Informed Consent...............................................................91
11.7
Patient Confidentiality .............................................................................................91
11.8
Investigator Compliance ..........................................................................................91
11.9
On-site Audits..........................................................................................................92
11.10 Investigator and Site Responsibility for Drug Accountability...................................92
11.11 Product Complaints and Medication Errors (Including Overdoses)...........................92
11.12 Closure of the Study.................................................................................................92
11.13 Record Retention .....................................................................................................93
12.0
USE OF INFORMATION.............................................................................................94
13.0
INVESTIGATOR AGREEMENT.................................................................................95
14.0
REFERENCES..............................................................................................................96
15.0
APPENDICES.............................................................................................................103
15.1
Multiple Myeloma Diagnostic Criteria...................................................................103
15.2
Eastern Cooperative Oncology Group Scale for Performance Status ......................103
15.3
Cockcroft-Gault Equation ......................................................................................104
15.4
Steroid Equivalent Doses .......................................................................................104
15.5
ISS Staging Criteria ...............................................................................................105
15.6
Charlson Comorbidity Scoring System Without Age Weighting ............................105
15.7
Activities of Daily Living Index.............................................................................106
15.8
Instrumental Activities of Daily Living Index ........................................................107
15.9
European Organization for Research and Treatment of Cancer (EORTC 
QLQ-C30 (version 3).............................................................................................108


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15.10 European Organization for Research and Treatment of Cancer (EORTC) 
Multiple Myeloma Module (QLQ-MY20)..............................................................110
15.11 EQ-5D-5L..............................................................................................................112
15.12 Response Criteria...................................................................................................115
15.13 Full Schedule of Events and PK Sampling Schedule (Schedules Prior to 
Implementation of Amendment 07)........................................................................116
15.14 Detailed Description of Amendments to Text .........................................................124
LIST OF TABLES
Table 1-1   
Most Common Treatment-Emergent Adverse Events in Ixazomib Studies, 
as of 27 March 2014...........................................................................................24
Table 6-1   
Study Drug Dose Adjustments ...........................................................................49
Table 6-2   
Study Drug Dose Modification for Hematologic Toxicities ................................50
Table 6-3   
Study Drug Dose Modification for Nonhematologic Toxicities ..........................51
Table 6-4   
Criteria for Study Drug Retreatment and Cycle Delays Subsequent to 
Hematologic and Nonhematologic Toxicities .....................................................52
Table 6-5   
Ixazomib Capsule Size and Color.......................................................................57
Table 7-1   
Response Assessment.........................................................................................70
LIST OF FIGURES
Figure 1-1   
Relationship Between Clinical Benefit (Stable Disease) From 
Single-Agent Ixazomib and Adverse Events (Grade 2 for 
Nonhematologic and Grade 3 for Hematologic) and AUC (N=44) in 
Patients With Relapsed/Refractory Multiple Myeloma .......................................31


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LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS
Abbreviation
Term
AE
adverse event
AL amyloidosis
(amyloid) light-chain amyloidosis
ANC
absolute neutrophil count
AUC
area under the curve
BCRP
breast cancer resistance protein
best response
the best response to initial therapy maintained for 2 cycles after the M-protein nadir 
is reached (enrollment criterion for this study)
BMA
bone marrow aspirate
CI
confidence interval
COVID-19
coronavirus disease 2019
CR
complete response
CT
computed tomography
CYP
cytochrome P450
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EORTC QLQ-MY20
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire Multiple Myeloma Module
EORTC QLQ-C30
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire Core 30
EOT
End of Treatment (visit)
EQ-5D-5L
5-Level classification system of the EuroQol 5-Dimensional Health Questionnaire
ESMO
European Society for Medical Oncology
FA
final analysis
FIRST
Study to Determine Efficacy and Safety of Lenalidomide Plus Low-dose 
Dexamethasone Versus Melphalan, Prednisone, Thalidomide in Patients With 
Previously Untreated Multiple Myeloma
FISH
fluorescence in situ hybridization
GCP
Good Clinical Practice
G-CSF
granulocyte colony stimulating factor
GI
gastrointestinal
GIMEMA
Italian Group for Hematologic Diseases in Adults
HRQL
health-related quality of life


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Abbreviation
Term
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
immunomodulatory drugs
IMWG
International Myeloma Working Group
IRB
institutional review board
IRC
independent review committee
ISS
International Staging System
ITT
intent-to-treat
IV
intravenous(ly)
IXRS
interactive voice/web response system
K-M
Kaplan-Meier
len/dex
lenalidomide and dexamethasone
MedDRA
Medical Dictionary for Regulatory Activities
MM
multiple myeloma
MP
melphalan and prednisone
MPT
melphalan/prednisone/thalidomide
MRD
minimal residual disease
MRI
magnetic resonance imaging
MRP2
multidrug resistanceassociated protein
MTD
maximum tolerated dose
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NDMM
newly diagnosed multiple myeloma
NFB
nuclear factor kappa-light chain enhancer of activated B-cells
NK
natural killer (cells)
OS
overall survival
PAD
bortezomib, Adriamycin, and dexamethasone
PD
progressive disease (disease progression)
PD2
second progressive disease (on next-line therapy)
PET
positron emission tomography


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Abbreviation
Term
PFS
progression-free survival, defined as the time from randomization to progressive 
disease or death from any cause
PFS2
progression-free survival 2, defined as the time from randomization to objective 
disease progression on next-line treatment or death from any cause
Pgp
P-glycoprotein
PI
proteasome inhibitor
PK
pharmacokinetic(s)
PN
peripheral neuropathy
PR
partial response
Rd
Revlimid (lenalidomide) and dexamethasone
RP2D
recommended phase 2 dose
RRMM
relapsed and/or refractory multiple myeloma
SAE
serious adverse event
SAP
statistical analysis plan
SCT
stem-cell transplantation
SD
stable disease
SNP
single-nucleotide polymorphism
Takeda
Takeda Development Center Americas, Inc
TEAE
treatment-emergent adverse event
TMA
thrombotic microangiopathy
TTNT
time to next-line therapy
TTP
time to progression
ULN
upper limit of the normal range
US
United States
VGPR
very good partial response
VZV
varicella-zoster virus


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1.0
BACKGROUND AND STUDY RATIONALE
1.1
Scientific Background
1.1.1
Disease Under Treatment
Multiple myeloma (MM) is a B-cell tumor of malignant plasma cells within the bone 
marrow, which accumulate in the bone marrow and result in bone marrow failure, bone 
destruction, hypercalcemia, and renal failure. Multiple myeloma constitutes approximately 
1% of all reported neoplasms and approximately 13% of hematologic cancers 
worldwide.[10] In the Americas and Western European countries, approximately 5 to 7 new 
cases of MM are diagnosed per 100,000 people each year.[10-12] Although less common in 
Asian countries, incidences of MM there 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.[13,14]
Multiple myeloma is sensitive to many cytotoxic drugs, including alkylating agents, 
anthracyclines, and corticosteroids, for both initial treatment and relapsed disease. Over the 
past 2 decades, significant achievements have been made in expanding treatment options for 
MM with novel therapies such as thalidomide, bortezomib, and lenalidomide and stem cell 
transplantation (SCT). These regimens have extended progression-free survival (PFS) and 
time to progression (TTP).[15-19]
Although autologous SCT has been shown to be associated with improved survival, 
historically this therapy has been limited to the younger (<65 years) MM population 
(because the risk of morbidity/mortality increases with increasing age) or those with 
significant comorbidities. However, as a result of improvements in SCT procedures and 
supportive care, and the recognition that some elderly patients are sufficiently vigorous to 
tolerate autologous SCT, it is increasingly common to provide autologous SCT to patients 
65 years of age or older. Nonetheless, because of the advanced age of MM patients (in the 
United States [US], the median age at diagnosis is 69 years), or because of significant 
comorbidities, the majority of patients are not considered candidates for autologous SCT and 
therefore do not benefit from the survival-prolonging transplant.
Despite advances in therapy and the advent of a newer generation of agents such as 
carfilzomib and pomalidomide, in almost all circumstances, this disease remains incurable, 
and there remains 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. The disease ultimately becomes refractory to approved 
therapies, leaving patients with no alternative treatment options. In an effort to expand the 
therapeutic armamentarium against MM with agents that target the proteasome, Takeda 
Development Center Americas, Inc (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 (IV) and subcutaneous VELCADE® (bortezomib) for Injection, the 
first-in-class, small molecule proteasome inhibitor developed by Takeda. Building on the


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efficacy seen with bortezomib in MM and other hematologic malignancies, Takeda has 
subsequently developed oral ixazomib to improve the pharmacology of the agent and 
provide a more convenient mode of drug administration.
Like VELCADE, ixazomib is a modified peptide boronic acid; specifically, ixazomib citrate 
is the citrate ester of the biologically active dipeptide boronic acid, ixazomib. Formulated to 
improve the chemical properties of ixazomib for clinical delivery, in physiological 
conditions, ixazomib citrate rapidly hydrolyzes to ixazomib, the active form that potently, 
reversibly, and selectively inhibits the proteasome. Ixazomib preferentially binds the 5 site 
of the 20S proteasome, similar to VELCADE; at higher concentrations, ixazomib also 
inhibits the activity of the 1 and 2 sites. Ixazomib demonstrates a faster dissociation rate 
from the proteasome than VELCADE, which may result in enhanced tumor penetration. 
Ixazomib exhibits antitumor activity in a broader range of tumor xenografts than VELCADE.
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 is the first oral proteasome inhibitor in clinical trials and is under evaluation for 
safety, tolerability, PK, pharmacodynamics, and efficacy. The clinical benefit of ixazomib 
continues to be studied in a comprehensive and global development plan that involves 
multiple company-sponsored clinical studies in several indications. 
Although 2 studies of IV ixazomib have been performed, the rest of the studies of ixazomib 
have used the oral formulation, which is the formulation planned for commercialization. 
Throughout this section and the remainder of this protocol, the ixazomib formulation 
described will be the oral formulation.
As of 27 March 2014, 1287 patients have been enrolled in clinical trials of oral ixazomib 
and have safety data. A total of 491 patients have received ixazomib in open-label, phase 1/2 
studies, and 796 patients have been treated in the phase 3, pivotal studies (with ixazomib or 
placebo in Study C16010 in relapsed/refractory MM [RRMM] and Study C16014 in newly 
diagnosed MM [NDMM], and counting the ixazomib arm only in Study C16011 in light 
chain [AL] amyloidosis). 
1.3.1
   
Ongoing Studies of Ixazomib 
Eighteen clinical studies of ixazomib are ongoing, including the 4 pivotal, phase 3 studies. 
To date, the development of ixazomib has focused on MM (RRMM and NDMM), with 
additional trials in a different yet related orphan disease, AL amyloidosis. These indications 
are currently being studied in ongoing, phase 3 clinical studies. Additionally, multiple 
research paths are being considered or are advancing to evaluate this drug across a number 
of treatment settings, in combination with commonly used agents, and in other therapeutic 
areas in oncology (solid tumors, lymphomas) and non-oncology (lupus nephritis). The 
strategy for later-stage development of ixazomib in solid tumors and advanced lymphomas 


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will be influenced by the antitumor activity and pharmacodynamic response observed during 
phase 1 development of ixazomib and other VELCADE lymphoma studies. Patient selection 
strategies may also be explored to maximize the efficacy of ixazomib in selected patient 
populations. 
The primary focus of each of the phase 1 clinical studies was the characterization of the 
safety and tolerability of the oral formulation of the drug, determination of the maximum 
tolerated dose (MTD) and a recommended phase 2 dose (RP2D), and establishment of the 
PK and pharmacodynamic properties. The ongoing clinical studies are exploring 
twice-weekly dosing in a 21-day cycle and weekly dosing in a 28-day cycle. 
Three studies (C16003, C16004, and C16007) included specific expansion cohorts to further 
evaluate antitumor activity and safety at the MTD/RP2D. The expansion cohorts in the 
2 MM studies (C16003 and C16004) were conducted in patients with RRMM who represent 
the highly heterogeneous population seen in current clinical practice in an attempt to 
understand the possible activity of ixazomib in patients with MM that have been previously 
exposed to several lines of agents, including agents also targeting the proteasome. The 
expansion phase in the AL amyloidosis study (C16007) was open to cohorts of patients who 
were either naïve to, or had been previously exposed to, proteasome inhibitors to better 
understand activity and safety. Two phase 1 studies are exploring the PK and safety of 
ixazomib in patients with RRMM in Asia (Study C16013, a PK study of ixazomib in 
combination with lenalidomide/dexamethasone [len/dex] after 1-3 prior lines of therapy) and 
Japan (Study TB-MC010034, 2 cohorts, of ixazomib single agent and in combination with 
len/dex). 
Three of the clinical studies in frontline MM (Studies C16005, C16006, and C16008) were 
designed with a phase 2 portion to explore relevant combinations with ixazomib such as 
len/dex or melphalan and prednisone (MP); the main purposes of the phase 2 portions of 
these studies are to characterize preliminary efficacy and safety profiles. The phase 2 
portions also explore quality of life, the documentation of minimal residual disease (MRD) 
in patients with a complete response (CR), and response in the subset of high-risk patients as 
determined by cytogenetics. 
Another phase 2 study is C16020, an open-label study of ixazomib, cyclophosphamide, and 
dexamethasone in adult patients with NDMM or RRMM requiring systemic treatment; the 
patients with NDMM must be treatment naïve and must not have undergone high-dose 
therapy followed by SCT because of age (≥65 years) or comorbidities (or they have declined 
for other reasons). The primary objective of this study is combined response rate. It is 
anticipated that approximately 70 patients will enroll in more than 20 sites worldwide.
Four phase 3, randomized, controlled, multicenter studies are ongoing:

Study C16010 is a placebo-controlled, double-blind study in which ixazomib is used 
in combination with len/dex in patients with RRMM who are enrolled in the 
treatment arm of the study. The study is being conducted at approximately 150 sites 
worldwide with an anticipated enrollment of approximately 703 patients. The 
primary endpoint is PFS. 

Study C16011 is an open-label, safety and efficacy study of dexamethasone plus 
ixazomib versus physician’s choice of a currently available treatment regimen 


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administered to patients with relapsed or refractory AL amyloidosis. The study is 
being conducted at approximately 65 sites worldwide with an anticipated enrollment 
of approximately 248 patients. There are 2 primary objectives in this study: 
hematologic response (partial response [PR]+very good partial response 
[VGPR]+CR) and 2-year rate of vital organ deterioration or death. 

Study C16014 is a double-blind study of len/dex plus ixazomib or placebo in patients 
with NDMM who are treatment naïve and who have not undergone high-dose 
therapy followed by SCT because of age (≥65 years) or comorbidities (or they have 
declined for other reasons). The primary objective of this study is PFS. This study is 
being conducted at 155 sites worldwide with anticipated enrollment of 
approximately 701 patients.

Study C16019 is a phase 3, randomized, placebo-controlled, double-blind study in 
adult patients with NDMM who have had a major response (PR or better) to 
standard-of-care induction therapy followed by autologous SCT. The primary 
endpoint of this study is PFS, with overall survival (OS) as the key secondary 
endpoint. The study is being conducted at more than 200 sites worldwide with an 
anticipated enrollment of approximately 652 patients.
All 4 studies also explore the impact of treatment on quality of life.
To further investigate the clinical pharmacology of ixazomib, 4 additional phase 1 clinical 
pharmacology studies are ongoing, 2 in special populations. Study C16009 was a 5-arm 
study designed to assess drug-drug interactions (cytochrome P450 [CYP] 3A strong inducers 
and inhibitors), food effect, and relative bioavailability (and safety and tolerability). This 
study was conducted in patients with advanced nonhematologic malignancy or lymphoma 
for which no effective standard treatment is available. Study C16016 is a study of absorption, 
distribution, metabolism, and excretion in patients with advanced solid tumors or lymphoma. 
The study is designed to assess mass balance, PK, total radioactivity, metabolism, and 
elimination. The 2 clinical pharmacology studies in special populations aim specifically to 
evaluate the effects of severe renal impairment/end-stage renal disease necessitating dialysis 
(C16015) or moderate/severe hepatic impairment (C16018) on the PK of ixazomib in 
patients with cancer. These studies have been designed with the overall strategic objective of 
providing PK data to inform development of scientifically guided ixazomib dosing 
guidelines for physicians treating these special patient populations. 
The current Study C16021 is the fifth global, phase 3 trial of ixazomib and the second 
exploring single-agent ixazomib in a maintenance setting.
1.3.2
   
Overall Clinical Experience
Clinical safety data include experience from patients who received multiple ixazomib 
treatment cycles followed by treatment-free periods and from patients who reduced or 
discontinued treatment. The emerging safety profile indicates that the adverse events (AEs) 
associated with ixazomib administration are generally manageable and reversible with dose 
modification and supportive care. Although some of these potential toxicities may be severe, 
they can be managed by clinical monitoring and standard medical intervention. The weekly 


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schedule that will be evaluated in this trial has been determined to be tolerable in other trials 
of ixazomib in MM. 
Ixazomib shows early signs of antitumor activity, as evidenced by at least a 50% reduction 
in disease burden in some MM patients, including patients who have been heavily pretreated 
and those who have been newly diagnosed with MM, and prolongs stabilization of the 
underlying disease in others, across all ongoing trials. The preliminary findings are 
favorable when considering historical and currently available therapies for the patient 
populations evaluated. Though additional data are needed to characterize the clinical benefit 
of this drug, the emerging data support expanded development of ixazomib for the treatment 
of patients with advanced malignancy. Weekly dosing appears to enable delivery of higher 
ixazomib doses for a longer period of time as compared with twice-weekly dosing.
As of 27 March 2014, the most common treatment-emergent AEs (TEAEs) in the Overall 
Safety population receiving ixazomib are shown in Table 1-1. 
Table 1-1   
Most Common Treatment-Emergent Adverse Events in Ixazomib 
Studies, as of 27 March 2014
Treatment-
Emergent 
Adverse Event
Overall 
Safety 
Population 
(n=1287)
Phase 1 or 2 (n=491)a
Phase 3 Studies (n=796)b
All
Single 
Agent 
(n=221)
Combin
ation 
Agent 
(n=220)
C16010
(Ixazomib 
or Placebo)
n=683
C16011
(Ixazomib 
Arm)
n=21
C16014
(Ixazomib 
or Placebo)
n=92
Number (%) of Patients
Diarrhea
423 (33)
230 (47)
95 (43)
116 (53)
179 (26)
2 (10)
12 (13)
Nausea
379 (29)
230 (47)
117 (53)
93 (42)
128 (19)
1 (5)
20 (22)
Fatigue
395 (31)
223 (45)
114 (52)
99 (45)
152 (22)
4 (19)
16 (17)
Rash (all rash 
terms)c
349 (27)
197 (40)
73 (33)
117 (53)
126 (18)
3 (14)
23 (25)
Constipation
324 (25)
134 (27)
50 (23)
76 (35)
164 (24)
3 (14)
23 (25)
Vomiting
277 (29)
181 (37)
90 (41)
73 (33)
80 (12)
2 (10)
14 (15)
Anemia
262 (20)
161 (33)
72 (33)
78 (35)
92 (13)
2 (10)
5 (5)
Thrombo-
cytopenia
260 (20)
114 (23)
48 (22)
57 (26)
129 (19)
0
19 (21)
a For phase 1 or 2 studies, single agent studies consist of C16003, C16004, C16007, and C16009; 
combination studies consist of C16005, C16006, C16008, C16013, and C16020; and “all” consists of 
single agent and combination studies and C16015, C16017, C16018, and TB_MC010034.
b For phase 3 studies, in C16010 and C16014, all patients also receive lenalidomide and dexamethasone; in 
C16011, ixazomib patients also receive dexamethasone. 
c There is some variety in the characterization and causality of reported rash, resulting in different Preferred 
Terms to describe it; the data here refer to all rash Preferred Terms. Not included here are cases classified 
as pruritus, erythemas, papulosquamous conditions, or exfoliative conditions. When these other terms are 
included, rash is generally 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.


