Clinical trial NCT03748953
Conditions: Multiple Myeloma
Keywords: Drug Therapy
Sponsor: Millennium Pharmaceuticals, Inc.
Start date: 2019-01-24; Completion date: 2023-12-06
Enrollment: 37 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to determine the long-term safety and tolerability of ixazomib maintenance therapy.

Detailed description:
The drug being tested in this study is called ixazomib. Ixazomib is being tested to slow disease progression and improve overall survival in Chinese participants who have newly diagnosed multiple myeloma (NDMM) who have had a major positive response to initial therapy and have not undergone stem cell transplantation (SCT). This study will look at the effect of ixazomib has on the length of time that participants are free of disease progression and their overall survival. After the implementation of Amendment 8, participants who received placebo-matching capsules before unblinding and have not yet experienced disease progression will cross over to receive ixazomib.

The study will enroll approximately 37 patients. Participants will be assigned to a single treatment group

• Ixazomib

All participants will be asked to take one capsule on Days 1, 8, and 15 of every 28-day cycle, for up to approximately 24 months (equivalent to 26 cycles \[if no cycle delays\], to the nearest complete cycle) or until documented progressive disease (PD) or intolerable toxicity, whichever occurs first.

This multi-center trial will be conducted in China. The overall time to participate in this study is until a total of approximately up to 60 months. Participants will make multiple visits to the clinic, and every 4 weeks until the next line of therapy begins for a follow-up assessment.

Arms: arm 1: Participants received ixazomib 3 milligrams (mg), capsules, orally, once on Days 1, 8, and 15 for Cycles 1 through 4, during which if the participants tolerated the initial dose, the dose was escalated to ixazomib 4 mg, capsules, orally, once on Days 1, 8, and 15 for Cycles 5 through 26, or until documented PD or intolerable toxicity, whichever occurred first (cycle length=28 days).
Interventions: intervention 1: Ixazomib
Intervention descriptions: intervention 1: Ixazomib Capsules

Protocol documents:
Prot_000.pdf: 
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Ixazomib
Clinical Study Protocol C16021 Amendment 10 (CCS), EudraCT Number: 2014-001394-13
Confidential
1
CLINICAL STUDY PROTOCOL C16021 AMENDMENT 10
Ixazomib
China Continuation: A Single-Arm, Open-Label Study of Oral Ixazomib Maintenance 
Therapy After Initial Therapy in Patients With Newly Diagnosed Multiple Myeloma Not 
Treated With Stem Cell Transplantation
Protocol Number:
C16021
Indication:
Multiple myeloma
Phase:
3
Sponsor:
Millennium Pharmaceuticals, Inc.
EudraCT Number:
2014-001394-13
Therapeutic Area:
Oncology
Protocol History
Original
Global
15 September 2014
Amendment 01
China
26 November 2014
Amendment 02
Global
14 June 2016
Amendment 03
China
07 September 2016
Amendment 04
China Continuation Study
02 November 2016
Amendment 05
Global, Substantial
28 September 2018
Amendment 06
China
28 September 2018
Amendment 07
Global (for use in all countries 
except China), Substantial
23 September 2020
Amendment 08
China Continuation Study
29 September 2020
Amendment 09
Global, Substantial
16 November 2021
Amendment 10
China Continuation Study
26 August 2022
Millennium Pharmaceuticals, Inc.
40 Landsdowne Street
Cambridge, MA USA 02139
Telephone: +1 (617) 679-7000
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Rationale for Amendment 10
This document describes the changes to the protocol incorporating Amendment 10. The primary 
rationale for this amendment is to clarify aspects of study conduct.
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 15.23.
Purposes for Amendment 10
The purposes of this amendment are to: 
1. Remove the reference to randomization throughout the protocol.
2. Remove reference to second progressive disease (PD2) throughout the protocol.
3. Clarify "vital signs" with a footnote in the Schedules of Events.
4. Clarify unblinding of patients off study.
5. Clarify language regarding procedures for reporting product complaints or medication
errors.
6. Clarify language in study conduct regarding the coronavirus disease 2019 pandemic.
7. Clarify definitions of some of the populations for analysis.
8. Remove the Independent Review Committee section.
9. Update the management of transverse myelitis for ixazomib to reflect evolving data.
10. Clarify reporting of patient-reported outcome questionnaires.
11. Clarify the wording of some secondary and exploratory study objectives.
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PROTOCOL SUMMARY
Study Title: China Continuation: A Single-Arm, Open-Label 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 30 total patients from China with newly diagnosed multiple 
myeloma (NDMM) who had a major response to initial therapy and who have not undergone stem 
cell transplantation (SCT). Prior to implementation of Amendment 08, 10 patients have been 
randomized and treated in the China Continuation. An additional ~20 patients are to be enrolled 
upon implementation of Amendment 08.
Study Objectives 
Primary