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The dose escalation phases of most trials reported in the IB have now completed enrollment, 
and gastrointestinal (GI) symptoms were found to be the common dose-limiting toxicities 
when the use of prophylactic anti-emetics was not permitted per protocol. In the expansion 
cohorts or phase 2 cohorts (per each study), the incidence and severity of GI symptoms is 
expected to be mitigated by the use of the RP2D, the ixazomib dose that was 1 dose level 
lower than the MTD (per each study), and standard clinical use of anti-emetics and 
antidiarrheal medications as deemed appropriate. Prophylactic anti-emetics have not been 
required as with other agents but (as outlined in Section 6.9) have been used according to 
standard practice and are effective.
Additional detailed information regarding the clinical experience of ixazomib may be found 
in the IB.
1.3.3
   
Pharmacokinetics and Drug Metabolism
Clinical PK data show that ixazomib has multi-exponential disposition with a rapid initial 
phase that is largely over by 4 hours. Ixazomib is rapidly absorbed with a median 
single-dose first time of occurrence of maximum (peak) ixazomib concentration of 
approximately 0.5 to 2.0 hours and a terminal disposition half-life after multiple dosing of 
approximately 5 to 7 days.[20] Results of a population PK analysis (N=137) show that there 
is no relationship between body surface area or body weight and clearance. Also, on the 
basis of stochastic simulations for fixed dose, exposures are independent of the individual 
patient’s body surface area.[21] 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.
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 CYPs and non-CYP enzymes/proteins. At clinically relevant 
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 recently concluded, 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) [22]; 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 


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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 recently completed DDI study, co-administration of ixazomib with rifampin decreased 
ixazomib Cmax by 54% and AUC by 74% (Study C16009, Arm 4).[22] 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
1.4.1
   
Rationale for Investigating Maintenance Therapy in Multiple Myeloma
Multiple myeloma is generally considered an incurable disease. Nonetheless, high-dose 
chemotherapy incorporating autologous SCT has been found to prolong PFS and OS in 
patients who are sufficiently fit to undergo the procedure. Although the introduction of 
modern agents, including immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs) 
such as thalidomide, VELCADE, lenalidomide, carfilzomib, and pomalidomide, has 
improved the survival of both patients who do and those who do not undergo SCT, OS 
among patients not receiving SCT remains inferior to OS among patients receiving SCT. For 
the former population, additional treatment strategies beyond initial therapy will be needed 
to improve survival. 
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 in prolonging PFS or OS or improving quality of life without 
shortening survival, and a favorable benefit:risk ratio.
1.4.1.1
   
History of Maintenance Therapy in Multiple Myeloma
The role of maintenance therapy in both the post-SCT and non-SCT settings has been 
extensively explored, but a positive benefit:risk profile has yet to be confirmed for 
maintenance therapy. 
Older Agents
A detailed review of the history of the clinical trials of maintenance therapy was published 
in 2012 by the International Myeloma Working Group (IMWG).[23] Initially, trials of 


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maintenance therapy consisted of continuation of chemotherapy with 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 because of the 
unfavorable safety profile. The IMiD thalidomide has been extensively studied as a single 
agent or in combination maintenance therapy in both patients undergoing and those not 
undergoing SCT. A progression-free survival benefit was generally observed across studies. 
Overall survival benefits were observed in some studies,[24] whereas a decrement in OS 
was observed in others.[25] High rates of discontinuation due to toxicity were observed in 
all studies. In addition, patients with high-risk cytogenetics had no incremental benefit with 
thalidomide maintenance therapy,[26,27] and in 1 study, patients experienced a decrement 
in benefit.[27]
Newer Agents
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 VELCADE have been 
conducted, both as part of a combination maintenance regimen and in direct comparison
with thalidomide.[28-30] In the GIMEMA (Italian Group for Hematologic Diseases in 
Adults) trial, maintenance with bortezomib and thalidomide (after bortezomib/melphalan/ 
prednisone/thalidomide induction) showed both PFS and OS benefit over bortezomib/ 
melphalan/prednisone induction with no maintenance therapy.[28]
The phase 3 HOVON/GMMG study investigated induction therapy leading to autologous 
SCT and subsequent maintenance therapy in patients with MM.[29] Induction therapy with 
the regimen of bortezomib, Adriamycin, and dexamethasone (PAD), followed by 
bortezomib maintenance was evaluated and compared with induction therapy using 
vincristine, Adriamycin, and dexamethasone 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 del17p13. However, the induction regimens in the 2 arms were 
different such that only the bortezomib maintenance arm received bortezomib during 
induction therapy, so the benefit of bortezomib as maintenance alone could not be 
independently assessed.
Additionally, lenalidomide has been assessed as maintenance therapy in 
3 placebo-controlled trials.[5,31,32] While all studies demonstrated a significant PFS 
advantage with lenalidomide maintenance therapy, only the Cancer and Leukemia Group B 
trial showed a possible OS benefit, and data regarding the impact of lenalidomide 
maintenance on the duration of response to subsequent therapy were limited.[32] In addition, 
offsetting the potential clinical benefit of lenalidomide maintenance was the increased 
incidence of new primary malignancies. Therefore, positive benefit:risk could not be 
established during the Committee for Medicinal Products for Human Use review to date.[33]
To understand whether ixazomib maintenance therapy affects the incidence of new primary 


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malignancies, the proposed trial includes a secondary endpoint assessing the incidence of 
new primary malignancies.
Recent Findings
Most recently, in 2013, the results of the phase 3 MM-020 study (Study to Determine 
Efficacy and Safety of Lenalidomide Plus Low-dose Dexamethasone Versus Melphalan, 
Prednisone, Thalidomide in Patients With Previously Untreated Multiple Myeloma
[FIRST]) were reported at the American Society of Hematology annual meeting. This study 
supports the concept of maintenance therapy. “Continuous” Revlimid and dexamethasone 
(Rd) was compared with fixed-duration Rd (for 18 cycles, or ~18 months) and 
fixed-duration melphalan/prednisone/thalidomide (MPT; for 12 cycles, or ~18 months). 
Continuous Rd showed improved PFS compared with fixed-duration Rd and MPT. In 
addition, there was rapid increase in PFS events after Rd maintenance therapy (both 
continuous and fixed duration) was stopped. Overall survival, however, was not statistically 
different among the arms; therefore, the clinical benefit of continuous therapy was not 
established, and the option of no maintenance followed by salvage therapy at relapse 
remains an alternative. Because the study did not compare continuous MPT with continuous 
Rd, it cannot be determined whether the apparent PFS advantage of continuous Rd is a 
phenomenon unique to lenalidomide-based therapy or whether continuous therapy is 
beneficial with other treatment choices.
1.4.1.2
   
Current Use of Maintenance Therapy in Multiple Myeloma
The use of maintenance therapy in clinical practice remains limited globally, with no 
universally accepted standard of care regarding maintenance therapy in non-SCT patients 
with NDMM. CancerMPact® surveys conducted by Kantar Health in 2012[34,35] found that 
maintenance therapy was administered to less than half of patients not undergoing SCT in 
most regions (Western European Union, 39.1%; US, 49.9%, Japan, 45.2%; and China, 
74.9%). This is most likely due to the lack of an evidence-based positive benefit:risk profile 
for drugs in the maintenance setting. Although lenalidomide is approved by the US Food 
and Drug Administration for treatment of patients with RRMM, the drug is currently 
prescribed off-label as maintenance therapy for about 50% of patients after SCT.
1.4.1.3
   
Current Guidance for Maintenance Therapy in Multiple Myeloma
To date, no maintenance therapy has received regulatory approval for use in patients with 
MM,[23] and a true standard of care has not been adopted. Current US National 
Comprehensive Cancer Network guidelines (version 2.2014)[36] support the use of 
VELCADE, lenalidomide, and thalidomide maintenance therapies while also highlighting 
concerns regarding cumulative toxicity with thalidomide therapy and an increased incidence 
of new primary malignancies with lenalidomide; VELCADE maintenance was described as 
being well tolerated. In contrast, current IMWG guidelines for non-SCT patients with 
NDMM[37] and European Society for Medical Oncology (ESMO) guidelines for the 
treatment of MM[38] do not recommend the routine use of maintenance therapy. The 2014 
IMWG consensus statement for the management, treatment, and supportive care of patients 
with MM not eligible for standard autologous SCT states, “The routine use of maintenance 
in transplantation-ineligible patients is not yet validated.”[39] The guidelines also point out 


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that the role of other novel agents in this setting is currently under evaluation. The ESMO 
2013 guidelines for the treatment of MM[38] state that for patients not undergoing SCT, 
“systematic maintenance therapy is [also] not recommended in elderly patients.”
In conclusion, maintenance therapy has not yet been proven to be a superior treatment 
strategy compared with the current paradigm of salvage therapy at relapse. Together with 
the lack of a universally accepted maintenance standard of care with a demonstrated survival 
benefit for maintenance therapy, there is justification to conclude that a phase 3, 
placebo-controlled trial is an appropriate approach for determining the efficacy of 
single-agent ixazomib maintenance therapy in the MM population not receiving SCT.
1.4.2
   
Rationale for Placebo Control
Maintenance therapy has not yet been proven to be a superior treatment strategy in patients 
not undergoing SCT compared with the current paradigm of salvage therapy at relapse. The 
lack of a universal maintenance standard of care and an evidence-based comparator with a 
demonstrated survival benefit for maintenance therapy in patients not undergoing SCT, 
together with the inclusion of optimal palliative care for all study participants and the 
availability of second-line therapy to all study participants after withdrawal from the study 
for any reason, provides a strong justification to run this placebo-controlled trial to 
determine the efficacy and safety of single-agent ixazomib maintenance therapy. 
1.4.3
   
Rationale for Ixazomib Schedule and Dose 
Ixazomib will be administered at a once-weekly dose of 3 mg and, if tolerated well after 
4 cycles (see Section 6.5), the dose will be increased to 4 mg to provide the maximum 
clinical benefit possible. The duration of maintenance therapy will be 24 months or until 
disease progression (PD) or unacceptable toxicity (whichever occurs first). Please see 
Section 1.4.3.1 and Section 1.4.3.2 below for the rationale for the schedule and dose, 
respectively. 
1.4.3.1
   
Schedule Rationale
The balance of benefit and risk is paramount in this phase 3 maintenance study. The study 
will administer ixazomib on a weekly dosing schedule, consistent with the other ixazomib 
pivotal trials. 
A 24-month duration of therapy was chosen for the proposed study. Although the optimal 
duration of maintenance therapy in MM is not yet established, clinical experience with the 
PI VELCADE has found that a 2-year, fixed-duration maintenance regimen yielded good 
clinical benefit in both the HOVON-65/GMMG-HD4 trial in the post-SCT setting[29] and 
the GIMEMA trial in the non-SCT setting.[28] In the former study, 1 of the 2 arms included 
a 2-year maintenance therapy period with VELCADE after VELCADE-containing initial 
therapy and autologous SCT. Significant PFS and OS advantages were seen in this arm 
compared with the alternative arm, which included 2 years of thalidomide maintenance 
following a non-PI-containing initial therapy and autologous SCT. In the GIMEMA study, 
maintenance with VELCADE and thalidomide for 24 months showed a PFS and OS benefit 
over no maintenance therapy. Because ixazomib is a boron-based proteasome inhibitor 
similar to VELCADE (having a similar site of action on the proteasome), these studies 


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suggest that 24 months of maintenance therapy is an acceptable duration for an ixazomib 
trial, particularly one with a focus on balancing long-term tolerability of maintenance 
therapy, good clinical response, and risk of toxicity. 
There are several potential reasons why a finite therapy duration is preferred over a 
treat-to-progression approach for maintenance therapy in patients with NDMM who do not 
receive SCT. The potential of maintenance therapy with a PI to prolong or deepen a 
patient’s response is anticipated to occur within the first 2 years of maintenance therapy, 
based on results of the GIMEMA trial.[28] With the goal of providing clinical benefit to the 
patient at a favorable benefit:risk ratio, a finite duration of therapy limits the period of time 
that a patient will be exposed to the toxicities of the drug. In addition, there is currently no 
evidence that continued treatment to progression derives any further clinical benefit. 
Moreover, patients have the chance of experiencing a treatment-free interval if their disease 
has not progressed after the 24 months of maintenance therapy. The potential for patients to 
develop treatment-resistant disease on prolonged therapy additionally supports a finite 
treatment duration of 24 monthsan important consideration for this newly diagnosed 
population who will inevitably experience relapse as part of the natural course of their 
disease.[40]
1.4.3.2
   
Dose Rationale
Considering that clinical experience with ixazomib has predominantly been in the RRMM 
setting, dose selection for this C16021 maintenance treatment trial was guided by 
exposure-response analyses of safety and efficacy data from the relapsed patient population. 
These analyses were designed to yield initial estimates of a biologically active 
exposure/dose range of ixazomib associated with disease control and acceptable tolerability. 
The overall objective was to use these results to select a dosing scheme that would ensure 
adequate tolerability for long-term treatment while maintaining drug exposures in the 
biologically active range (ie, those associated with disease control in the relapsed setting 
where growth arrest/stable disease [SD] is a relevant indicator of biological activity).
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 (similar to this 
C16021 phase 3 study) in RRMM patients, were used in a preliminary exposure-response 
(safety/efficacy) analysis. All available data from patients with both PK and safety/efficacy 
information (N=44) were included in the analysis. Data were available over a wide dose 
range (0.5-3.95 mg/m2), corresponding to a fixed-dose range of approximately 1 to 8.9 mg. 
The metric of exposure was the area under the plasma concentration versus time curve per 
day (derived from individual clearance values on the basis of population PK) for both the 
exposure/safety analysis and the exposure/efficacy analysis.
For the safety analysis, 7 commonly occurring toxicities were evaluated, both hematologic 
(anemia, thrombocytopenia, and neutropenia) and nonhematologic (fatigue, rash, peripheral 
neuropathy [PN], and diarrhea). The highest grade of toxicity over the treatment duration 
was used for each patient in the logistic regression analysis. The nonhematologic AE data 
were categorized into ≥Grade 2 versus ≤Grade 1; the hematologic AE data were categorized 
into ≥Grade 3 versus ≤Grade 2. The data were categorized in this way because maintenance 
treatment is expected to have a tolerable AE profile and contribute to acceptable quality of 




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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 C16021 maintenance 
study. Patients entering Study C16021 will likely be symptom free, and when they start 
maintenance therapy, they will not have been previously exposed to ixazomib. 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 (see Section 6.5), increase the dose to 4 mg to 
provide the maximum possible clinical benefit.[41]
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 nonhematologic AEs and of Grade 3 or higher 
hematologic AEs are reduced by approximately 10% to 20% compared with 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 and 
NDMM settings.
Nonetheless, to provide patients the opportunity to derive maximum clinical benefit (without 
prohibitive toxicity), 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 of Grade 2 or above 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 in Cycles 1 through 4 will not 
dose escalate (see Section 6.5). The selection of the time point for dose escalation in patients 
tolerating ixazomib was based on the observation that patients’ 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.
1.4.4
   
Rationale for Minimal Residual Disease Assessment
The assessment of residual tumor cells persisting after therapy, or 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.[42-49] As a result, molecular MRD analysis is currently used 
for risk stratification, and assessment of therapy-induced reduction in tumor burden and 
regrowth after chemotherapy in these indications.[50]  
Recent studies have suggested that MRD assessment may also play a role in the MM 
treatment paradigm. Specifically, numerous reports have shown that molecular MRD status 
(ie, absence of MRD) is predictive of PFS and OS in MM patients.[51-54]  
In this study, a serial assessment of MRD in CR patients will be performed to characterize 
the benefit of ixazomib maintenance therapy versus placebo in terms of improving or 
maintaining the depth of response.


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1.4.4.1
   
Assessment of Minimal Residual Disease
In patients with confirmed or suspected CR at study entry, during the screening bone 
marrow aspirate (BMA) procedure, an additional BMA sample for MRD will be collected. 
In addition, all patients in CR at Cycle 13 and at the End of Treatment visit (EOT) 
(approximately 24 months [equivalent to 26 cycles, if no cycle delays]) will have BMA 
samples collected for MRD at those 2 time points (unless already done within the most 
recent 2 cycles); BMA samples for MRD will also be obtained in patients in CR who stop 
therapy before Cycle 26. For all other patients, when a BMA is performed to confirm 
suspected CR, an additional BMA sample for MRD will be collected.
Minimal residual disease will be evaluated using multiparametric flow cytometry, and 
remaining cells, if available, will be used for the assessment of MRD using a sequencing 
methodology.
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. Time 
to progression will also be evaluated in patients who have a CR, regardless of MRD status. 
This provides another way to identify and describe the value of maintenance therapy for 
patients with MM.
1.4.4.2
   
Rationale for Mutational Analyses
The heterogeneity of clinical results with MM therapeutics is partly related to variation in 
the molecular subtypes of MM 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 MM (a validated gene expression 
model of high-risk MM is defined by deregulated expression of genes mapping to 
chromosome 1)[55-57] or to outcome after single-agent VELCADE therapy.[58,59] 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).[60] Similar studies with samples from VELCADE clinical trials highlighted the link 
between mutations in these pathways and response to the PI.[61] Mutational analysis of 
tumor samples from patients with RRMM highlights the prevalence of RAS/RAF pathway 
mutations and their potential impact on clinical outcomes.[61,62]
In this clinical study, the link between the presence of specific gene mutations in key 
pathways, such as RAF/RAS, and the maintenance of clinical response will be tested using 
archival tumor samples and (if available) a portion of BMA samples used for MRD 
assessment and those obtained after PD. These hypotheses will be tested in all patients. 
Additional analyses of tumor molecular characteristics may be performed to identify 
biomarkers that may be clinically meaningful in this study.


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1.4.5
   
Rationale for Blood-Based Biomarkers and Antibody Titers
1.4.5.1
   
Single-Nucleotide Polymorphism Analyses
Recent data identify host variation, specifically germline DNA variants in proteasome 
subunits and the nuclear factor kappa-light chain enhancer of activated B-cells (NFB) 
pathway, as factors that might contribute to VELCADE clinical activity. For example, in 
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 PSMB1 gene has been observed. In this study, a blood sample 
will be collected at baseline for the assessment of P11A SNP and other SNPs potentially 
associated with differential benefit:risk ratios during treatment with ixazomib.
1.4.5.2
   
Antibody Levels Against Common Pathogens, and Lymphocyte Phenotyping
Patients undergoing antineoplastic therapy are immunocompromised and may be at high risk 
for infection with common pathogens. Additionally, by interfering with intracellular protein 
homeostasis, PIs may be cytotoxic not only to malignant plasma cells but also potentially to 
normal plasma cells and lymphocytes, contributing to the loss of protective antibodies. The 
proposed study includes an exploratory endpoint of measuring antibody levels against 
3 common pathogens that most patients have either been vaccinated against or have been 
exposed to: measles, varicella-zoster virus, and tetanus. Lymphocyte phenotyping will also 
be performed to study the effect of proteasome inhibition on lymphocyte subpopulations: B 
cells, T cells, and natural killer (NK) cells. Blood samples will be collected at screening; at 
Cycles 7, 13, and 19; at EOT; and every 6 months during the PFS Follow-up period.
1.5
   
Potential Risks and Benefits
As of 27 March 2014, 1287 patients make up the oral ixazomib Safety population. Clinical 
safety data include 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) 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 (see Section 6.9). 
It is possible that ixazomib used as maintenance therapy 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, patients are monitored closely for anticipated toxicities. Guidance for the 
management of AEs is given in Section 6.9. Procedures for modifying doses are discussed in 
Section 6.4; drug dosage can be modified by either reducing the dose administered or 
interrupting the 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 ixazomib in MM.
Ixazomib has shown 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. To date, antitumor activity has been seen with ixazomib 


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administered as a single agent, when combined with established therapies, and across all 
malignancies studied, including advanced solid tumors, non-Hodgkin lymphoma, RRMM, 
relapsed or refractory AL amyloidosis, and NDMM. Weekly dosing appears to enable 
delivery of higher ixazomib doses for a longer period than twice-weekly dosing.
This trial will be conducted in compliance with the protocol, Good Clinical Practice (GCP), 
applicable regulatory requirements, and International Conference on Harmonisation (ICH) 
guidelines.


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2.0
   
STUDY OBJECTIVES
Note, assessment of several study objectives was completed at the time of the first interim 
analysis (IA). Upon implementation of Amendment 07, data collected after the first interim 
analysis will be used to assess OS, PFS2, patient reported outcomes, and safety only. The 
full list of study objectives is retained here for reference. 
2.1
   
Primary Objective
The primary objective of this study is:

To determine the effect of ixazomib maintenance therapy on PFS, defined as the 
time from randomization to PD or death from any cause, compared with placebo, in
patients with NDMM who have had a major response—defined as CR, VGPR, or 
PR—to initial therapy and who have not undergone SCT
2.2
   
Key Secondary Objective
The key secondary objective is:

To determine the effect of ixazomib maintenance therapy on OS compared with 
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 and on 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 the time from randomization to objective disease 
progression on next-line treatment or death from any cause

To determine the effect of ixazomib maintenance therapy on the time to next-line 
therapy (TTNT)

To determine the effect of ixazomib maintenance therapy on the time to end of 
next-line therapy

To determine the effect of ixazomib maintenance therapy on duration of next-line 
therapy

To assess the incidence of new primary malignancy in patients receiving ixazomib 
maintenance therapy

To evaluate the frequency of conversion from MRD positive to MRD negative, or 
the maintenance of MRD negativity, using 8-color flow cytometry 


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
To assess the correlation between MRD status (detected using 8-color flow 
cytometry) 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 including, but not limited to, del17, t(4;14), and t(14;16) 

To determine the long-term safety and tolerability of ixazomib maintenance therapy

To assess health-related quality of life (HRQL) as measured by the global health 
domain of the EORTC QLQ-C30 in patients who receive ixazomib maintenance 
therapy 

To assess the correlation between frailty status and PFS and OS in patients receiving 
ixazomib maintenance therapy

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, in patients receiving 
ixazomib maintenance therapy
2.4
   
Exploratory Objectives
The exploratory objectives are:

To determine 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 in patients 
with polymorphisms in proteasome and NFB-related genes, such as PSMB1 and 
TRAF3

To evaluate the frequency of conversion from MRD positive to MRD negative, or 
the maintenance of MRD negativity, using sequencing

To evaluate the concordance between MRD assessment using flow and sequencing 
methodologies

To assess the correlation between MRD status (detected using next-generation 
sequencing) and PFS and OS, using bone marrow aspirates.

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 from patients who exhibit PD

To determine the effect of ixazomib maintenance therapy on lymphocyte 
subpopulations (T, B, and NK cells) and on normal plasma cell function as measured 
by levels of antibodies against common pathogens, such as varicella-zoster virus 
(VZV), tetanus, and rubeola (measles), during the course of therapy 


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
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 and EQ-5D-5L instruments 

To evaluate health utilization (HU) of ixazomib maintenance therapy


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3.0
   
STUDY ENDPOINTS
Note, assessment of several study endpoints was completed at the time of the first IA. Upon 
implementation of Amendment 07, data collected after the first IA will be used to assess OS, 
PFS2, patient reported outcomes, and safety only. The full list of study endpoints is retained 
here for reference. 
3.1
   
Primary Endpoint
The primary endpoint is: 

Progression-free survival, defined as the time from randomization to the first 
occurrence of PD, as evaluated by an independent review committee (IRC), or death 
from any cause, whichever occurs first
3.2
   
Key Secondary Endpoint
The key secondary endpoint is:

Overall survival, measured as the time of randomization to the date of death
3.3
   
Other Secondary Endpoints
The other secondary endpoints are:

Best response achieved or maintained (including PR, VGPR, and CR) before PD or 
to subsequent therapy, and duration of CR

Time to progression, measured as the time from randomization to the date of first 
documented PD

Progression-free survival 2, defined as the time from randomization to objective 
disease progression on next-line treatment or death from any cause

TTNT

Time to end of next-line therapy

Duration of next-line therapy

Incidence of new primary malignancies

Conversion rate from MRD positive to MRD negative, or the maintenance of MRD 
negativity, using 8-color flow cytometry

Correlation of MRD status (detected using 8-color flow cytometry) with PFS and OS

Overall survival and PFS in high-risk cytogenetic populations characterized by 
individual or multiple cytogenetic abnormalities including, but not limited to, 
patients carrying del17, t(4;14), or t(14;16)

Long-term safety and tolerability, measured by Eastern Cooperative Oncology 
Group (ECOG) Performance Status, AEs, serious adverse events (SAEs), and 
assessments of clinical laboratory values 


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
Health-related quality of life, as measured by the global health domain of the
EORTC QLQ-C30 questionnaire

Correlation between frailty status and PFS and OS

Ixazomib plasma concentration-time data

Time to resolution and time to improvement of PN events graded at each subsequent 
monthly visit until resolution of PN, the start of an alternative antineoplastic 
treatment, or 6 months after PD, whichever occurs first
3.4
   
Exploratory Endpoints 
The exploratory endpoints are:

Rate of increase in tumor burden, measured by M-protein level, after PD before the 
start of next-line therapy

Maintenance of response, PFS, and OS in patients with mutations in the RAS/RAF 
pathway or other key genes in MM

Progression-free survival and OS in patients with polymorphisms in proteasome and 
NFB-related genes, such as PSMB1 and TRAF3

Frequency of conversion from MRD positive to MRD negative, or the maintenance 
of MRD negativity, using sequencing

Concordance between MRD assessment using flow and sequencing methodologies

Correlation of MRD status (detected using next-generation sequencing) with PFS 
and OS 

Identification of mechanisms of treatment-emergent resistance in tumors from 
patients who exhibit PD

Lymphocyte subpopulations (T, B, and NK cells) and antibody levels against 
common pathogens, such as VZV, tetanus, and rubeola

Health-related quality of life in patients, as measured by the function and symptom 
domains of the EORTC QLQ-C30 instrument and by the EORTC QLQ-MY20 and 
EQ-5D-5L questionnaires

Assessment of HU by collecting the number of medical encounters 


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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 who have not undergone SCT. Patients who have not undergone SCT 
have not done so because of frailty due to advanced age (eg, 65 years) or comorbidity or 
because they decline SCT for other reasons. The Study Overview Diagram depicts the study 
design.
Screening and Randomization
The purpose of the study is to evaluate the role of maintenance therapy with ixazomib 
(compared with matching placebo) in patients who, in their initial therapy before study 
enrollment, have been treated to achieve a major response category (PR or better) that is 
judged to be their best response by the investigator/treating physician. Patients must also 
have had a documented PR, VGPR, or CR at screening and met all additional 
inclusion/exclusion criteria. A Takeda project clinician or designee will confirm patient
eligibility before randomization by the investigator and will ensure that the documentation 
adequately captures the reasons for not proceeding to SCT. The initial therapy permitted is 
any standard of care MM therapy.
Eligible and consenting patients are to be randomized no later than 60 days after the last 
dose of the initial therapy. Randomization will occur in a 3:2 ratio to ixazomib or matching 
placebo. Approximately 700 patients are planned to be enrolled in this study at 
approximately 200 sites worldwide. Because this is a global study, during the conduct of the 
trial the sponsor may choose to limit patient enrollment in specific regions or countries to 
maintain adequate representation across the regions participating in the study.
There are 4 stratification factors: initial therapy (PI-containing or not); International Staging 
System (ISS) stage before initial therapy (stage I or II vs stage III); age at time of 
randomization (<75 vs 75 years); and response to initial therapy, as measured during 
screening (CR or VGPR vs PR). 
Study Treatment
Patients will receive blinded ixazomib or matching placebo capsules (both hereafter referred 
to as “study drug”) orally on Days 1, 8, and 15 of every 28-day cycle. 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 the interval during which any enrolled 
patient is receiving study drug; 28-day treatment cycles will be used throughout this period. 
Patients will have study assessments performed at regular treatment-cycle intervals while 
they are participating in the study: 3 times during the first cycle (weekly; Days 1, 8, and 15), 
twice during the second cycle (Days 1 and 8), and then once per treatment cycle for the 


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remainder of their participation in the Treatment period, for approximately 24 months 
(equivalent to 26 cycles [if no cycle delays], to the nearest complete cycle) or until they 
experience PD or unacceptable toxicity, whichever occurs first. The exception to this is 
patients who have their dose increased at Cycle 5; these patients will have study assessments 
performed twice during Cycle 5 (on Days 1 and 8).
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 for every 
cycle through the first PD. Independent review committee response evaluations are for 
endpoint determinations only and will not be shared with investigators. Dose-modification 
guidelines are given in Section 6.3. 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.
The first IA has been conducted (data cutoff date 12 August 2019) and the primary endpoint 
of PFS was statistically significant. As such, upon implementation of Amendment 07, all 
central laboratory efficacy measures of disease response/progression are discontinued. No 
further IRC response or progression evaluations will be performed. Investigators should 
continue to assess disease response/progression according to IMWG criteria using local 
efficacy laboratory measures for documentation of initial disease progression and PFS2.
Patients will receive study treatment for a maximum duration of approximately 24 months 
(equivalent to 26 cycles [if no cycle delays], to the nearest complete cycle) 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 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, unless next-line therapy is started before 30 days after the last dose of study drug, in 
which case the EOT visit should occur before the start of the next-line therapy.
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. After PD occurs, the date and characteristics of PD2, and disease status, will 
be assessed by the treating physician/investigator according to the IMWG criteria, and 
reported.
Progression-Free Survival Follow-up and Progressive Disease Follow-up
If a patient completes 24 months of study treatment 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 during the PFS Follow-up period, the 


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patient enters the PD Follow-up period and continues to be followed every 12 weeks until 
initiation of next-line 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 
next-line therapy by the investigator/treating physician. 
Progression-Free Survival 2 Follow-up and Overall Survival Follow-up
Patients who start next-line 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 2 IAs and 1 final 
analysis (FA) in the study. The first IA will be the FA (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. Additionally, for patients who have not yet had 
progressive disease at the first IA, central efficacy and investigator assessments for protocol 
purposes will be stopped and not recorded in the electronic case report form (eCRF). 
However, investigator assessment of response will continue to be collected for patients who 
have initiated next line therapy, for the purpose of supporting the PFS2 endpoint (see 
Schedule of Events).
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. Upon implementation of Amendment 07, the IRC will no longer assess disease 
response and PD. See Section 9.0 for more information. 
The Schedule of Events and the Study Endpoint and Follow-up Period 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. 
Eastern Cooperative Oncology Group 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.[63]


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4.2
   
Number of Patients
Approximately 700 patients will be enrolled in this study from approximately 200 study 
centers globally. Enrollment is defined as being randomized to a study drug. Randomization 
is 3:2 treatment:control, so approximately 420 patients are expected to be enrolled in the 
ixazomib arm and approximately 280 patients in the placebo arm.
4.3
   
Duration of Study
Patients will be treated for approximately 24 months (equivalent to 26 cycles [if no cycle 
delays], to the nearest complete cycle) or until documented PD or intolerable toxicity, 
whichever occurs first. Subsequent to the 24-month Treatment period or removal from study 
therapy due to PD or toxicity, patients will be followed for clinical status, disease status, 
subsequent therapies, HRQL, new primary malignancy, and survival.
It is anticipated that this study will last for approximately 78 to 106 months, including a 42-
month Enrollment period, a 24-month Treatment period, and an additional 12- to 40-month 
Follow-up period from the time at which the last patient has the opportunity to complete 
study therapy, depending on the death events for the final OS analysis. 


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5.0
   
STUDY POPULATION
Adult patients aged 18 years or older with a confirmed diagnosis of symptomatic NDMM 
who have been treated to best response with initial MM therapy for 6 to 12 months and who 
have achieved a major response (CR, VGPR, or PR) while receiving that regimen will be 
eligible for this study. These patients will not have undergone SCT, and the reasons will be 
thoroughly documented. The initial therapy permitted is any standard of care MM therapy.
5.1
   
Inclusion Criteria
Each patient must meet all the following inclusion criteria to be randomized to treatment:
1. Adult male or female patients aged 18 years or older with a confirmed diagnosis of 
symptomatic NDMM according to standard criteria (see Section 15.1).
2. Completed 6 to 12 months (2 weeks) of initial therapy, during which the patient 
was treated to best response, defined as the best response maintained for 2 cycles 
after the M-protein nadir is reached. 
3. Documented major response (PR, VGPR, CR) according to the IMWG uniform 
response criteria, version 2011, after this initial therapy.
4. Female patients who: 

Are postmenopausal for at least 1 year before the screening visit, OR

Are surgically sterile, OR

If they are of childbearing potential, agree to practice 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, 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, 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.)
5. 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.


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6. Availability of complete documentation for:

Details of initial disease state, initial therapy, and response

Cytogenetics assessment at diagnosis (cytogenetic assessment performed after 
diagnosis must be approved by a Takeda project clinician or designee)

ISS staging at diagnosis (requiring 2-microglobulin and serum albumin results)
7. Eastern Cooperative Oncology Group Performance Status of 0 to 2 (see 
Section 15.2).
8. Suitable venous access for the study-required blood sampling and consent for the 
specific amounts that will be taken.
9. Patient is willing and able to adhere to the study visit schedule and other protocol 
requirements including blood sampling and bone marrow aspiration.
10. Patients must meet the following clinical laboratory criteria at study entry:

Absolute neutrophil count (ANC) 1,000/mm3 without growth factor support 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).

Alanine aminotransferase and aspartate aminotransferase 3ULN.

Calculated creatinine clearance 30 mL/min (using the Cockcroft-Gault equation 
[Section 15.3]).
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 after, or was not responsive to, initial therapy.
2. Prior SCT.
3. Radiotherapy within 14 days before randomization.
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.


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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, uncontrolled 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 St. John’s wort within 14 days 
before randomization.
12. Ongoing or active infection, known human immunodeficiency virus positive, active 
hepatitis B or C infection.
13. Comorbid systemic illnesses or other severe concurrent disease that, 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.
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 30 days before randomization.


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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 study drug should be modified as 
needed to accommodate patient tolerance to treatment; this may include symptomatic 
treatment, dose interruptions, and adjustments of dose. 
Patients will receive oral ixazomib or matching placebo weekly (Days 1, 8, and 15) in each 
28-day cycle. The dose will be 3 mg during Cycles 1 through 4 and may be escalated to 
4 mg thereafter if the patient has tolerated the initial dose (see Section 6.5). All doses must 
be taken as outlined in the Schedule of Events. During the first cycle of treatment, all 
patients will receive doses of ixazomib or placebo capsules in the clinic. During the second 
cycle of treatment, all patients will receive the Day 1 and Day 8 doses in the clinic; patients 
will take the Day 15 dose at home as directed. 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 the
Ixazomib Pharmacokinetic Sampling Schedule). All other doses may be taken at home. 
Of particular note, the Cycle 5 Day 1 dose will be taken in the clinic after determination of 
whether the study drug dose should be escalated from 3 mg to 4 mg, and patients whose 
dose is escalated will have the Cycle 5 Day 8 dose given in the clinic also.
Refer to the Study Manual for additional instructions regarding study drug administration.
6.2
   
Test Article (Ixazomib Capsules and Matching Placebo Capsules)
Ixazomib capsules will be supplied as single capsules 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.
Ixazomib capsules and matching placebo capsules will be hereafter referred to as “study 
drug” when detailing blinded study procedures.
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 each 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 and no sooner than 2 hours after a meal. 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. Section 6.14 gives 
information about returning unused medication.


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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 Schedule of Events. Toxicity will be evaluated according 
to the NCI CTCAE, Version 4.03, effective 14 June 2010.[63] These criteria are provided in 
the Study Manual. 
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 three 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 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/patient (eg, Grade 2 chronic 
kidney disease due to underlying MM).
If the patient fails to meet the above-cited criteria for retreatment, initiation of the next cycle 
of treatment should be delayed for 1 week. After 1 week, the patient should be re-evaluated 


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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. Should 
the start of the next cycle need to be delayed 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 
absolute neutrophil count (ANC) 
≤0.75109/L on an ixazomib/ placebo 
dosing day (other than Day 1)
Study drug dose should be withheld. Complete blood count with 
differential should be repeated at least weekly or more frequently 
until the ANC and/or platelet counts have exceeded the prespecified 
values (ANC ≥1.0×109/L; platelet count ≥75×109/L). Upon 
recovery, 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 6.4.1: 

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 timingie, a toxicity after Day 15 dosing such that a 
dose reduction was not required at that point in the cyclethen 
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.
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.


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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 and symptoms: 
asymptomatic, without pain or loss 
of function, clinical or diagnostic 
observations only
Worsening Grade 1 
peripheral neuropathy (ie, 
Grade 1 with pain) or 
Grade 2
Hold study drug until resolution to 
≤Grade 1 without pain or baseline.
Grade 2 signs and symptoms: 
moderate symptoms, limiting 
instrumental activities of daily 
living
New or worsening Grade 2 
peripheral neuropathy with 
pain or Grade 3
Hold 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 and symptoms: 
severe symptoms, limiting self-
care activities of daily living, 
assistive device indicated
New or worsening Grade 4 
peripheral neuropathy
Discontinue study drug.
Grade 2 Rash
Symptomatic recommendations 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 on the basis of within-cycle 
criteria or subsequent cycle criteria but not both for the same cycle.
Grade 4 Nonhematologic 
Toxicities 
Consider permanently discontinuing study drug, except in the case where the 
investigator determines that the patient is obtaining a clinical benefit and has 
discussed this with the project clinician or designee. If study drug is 
continued, the dose should be reduced by at least 1 level.
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 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. 
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.


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Table 6-4   
Criteria for Study Drug Retreatment and Cycle Delays Subsequent to 
Hematologic and Nonhematologic Toxicities
Criteria
Action
Both hematologic and 
nonhematologic events
Delay therapy 1 week.
Re-evaluate patient; if still not resolved, delay therapy 1 additional week.
Hematologic and 
nonhematologic events 
not resolved after 1-
week treatment delay
If initiation of subsequent therapy needs to be delayed for more than 2 weeks 
because of incomplete recovery from treatment-related toxicity, the dose of 
ixazomib will be reduced by 1 dose level as outlined in Table 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 at a later cycle 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 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 drug-drug interaction 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 Treatment 
period of the study:

St. John’s wort

Any antineoplastic treatment with activity against MM, other than study drugs

Radiation therapy (note that, in general, the requirement for local radiation therapy 
indicates PD)

Platelet transfusions to help patients meet eligibility criteria


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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 the 
first dose of the study drug 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) 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.
Long-acting growth factors (eg, pegylated G-CSF) are not permitted, however.

Erythropoietin will be allowed in this study.

Patients should be transfused with red cells and platelets as clinically indicated.

Patients who are receiving bisphosphonates for previously identified lytic destruction 
of bone or with osteopenia may continue treatment according to the American 
Society of Clinical Oncology Clinical Practice Guidelines or 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. 

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 should be avoided in patients with impaired renal 
function, given reported renal failure induced by these drugs 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

If they are of childbearing potential, agree to practice 2 effective methods of 
contraception from the time of signing of the informed consent form through 90 days 
after the last dose of study drug, or


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
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. Antiviral therapy such as acyclovir, valacyclovir, or other antivirals 
may be initiated as clinically indicated. 
Nausea 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.
Erythematous Rash With or Without Pruritus
Rash may range from limited erythematous areas, macular or small papular bumps that may 
or may not be pruritic over a few areas of the body, to a more generalized eruption that is 
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 or 2 in severity. As in any other oncology trial, rash may occur in patients 
receiving placebo and in patients receiving ixazomib. If rash occurs, consideration should be 
given to alternate causes of the rash such as concomitant medications, infections, etc.


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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 15.4]) is permitted. Management of a Grade 3 rash may require intravenous 
antihistamines or corticosteroids. Administration of ixazomib (and 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. 
Ixazomib administration should be modified according to 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. Thrombotic 
microangiopathy (TMA), including thrombotic thrombocytopenia purpura and hemolytic 
uremic syndrome, are rare, serious blood disorders that cause low levels of platelets and red 
blood cells, and result in blood clots in small blood vessels. Symptoms may include fatigue, 
fever, bruising, nose bleeds, and decreased urination. These disorders, including fatal cases, 
have been reported in patients receiving ixazomib. TMA should be managed 
symptomatically according to standard medical practice.
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. Ixazomib administration should be modified according to 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.


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Fluid Deficit
Dehydration should be avoided because ixazomib may cause vomiting, diarrhea, and 
dehydration. Acute renal failure has been reported in patients treated with ixazomib, 
commonly in the setting of the previously noted gastrointestinal toxicities and dehydration.
Fluid deficit should be 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 or diuretics to manage their blood pressure (for either hypotension or 
hypertension) should be managed according to standard clinical practice, including 
considerations for dose adjustments of their concomitant medications during the course of 
the trial. Fluid deficit should be corrected before initiation of study drug and as needed 
during treatment to avoid dehydration.
Posterior Reversible Encephalopathy Syndrome
Posterior reversible encephalopathy syndrome has been reported with ixazomib. This 
condition is characterized by headache, seizures, and visual loss, and abrupt increase in 
blood pressure. Diagnosis may be confirmed by magnetic resonance imaging (MRI) or 
computed tomography (CT). If the syndrome is diagnosed or suspected, symptom-directed 
treatment should be maintained until the condition is reversed by control of hypertension or 
other instigating factors.
Transverse Myelitis
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 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. 


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Treatment assignments will be obtained through the interactive voice/web response system 
(IXRS) according to the procedures outlined in the Study Manual. Information regarding the 
treatment assignments will be kept securely at Takeda or designee, per its standard operating 
procedures. Emergency unblinding, if necessary, will be conducted via the IXRS.
Records of the patient number, the date the study drug 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 or to treat an AE, the investigator will contact the 
Takeda project clinician or designee (contact information is in the Study Manual). In these 
cases, a decision to break the blind must be reached by the Takeda project clinician or 
designee and the investigator. The investigator, or designee, may break the blind through the 
IXRS independent of the Takeda project clinician or designee in the following 2 situations:
a) If the patient experiences an AE/safety issue that is considered to be an emergency by the 
investigator that requires specific knowledge of the blinded study treatment to properly treat. 
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.
b) When a study patient has documented disease progression, the investigator should 
unblind the patient to determine the study treatment assignment and take this information 
into account in planning the patient’s second-line therapy. The Takeda project clinician or 
designee does not need to be contacted to break the blind to inform decisions for subsequent
therapy when a patient has disease progression.
6.11
   
Description of Investigational Agents
The ixazomib 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
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 Ixazomib IB and Pharmacy Manual.
6.12
   
Preparation, Reconstitution, and Dispensation
The study drug is dispensed in a blister pack in a child-resistant carton.