To determine the long-term safety and tolerability of ixazomib maintenance therapy
Secondary

To determine progression-free survival (PFS), defined as the time from date of first dose to
progressive disease (PD) or death from any cause, in patients in China 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

To determine overall survival (OS)

To determine whether response at study entry is improved or maintained

To determine time to progression

To determine time to next-line therapy

To assess the incidence of new primary malignancy in patients receiving 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
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Overview of Study Design: The China Continuation part of Study C16021 was originally designed 
as a randomized, double-blind, placebo-controlled, multicenter study in patients in China with 
NDMM who have not undergone SCT. Upon implementation of Amendment 08, the China 
Continuation will now be a single-arm, open-label study of ixazomib maintenance for patients in 
China 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 enrolled under Amendment 08 will be enrolled based on the 
same eligibility criteria; patients will be considered enrolled when they have been entered into the 
interactive voice/web response system (IXRS) and have received the first dose of study drug. 
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. Upon implementation of Amendment 08, all patients will receive open-label ixazomib. New 
eligible and consenting patients are to be enrolled no later than 60 days after the last dose of initial 
therapy. For patients who were previously randomized to the placebo arm who reconsent and cross 
over to ixazomib, reconsenting more than 60 days after the last dose of initial therapy is permitted. 
Patients will receive ixazomib capsules (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, and disease response assessments will be conducted, as will HRQL assessments 
with an emphasis on tolerability 
. After documented PD, subsequent therapy
will be determined by the investigator/treating physician. There will be 1 IA and a final analysis 
(FA) for the study. The IA is the primary analysis for this study and will be performed approximately 
12 months after the additional ~20 patients have been enrolled under Amendment 8. The safety and 
efficacy endpoints will be assessed in the overall Chinese patient population (patients from China 
who were enrolled in the ixazomib arm of the C16021 global study, patients in the ixazomib arm of 
the China Continuation before implementation of Amendment 08, all patients enrolled in the China 
Continuation under Amendment 08, and patients who were randomized to the placebo arm before 
implementation of Amendment 08 and who crossed over to the ixazomib arm). The FA will be 
performed when all patients in the China Continuation are off treatment and have completed the End 
of Treatment (EOT) visit, or upon termination of the study by the sponsor, whichever occurs earlier. 
Descriptive statistics will be used to summarize patient data collected after the IA. 
Study Population: Adult patients in China 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.
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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. Note, patients previously randomized to the placebo arm 
who reconsent and cross over to ixazomib may receive up to 24 months (26 cycles) of ixazomib 
treatment. 
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, and OS Follow-up periods for clinical status, 
disease status, HRQL, new primary malignancy, and survival.
The study will last until all patients in the China Continuation are off study treatment and have 
completed the EOT visit, or upon termination of the study by the sponsor, whichever occurs earlier.
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SCHEDULES OF EVENTS—AMENDMENT 08 AND BEYOND
Amendment 08 changes the China Continuation from a double-blind, placebo-controlled design 
to an open-label, single-arm design (ixazomib only). Given the positive results from the C16021 
global study and the fact that the C16021 China Continuation is still open to enrollment, the 
sponsor does not believe it is appropriate to continue enrolling patients into a randomized, 
placebo-controlled maintenance study. The Center for Drug Evaluation (CDE), National 
Medical Products Administration (NMPA) acknowledged that it will be difficult to continue 
enrolling patients into the placebo arm of the C16021 China Continuation. The CDE suggested 
that the sponsor amend the study into a single arm study, so as to collect more efficacy and 
safety data from Chinese patients receiving ixazomib. This amendment describes modifications 
to the China Continuation study procedures for patients who are still on treatment, who are in 1 
of the follow-up periods, or who will be enrolled after this amendment takes effect. 
For ease of study conduct, the Schedule of Events has been modified to apply to the remainder 
of the study. Two separate schedules—the “Schedule of Events for Patients Randomized to 
Ixazomib + Newly Enrolled Patients” and the “Schedule of Events for Crossover Patients”—
have been created to clarify the procedures for different patients (as detailed in the bullets 
below). The Schedule of Events in effect prior to Amendment 08 has been moved to 
Section 15.13.

Patients enrolled prior to implementation of Amendment 08: Prior to implementation 
of Amendment 08, 10 patients had been randomized and treated in the China 
Continuation. All patients continuing in the study under Amendment 08 must be 
reconsented.
o
Patients still on treatment: Patients who were randomized to study drug 
(ixazomib or placebo) prior to implementation of Amendment 08 and who are 
still on study treatment will complete their current cycle of treatment, following 
the previous Schedule of Events (see Section 15.13), and be unblinded. 