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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. See the Pharmacy Manual for more information. 
6.14
   
Storage, Handling, and Accountability
On receipt at the investigative site, study drug should remain in the blister pack and carton 
provided until use or dispensation. The study drug should be stored as indicated on the drug 
label. All excursions that occur during the site storage or during transportation from depot to 
the site should immediately be brought to the sponsor’s attention for assessment and 
authorization for continued use. Ensure that the drug is used before the retest expiry date 
provided by Takeda. Expiry extensions will be communicated accordingly with updated 
documentation to support the extended shelf life.
Study drug dispensed to the patient for take-home dosing should remain in the blister 
packaging and carton until the point of use. Patients are permitted to transport study drug 
from the site to home at room temperature. If circumstances due to the COVID-19 pandemic
prevent a patient from attending the study site, sites may use alternative strategies to deliver
study drug to patients (eg, via courier or site staff), per local standard practice and 
regulations, and with prior approval from the investigator and sponsor’s project 
clinician/designee. Comprehensive instructions should be provided to the patient to ensure 
compliance with dosing procedures. Patients who are receiving take-home medication 
ordinarily should be given only 1 cycle of medication at a time. More than 1 cycle of 
medication may be dispensed on a case-by-case basis for holidays, travel, or other 
circumstances upon discussion with the investigator and sponsor’s project clinician/designee 
(note: patients in France are only permitted to receive 1 cycle of medication at a time). 
Patients should be instructed to store the medication according to the storage conditions that 
are indicated on the drug label. Patients should be instructed to return their empty or 
partially used 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. If circumstances due to the COVID pandemic prevent a 
patient from attending the study site, drug packs and dosing diaries should be returned at the 
next available on-site clinic visit. Any excursions in temperature should be reported 
immediately 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. 


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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 with the highest respect for the individual participants in 
accordance with the requirements of this clinical study protocol and also in accordance with 
the following:

The ethical principles that have their origin in the Declaration of Helsinki.

ICH E6 GCP: Consolidated Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws, 
clinical trial disclosure laws, and regulations.
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 Manual. 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 the 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 the 
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 enrollment 
code will not be reused, and the patient will not be allowed to re-enter the study.
7.4
   
Study Procedures
In acknowledgement of hospital, local, state, or national government restrictions, or other 
site-related factors caused by the COVID-19 pandemic prevent investigators from 
conducting the study according to the Schedule of Events at the clinical study site,
investigators may continue patients in the study despite departure from the Schedule of 
Events. Investigators are expected to evaluate the impact to the safety of the study 
participants and site personnel for patients to continue. In evaluating such requests, the 
investigator/study site staff will give the highest priority to the safety and welfare of the 
patients. Patients must be willing and able to continue taking study medication and remain 
compliant with the protocol. For patients who are impacted by these unavoidable 


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circumstances, any procedures not conducted per the study protocol will be documented in 
the eCRF. 
If a patient misses an in-person study visit, the investigator/study team staff will speak 
directly with the patient by telephone or other medium (eg, a computer-based video 
communication) during each visit window to assess subject safety and overall clinical status. 
During this contact with the patient, the study site physician or other qualified site staff 
should at a minimum conduct AE collection and an assessment of clinical symptoms. Other 
study assessments may be collected remotely as is feasible and may involve audio or video 
recording. Assessments/procedures that cannot be completed during the protocol-specified 
window because a site visit is done remotely (eg, complete physical examination, symptom-
directed physical examination, weight, ECOG performance status, HU) are waived.
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 7-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 7-day window also is permissible 
for study days not specified in this Schedule of Events.
Refer to the Schedule of Events for timing of assessments. Additional details are provided as 
necessary in the sections that follow.
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. 
As of Amendment 07, patients remaining on study treatment will need to be reconsented
before dosing on Day 1 of the next full treatment cycle. Patients who are in one of the 
Follow-up periods must also be reconsented. Consenting/reconsenting should be done in 
person. Remote consenting/reconsenting is permitted as long as the process adheres to site, 
IRB/IEC, and GCP standards and local regulations.
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 the following. 

Diagnosis of MM (Section 15.1) and initial ISS staging (based on serum albumin and 
2-microglobulin levels) (Section 15.5), including biochemistry, serum protein 
electrophoresis, urine protein electrophoresis, serum/urine immunofixation, serum 
free light chains, bone marrow results, and lactate dehydrogenase (LDH) levels.


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
Cytogenetic evaluation should be performed at diagnosis (or after diagnosis, only 
with approval from the Takeda project clinician or designee) using fluorescence in 
situ hybridization (FISH) and/or conventional cytogenetics (karyotyping); if only 1 
test is available, FISH is preferred. At a minimum, this should include reporting of 2 
of the following 3 high-risk abnormalities, listed in order of preference: del17, 
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 
informed consent form (ICF) will be developed to permit cytogenetic evaluation on 
BMA samples.

Multiple myeloma-directed therapy including initial therapies and dates and 
clinically significant toxicities 

Disease response evaluations during and at the end of initial therapy. Patients must 
have been treated to their best response to initial therapy, defined as the best 
response maintained for 2 cycles after the M-protein nadir is reached. The best 
response must have been PR or better.
NOTE: To minimize clinically redundant procedures, the investigator may choose to 
use the Screening visit to serve as the clinical evaluation of disease status after initial 
therapy, as long as all requirements for screening are met.

Review of all current medications, prior radiation (as permitted >14 days before 
randomization for symptomatic bone lesion or >5 years before randomization for 
another malignancy), and the patient’s current smoking status.
Refer to the Schedule of Events for specific time requirements and windows.
7.4.4
   
Physical Examination
A physical examination will be completed per standard of care at the times specified in the 
Schedule of Events. Symptom-directed examinations should include examination of organ 
systems related to patient symptoms to document potential AEs, AE severity, or AE 
resolutions. 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 
Schedule of Events. Height will be measured only at the Screening visit.
7.4.6
   
Eastern Cooperative Oncology Group Performance Status
Performance status will be assessed using the ECOG Performance Scale (see Section 15.2) 
at the time points specified in the Schedule of Events. 


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7.4.7
   
Frailty Status
Patients’ frailty status will be assessed at the Screening visit on the basis of 4 components: 
age, the Charlson Comorbidity Scoring System without age weighting (see Section 15.6), 
the Katz Index of Independence in Activities of Daily Living (see Section 15.7), and the 
Lawton Instrumental Activities of Daily Living Scale (see Section 15.8).
Specifically, ages of <75, 75-80, and >80 years correspond to frailty scores of 0, 1, and 2, 
respectively. Charlson Comorbidity Scoring System scores of ≤1 and ≥2 correspond to 
frailty scores of 0 and 1, respectively. Katz Index of Independence in Activities of Daily 
Living scores of >4 and ≤4 correspond to frailty scores of 0 and 1, respectively. Instrumental 
Activities of Daily Living Scale scores of >5 and ≤5 correspond to frailty scores of 0 and 1, 
respectively. The sum of the 4 frailty scores equals the total frailty score. A total frailty 
score of 0 corresponds to a frailty status of fit; a total score of 1, to unfit; and a total score of 
2 or more, to frail.[7,8]
7.4.8
   
Pregnancy Test
A serum pregnancy test will be performed for women of childbearing potential at screening, 
predose on Cycle 1 Day 1, 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 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 upon request by IEC/IRBs or if 
required by local regulations.
7.4.9
   
Concomitant Medications and Procedures
Concomitant medications and therapy will be recorded from the first dose of the study drug 
through 30 days after the last dose of study drug (see the Schedule of Events). 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.
7.4.10
   
Adverse Events
Monitoring of AEs, serious and nonserious, will be conducted throughout the study as 
specified in the Schedule of Events. Refer to Section 10.0 for details regarding definitions, 
documentation, and reporting of pretreatment events, AEs, and SAEs. 
7.4.11
   
Enrollment
A patient is considered to be enrolled in the study when the patient has been randomized to 
study treatment.
Procedures for completing the enrollment information are described in the Study Manual.


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7.4.12
   
Electrocardiogram
A 12-lead ECG will be conducted at screening. It may be repeated as clinically indicated 
during the study at the discretion of the investigator. Electrocardiogram data to be obtained 
include PR interval, QRS interval, and QT interval.
7.4.13
   
Clinical Laboratory Evaluations
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 the central laboratory. Hematology and chemistry panels may be 
collected up to 3 days before Day 1 dosing and 24 hours before Day 8 and Day 15 dosing 
(when required). Local laboratory evaluations may be performed more frequently at the 
investigator’s discretion (eg, 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 Manual. 
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 before starting the 
next cycle of treatment.
Patient eligibility should be decided using central laboratory results. If central lab results are 
not available at the time of randomization, local laboratory results may be used as long as 
samples are also sent to the central laboratory before the patient is randomized. The central 
laboratory results will be used as reference for all response assessments. For situations 
where the local sample results are borderline in terms of meeting eligibility, the site is 
discouraged from relying on the local laboratory results for eligibility determination and 
encouraged to confirm eligibility using the central lab results. Such situations should be 
discussed with the Takeda project clinician or designee. The Takeda project clinician or 
designee will review the local and central laboratory eligibility results to ensure that the two 
are consistent. 
Progressive disease should be documented and confirmed (by medical review of data; 
confirmatory testing should be done for biochemical changes but for bone sites, for example, 
this may not be appropriate). Before an investigator discontinues a patient from treatment 
for PD, the pertinent data must be confirmed by a Takeda project clinician or designee. If 
another therapy must be started immediately (within the next 10 business days), the 
investigator should provide the rationale to the Takeda project clinician or designee. In 
situations where the local results are borderline in terms of meeting criteria for PD, the site 
is discouraged from using only the local laboratory results.


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Upon implementation of Amendment 07, centralized clinical laboratory assessments of 
response and progression are no longer required and local laboratories are to be used. Safety 
laboratory evaluations will also be performed by a local laboratory. 
Clinical Chemistry, Hematology, Urinalysis, Serology, and Lymphocyte Phenotyping
Blood samples for analysis of the following clinical chemistry, hematologic, and serologic 
parameters and urine samples for urinalysis will be obtained as specified in the Schedule of 
Events.
Hematology

Hemoglobin

Hematocrit

Platelet (count)

Leukocytes with differential

Neutrophils (absolute neutrophil count [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


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Serology and Lymphocyte Phenotyping

Measles

VZV

Tetanus

Quantification of B cells, T cells, and NK cells
7.4.14
   
Health Utilization Data Collection
During the Treatment and Follow-up periods indicated in the Schedule of Events, all 
medical care encounters since the previous collection will be collected from all patients, 
regardless of the reason for the medical care encounter. Examples of data to be collected are 
number and duration of medical care encounters, such as inpatient/outpatient admissions, 
homecare, and time of work loss.
If needed due to the COVID-19 pandemic, HU data may be obtained over the telephone 
and/or via patient medical records, as needed.
7.4.15
  
Quality of Life Assessment (European Organization for Research and 
Treatment of Cancer)
The HRQL assessments (EORTC QLQ-C30 and EORTC QLQ-MY20; see Sections 15.9
and 15.10) will be completed by the patient as specified in the Schedule of Events. The 
EORTC QLQ-C30 incorporates 5 functional scales (physical functioning, role functioning, 
emotional functioning, cognitive functioning, and social functioning), 1 global health status 
scale, 3 symptom scales (fatigue, nausea and vomiting, and pain), and 6 single item scales 
(dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). 
The EORTC QLQ-MY20 multiple myeloma module (20-items) 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 
take about 15 minutes to administer. The instruments consist of a total of 50 items and have 
been validated and used in many countries.
These assessments should be completed during the study visit, before other assessments are 
performed or study drug is taken. During the PFS2 Follow-up period only, the EORTC 
QLQ-C30, EORTC QLQ-MY20, and HU are to be done twice—ideally once approximately 
12 weeks after the start of next-line therapy and again 12 weeks later, as specified in the 
Schedule of Events. 
These patient-reported outcome questionnaires are preferred to be completed by patients in 
the clinic but, if needed due to the COVID-19 pandemic, the questionnaires may be
completed at the patient’s home using mailed paper versions of the questionnaires. In the 


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case of paper-based questionnaires, only copies of questionnaires supplied by Takeda or
ordered from the publisher may be used.
7.4.16
   
Utility Measurement
The EQ-5D-5L (see Section 15.11) consists of 2 pages: the EQ-5D-5L 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), 
each rated on 5 levels. The EQ VAS records the respondent’s self-rated health on a 20-cm, 
vertical, visual analogue scale ranging from 0 (worst imaginable health state) to 100 (best 
imaginable health state). 
The EQ-5D-5L will be administered as specified in the Schedule of Events; at time points 
when a clinic visit is not required, or if needed due to the COVID-19 pandemic, the EQ-5D-
5L questionnaire may be administered over the telephone, and site staff may enter the data 
from the patient.
7.4.17
   
Bone Marrow Aspiration
7.4.17.1    
Local Laboratory Evaluations
Disease Assessment
A BMA will be obtained at screening for disease assessment. In addition, a BMA will be 
obtained at any time during the study to assess CR or to investigate suspected PD. All of 
these evaluations will be performed locally. 
For patients with a confirmed or suspected CR at study entry, during the screening BMA 
procedure, an additional BMA specimen should be obtained for MRD evaluation by the 
central laboratory, as discussed below (Section 7.4.17.2). 
Determination of the /λ immunoglobulin light-chain ratio by immunohistochemistry or 
immunofluorescence should be performed to assess for stringent CR when a CR has been 
documented. A bone marrow biopsy can additionally be performed per local standards for 
disease assessments.
Upon implementation of Amendment 07, BMA is not required for central laboratory
assessment of CR for protocol purposes. Investigators may continue to take BMA per 
standard of care for response assessment, per IMWG criteria.
7.4.17.2    
Central Laboratory Evaluations
Minimal Residual Disease in Patients With a Complete Response
In patients with a confirmed or suspected CR at study entry, during the screening BMA 
procedure, an additional BMA sample for central evaluation of MRD will be collected. In 
addition, all patients in CR at Cycle 13 and at EOT (approximately 24 monthsequivalent 
to 26 cycles [if no cycle delays]) will have BMA samples collected for MRD at those 2 time 
points (unless already done within the most recent 2 cycles); BMA samples for MRD will 
also be obtained in patients in CR who stop therapy before Cycle 26. For all other patients, 


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when a BMA is performed to confirm a suspected CR, an additional BMA sample for MRD 
will be collected.
Eight-color flow cytometry will be performed to determine MRD. In addition, and if 
portions of the samples are available after flow cytometry, sequencing technology will also 
be used for the assessment of MRD. The concordance between flow and sequencing 
methodology readouts will be assessed. 
Archival tumor material (BMA as unstained [preferred] or stained slides) from disease 
diagnosis and any other available prestudy time points (when the patient has a high disease 
burden) is to be used for the identification of the MM tumor clone, which will then be 
followed in the serial MRD BMA samples obtained during the study. Bone marrow biopsy 
samples will not be accepted for this purpose. If not available at screening, the archival 
BMA sample may be submitted at any time during the study. These samples will be 
processed according to the Laboratory Manual, stored by the central lab, and analyzed in 
batches. Because these samples are consumed in the analysis, archival marrow material 
cannot be returned to the investigator.
All BMA MRD samples are required to be sent to the central laboratory immediately after 
collection.
Upon implementation of Amendment 07, BMA is not required for central laboratory
assessment of CR or for MRD for protocol purposes. Investigators may continue to take 
BMA per standard of care for response assessment, per IMWG criteria.
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 tumor DNA from BMA samples originally used for the 
assessment of MRD, as available.
Unless otherwise noted, BMA samples for MRD or for molecular analysis are required to be 
sent to the central laboratory for processing immediately after collection.
Upon implementation of Amendment 07, BMA is not required for central laboratory
assessment of MRD or molecular analysis for protocol purposes. Investigators may continue 
to take BMA per standard of care for response assessment, per IMWG criteria.
7.4.18
   
Blood-Based Biomarker Analyses
One blood sample will be collected at screening for testing the candidate biomarker 
relationship to response or resistance and to long-term clinical benefits, such as OS and PFS, 
of ixazomib therapy. Polymorphisms in mechanism- and pathway-related genes, including 
proteasome subunits and NFB regulators, such as P11A, NFKB1, TRAF3, and IKB, will be 
assessed. Recent data have identified host variation, specifically germline DNA variants in 
proteasome subunits[64] and the NFB pathway,[65] as potential important contributors to 
PI clinical activity. 
Details regarding the preparation, handling, and shipping of samples are provided in the 
Study Manual.


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7.4.19
   
Imaging Assessments
Skeletal survey of disease will be performed at screening (within 8 weeks before 
randomization is acceptable). At least the following areas should be assessed: head, neck, 
chest, abdomen, pelvis, arms, and legs. For patients with documented extramedullary 
disease at the time of diagnosis, other assessments and scans, such as a CT, positron 
emission tomography (PET)CT, or MRI, may be required to better delineate the sites and 
measurements of extramedullary disease at the time of screening. This imaging will also be 
used to delineate the extent of bone disease, sites and measurements of extramedullary 
disease, and PET positivity consistent with active MM. Additional assessments can be 
performed at the discretion of the investigator (ie, for suspected new lesions or PD or CR). 
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. 
7.4.20
   
Quantification of M-Protein
A blood sample and urine sample will be obtained at screening and at the time points 
specified in the Schedule of Events. 
Upon implementation of Amendment 07, all central laboratory assessments of response and 
progression are discontinued. Investigators should continue to assess disease 
response/progression according to IMWG criteria (including use of local efficacy laboratory 
measures), as well as initial disease progression, PFS2, and start of subsequent therapies. 
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 specified in the Schedule of Events. Quantitative IgD 
and IgE will be performed 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). 
Upon implementation of Amendment 07, this sample is no longer needed. 
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 Schedule of Events.
Upon implementation of Amendment 07, all central laboratory assessments of response and 
progression are discontinued. Investigators should continue to assess disease 
response/progression according to IMWG criteria (including use of local efficacy laboratory 
measures) for documentation of initial disease progression and PFS2. 
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 Schedule of Events. Undetectable M-protein by 


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protein electrophoresis in both serum and urine will lead the central laboratory to perform 
immunofixation testing in both serum and urine.
Upon implementation of Amendment 07, all central laboratory assessments of response and 
progression are discontinued. Investigators should continue to assess disease 
response/progression according to IMWG criteria (including use of local efficacy laboratory 
measures) for documentation of initial disease progression and PFS2.
7.4.24
   
Disease Response Assessment
Patients will be assessed for disease response according to the IMWG uniform response 
criteria, version 2011 (see Section 15.12).[66]
Response assessments are made on the basis of central laboratory data and should occur at 
Day 1 of every cycle during the Treatment period beginning with Cycle 2 Day 1, at EOT, 
and every 4 weeks during the PFS Follow-up period until PD (see the Schedule of Events). 
Upon implementation of Amendment 07, all central laboratory assessments of response and 
progression are discontinued. Investigators should continue to assess disease response/ 
progression according to IMWG criteria (including use of local efficacy laboratory 
measures) for documentation of initial disease progression and PFS2 (see the updated 
Schedule of Events for Amendment 07).
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
Complete response must be confirmed with follow-up assessments of serum protein 
electrophoresis, urine protein electrophoresis, immunofixation of blood and urine, and serum 
free light chains as outlined in Section 15.12. One bone marrow assessment must occur to 
document CR; no second bone marrow confirmation of CR is needed. 
Please note that to determine a response of stringent CR, bone marrow 
immunohistochemistry or immunofluorescence for kappa/lambda ratio should be performed 
for all patients suspected to be in CR to meet this response category’s requirements.
As of Amendment 07, no central laboratory bone marrow assessment is required to 
document CR.
At any point during treatment, patients suspected of having PD will have response 
assessments repeated to confirm PD (ie, 2 sets of response assessments at least 1 week apart).


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7.4.25
   
Pharmacokinetic Measurements
Plasma concentrations of ixazomib (the complete hydrolysis product of ixazomib citrate) 
will be measured using a validated liquid chromatography tandem-mass spectrometry assay. 
Details regarding the preparation, handling, and shipping of the PK samples are provided in 
the Study Manual. Blood samples (3 mL) for the determination of plasma concentrations of 
ixazomib (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.
Upon implementation of Amendment 07, no further PK sample collection will be performed, 
as all ongoing patients have completed at least 10 cycles of treatment. The PK Sampling 
Schedule has been moved to Section 15.13 for reference. 
7.4.26
   
Follow-up Assessment for Progression-Free Survival, Progressive 
Disease, Progression-Free Survival 2, and Overall Survival
At EOT, patients will enter a Follow-up period for PFS, PD, PFS2, and/or OS. See the 
Schedule of Events for assessments during each period. See the Study Overview 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.
7.4.26.1    
Progression-Free Survival Follow-up and Progressive Disease Follow-up
Patients who complete 24 months 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 
next-line therapy by the investigator/treating physician.
Upon implementation of Amendment 07 in the PFS and PD Follow-up periods, the EORTC 
QLQ-C30, EORTC QLQ-MY20, and EQ-5D-5L questionnaires and the HU assessment will 
be administered every 12 weeks.
7.4.26.2    
Progression-Free Survival 2 Follow-up and Overall Survival Follow-up
Patients who start next-line therapy (regardless of when) will enter the PFS2 Follow-up 
period. The next-line 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. 


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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. 
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 all 
MM treatments (drug regimen, interval, dose, start/stop date). 
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 
posttreatment follow-up. In addition, new primary malignancies that occur during 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. 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 the maximum treatment duration of approximately 24 months

Progressive disease or death at any time after the completion of Cycle 1
Before an investigator discontinues a patient from treatment for PD, the pertinent data must 
be confirmed by a Takeda project clinician or designee. Patients will attend an EOT visit 30 
days (1 week) after receiving their last dose of the study drug and will continue to be 
followed for other follow-up assessments specified in the Schedule of Events. Also refer to 
the Schedule of Events for EOT visit assessments.
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. The study will be considered complete after all 
patients have completed the OS Follow-up period (ie, all patients have died or the study has 
been terminated) or withdrawn from the study (see Section 7.10).


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7.9
   
Discontinuation of Treatment With Study Drug
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 or investigator

Lost to follow-up

Pregnancy (patient must be discontinued)

Other
Once study drug has been discontinued, all study procedures outlined for the EOT visit will 
be completed as specified in the Schedule of Events. 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:

Lost to follow-up

Study terminated by sponsor

Withdrawal by patient

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.


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8.0
   
STATISTICAL AND QUANTITATIVE ANALYSES
The first IA has been conducted (data cutoff date 12 August 2019) and the primary endpoint 
of PFS based on IRC assessment was statistically significant. The description of statistical 
methods and analyses presented below reflects the full design of the study so to retain all 
statistical considerations. 
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 percentage per category for categorical data. The 
Kaplan-Meier (K-M) 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. 
Details for the statistical analysis will be provided in the statistical analysis plan (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 whether ixazomib improves PFS as 
compared with placebo. To obtain an adequate statistical power for OS, however, the study 
will not be stopped after the PFS analysis even if a significant PFS is observed.
A total of approximately 700 patients will need to be randomized in a 3:2 ratio into the 2 
treatment arms, assuming an average enrollment rate of approximately 9 patients/month for 
the first 12 months and approximately 20 patients/month thereafter. The total sample size is 
calculated on the basis of 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 
FA (and the only analysis) for PFS for statistical testing purposes. If the test for PFS is 
significant at the first IA, then OS will be tested at this first IA and at the subsequent IA, and 
at the FA if needed.
The first IA for OS (FA for PFS) will be performed when approximately 392 IRC-assessed 
PFS events have been observed or approximately 10 months after the last patient has been 
enrolled, whichever occurs later. The PFS will be tested in the ITT population with a 2-sided 
alpha = 0.04. In addition, PFS will be tested in parallel with 2-sided alpha = 0.01, using the 
Hochberg testing approach, in 3 prespecified subgroups: 1) ISS stage III, 2) patients aged 
≥75 years, and 3) patients who had a CR or VGPR to initial therapy.
With 392 IRC-assessed PFS events, the study will have 90% power to detect a hazard ratio 
for PFS of 0.71 (median PFS of 11 months for control vs 15.5 months with treatment) using 
a 2-sided log-rank test at a 2-sided alpha level of 0.04 and assuming a drop-out rate of 
approximately 20% at Month 20. This will be the FA for PFS for statistical testing purposes, 
with the opportunity to claim PFS benefit. If the test for PFS is not statistically significant in 
any population (in the ITT population or any of the 3 subgroups), the study will be deemed 
unsuccessful, and no further testing will be conducted. 


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If the test for PFS is significant at the first IA, OS will be tested. If the OS results are 
statistically significant at either the first or second IA, the study can be stopped early, and 
this OS analysis will be the FA for formal hypothesis testing of OS. Otherwise, 
determination of whether the final number of OS events might increase will occur at the 
second IA.
The total event size calculation for OS is based on the adaptive sample size reassessment 
approach, which, in this study, is an adaptive event size reassessment approach. The 
minimum event size of 295 death events is based on an optimistic assumption of a hazard 
ratio of 0.71 (ie, median OS of 70 months for the ixazomib arm vs 50 months for the 
placebo arm, for a 41% improvement with ixazomib), with 80% power at a 2-sided level of 
significance of 0.04. The O’Brien-Fleming alpha spending function (the Lan-Demets 
method) is used to calculate the significance boundary on the basis of the observed number 
of death events at each IA, with a total of 295 OS events for the FA.
The second IA for OS will be performed when approximately 206 death events have been 
observed. 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 393 death events. No futility analysis will be performed in the study. 
The event size adaptation rule is a prespecified stepwise function to avoid the problem of 
back calculation resulting from an 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 conduct of this study.
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, an enrollment code 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 4 factors: initial therapy (PI-containing or not), ISS stage before initial therapy 
(stage I or II vs stage III), age at time of randomization (<75 vs 75 years), and best 
response to initial therapy, as measured during screening (CR or VGPR vs PR).


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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 population: The Per-Protocol population is a subset of the ITT population. 
The Per-Protocol 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 Per-Protocol population will be made before 
unblinding 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, missing data will be 
imputed; imputation will be based primarily on published instrument-specific methods. 
Other missing data imputation methods such as last observation carried forward and 
multiple imputation may be explored as sensitivity analyses for patient-reported outcomes 
data.
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, sex, 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 testing order:
1. At the first IA—PFS as assessed by the IRC in the ITT population (primary 
endpoint) (see Section 8.1.1) and PFS as assessed by the IRC in 3 prespecified 
subgroups: a) ISS stage III; b) patients aged ≥75 years; and c) patients with a 
response of CR or VGPR to initial therapy;
2.
OS (key secondary endpoint) at the IAs or FA.
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). Due to the closed sequential 


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testing property, the family-wise type I error is strongly controlled for both the primary 
endpoint and key secondary endpoints (see Section 8.1.10).
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 the primary endpoint, PFS, will be based on the ITT population using 
IRC-assessed progression data. Progression-free survival is defined as the time from the date 
of randomization to the date of first documentation of PD or death from any cause, 
whichever occurs first. Patients without documentation of PD will be censored at the date of 
the last response assessment that is SD or better. 
PFS will be analyzed approximately 10 months after the last patient has been enrolled or 
when approximately 392 IRC-assessed 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 0.04. 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. 
Sensitivity analyses for PFS include:

Progression-free survival as assessed by the investigator will be analyzed in the ITT 
population.

Progression-free survival as assessed by the IRC will be analyzed in the Per-Protocol 
population if more than 5% patients are excluded from this analysis.
Progression-free survival assessed by the IRC using different censoring mechanisms (eg, not 
censoring for patients who discontinue treatment and go on alternative antineoplastic 
therapy) will be analyzed in the ITT population. Details of different censoring approaches 
will be included in the SAP.
Subgroup analyses will be performed for PFS relative to baseline stratification factors and 
demographic data such as sex, race, and age. In addition, a stepwise Cox model will be 
implemented to identify potential predictive factors using relevant demographic or 
diagnostic covariates. 
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 on the 
basis of 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 and control 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 


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K-M survival curves and K-M medians (if estimable), along with their 2-sided 95% CIs, will 
also be provided for each study group.
To adjust for the potential effects of subsequent therapies after patients discontinued study 
treatment, the following 2 methods may be used:

Marginal Structural Models (MSM) by Robins et al [67]

Inverse Probability of Censoring Weighted (IPCW) method by Robins and 
Finkelstein [68]
Subgroup analyses will be performed for OS relative to baseline stratification factors and 
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.
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 the study, duration of CR, TTP and PFS2, TTNT, the time to the end of 
next-line therapy, and duration of the next line of therapy.
Disease responserelated endpoints will be analyzed using IRC-assessed response rate.
Best Response During the Treatment Period
The percentage of each response category (CR, VGPR, and PR) and of the combination 
CR + VGPR will be determined. A chi-square test will be used to compare the best response 
during the treatment period between those 2 arms. 
Duration of Complete Response
Duration of CR is defined as the time from the date of randomization (for those who had a 
CR at randomization) or the date of CR (for those in whom CR was achieved during the 
treatment period) to the date of first documentation of PD. Responders without 
documentation of PD will be censored at the date of the last assessed CR. Duration of CR 
will be summarized descriptively using the K-M method.
Time to Progression
Time to progression is defined as the time from the date of randomization to the date of first 
documentation of PD. Patients without documentation of PD at the time of analysis will be 
censored at the date of the last response assessment. Time to progression will be analyzed on 
the basis of the ITT population using methods similar to those used for PFS.
Progression-Free Survival 2
Progression-free survival 2 is defined as PFS on next-line therapy: the time from 
randomization to objective disease progression on next-line treatment or death from any 
cause. Patients who do not have documented PD while on next-line therapy will be censored 


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at the date of the last assessment of SD or better. Progression-free survival 2 will be 
determined by the treating physician/investigator, and the analysis of PFS2 will be based on 
the ITT population using methods similar to those used for PFS.
Time to Next-Line Therapy
TTNT is defined as the time from the date of randomization to the date of the first dose of 
next-line antineoplastic therapy. TTNT will be analyzed on the basis of the ITT population. 
Patients who have not started next-line therapy will be censored at the last known contact 
date. 
Time to End of 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-line antineoplastic therapy. Time to end of next-line therapy will be 
analyzed on the basis of the ITT population. Patients who are still receiving next-line 
therapy will be censored at the date of the last dose. 
Correlation Between Frailty Status and Progression-Free Survival and Overall 
Survival
An unadjusted stratified Cox model including frailty status (fit, unfit, or frail) and treatment 
will be used to estimate the hazard ratio and 95% CIs for the treatment effect and frailty 
status using stratification factors for both PFS and OS. A status of fit will be compared with 
a status of unfit or frail.
Duration of the Next Line of Therapy
Duration of next-line therapy is defined as the time from the date of the first dose of the line 
of antineoplastic therapy coming after study treatment to the date of the last dose. Duration 
of next-line therapy will be analyzed for patients in the ITT population who actually 
received next-line therapy. Patients who are still receiving next-line therapy will be censored 
at the date of the last dose. Duration of next-line 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 the EORTC QLQ-C30 
and EORTC QLQ-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 minimally 
important difference 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.


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The change from baseline in subscale scores will be presented using cumulative distribution 
function figures. The subscale scores will also be analyzed using mixed models by 
incorporating the measurements across all available time points.
8.1.7.2
   
Health Economics Analysis Using Medical Resource Utilization and Utility
EQ-5D-5L scores will be summarized in descriptive statistics for treatment arms. 
Health utilization data will be summarized in descriptive statistics of medical encounters 
(length of stay, inpatient, outpatient, and reason) and number of missing days from work or 
other activities by patient and caregiver for treatment arms.
8.1.8
   
Pharmacokinetics/Pharmacodynamics/Biomarkers
8.1.8.1
   
Pharmacokinetic Analysis
Pharmacokinetic 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
   
Minimal Residual Disease Analysis
Minimal residual disease negativity is defined as the absence of MRD and MRD positivity is 
defined as the presence of MRD. The MRD assessment will be performed using BMA 
samples tested using both flow cytometry and sequencing methodologies. The conversion 
rate from MRD positive to MRD negative and the maintenance of MRD negativity will be 
assessed at Cycle 13 and at EOT (approximately 24 months [equivalent to 26 cycles, if no 
cycle delays]) and compared between the 2 arms. Minimal residual disease negativity will 
also be reported in all patients who achieve a CR, regardless of whether they receive 
ixazomib or placebo during the study. The rate of achievement of CR MRD negativity 
during maintenance will also be compared between the 2 treatment groups. 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 in the subset 
of patients for whom both readouts are available.
8.1.8.3
   
Biomarker Analysis
Progression-free survival, 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 NFB regulatory genes 
such as NFKB1, TRAF3, and IKB.
Overall Survival and Progression-Free Survival in High-Risk Populations 
Overall survival and PFS in high-risk populations, defined as patients carrying mutations 
including, but not limited to, del17, t(4;14), or t(14;16), will be analyzed using a 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 
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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

Drug-related TEAEs

Grade 3 or higher TEAEs

Grade 3 or higher drug-related TEAEs

The most commonly reported TEAEs (ie, those reported by 10% of all patients)

Serious adverse events
A listing of TEAEs 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. Eastern Cooperative Oncology Group 
Performance Scores will be summarized using a shift table.
Shift tables for laboratory parameters will be generated for changes in NCI CTCAE grade 
from baseline to the worst postbaseline value. Graphical displays of key safety parameters, 
such as scatter plots of baseline versus worst postbaseline values, may be used to understand 
the ixazomib safety profile.
All concomitant medications collected from the first dose of study drug throughout the study 
period will be classified to preferred terms according to the World Health Organization drug 
dictionary.
Additional safety analyses may be performed to most clearly enumerate rates of toxicities 
and to further define the safety profile of ixazomib.
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:


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
Incidence proportions, defined as the percentage of the subjects reporting any new 
primary malignancy in the Safety population with available information

Incidence rates, defined as 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, will be provided along with their 95% CIs. For 
incidence rates, the relative risks, along with their 95% CIs, will be calculated using an 
exponential regression model for lifetime data (assuming constant hazards). 
Because of the distinct nature of hematologic and nonhematologic neoplasms, and the 
emerging signals of new primary malignancies for IMiDs, analyses of new primary 
malignancies may be performed separately for hematologic and nonhematologic 
malignancies.
8.1.9.2
  
Time to Resolution and Improvement of Peripheral Neuropathy Events
Peripheral neuropathy is defined as the TEAE in the High Level Term of Peripheral 
neuropathies NEC (not elsewhere classified) according to MedDRA. 
A PN event is considered to be resolved if its final outcome is resolved with no subsequent 
PN event of the same Preferred Term occurring on the resolution date or on the day before 
and the day after. A PN event is considered to be improved if the event improves from the 
maximum grade; that is, 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 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 events; 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.
8.1.10
   
Interim Analyses
There are 2 planned IAs. The first IA will be performed when approximately 392 of the 
IRC-assessed PFS events have occurred or approximately 10 months after the last patient 
has been enrolled, whichever occurs later. This IA is expected to occur approximately 50 


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months after the first patient is enrolled. This is the primary analysis and the only analysis of 
PFS for statistical testing purposes and the first IA for OS. 
At the first IA, PFS will be tested in both the ITT population and in 3 prespecified 
subgroups. The subgroup testing strategy includes 2 major components: a) preservation of 
the ability to detect the overall treatment effect using a reduced overall significance level of 
alpha = 0.04, which will be used for the ITT population; and b) test of treatment effect for 
the 3 prespecified subgroups: 1) ISS stage III, 2) patients aged ≥75 years, and 3) CR or 
VGPR to initial therapy. Subgroup testing will be conducted using the remaining alpha = 
0.01 and the Hochberg procedure for multiplicity correction (refer to the SAP for proof of 
strong control of the Type I error rate). Because the size of the treatment effect may be 
substantially greater in a prespecified subgroup than in the overall study population, analysis 
of patients in each subgroup at a stringent significance level may still provide a statistically 
significant outcome. 
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).
If the test for PFS is not statistically significant in any population (the ITT or any of the 3 
subgroups), the study will be stopped.
The second IA will be performed when approximately 206 deaths (approximately 70% of 
the total expected 295 deaths, the minimal number of events for the OS final analysis) have 
been observed. 
For the testing of OS, alpha spending for the first and second IAs will always be based on 
the observed events (information fraction) and a total of 295 death events with a different 
adjustment of the critical value at OS FA testing (Cui, Hung, and Wang [CHW] test 
statistics [69] used for the primary analysis of OS at FA) based on the following scenarios:

If PFS in the ITT population is significant, and PFS in at least 1 subgroup is not 
significant, then OS in the ITT population will be tested using a total alpha of 0.04. 

If PFS in the ITT is significant and PFS in all 3 subgroups is significant, then OS in the 
ITT population will be tested with a total alpha of 0.05. 

If PFS in the ITT population is not significant, and PFS in at least 1 subgroup is 
significant, then no formal ITT OS testing will be conducted.
The family-wise error rate for the 4 null hypotheses for PFS and the 1 hypothesis for OS for 
the overall study population is controlled using a prespecified, 2-sided 0.05 level of 
significance. The proof of strong control of the type I error rate for testing PFS and OS in 
the ITT population and PFS in the subgroup populations is shown in the SAP. Because of 
the closed sequential testing property, the family-wise error rate is strongly controlled for 
both the primary endpoint and the 3 key secondary endpoints. 
The IAs will be conducted by the independent statistical center and will be presented for 
review to the IDMC. During the closed session of the IDMC meeting, 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 the final adaptation 


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decision to the sponsor’s executive committee. 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 the PFS Follow-up period; does not apply to PFS2 
assessment) from the study and determine disease status (response and PD). Data from the 
IRC will not be provided back to the investigators during the conduct of the study. 
As of Amendment 07, analysis of the primary endpoint of PFS has been completed for this 
study and no further IRC review of disease evaluation data will take place. 
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. If 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 receive 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 SAEs, 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.


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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
   
Adverse Event Definition
Adverse event (AE) means any untoward medical occurrence in a patient or subject 
administered a pharmaceutical product; the untoward medical occurrence does not 
necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product whether 
or not it is related to the medicinal product. This includes any newly occurring event, or a 
previous condition that has increased in severity or frequency since the administration of 
study drug.
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is 
considered by the investigator to be a clinically significant change from baseline. 
10.1.3
   
Serious Adverse Event Definition
Serious AE (SAE) means any untoward medical occurrence that at any dose:

Results in death.

Is life-threatening (refers to an AE in which the patient was at risk of death at the 
time of the event. It does not refer to an event which hypothetically might have 
caused death if it were more severe).

Requires inpatient hospitalization or prolongation of an existing hospitalization
(see clarification in the paragraph 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 


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drug abuse; any organism, virus, or infectious particle (eg, prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or nonpathogenic, is 
considered an infectious agent.
Overdose in and of itself is not an SAE. If an overdose results in an SAE, an SAE form 
should be completed and sent to Cognizant (refer to Section 10.2).
In this study, intensity for each AE, including any lab abnormality, will be determined using 
the NCI CTCAE, Version 4.03, effective date 14 June 2010.[63] Clarification should be 
made between an SAE and an AE that is considered severe in intensity (Grade 3 or 4), 
because the terms serious and severe are NOT synonymous. The general term severe is often 
used to describe the intensity (severity) of a specific event; the event itself, however, may be 
of relatively minor medical significance (such as a Grade 3 headache). This is NOT the 
same as serious, which is based on patient/event outcome or action criteria described above 
and is usually associated with events that pose a threat to a patient’s life or ability to 
function. A severe AE (Grade 3 or 4) does not necessarily need to be considered serious. For 
example, a white blood cell count of 1000/mm3 to less than 2000 is considered Grade 3 
(severe) but may not be considered serious. Seriousness (not intensity) serves as a guide for 
defining regulatory reporting obligations.
10.2
   
Procedures for Recording and Reporting Adverse Events and Serious 
Adverse Events
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 emailing or faxing the SAE Form within 24 hours after becoming 
aware of the event. The SAE Form, created specifically by Takeda, will be provided to each 
clinical study site. A sample of the SAE Form may be found in the Study Manual. Follow-
up information on the SAE or serious pretreatment event may be requested by Takeda. SAE 
report information must be consistent with the data provided on the eCRF.
The paper SAE forms should be submitted via fax (see fax numbers below) within 24 hours
of awareness. In case of fax, site personnel must confirm successful transmission of all 
pages and include an email address on the fax cover sheet so that an acknowledgment of 
receipt can be returned via email within 1 business day. Email submission of paper SAE 
forms with a PDF attachment should only be used in the case where fax is not possible 
within 24 hours of receiving the event. In case of email, site personnel must confirm 
successful transmission by awaiting an acknowledgment of the receipt via email within 1 
business day. If SAEs are reported via fax or by email, the EDC application must be updated 
as soon as possible with the appropriate information.


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SAE Reporting Contact Information
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 lab abnormality, will be determined using the 
NCI CTCAE, Version 4.03, effective date 14 June 2010.[63] The criteria are provided in the 
Study Manual.
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 Adverse Events and Period of Observation
Adverse events, 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. AEs 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).

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


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after administration of the last dose of study drug or the start of subsequent 
antineoplastic therapy, whichever occurs first, and recorded in the eCRF. After this 
period, only related SAEs must be reported to the Takeda Department of 
Pharmacovigilance or designee. Serious adverse events 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 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, whichever 
occurs first. The IDMC will also receive reports of all cases of new primary 
malignancies occurring during the trial. 
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 emailing or 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 or within 90 days of the patient’s last dose of study drug, the 
sponsor must also be contacted immediately by emailing or faxing a completed Pregnancy 
Form to the Takeda Department of Pharmacovigilance or designee (see Section 10.2). Every 
effort should be made to follow the pregnancy for the final pregnancy outcome.


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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 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
   
Electronic Case Report Form Completion 
Takeda or 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.
Electronic case report forms 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.
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 a designee, will retain the eCRF data and corresponding audit trails. A copy of 
the final archival eCRF in the form of a compact disk 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


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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 because of the COVID-19 
pandemic, alternative monitoring approaches such as remote source data verification or 
telephone contact may be used to ensure data quality and integrity and maintain patient 
safety. Alternative monitoring approaches should be used only where allowed by the local 
health authority and permitted by the IRB/IEC.
11.5
   
Ethical Considerations
The study will be conducted with the highest respect for the individual participants (ie, 
patients) according to the protocol, the ethical principles that have their origin in the 
Declaration of Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. 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 
either the patient or his/her guardian or 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.
Upon implementation of Amendment 07, patients on study treatment must be reconsented 
before dosing on Day 1 of the next full treatment cycle. Patients who are in one of the 
Follow-up periods must also be reconsented.
Written consent documents will embody the elements of informed consent as described in 
the Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with 
all applicable laws and regulations.
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 


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to eliminate an immediate hazard or hazards to patients. Takeda, or a 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 a designee, if circumstances 
permit, to discuss the planned course of action. Any departures from the protocol must be 
documented.
11.9
   
On-site Audits
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 a 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 Overdoses)
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 in and of themselves are not AEs. If a product complaint is associated 
with an SAE, a Takeda SAE Form should be completed and sent to Cognizant (refer to 
Section 10.2).
A medication error is a preventable event that involves an identifiable patient and that leads 
to inappropriate medication use, which may result in patient harm. Whereas overdoses 
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.