Patients who are in the placebo arm who have not yet experienced disease 
progression will have the opportunity to cross over to ixazomib 
maintenance, based on the investigator’s judgement and the patient’s 
informed consent. Patients who cross over will follow the “Schedule of 
Events for Crossover Patients” starting at Crossover Cycle 1 Day 1. 
Patients in the placebo arm who do not cross over should complete an 
End of Treatment visit and discontinue the study. 

Patients who are in the ixazomib arm will continue to receive ixazomib 
maintenance. Patients who reconsent will follow the “Schedule of Events 
for Patients Randomized to Ixazomib + Newly Enrolled Patients” 
according to their current cycle of treatment.
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o
Patients in the progression-free survival (PFS) Follow-up Period: All patients 
will be unblinded.

Patients in the placebo arm who have discontinued study treatment but 
who have not yet experienced disease progression or started alternative 
therapy have the opportunity to cross over to ixazomib maintenance. The 
decision to cross over is based on the investigator’s judgement and the 
patient’s informed consent. Patients who cross over will follow the 
“Schedule of Events for Crossover Patients” starting at Crossover Cycle 1 
Day 1. Patients in the placebo arm who do not cross over will discontinue 
the study.

Patients in the ixazomib arm who reconsent should continue on study and 
follow the “Schedule of Events for Patients Randomized to Ixazomib + 
Newly Enrolled Patients” according to the PFS Follow-up Period 
schedule. 
o
Patients in the PFS2 or Overall Survival (OS) Follow-up Periods: All patients 
will be unblinded.

Patients in the placebo arm will discontinue the study. No crossover to the 
ixazomib arm is permitted in these patients who have experienced 
primary disease progression or who have initiated alternative therapy.

Patients in the ixazomib arm who reconsent will continue on study and 
follow the “Schedule of Events for Patients Randomized to Ixazomib + 
Newly Enrolled Patients” according to the OS Follow-up Period 
schedule. Note, the PFS2 Follow-up period has been removed in Protocol 
Amendment 08; patients previously in PFS2 follow-up will be followed 
in the OS follow-up period. 
o
Patients Off Study: All these patients will be unblinded.

Patients to be enrolled after implementation of Amendment 08: Approximately 
20 additional patients with NDMM who responded to initial treatment will be enrolled in 
the C16021 China Continuation, for a total of approximately 30 patients overall. All 
newly enrolled patients will receive ixazomib maintenance and will follow the 
“Schedule of Events for Patients Randomized to Ixazomib + Newly Enrolled Patients.” 
For newly enrolled patients, ixazomib must be initiated within 5 days of the patient 
being entered into the IXRS system.
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Schedule of Events for Patients Randomized to Ixazomib + Newly Enrolled Patients—Amendment 08 and Beyond
Study Procedures
Screening
Treatment Period
EOT a
Follow-up b
28-Day Cycles b
PFS
PD
OS
Cycle
Cycle 1
Cycle 2
Cycle 3
Cycles 
4–5
Cycle 
5 c
Cycles 
6-26
Every 
4 Wk 
Until PD
Every 
4 Wk 
After PD 
Until 
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 
(reconsent) d
X
Inclusion/exclusion 
Criteria e
X
Demographics
X
Complete medical 
history and disease 
staging
X
Complete physical 
examination, including 
for PN 
X
X f
Symptom-directed 
physical examination, 
including for PN f
X
X
X
X
X
X
X
ECOG Performance 
Status f
X
X
X
X
X
X
X
X
Frailty status g
X
Vital signs f
X
X
X
X
X
X
X
X
X
Height (cm)
X
Weight (kg) f
X
X
X
X
X
X
X
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Schedule of Events for Patients Randomized to Ixazomib + Newly Enrolled Patients—Amendment 08 and Beyond
Study Procedures
Screening
Treatment Period
EOT a
Follow-up b
28-Day Cycles b
PFS
PD
OS
Cycle
Cycle 1
Cycle 2
Cycle 3
Cycles 
4–5
Cycle 
5 c
Cycles 
6-26
Every 
4 Wk 
Until PD
Every 
4 Wk 
After PD 
Until 
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
12-lead ECG
X
EORTC QLQ-C30 h
X
X
X
X
X
X
X
X
X
Imaging disease 
assessment i
X
Investigator assessment
of disease 
response/status
X
X
X
X
X
X
X
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Schedule of Events for Patients Randomized to Ixazomib + Newly Enrolled Patients—Amendment 08 and Beyond
Study Procedures
Screening
Treatment Period
EOT a
Follow-up b
28-Day Cycles b
PFS
PD
OS
Cycle
Cycle 1
Cycle 2
Cycle 3
Cycles 
4–5
Cycle 
5 c
Cycles 
6-26
Every 
4 Wk 
Until PD
Every 
4 Wk 
After PD 
Until 
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 (SPEP) f
X
X p
X
X
X
X
X
X
X
M-protein (UPEP 
[24-hr urine]) f
X
X p
X
X
X
X
X
X
X
SFLC assay f
X
X p
X
X
X
X
X
X
X
Immunofixation: serum 
and urine f, q
X
X p
X
X
X
X
X
X
X
Quantification of Ig f, r
X
X p
X
X
X
X
X
X
X
Bone marrow aspiration
(BMA)
Disease assessment 
BMA (local lab) s
X
Progressive disease 
BMA (local lab) t
Progressive disease BMA specimen is requested at any time of progressive disease confirmation
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Abbreviations: BMA=bone marrow aspirate; COVID-19: coronavirus disease 2019; CT=computed tomography; EC: ethics committee; ECG=electrocardiography; 
ECOG=Eastern Cooperative Oncology Group; EORTC=European Organization for Research and Treatment of Cancer; EOT=End of Treatment; 
 