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Within 1 year after 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 after premature closure, Takeda must notify the competent authorities and 
IECs of any member state where the study is being conducted, providing the reasons for 
study closure.
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 by Takeda 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 C16021 Amendment 09: A Phase 3, Randomized, Placebo-Controlled,
Double-Blind Study of Oral Ixazomib Maintenance Therapy After Initial Therapy in 
Patients With Newly Diagnosed Multiple Myeloma Not Treated With Stem Cell 
Transplantation
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
   
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52nd ASH Annual Meeting and Exposition; 4-7 December; Orlando, FL.
65.
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.
66.
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.
67.
Robins JM, Hernan MA, Brumback B. Marginal structural models and causal 
inference in epidemiology. Epidemiology 2000;11(5):550-60.
68.
Robins JM, Finkelstein DM. Correcting for noncompliance and dependent censoring 
in an AIDS Clinical Trial with inverse probability of censoring weighted (IPCW) 
log-rank tests. Biometrics 2000;56(3):779-88.
69.
Cui H, Matsui K, Omura S, Schauer SL, Matulka RA, Sonenshein GE, et al. 
Proteasome regulation of activation-induced T cell death. Proceedings of the 
National Academy of Sciences of the United States of America 1997;94(14):7515-
20.
70.
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. 
Toxicity and response criteria of the Eastern Cooperative Oncology Group. 
American Journal of Clinical Oncology 1982;5(6):649-55.
71.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. 
Nephron 1976;16(1):31-41.


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72.
Knoben J, Anderson P. Handbook of Clinical Drug Data, 6th ed.: Drug Intelligence 
Pub, Inc.; 1988.
73.
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.
74.
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.
75.
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
   
Multiple Myeloma Diagnostic Criteria
International Myeloma Working Group 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.
15.2
   
Eastern Cooperative Oncology Group Scale for Performance Status
Grade
Description
0
Normal activity. Fully active, able to carry on all predisease performance without restriction
1
Symptoms but ambulatory. Restricted in physically strenuous activity, but ambulatory and 
able to carry out work of a light or sedentary nature (eg, light housework, office work)
2
In bed <50% of the time. Ambulatory and capable of all self-care, but unable to carry out any 
work activities. Up and about more than 50% of waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to 
bed or chair
5
Dead
Source: Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET et al. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5 (6):649-55.[70]


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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.[71]
15.4
   
Steroid Equivalent Doses
Approximate equivalent doses:
Steroid
Glucocorticoid
Anti-inflammatory
(mg)
Mineralocorticoid
(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.[72]


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15.5
   
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 nor 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.[73]
Abbreviations: ISS=International Staging System.
a There are two categories for stage II: serum ß2-microglobulin <3.5 mg/L but serum albumin <3.5 g/dL; or 
serum 2-microglobulin 3.5 to <5.5 mg/L irrespective of the serum albumin level.
15.6
   
Charlson Comorbidity Scoring System Without Age Weighting 
Source: Charlson et al. 1987.[9]


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15.7
   
Activities of Daily Living Index
Source: Hartford Institute of Geriatric Nursing, ConsultGeriRN.org, General Assessment Try This, accessed 24 
May 2014: Issue 2, Revised 2012 (consultgerirn.org/uploads/File/trythis/try_this_2.pdf): Katz Index of 
Independence in Activities of Daily Living.


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15.8
   
Instrumental Activities of Daily Living Index
Source: Hartford Institute of Geriatric Nursing, ConsultGeriRN.org, General Assessment Try This, accessed 24 
May 2014: Issue 23, Revised 2013 (consultgerirn.org/uploads/File/trythis/try_this_23.pdf): The Lawton 
Instrumental Activities of Daily Living Scale.


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15.9
   
European Organization for Research and Treatment of Cancer (EORTC 
QLQ-C30 (version 3)




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15.10    
European Organization for Research and Treatment of Cancer 
(EORTC) Multiple Myeloma Module (QLQ-MY20)




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15.11    
EQ-5D-5L


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15.12    
Response Criteria
Source: Rajkumar SV, et al. 2011.[74] (adapted from Durie et al.[66] and Kyle et al.[75] with permission).


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15.13 Full Schedule of Events and PK Sampling Schedule (Schedules Prior to Implementation of Amendment 07)
SCHEDULE OF EVENTS
Study Procedures
Screening
Treatment Period
EOTa
Follow-upb
28-Day Cyclesb
PFS
PD
PFS2
OS
Cycle
C1
C2
C3
C4–C5
C5c
C6-C26
Every 
4 Wk 
Until PD
Every 
4 Wk After 
PD Until 
Next-Line 
Therapy
Every 12 
Wk Until 
PD2 on 
Next-Line 
Therapy
Every 12 Wk 
After PD on 
Next-Line 
Therapy
Days
-28 to -1
1
8
15
1
8
1
1
8
1
Window
±2 Days
+1 Wk
±1 Wk
±1 Wk
±1 Wk
±1 Wk
Informed consent
X
Inclusion/exclusion 
Criteriad
X
Demographics
X
Complete medical 
history and disease 
staging
X
Complete physical 
examination, 
including for PN
X
X
Symptom-directed 
physical 
examination, 
including for PN
X
X
X
X
X
X
X
ECOG Performance 
Status
X
X
X
X
X
X
X
X
Frailty statuse
X
Vital signs
X
X
X
X
X
X
X
X
X
Height (cm)
X
Weight (kg)
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
C5c
C6-C26
Every 
4 Wk 
Until PD
Every 
4 Wk After 
PD Until 
Next-Line 
Therapy
Every 12 
Wk Until 
PD2 on 
Next-Line 
Therapy
Every 12 Wk 
After PD on 
Next-Line 
Therapy
Days
-28 to -1
1
8
15
1
8
1
1
8
1
Window
±2 Days
+1 Wk
±1 Wk
±1 Wk
±1 Wk
±1 Wk
M-protein (UPEP 
[24-hr urine])
X
Xn
X
X
X
X
X
X
X
SFLC assay
X
Xn
X
X
X
X
X
X
X
Immunofixation: 
serum and urineo
X
Xn
X
X
X
X
X
X
X
Quantification of Igp
X
Xn
X
X
X
X
X
X
X
Bone marrow 
aspiration (BMA)
Disease 
assessment 
BMA (local 
lab)q
X
MRD BMA in 
patients with 
confirmed or 
suspected CR
(central lab)r
X
X (C13)
X
Additional MRD BMA specimen is requested at the time of first CR (may be 
collected during the BMA procedure for CR confirmation)
Archival BMA 
samples
X 
(if N/A at 
this time, 
can be 
submitted 
later)


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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
C5c
C6-C26
Every 
4 Wk 
Until PD
Every 
4 Wk After 
PD Until 
Next-Line 
Therapy
Every 12 
Wk Until 
PD2 on 
Next-Line 
Therapy
Every 12 Wk 
After PD on 
Next-Line 
Therapy
Days
-28 to -1
1
8
15
1
8
1
1
8
1
Window
±2 Days
+1 Wk
±1 Wk
±1 Wk
±1 Wk
±1 Wk
Progressive 
disease BMA 
(local and 
central lab)t 
Progressive disease BMA specimen is requested at any time of progressive disease confirmation
Blood sample for 
germline DNA 
biomarker analysis
X
Abbreviations: BMA=bone marrow aspirate; C=study cycle; CT=computed tomography; ECG=electrocardiography; ECOG=Eastern Cooperative Oncology 
Group; EORTC=European Organization for Research and Treatment of Cancer; EOT=End of Treatment; EQ-5D-5L=5-level classification system of the 
EuroQol 5 Dimensional Health Questionnaire; HU=health utilization; Ig=immunoglobulins; MRD=minimal residual disease; MRI=magnetic resonance 
imaging; N/A=not available; OS=overall survival; PD=progressive disease (disease progression); PD2=second PD (on next-line therapy); PET=positron 
emission tomography; PFS=progression-free survival, defined as time from randomization to PD or death from any cause; PFS2=time from randomization to 
objective disease progression on next-line treatment or death from any cause; PN=peripheral neuropathy; QLQ-C30=Quality of Life Questionnaire Core 30 
(questions); QLQ-MY20=Quality of Life Questionnaire Multiple Myeloma Module (20 questions); SFLC=serum free light chain; SPEP=serum protein 
electrophoresis; UPEP=urine protein electrophoresis; wk=week(s).
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 Development Center Americas, Inc (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 Before an investigator discontinues a patient from treatment for PD, the pertinent data must be confirmed by a Takeda project clinician or designee.
b For Cycle 4 and 5 and Cycle 6 through 26 procedures, all cycles are meant unless numbers are given in parentheses, indicating the specific cycles meant. For 
PFS and PD follow-up, exceptions to the follow-up interval of every 4 weeks are given in parentheses.
c Cycle 5 Day 8 assessments should be done only for patients who have the dose escalated after Cycle 4.
d Confirmation of patient eligibility by the Takeda project clinician or designee is required before randomization.
e Patients’ frailty status is classified as fit, unfit, or frail on the basis of 4 components: age, the Katz Index of Independence in Activities of Daily Living, the 
Lawton Instrumental Activities of Daily Living Scale, and the Charlson Comorbidity Scoring System.[7-9]
f
Patient-reported outcomes and HU assessment (ie, number of medical encounters) should be completed before any other study procedures are performed or 


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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
C5c
C6-C26
Every 
4 Wk 
Until PD
Every 
4 Wk After 
PD Until 
Next-Line 
Therapy
Every 12 
Wk Until 
PD2 on 
Next-Line 
Therapy
Every 12 Wk 
After PD on 
Next-Line 
Therapy
Days
-28 to -1
1
8
15
1
8
1
1
8
1
Window
±2 Days
+1 Wk
±1 Wk
±1 Wk
±1 Wk
±1 Wk
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-5L questionnaire may be administered over the 
telephone.
g A skeletal survey to assess status of bone disease and extramedullary disease will be done at screening (within 8 weeks before randomization) for all patients. 
Additional assessments can be done at the discretion of the investigator (ie, for suspected increased or new bone lesions or PD). 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.
h Information about disease response/status should be collected during the PFS2 Follow-up period, until PD2 has occurred during next-line therapy.
i
Study drug must be initiated within 5 days after randomization. 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 (see Section 6.5). If dose escalation was inadvertently missed at Cycle 5, escalation at a later cycle may be performed with permission from 
the Takeda project clinician or designee.
j
When PN occurs, each subsequent monthly evaluation will record the grade of PN at that visit. (This is in contrast to other adverse events 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 the PN, 2) the start of a second-line alternative antineoplastic treatment, or 3) 6 months after PD has 
occurredwhichever occurs first.
k A serum pregnancy test will be performed for women of childbearing potential during screening, predose on Cycle 1 Day 1, and at the EOT visit, or more 
frequently as required per local regulations. 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 study drug is administered.
l
Clinical laboratory evaluations will be performed by a central laboratory (see Section 7.4.13 and the Laboratory Manual). For dosing decisions, local 
hematology and chemistry laboratory results may be used; however, samples must still be sent to the central laboratory also. Hematology and chemistry panels 
may be collected up to 3 days before Day 1 dosing and 24 hours before Day 8 and Day 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). 
m Blood samples for serology will be used to measure antibody levels against measles, varicella-zoster virus, and tetanus and to quantify B cells, T cells, and 
natural killer cells.


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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
C5c
C6-C26
Every 
4 Wk 
Until PD
Every 
4 Wk After 
PD Until 
Next-Line 
Therapy
Every 12 
Wk Until 
PD2 on 
Next-Line 
Therapy
Every 12 Wk 
After PD on 
Next-Line 
Therapy
Days
-28 to -1
1
8
15
1
8
1
1
8
1
Window
±2 Days
+1 Wk
±1 Wk
±1 Wk
±1 Wk
±1 Wk
n If the screening test was performed more than 14 days before the first dose, the test will be repeated at baseline.
o Immunofixation is also 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).
p Blood samples for IgM, IgG, and IgA will be obtained throughout the study at the time points specified. Quantitative IgD and IgE measurement will be done at 
screening (and baseline if needed) only, except for the rare patient who has IgD or IgE multiple myeloma, for whom quantitative measurement for that 
antibody will be done at the same time points as, and in addition to, IgM, IgG, and IgA measurements.
q BMA for disease assessment is to be evaluated at a local laboratory at screening. BMA with local assessment should be repeated if the patient has reduction of 
serum and urine M-protein consistent with possible CR or when indicated to investigate suspected PD.
r
In patients with confirmed or suspected CR at study entry, during the screening BMA procedure, an additional BMA sample for central evaluation of MRD 
will be collected. In addition, all patients in CR at Cycle 13 and at EOT (approximately 24 months [equivalent to 26 cycles, if no cycle delays]) will have BMA 
samples collected for MRD at those 2 time points (unless already done within the most recent 2 cycles); BMA samples for MRD will also be obtained in 
patients in CR who stop therapy before Cycle 26. For all other patients, when a BMA is performed to confirm suspected CR, an additional BMA sample for 
MRD will be collected. All BMA samples for MRD are required to be sent to the central laboratory for processing immediately after collection.
s Archival tumor material from the time of diagnosis and any available other prestudy time points (when the patient has a high disease burden) is to be used for 
the identification of the MM tumor clone, which will then be followed in the serial MRD BMA samples obtained during the study. The material should consist 
of BMA as unstained slides (preferred) or stained slides. Bone marrow biopsy samples will not be accepted. If not available at screening, the archival BMA 
sample may be submitted at any time during the study.
t
An additional BMA for patients who have PD is optional but highly recommended and should be collected at any time PD is suspected or before starting a new 
therapy. This marrow will be evaluated locally. In addition, when this BMA is collected to investigate suspected PD, a second pull for molecular analysis 
should be made and sent to the central laboratory immediately after collection.


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IXAZOMIB PHARMACOKINETIC SAMPLING SCHEDULE
Cycle 1
Cycle 2
Cycles 3-5
Cycle 5a
Cycles 6-10
Day 1
Day 8
Day 15
Day 1
Day 8
Day 1
Day 8
Day 1
1 Hour Postdose 
(15 Minutes)
4 Hours Postdose 
(45 Minutes)
Predoseb
Predoseb
Predoseb
Predoseb
Predoseb
Predoseb
Predoseb
X
X
X
X
X
X
X
X
X
a The Cycle 5 Day 8 sample should be obtained only for patients who have dose escalated after Cycle 4.
b All predose pharmacokinetic assessments should occur within 4 hours of dosing. If a predose sample is drawn from a patient and the patient does 
not receive a dose on that protocol visit day, a second predose sample does not need to be drawn on the subsequent visit where the dose is 
administered. All future visits should be done per the protocol.


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15.14 Detailed Description of Amendments to Text
The primary sections of the protocol affected by the changes in Amendment 09 are 
indicated. The corresponding text has been revised throughout the protocol.
Change 1: Change the legal entity name of the sponsor.
The change occurs on the Cover Page:
Initial 
wording:
Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda 
Pharmaceutical Company Limited
40 Landsdowne Street
Cambridge, MA 02139, USA
Telephone: +1 (617) 679-7000
Amended or 
new 
wording:
Takeda Development Center Americas, IncMillennium Pharmaceuticals, Inc, a 
wholly owned subsidiary of Takeda Pharmaceutical Company Limited
40 Landsdowne Street95 Hayden Avenue
CambridgeLexington, MA 02139421, USA
Telephone: +1 (617) 679-7000
Rationale for Change: To reflect the new legal entity name for the sponsor of Takeda 
Development Center Americas rather than Millennium.
The following sections also contain this change:

Schedule of Events.

List of Abbreviations and Glossary of Terms.

Section 1.1.1 Disease Under Treatment.

Section 1.1.2 Ixazomib: Takeda’s Next-Generation Proteasome Inhibitor.

Section 1.4.3.2 Dose Rationale.

Section 4.1 Overview of Study Design.

Section 5.1 Inclusion Criteria.

Section 6.3 Dose-Modification Guidelines.

Section 6.5 Criteria for Dose Escalation at Cycle 5.

Section 6.7 Permitted Concomitant Medications and Procedures.

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 Study Procedures.


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
Section 7.4.3 Medical History.

Section 7.4.13 Clinical Laboratory Evaluations.

Section 7.4.15   
Quality of Life Assessment (European Organization for Research and
Treatment of Cancer).
Change 2: Clarify language regarding procedures for reporting product complaints or 
medication errors.
The change occurs in Section 11.11 Product Complaints and Medication Errors (Including 
Overdoses):
Initial 
wording:
A product complaint is a verbal, written, or electronic expression that implies 
dissatisfaction regarding the identity, strength, purity, quality, or stability of a 
drug product. Individuals who identify a potential product complaint situation 
should immediately 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 


Ixazomib
Study C16021
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Protocol Incorporating Amendment 09
16 November 2021
Confidential
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, a Takeda SAE Form should be 
completed and sent to Cognizant (refer to Section 10.2).
A medication error is a preventable event that involves an identifiable patient 
and that leads to inappropriate medication use, which may result in patient 
harm. Whereas overdoses 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: To clarify proper reporting procedures for product complaints and 
medication errors.
Change 3: Clarify language in study conduct regarding the coronavirus disease 2019 (COVID-
19) pandemic.
The change occurs in Section 6.14 Storage, Handling, and Accountability:
Initial 
wording:
Study drug dispensed to the patient for take-home dosing should remain in the 
blister packaging and carton until the point of use. Patients are permitted to 
transport study drug from the site to home at room temperature. In case of 
extenuating circumstances that prevent a patient from attending the study site 
(eg, the coronavirus disease 2019 [COVID-19] pandemic), sites may use 
alternative strategies to deliver study drug to patients (eg, via courier or site 
staff), per local standard practice and regulations, and with prior approval from 
the investigator and sponsor’s project clinician/designee. Comprehensive 
instructions should be provided to the patient to ensure compliance with dosing 


Ixazomib
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Confidential
procedures. Patients who are receiving take-home medication ordinarily should 
be given only 1 cycle of medication at a time. More than 1 cycle of medication 
may be dispensed on a case-by-case basis for holidays, travel, or other 
circumstances upon discussion with the investigator and sponsor’s project 
clinician/designee (note: patients in France are only permitted to receive 1 
cycle of medication at a time). Patients should be instructed to store the 
medication according to the storage conditions that are indicated on the drug 
label. Patients should be instructed to return their empty or partially used
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. In case of extenuating circumstances 
that prevent a patient from attending the study site (eg, the COVID-19 
pandemic), drug packs and dosing diaries should be returned at the next 
available on-site clinic visit. Any excursions in temperature should be reported 
immediately and dealt with on a case-by-case basis. 
Amended or 
new 
wording:
Study drug dispensed to the patient for take-home dosing should remain in the 
blister packaging and carton until the point of use. Patients are permitted to 
transport study drug from the site to home at room temperature. In case of 
extenuatingIf circumstances due to the COVID-19 pandemicthat prevent a 
patient from attending the study site (eg, the coronavirus disease 2019 
[COVID 19] pandemic), sites may use alternative strategies to deliver study 
drug to patients (eg, via courier or site staff), per local standard practice and 
regulations, and with prior approval from the investigator and sponsor’s project 
clinician/designee. Comprehensive instructions should be provided to the 
patient to ensure compliance with dosing procedures. Patients who are 
receiving take-home medication ordinarily should be given only 1 cycle of 
medication at a time. More than 1 cycle of medication may be dispensed on a 
case-by-case basis for holidays, travel, or other circumstances upon discussion 
with the investigator and sponsor’s project clinician/designee (note: patients in 
France are only permitted to receive 1 cycle of medication at a time). Patients 
should be instructed to store the medication according to the storage conditions 
that are indicated on the drug label. Patients should be instructed to return their 
empty or partially used 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. In case of 
extenuating If circumstances due to the COVID pandemicthat prevent a 
patient from attending the study site (eg, the COVID-19 pandemic), drug packs 
and dosing diaries should be returned at the next available on-site clinic visit. 
Any excursions in temperature should be reported immediately and dealt with 
on a case-by-case basis. 
Rationale for Change: Clarified that alternative strategies can occur only for circumstances 
related to the COVID-19 pandemic.


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The following sections also contain this change:

Schedule of Events.

Section 7.4 Study Procedures.

Section 7.4.14 Health Utilization Data Collection.

Section 7.4.15   
Quality of Life Assessment (European Organization for Research and
Treatment of Cancer).

Section 7.4.16 Utility Measurement.
Change 4: Clarify local laboratory assessment recordings.
The change occurs in the Schedule of Events: 
Added text:
Added the following sentence to footnote "i":
Local laboratory assessments are not recorded in the electronic data
capture (EDC).
Rationale for Change: Clarified that local laboratory assessments are not recorded in the 
EDC.



SAP_000.pdf: 


Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title:  Phase 3, Randomized, Placebo-Controlled, Double-Blind Study of Oral Ixazomib 
Maintenance Therapy After Initial Therapy in Patients With Newly Diagnosed Multiple 
Myeloma Not Treated With Stem Cell Transplantation
NCT Number: NCT02312258
SAP Approve Date: 20 September 2019
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable (PPD) information 
or company confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.


Ixazomib 
Statistical Analysis Plan, Study C16021
1
STATISTICAL ANALYSIS PLAN
A Phase 3, Randomized, Placebo-Controlled, Double-Blind Study of Oral Ixazomib 
Maintenance Therapy After Initial Therapy in Patients With Newly Diagnosed Multiple 
Myeloma not Treated With Stem Cell Transplantation
Protocol #: C16021
SAP Version:
Date of Statistical Analysis Plan:
Final 1.0
20 September 2019
Approval Signatures
Date
Date
Date
Date
Date
PPD
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ble
rm
ci
Date
Date
n
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Ixazomib 
Statistical Analysis Plan, Study C16021
2
TABLE OF CONTENTS
LIST OF TABLES...............................................................................................................3
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS ............................................4
1. INTRODUCTION............................................................................................................6
1.1 Study Design..............................................................................................................6
1.2 Study Objectives ........................................................................................................7
2. POPULATIONS FOR ANALYSIS..................................................................................9
2.1 Intent-to-Treat Population...........................................................................................9
2.2 Safety Population .......................................................................................................9
2.3 Per-Protocol (PP) population ....................................................................................10
3. HYPOTHESES AND DECISION RULES.....................................................................10
3.1 Statistical Hypotheses...............................................................................................10
3.2 Statistical Decision Rules .........................................................................................10
4. INTERIM ANALYSIS...................................................................................................11
4.1 Interim Analysis .......................................................................................................11
4.2 Independent Data Monitoring Committee.................................................................13
4.3 Independent Review Committee...............................................................................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 Baseline Disease Characteristics.................................................20
5.6.1 Demographics....................................................................................................20
5.6.2 Medical History.................................................................................................21
5.6.3 Disease Status at Initial Diagnosis......................................................................21
5.6.4 Disease Status at Study Entry.............................................................................21
5.6.5 Bone Marrow Cytogenetic at Initial Diagnosis...................................................22
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......................................................................27
5.8.3 Other Secondary Efficacy Endpoints and Analyses ............................................29
5.9 Pharmacokinetic and Biomarker Analysis.................................................................33
5.9.1 Pharmacokinetic Analyses .................................................................................33
5.9.2 Biomarker Analysis ...........................................................................................33
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Statistical Analysis Plan, Study C16021
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5.9.3 Minimal Residual Disease Analysis ...................................................................33
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....37
5.11 Safety Analyses ......................................................................................................38
5.11.1 Adverse Events................................................................................................38
5.11.2 Laboratory Data...............................................................................................41
5.11.3 Electrocardiograms ..........................................................................................42
5.11.4 Vital Signs .......................................................................................................42
5.11.5 Eastern Cooperative Oncology Group (ECOG) Performance Status .................42
5.11.6 Other Safety Assessments ................................................................................43
6. CHANGES TO PLANNED ANALYSES FROM PROTOCOL .....................................43
7. PROGRAMMING CONSIDERATIONS .......................................................................43
7.1 Statistical Software...................................................................................................43
7.2 Rules and Definitions ...............................................................................................43
8. REFERENCES...............................................................................................................44
LIST OF TABLES
Table 5-1 
Censoring Rules for PFS Primary Analysis Based on FDA Guidance..........25
Table 5-2 
Handling of missing assessment and censoring for PFS Sensitivity 
Analysis based on EMA guidance ...............................................................26
Table 5-3 
List of subgroups.........................................................................................27
Table 5-4 
Censoring for PFS2 For Those Who have Received Second line Therapy 
following Study Treatment..........................................................................31
Table 5-5 
Censoring for PFS2 for Those Who have not received Second Line of 
Therapy.......................................................................................................31
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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Ixazomib 
Statistical Analysis Plan, Study C16021
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LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS
Abbreviation
Term
AE
adverse event
AECI
adverse event clinical importance
AESI
adverse event special interest
ALC
absolute lymphocyte count
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical
BM
bone marrow
BMA
bone marrow aspirate
BUN
blood urea nitrogen
CDF
cumulative distribution function
CI
confidence interval
CO2
carbon dioxide
CR
complete response 
del
deletion
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EORTC QLQ-
MY20
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire Multiple Myeloma Module
EORTC QLQ-C30
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire Core 30
EOT
End of Treatment (visit)
EQ-5D
EuroQol 5-Dimensional Health Questionnaire
EQ-5D-5L
5-Level classification system of the EuroQol 5-Dimensional Health Questionnaire
FA
final analysis
FLC
free light chain
HR
hazard ratio
HRQOL
health related quality of life
HU
health utilization
IA
interim analysis
IDMC
independent data monitoring committee
IMiD
immunomodulating drugs
IMWG
International Myeloma Working Group
IPCW
Inverse Probability of Censoring Weighted
IRC
independent review committee
ISC
independent statistical center
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Ixazomib 
Statistical Analysis Plan, Study C16021
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Abbreviation
Term
ISS
International Staging System
ITT
intent-to-treat
IXRS
interactive web/voice response system
LDH
lactate dehydrogenase
LOCF
last observation carried forward
MedDRA
Medical Dictionary for Regulatory Activities
MID
minimally important difference
MM
multiple myeloma
MRD
minimal residual disease
MSM
marginal structural model
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NDMM
newly diagnosed multiple myeloma
NEC
not elsewhere classified
NFB
nuclear factor kappa-light-chain-enhancer of activated B cells
NK
natural killer (cells)
NPM
new primary malignancy
OS
overall survival
PD
progressive disease 
PFS
progression-free survival
PFS2
time from randomization to objective disease progression on next-line treatment or 
death from any cause
PK
pharmacokinetic(s)
PN
peripheral neuropathy
PP
per-protocol
PR
partial response 
PRO
patient-reported outcome
RISS
Revised International Staging System
SAE
serious adverse event
SAP 
statistical analysis plan
SCT
stem cell transplant/therapy
SD
stable disease
TEAE
treatment-emergent adverse event
TTNT
time to next-line therapy
TTP
time to progression
VGPR
very good partial response
VZV
varicella-zoster virus
WBC
white blood cell (count)
WHO
World Health Organization
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Ixazomib 
Statistical Analysis Plan, Study C16021
6
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 and
analytical deficiencies. Specifically, this plan has the following purpose:
To prospectively (a priori) 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 phase 3, randomized, double-blind, placebo-controlled, multicenter study in 
patients with newly diagnosed multiple myeloma (NDMM) not receiving stem cell 
transplantation (SCT). Patients who have not undergone SCT may not have done so because 
of frailty due to advanced age (eg, ≥65 years) or comorbidity or because they declined SCT 
for other reasons.
Patients must have received initial therapy, for 6 to 12 months, according to standard of care 
before study enrollment and have been treated to a major response category (partial response 
[PR] or better) that is judged to be their best response by the investigator/treating physician.
Partial response, very good partial response (VGPR), or complete response (CR) must be 
documented at screening, and patients must have met all additional inclusion/exclusion 
criteria. Eligible and consenting patients are to be randomized no later than 60 days after the 
last dose of initial therapy. Randomization will occur in a 3:2 ratio of ixazomib or matching 
placebo. Approximately 700 patients are planned to be enrolled in this study. 
There are 4 stratification factors: initial therapy (proteasome-inhibitor–containing or not), 
International Staging System (ISS) status before initial therapy (stage I or II vs stage III), 
age (< 75 vs ≥75 years) at randomization, and response to initial therapy as measured 
during screening (CR or VGPR vs PR).
Patients will receive blinded ixazomib or matching placebo capsules (both hereafter referred 
to as “study drug”) orally on Days 1, 8, and 15 of every 28-day cycle. The starting dose will 
be 3 mg of study drug, which—if tolerated during the first 4 cycles—will be escalated to 
4 mg beginning with Cycle 5 Day 1. The treatment period will be approximately 24 months 
(equivalent to 26 cycles [if no cycle delays], to the nearest complete cycle) or until patients 
experience PD or unacceptable toxicity, whichever occurs first.
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Ixazomib 
Statistical Analysis Plan, Study C16021
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The primary endpoint of progression-free survival (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 and the first IA for OS. The second IA and the 
FA are for OS. An independent data monitoring committee (IDMC) will review safety and 
efficacy data at the IAs and safety data at regularly scheduled meetings. An independent 
review committee (IRC) will assess disease response or progressive disease (PD) according 
to the International Myeloma Working Group (IMWG) uniform response criteria, version 
2011 [1].
1.2
Study Objectives
The primary objective is:

To determine the effect of ixazomib maintenance therapy on PFS, defined as the time 
from randomization to PD or death from any cause, compared with placebo, in patients 
with NDMM who have had a major response defined as CR, VGPR, or PRto initial 
therapy and who have not undergone SCT
The key secondary objective is:

To determine the effect of ixazomib maintenance therapy on overall survival (OS)
compared with placebo
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 and on 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 the time from randomization to objective disease progression on next-
line treatment or death from any cause

To determine the effect of ixazomib maintenance therapy on the time to next-line 
therapy (TTNT)

To determine the effect of ixazomib maintenance therapy on the time to end of next-line 
therapy

To determine the effect of ixazomib maintenance therapy on duration of next-line 
therapy
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Statistical Analysis Plan, Study C16021
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∀
To assess the incidence of new primary malignancy in patients receiving ixazomib 
maintenance therapy
∀
To evaluate the frequency of conversion from minimal residual disease (MRD) positive 
to MRD negative, or the maintenance of MRD negativity, using 8-color flow cytometry 
∀
To assess the correlation between MRD status (detected using 8-color flow cytometry) 
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 including, but not limited to, del17, t(4;14), and t(14;16) 
∀
To determine the long-term safety and tolerability of ixazomib maintenance therapy
∀
To assess health-related quality of life (HRQOL) as measured by the global health 
domain of the European Organization for Research and Treatment of Cancer Quality of 
Life Questionnaire Core 30 (EORTC QLQ-C30) in patients who receive ixazomib 
maintenance therapy 
∀
To assess the correlation between frailty status and PFS and OS in patients receiving 
ixazomib maintenance therapy
∀
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, 
in patients receiving ixazomib maintenance therapy
The exploratory objectives are:
CCI
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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Ixazomib 
Statistical Analysis Plan, Study C16021
9
2.
POPULATIONS FOR ANALYSIS
2.1
Intent-to-Treat Population
The Intent-to-Treat (ITT) population is defined as all patients who are randomized with post 
randomization data available. Patients will be analyzed according to the treatment they were
randomized to receive, regardless of any errors of dosing.
The ITT population will be used for the primary, secondary efficacy analyses, and resource 
utilization and patient-reported outcome (PRO) analyses.
2.2
Safety Population
The safety population is defined as all patients who receive at least 1 dose of ixazomib or 
placebo. Patients will be analyzed according to the treatment they actually receive. Patients 
who receive any dose of ixazomib will be included in the ixazomib arm, and patients who 
only receive 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 medications, laboratory tests, and vital signs.
CCI
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Ixazomib 
Statistical Analysis Plan, Study C16021
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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 affect 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
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, with the following testing order:
1. At the first IA—PFS as assessed by the IRC in the ITT population (primary endpoint) 
and PFS as assessed by the IRC in 3 prespecified subgroups: a) ISS stage III; b) patients 
aged ≥75 years; and c) patients with a response of CR or VGPR to initial therapy;
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Statistical Analysis Plan, Study C16021
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2.
OS (key secondary endpoint) at the IAs or FA.
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 [2]). The initial alpha allocation 
and propagation of alpha across ITT PFS, Subgroup PFS, and ITT OS is detailed in the 
graph below. Because this graph leads to a consonant testing procedure, family-wise type I 
error rate is strongly controlled for all three endpoints (Bretz and Maurer, 2009[3]). 
The testing procedure will proceed as follows. First, α= 0.04 and α= 0.01 will be assigned to 
test PFS in the ITT population and 3 pre-specified subgroups, respectively. If PFS in ITT 
test is significant, then α= 0.04 originally assigned to PFS in ITT will be propagated (i.e. 
relocated) to OS test in ITT. Similarly, if PFS is tested significantly in all 3 subgroups, then 
α= 0.01 originally assigned to PFS in subgroups will be propagated to test OS in ITT 
population. Although the graphical approach allows OS to be tested at α= 0.01 in the event 
that PFS in all 3 subgroups is significant, but PFS in the ITT population is not, the study 
may be stopped due to the fact that PFS in ITT is not significant.
All other efficacy endpoints will be tested at a 2-sided alpha level of 0.05.
4.
INTERIM ANALYSIS
4.1
Interim Analysis
There are 2 planned IAs. The first IA will be performed when approximately 392 of the 
IRC-assessed PFS events have occurred or approximately 10 months after the last patient 
has been enrolled, whichever occurs later. This IA is expected to occur approximately 50 
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Statistical Analysis Plan, Study C16021
12
months after the first patient is enrolled. This is the primary analysis and the only analysis of 
PFS for statistical testing purposes and the first IA for OS. 
At the first IA, PFS will be tested in both the ITT population and in 3 prespecified 
subgroups. The subgroup testing strategy includes 2 major components: a) preservation of 
the ability to detect the overall treatment effect using a reduced overall significance level of 
alpha = 0.04, which will be used for the ITT population; and b) test of treatment effect for 
the 3 prespecified subgroups: 1) ISS stage III, 2) patients aged ≥75 years, and 3) CR or 
VGPR to initial therapy. Subgroup testing will be conducted using the remaining alpha = 
0.01 and the Hochberg procedure for multiplicity correction (refer to the Section 3.2 for 
proof of strong control of the Type I error rate). Because the size of the treatment effect may 
be substantially greater in a prespecified subgroup than in the overall study population, 
analysis of patients in each subgroup at a stringent significance level may still provide a 
statistically significant outcome. 
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).
If the test for PFS is not statistically significant in any population (the ITT or any of the 3 
subgroups), there will be no formal hypothesis conducted afterwards. 
The second IA will be performed when approximately 206 deaths (approximately 70% of 
the total expected 295 deaths, the minimal number of events for the OS final analysis) have 
been observed. 
For the testing of OS, alpha spending for the first and second IAs will always be based on 
the observed events (information fraction) and a total of 295 death events with a different 
adjustment of the critical value at OS FA testing (Cui-Hung-Wang test statistics [4] used for 
the primary analysis of OS at FA) based on the following scenarios:

If PFS in the ITT population is significant, and PFS in at least 1 subgroup is not 
significant, then OS in the ITT population will be tested using a total alpha of 0.04. 

If PFS in the ITT is significant and PFS in all 3 subgroups is significant, then OS in the 
ITT population will be tested with a total alpha of 0.05. 

If PFS in the ITT population is not significant, and PFS in at least 1 subgroup is 
significant, then no formal ITT OS testing will be conducted.
The family-wise error rate for the 4 null hypotheses for PFS and the 1 hypothesis for OS for 
the overall study population is controlled using a prespecified, 2-sided 0.05 level of 
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Statistical Analysis Plan, Study C16021
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significance. The proof of strong control of the type I error rate for testing PFS and OS in 
the ITT population and PFS in the subgroup populations is shown in Section 3.2. Because of 
the closed sequential testing property, the family-wise error rate is strongly controlled for 
both the primary endpoint and the key secondary endpoint. 
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 [4] will be used 
in the FA of OS to protect the type I error.
4.2
Independent Data Monitoring Committee
An independent data monitoring committee (IDMC) supported by an independent 
statistician from an independent statistical center (ISC) will review safety and efficacy data 
at planned IAs. The IDMC will provide a recommendation regarding study continuation 
based on the safety and efficacy parameters. If the study is terminated early on the basis of
the IDMC recommendation, the sponsor 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 (36 in the ixazomib 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 prespecified in the IDMC charter.
Study accrual will not be interrupted because of the scheduled safety reviews. The IDMC or
ixazomib study team may request an ad hoc meeting for any reason, including a significant
unexpected safety event, unplanned unblinding of study results, follow-up of an observation
during a planned IDMC meeting, or a report external to the study, such as publication of
study results from a competing product. At each review, subject incidence rates of AEs
(including all serious AEs [SAEs], treatment-related AEs, serious treatment-related events, 
and events resulting in the 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 safety 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 
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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.
4.3
Independent Review Committee
An independent review committee (IRC), blinded to treatment arm assignments and 
investigator determination of response, 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), according to IMWG 
criteria [1] as specified in the IRC charter. IRC will not review disease evaluation data 
during next line therapy for those patients who have reached PD2. 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 will be displayed by
the number of observations, mean, and standard deviation, median, minimum, and 
maximum for continuous variables, and the number and percentage per category for 
categorical data. The Kaplan-Meier (KM) survival curves and 25th, 50th (median), and 75th 
percentiles will be provided along with their 2-sided 95% confidence intervals (CIs) for 
time-to-event data.
5.1
Sample Size Justification
The primary objective of this study is to determine whether ixazomib improves PFS as 
compared with placebo. To obtain an adequate statistical power for OS, however, the study 
will not be stopped after the PFS analysis even if a significant PFS is observed.
A total of approximately 700 patients will need to be randomized in a 3:2 ratio into the 2 
treatment arms, assuming an average enrollment rate of approximately 9 patients/month for 
the first 12 months and approximately 20 patients/month thereafter. The total sample size is 
calculated on the basis of 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 
FA (and the only analysis) for PFS for statistical testing purposes. If the test for PFS is 
significant at the first IA, then OS will be tested at this first IA and at the subsequent IA, and 
at the FA if needed.
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The first IA for OS (FA for PFS) will be performed when approximately 392 IRC-assessed 
PFS events have been observed or approximately 10 months after the last patient has been 
enrolled, whichever occurs later. The PFS will be tested in the ITT population with a 2-sided 
alpha = 0.04. In addition, PFS will be tested in parallel with 2-sided alpha = 0.01, using the 
Hochberg testing approach, in 3 prespecified subgroups: 1) ISS stage III, 2) patients aged 
≥75 years, and 3) patients who had a CR or VGPR to initial therapy.
With 392 IRC-assessed PFS events, the study will have 90% power to detect a hazard ratio 
for PFS of 0.71 (median PFS of 11 months for control vs 15.5 months with treatment) using 
a 2-sided log-rank test at a 2-sided alpha level of 0.04 and assuming a drop-out rate of 
approximately 20% at Month 20. This will be the FA for PFS for statistical testing purposes, 
with the opportunity to claim PFS benefit. If the test for PFS is not statistically significant in 
any population (in the ITT population or any of the 3 subgroups), the study will be deemed 
unsuccessful, and no further testing will be conducted. 
If the test for PFS is significant at the first IA, OS will be tested. If the OS results are 
statistically significant at either the first or second IA, the study can be stopped early, and 
this OS analysis will be the FA for formal hypothesis testing of OS. Otherwise, 
determination of whether the final number of OS events might increase will occur at the 
second IA.
The total event size calculation for OS is based on the adaptive sample size reassessment 
approach, which, in this study, is an adaptive event size reassessment approach. The 
minimum event size of 295 death events is based on an optimistic assumption of a hazard 
ratio of 0.71 (ie, median OS of 70 months for the ixazomib arm vs 50 months for the 
placebo arm, for a 41% improvement with ixazomib), with 80% power at a 2-sided level of 
significance of 0.04. The O’Brien-Fleming alpha spending function (the Lan-Demets 
method) is used to calculate the significance boundary on the basis of the observed number 
of death events at each IA, with a total of 295 OS events for the FA.
The second IA for OS will be performed when approximately 206 death events have been 
observed. 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 393 death events. No futility analysis will be performed in the study. 
The event size adaptation rule is a prespecified stepwise function to avoid the problem of 
back calculation resulting from an event size corresponding to either barely promising or 
highly promising interim results. The event size adaptation rule will be designed by the 
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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 conduct of this study.
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).
5.2
Randomization and Stratification 
The randomization scheme will be generated by an independent statistician 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 interactive voice/web response system
(IXRS).
Eligible patients will be randomized in a 3:2 ratio to receive ixazomib or placebo treatment 
arms, stratified by initial therapy (proteasome inhibitor-containing or not), ISS status before 
initial therapy (stage I or II vs stage III), age (< 75 vs 75 years) at randomization, and best 
response to initial therapy (CR or VGPR vs PR) assessed by 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 the IDMC by an ISC. The
formal IA analyses will also be conducted by an ISC for the IDMC. One unblinded 
submission working group might be formed to prepare a submission package and/or work 
with Agencies for submission purposes at IA. 
Refer to Section 4.2 for the roles and responsibilities of the 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.
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In general, missing data will be treated as missing, and no data imputation will be applied,
unless otherwise specified. For PRO data, primarily missing data imputation will be based 
on published instrument specific methods. Other missing data imputation methods such as 
last observation carried forward (LOCF) and the multiple imputation method may be 
explored as sensitivity analyses for PRO data.
5.4.1.1
Missing/Partial Dates in Screening Visit
The following rules apply to dates recorded during the Screening visits:

If only the day component is missing, the first day of the month will be used if the year 
and the month are the same as those for the first dose of study drug. Otherwise, the 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 indicate that the date is earlier. 

If only a year is present, and it is not the same as the year of the first dose of study drug, 
the 15th of June will be used, unless other data indicate that the date is earlier.
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
–
If month and year are the same as month and year of first dose date, then impute to 
first dose date 
–
If month and year are different than month and year of first dose date, then impute to 
first date of the month 

If year is known but day and month are missing
–
If year is same as year of 1st dose date, then 1st dose date will be used instead
–
If year is different than year of 1st dose date, then 1st of January of the year will be 
imputed. 

If all is missing, then it is imputed with 1st dose date.
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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,
–
If YYYY < year of last dose, then 31st of December will be imputed
–
If YYYY = year of last dose, then 31st of December will be imputed 
–
If YYYY > year of last dose, then 1st of January will be imputed 

If all are missing, then impute date to 31st of December, in the year of last dose.
Imputing missing AE stop date is not mandatory if AE is regarded as ongoing. However, if it 
is to be done, the rules are outlined above. If 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
–
If year is known, but day and month are missing, then 1st of January of the year will 
be imputed

If all is missing, then impute date to Date of Birth (DOB) 
–
If DOB is not available but age is available, then estimate DOB by using screening 
date and age (age = screening date – DOB) 
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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, 
–
If YYYY < year of last dose, then 31st of December will be imputed 
–
If YYYY = year of last dose, then 31st of December will be imputed 
–
If YYYY > year of last dose, then 1st of January will be imputed 

If all is missing, then impute date to 31st of December in the year of last dose 
Imputing missing concomitant therapies is optional. However, if it is to be done, the rules are 
outlined above. If subject dies, then use death date for concomitant therapies stop date. After 
the imputation, all imputed dates are checked against the start dates to ensure stop date does 
not occur before start date. If the imputed stop date occurs prior to start date, then keep the 
imputed date same as the start date.
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, 
–
If the onset month and year are the same as the month and year of last dose with 
study drug, the day of last dose + 1 will be imputed.
–
If the onset month and year are not the same as the month and year of last dose with 
study drug, the first day of the month is imputed. 

When only a year is present, 
–
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.
–
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.
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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 assessing PD, the disease nadir will be 
considered as study entry (or sometime later as appropriate).
5.4.3
Windowing of Visits
All data will be categorized based on the scheduled visit at which they are collected. These 
visit designators are predefined values that appear as part of the visit tab in the electronic 
case report form (eCRF).
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 (PD/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 to discontinue from the treatment, patients on-going on treatment, 
patients participating in any follow-up, patients with dose escalation at C5D1, patients 
discontinued from the study, and primary reason to discontinue from the study. All 
percentages will be based on the number of patients in the ITT population.
A listing will present data concerning patient disposition.
5.6
Demographics and Baseline Disease Characteristics
5.6.1
Demographics
Demographics will be summarized by treatment groups in a descriptive fashion in the ITT 
population. Baseline demographic data to be evaluated will include age, sex, race, ethnicity, 
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height, weight, and other parameters as appropriate. 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, akaylator containing, monoclonal antibody, as appropriate.
The duration of prior induction regimens will be summarized by treatment groups.
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, 
- macroglobulin, 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, and time from the first dose of induction to study entry will be 
summarized for all patients.
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, 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, extramedullary disease, and comorbidity status 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). 
2

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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 
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 in the high-risk category 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. 
[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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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 End of Treatment (EOT) 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. A 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.
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), or until documented disease progression or intolerable toxicities, whichever 
comes first.
The number of patients who have been escalated at Cycle 5 Day 1, and number of patients 
who didn’t escalate at Cycle 5 Day 1 will be summarized. For those who didn’t escalate, 
their reasons of no escalation will be displayed. 
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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 known visit. 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 median 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 
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 escalated 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.
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5.7.2.3
Treatment Modifications
Dose modification on each study drug due to adverse event will be summarized by Cycle 1 -
26, Cycles 1- 4, 5 - 8, 9- 12, 13 - 16, 17 -20, 21 -24, and 25 - 26 and total for each treatment 
group in the safety population. Action on drug will be summarized using the similar manner.
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 1 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. The details regarding the handling of missing assessments and 
censoring for PFS analysis are presented in Table 5-1.
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 
Disease progression documented prior to 
randomization**
Date of randomization
Date of randomization
Censored
Censored
Disease progression documented between 
scheduled visits 
Date of documented disease progression 
Event
No documented death or disease progression 
Date of last adequate assessment*
Censored
Lost to follow-up, withdraw consent before 
any documented death or disease 
progression
Date of last adequate assessment*
Censored 
Death or progression after more than one
missed visit
Date of last adequate assessment*
Censored
Alternate antineoplastic therapy started prior 
to disease progression 
Date of last adequate assessment* prior to 
starting alternate antineoplastic therapy 
Censored
Death before first assessment
Date of death
Event
Death between adequate assessment visits
Date of death
Event
* Adequate disease assessment is defined as there is sufficient data to evaluate a patient’s disease status.
**Patients will be considered major protocol deviation, and excluded from PP population.
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5.8.1.1
Primary Efficacy Endpoint
PFS will be analyzed when approximately 392 IRC-assessed PFS events have occurred or 
approximately 10 months after the last patient has been enrolled, 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 0.04 for ITT population, and a 2-sided alpha level of 0.01 in 
3 prespecified subgroups (see Section 3.2) using Hochberg testing approach. 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 
median PFS (if estimable), along with their 2-sided 95% CIs, will also 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.
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 may 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. Besides treatment and the stratification factors, the model 
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may include the following significant covariates including, but not limited to, treatment arm, 
age; race (white; non-white); ECOG score at study entry (0 or1, 2), cytogenetic test (high 
risk, other), , ISS (I, II or III), revised ISS (I or II, III), , frailty status, MRD status at study 
entry, etc.
The plan of subgroups for PFS is presented in the Table 5-3 below with a few identified key 
subgroups:
Table 5-3
List of subgroups
Subgroup
Definition of Group
Age
< 65 years, ≥65 and < 75 years, ≥75 years
Age
< 75 years, ≥75 years (as one stratification factor)
Pre-induction ISS stage
I, II, III
Pre-induction ISS stage
I or II, III (as one stratification factor)
Revised ISS stage at initial diagnosis
I, II, III, unclassifiable
Sex
male, female
Race
white, Asian, other
Region
APAC, EMEA, other 
Best response to initial therapy
CR or VGPR, PR (as one stratification factor)
Response at study entry
CR, VGPR, PR
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, PI naive (as one stratification factor)
Induction regimen
IMiD exposed, IMiD naive
Frailty Status
fit, unfit, frail
MRD status at study entry 
Known positive, known negative, unknown 
Patient ineligibility categories to SCT * 
age, comorbidity, other 
* Patient ineligibility to SCT will be categorized by hierarchical order. First identify age, then identify 
comorbidity among the rest, and then group all the rest as other.
Additional exploratory analysis may be performed if deemed necessary.
5.8.2
Key Secondary Efficacy Endpoint
There is 1 key secondary endpoint: OS.
Overall survival 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. Overall survival will be analyzed based on the ITT population.
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A 2-sided, stratified log-rank test will be used to compare the treatment groups with respect
to OS. The test significance level at the IA and FA is decided by the O’Brien-Fleming alpha
spending function (the Lan-DeMets method [4]). 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 stratified stepwise Cox regression model may 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 the following significant covariates
including, but not limited to, treatment arm, age; race (white; non-white); ECOG score at 
study entry (0 or1, 2), cytogenetic test (high risk, other), ISS (I, II or III), revised ISS (I or II, 
III), , frailty status, MRD status at study entry, 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 Robins, Hernan and Brumback (2000) [5]

Inverse Probability of Censoring Weighted (IPCW) method by Robins and Finkelstein 
(2000) [6]
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 (<75, ≥75), 
race(white, non-white), ECOG score (0 or 1, 2), induction therapy(PI exposed , PI naive),
induction therapy (IMiD exposed, IMiD navie), response to prior therapy (CR or VGPR,
PR), , presence of extramedullary plasmacytomas (yes, no), presence of lytic bone lesions 
(yes, no), hemoglobin, platelets, creatinine clearance, albumin, corrected calcium, LDH and 
MRD status. Potential time-fixed covariates at initial diagnosis are type of myeloma (IgA, 
other), ISS (I or II, III), RISS (I or II, III or unclassifiable), cytogenetic abnormalities (high 
risk, others), , MRD status at study entry (known positive, known negative, unknown), 
frailty status at study entry(fit, unfit, frail), patient eligibility to SCT categories . 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, M-protein value at each study visit and 
progression/relapse. 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 
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weight calculations. If there are more than 5% missing in the baseline 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 (HRs), 95% confidence intervals for HRs, 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 before 
PD or to 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 positive to MRD negative, maintenance of 
MRD negativity, correlation between MRD status and PFS/OS, and correlation between 
frailty status and PFS/ OS.
Disease response-related endpoints prior to PD will be analyzed using IRC-assessed 
responses.
Other efficacy analyses such as PFS or OS from start of induction therapy, may be 
performed as needed.
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.
For patients entered into study with PR response, the percentage of maintaining PR as best 
confirmed response, and convert to VGPR/CR as best confirmed response will be displayed. 
For patients entered into study with VGPR response, the percentage of maintaining VGPR 
as best confirmed response, and convert to CR as best confirmed response will be displayed. 
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For patients entered into study with CR response, the percentage of maintaining CR as best 
confirmed response will be displayed.
For patients entered into study with CR response, the percentage of 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)
Time to progression is defined as the time from the date of randomization to the date of first 
documentation of PD. Patients without documentation of PD at the time of analysis will be 
censored at the date of last response assessment. Patients who take alternative antineoplastic
therapy prior to progression, or die during treatment will also be censored at the date of last 
response assessment. Time to progression 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 is defined as the time from the date of randomization to the date 
of first documentation of PD (as assessed by investigator) on the next-line antineoplastic 
therapy or death due to any cause, whichever occurs first. 
Progression-free survival 2 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 assessments 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 visit date
Censored
Lost to follow-up, withdraw consent before 
any documented death or disease progression 
during second line therapy
Date of last visit date
Censored 
Start of third line therapy prior to the disease 
progression during second line therapy
Date of 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 therapy 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.
Time to End of 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.
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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 next line of 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 population. 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 PS in Cytogenetic Risk population
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 individual cytogenetic
abnormalities del17, t(4;14), t(14;16) and ampl 1q if data permit.
Correlation Between Frailty Status and Progression-Free Survival and Overall 
Survival
Patients’ frailty status will be assessed on the basis of 4 components: age, the Charlson 
Comorbidity Scoring System, the Katz Index of Independence in Activities of Daily Living, 
and the Lawton Instrumental Activities of Daily Living Scale.
Specifically, ages of < 75, 75 to 80, and > 80 years correspond to frailty scores of 0, 1, and 
2, respectively. Charlson Comorbidity Scoring System scores of ≤1 and ≥2 correspond to 
frailty scores of 0 and 1, respectively. Katz Index of Independence in Activities of Daily 
Living scores of > 4 and ≤4 correspond to frailty scores of 0 and 1, respectively.
Instrumental Activities of Daily Living Scale scores of > 5 and ≤5 correspond to frailty 
scores of 0 and 1, respectively. The sum of the 4 frailty scores equals the total frailty score.
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A total frailty score of 0 corresponds to a frailty status of fit; a total score of 1, to unfit; and a 
total score of 2 or more, to frail.
An unadjusted stratified Cox model including frailty status (fit, unfit, frail) and treatment 
will be used to estimate the hazard ratio and 95% CIs for the treatment effect and frailty 
status using the stratification factors for both PFS and OS. A status of “fit” will be compared 
with a status of “unfit” or “frail.”
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.
Pharmacokinetic (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, at Cycle 12/13 (after
approximately 12 months of treatment) and at EOT (approximately 24 months) in all the 
VGPR and CR patients independent of study arm, unless already done with the most recent 
2 cycles.
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
CCI
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
For patients who were MRD- at study entry: treatment vs. control.

For patients who were MRD+ at study entry and converted to MRD – at any time point 
post study entry: treatment vs. control.

For patients who were MRD+ at study entry and still maintain MRD+ at any time point 
post study entry: treatment vs. control.
The rate of maintaining 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
treatment and control arms. The rate of maintaining 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 maintaining 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 analysis 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. 
Additional sensitivity analysis will be performed for MRD by assuming patients are MRD 
positive when the MRD status is missing or not evaluable.
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5.10
Analyses of Patient-Reported Outcomes and Health Economics
5.10.1
Patient-Reported Outcomes (PROs)
Descriptive Statistics 
Health-related QOL will be assessed using the cancer-specific EORTC QLQ-C30 
(Table 5-6) and EORTC QLQ-MY20 (Table 5-7). The EORTC QLQ-C30 contains 30 items 
across 5 functional scales, 9 symptom scales and a global health status/QOL scale. Items 1 -
28 have 4 response levels (not at all, a little, quite a bit, and very much) and items 29 and 30 
rely on a 7-point numeric rating scale. A summary score of EORTC QLQ-C30 will be 
calculated from the mean of 13 of the 15 EORTC QLQ-C30 subscales (the Global health 
status/Quality of Life scale and the Financial Difficulties scale are not included).
The EORTC QLQ-MY20 has 20 items across 2 functional subscales and 2 symptoms scales.
Raw scores from both the EORTC QLQ-C30 and MY20 are converted into scale scores 
ranging from 0 to 100. For the functional subscales and the global health status/QOL 
subscale, higher scores represent better QOL; for the symptom subscales, lower scores
represent better QOL.
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 
observations may be used: 
1.) based on cycle visit, and 
2.) based on 4-week intervals from study entry.
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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
Abbreviations: EORTC QLQ-C30 = European Organization for Research and 
Treatment of Cancer Quality of Life Questionnaire Core 30.
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
Abbreviations: EORTC QLQ-MY20 = European Organization for Research and 
Treatment of Cancer Quality of Life Questionnaire Multiple Myeloma Module.
Analysis Based on Minimally Important Difference (MID)
For the summary score and each subscale score of EORTC QLQ-C30 as well as each 
subscale score of EORTC QLQ-MY20, the number and percentage of patients with either a 
stable score or an improvement in score from study entry based on minimally important 
differences (MIDs) of 10 (primary analyses) [7] - [9] and 5 (sensitivity analyses) [10] will be 
summarized by treatment group over time. Specifically, patients with a change from study 
entry 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”.
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Analysis based on Linear mixed effects model by incorporating covariates
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. Analyses based on the 4-week 
interval timescale may be considered.
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.
Missing Data
Details of scoring and initial handling of missing data are included in the EORTC QLQ-C30 
and QLQ-MY-20 scoring guidelines.
Missing data patterns will be examined. As sensitivity analyses, 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.
5.10.2
Health Economics Analysis Using Medical Resource Utilization and Utility
EQ-5D-5L item scores as well as EQ-5D-5L Visual Analogue Scale (VAS) will be 
summarized in descriptive statistics for treatment arms over time in a manner consistent with 
the analyses above. 
Compliance for EQ-5D-5L will also be summarized by number of expected and number and 
percentage of received by treatment group over time.
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HU data will be summarized in descriptive statistics of medical encounters (number and 
rates of encounters, reasons for encounters, and length of stay). Categories of interest 
include ICU visits, non-ICU visits, emergency department visits, and outpatient visits.
Further modeling may be performed separately at 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 baseline in the patient’s vital signs, weight, and clinical laboratory results using the
safety population. Exposure to the study drug regimen and reasons for discontinuation will
be tabulated.
5.11.1
Adverse Events
5.11.1.1
Adverse Events
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). All AEs will be presented in a by-patient listing. Treatment-emergent AEs
(TEAEs) 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. 
Adverse events will be tabulated according to MedDRA by system organ class, high level 
term, and preferred term and will include the following categories: 

Treatment-emergent AEs

Drug-related treatment-emergent AEs

Grade 3 or higher treatment-emergent AEs (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 study drug discontinuation

AEs in Cycle 1-4 that prevented dose escalation at Cycle 5
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Patients with the same AE more than once will have that event counted only once within 
each body system, once within each high level term, and once within each preferred term.
Treatment-emergent AEs will also be summarized by the National Cancer Institute Common
Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. Patients with the 
same AE more than once will have the maximum intensity of that event counted within each 
body system, once within each high level term, and once within each preferred term. 
The most commonly reported treatment-emergent AEs (ie, those events reported by 10% 
of any treatment arm) will be tabulated by preferred term. Patients with the same AE more 
than once will have that event counted only once within each preferred term.
An overall summary AE table will include numbers and percentages of patients who had at 
least one AE, drug-related AE, grade 3 or higher AE (also grade 3 and 4 AE respectively), 
grade 3 or higher drug-related AE (also grade 3 and 4 drug-related AE respectively), SAEs, 
drug-related SAE, AE resulting in discontinuation, and on-study deaths. On-study death is 
defined as the death that occurs between the first dose of any study drug and within 30 days 
of the last dose of any study drug.
All concomitant medications collected from screening through the study period will be
classified to preferred terms according to the World Health Organization (WHO) drug
dictionary.
Additionally, by-patient listings and summary tables of the AE of special interest (AESI) 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 
Two types of incidence rates will be calculated for the safety population based on the new
primary malignancy (NPM) 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. 
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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.
Time to Resolution and Improvement of Peripheral Neuropathy (PN) Events
Peripheral neuropathy (PN) is defined as the treatment emergent AEs including neuropathy 
peripheral, peripheral motor neuropathy, peripheral sensory neuropathy, and peripheral 
sensorimotor neuropathy.
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 with ≥ 3 PN events if data permit.
5.11.1.2
Serious Adverse Events
The number and percentage of patients experiencing at least 1 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).
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Statistical Analysis Plan, Study C16021
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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). 
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 
regimen 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 of (x-1)% (mainly for < 5% for CR)
will be used.
If a patient has repeated laboratory values for a given time point, the value from the last 
evaluation will be used.
Laboratory test results will be summarized according to the scheduled sample collection 
time point. Change from baseline will also be presented. Unscheduled laboratory test results 
will be listed and included in laboratory shift tables. The parameters to be analyzed are as 
follows:

Hematology: hemoglobin, absolute neutrophil count (ANC), platelets counts,
lymphocytes 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 CTCAE grade.
Parameters to be tabulated will include:

Hematology: ANC, hemoglobin, platelets, lymphocytes and leukocytes

Serum chemistry: ALT, AST, ALP, creatinine, total bilirubin, corrected calcium, 
magnesium, potassium, sodium, and phosphate
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Statistical Analysis Plan, Study C16021
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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/SGPT, 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 
Electrocardiograms (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 baseline and each of the subsequent 
time points. Categories of changes from baseline (≥ 30 msec and ≥ 60 msec) will be 
summarized as well. Maximum QTc intervals and maximum changes from baseline will also 
be summarized similarly in a separate display.
Electrocardiogram 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, 
respiratory rate, and body weight, will be summarized over time for each treatment arm.
Change from baseline will also be presented.
A by-patient listing will also be presented.
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.
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Statistical Analysis Plan, Study C16021
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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 Ixazomib, 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 C16021
amendment 2 (Protocol amendment dated 14 June 2016) and amendment 5 (Protocol 
amendment dated 28 September 2018).
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.
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Statistical Analysis Plan, Study C16021
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8.
REFERENCES
1. Durie BG, Harousseau JL, Miguel JS, Blade J, Barlogie B, Anderson K, et al. 
International uniform response criteria for multiple myeloma. Leukemia 2006; 20(9): 
1467-73. 
2. Lan K, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika
1983;70:659-63.
3. Bretz F, Maurer W, Brannath W and Posch M. A graphical approach to sequentially 
rejective multiple test procedures. Statist. Med. 2009; 28: 586-604 
4. Cui L, Hung HM, and Wang SJ. Modification of sample size in group sequential clinical 
trials. Biometrics 1999; 55:853–857.
5. Robins JM, Hernan M, Brumback B. Marginal strucural models and causal inference in 
epidemiology. Epidemiology 2000; 11(5): 550-560.
6. Robins JM and Finkelstein DM. Correcting for Noncompliance and Dependent 
Censoring in an AIDS Clinical Trial with Inverse Probability of Censoring Weighted 
(IPCW) Log-Rank Tests. Biometrics 2000; 56: 779-788. 
7. Osoba D, Rodrigues G, Myles J, Zee B, Pater J. Interpreting the significance of changes 
in health-related quality-of-life scores. J Clin Oncol 1998;16:139–44.
8. Cella D, Pickard AS, Duh MS, et al. Health-related quality of life in patients with 
advanced renal cell carcinoma receiving pazopanib or placebo in a randomized phase III 
trial. Eur J Cancer. 2012 Feb;48(3):311-23.
9. Kvam AK, Fayers PM, Wisloff F. Responsiveness and minimal important score 
differences in quality-of-life questionnaires: a comparison of the EORTC QLQ-C30 
cancer-specific questionnaire to the generic utility questionnaires EQ-5D and 15D in 
patients with multiple myeloma. Eur J Haematol. 2011;87(4):330-337.
10. Stewart AK, Dimopoulos MA, Masszi T, et al. Health-Related Quality-of-Life Results 
From the Open-Label, Randomized, Phase III ASPIRE Trial Evaluating Carfilzomib, 
Lenalidomide, and Dexamethasone Versus Lenalidomide and Dexamethasone in 
Patients With Relapsed Multiple Myeloma. J Clin Oncol. 2016 Nov 10;34(32):3921-
3930. 
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