; GCP: Good Clinical Practice; 
 Ig=immunoglobulins; IRB: 
institutional review board; IXRS: interactive voice/web response system; MRD=minimal residual disease; MRI=magnetic resonance imaging; N/A=not available; 
OS=overall survival; PD=progressive disease (disease progression); PET=positron emission tomography; PFS=progression-free survival, defined as time from date of 
first dose to PD or death from any cause; PFS2=progression-free survival 2, defined as time from date of first dose 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); 
 
 SFLC=serum free light chain; SPEP=serum protein electrophoresis; UPEP=urine protein electrophoresis.
Tests and procedures should be performed on schedule but, unless otherwise specified, occasional changes are allowable within a 2-day window during Cycles 1-5 and 
within a 7-day window during Cycle 6 and beyond for holidays, vacations, and other administrative reasons; a longer window is allowable after discussion with the 
Millennium Pharmaceuticals, Inc. (Millennium) project clinician or designee. If the study schedule is shifted, assessments must be shifted to ensure that collection of 
assessments is completed before dosing. These windows are also 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 Millennium 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 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. For patients enrolled prior to implementation of Amendment 08 and still on study treatment, before dosing on Day 1 of the next full treatment 
cycle, all patients must be reconsented. Patients randomized to the ixazomib arm prior to implementation of Amendment 08 who are in 1 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/EC, and GCP standards and local regulations. 
e Confirmation of patient eligibility by the Millennium project clinician or designee is required before enrollment.
f
Patients must present to the study site for all visits shown in the Schedule of Events during Cycles 1-5 to ensure proper safety, efficacy, and PK monitoring. 
Alternative methods for administering study procedures/assessments may be considered for Cycle 6 and beyond when it is not possible for the patient to come to the 
study site due to extenuating circumstances (eg, due to the COVID-19 pandemic). Alternative methods should be considered for performing the assessments by other 
means than the patient presenting to the clinic (eg, remote assessment, having lab assessment performed at a facility closer to the patient’s home, etc). If an in-clinic 
visit is not possible, the permitted alternatives are as follows. These assessments/procedures may be waived: symptom-directed physical examination, ECOG 
performance status, vital signs, weight, whole blood, 
. These assessments/procedures may be deferred until the next in-clinic 
visit: SPEP, UPEP, serum free light-chain assay, immunofixation, quantification of immunoglobulins, BMA, and biopsy. These assessments/procedures may be 
performed locally if possible and, if not, may be deferred until the next in-clinic visit: hematology and chemistry laboratory tests. 
g 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 [1-3].
h Patient-reported outcomes 
 should be completed before any other study procedures are performed or study 
drug is administered. Patient-reported outcome questionnaires are preferred to be completed by patients in the clinic, but if needed due the COVID-19 pandemic, the 
EORTC QLQ-C30 
 questionnaires may be completed at the patient’s home using paper versions of the questionnaires. At time points when a 
clinic visit is not required, or if needed due the COVID-19 pandemic, 
 
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i
A skeletal survey to assess status of bone disease and extramedullary disease will be done at screening (within 8 weeks before date of first dose) 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.
j
Upon implementation of Amendment 08, all patients will receive open-label oral ixazomib. Patients will receive ixazomib on Days 1, 8, and 15 of every 28-day cycle.

Patients enrolled prior to implementation of Amendment 08: Prior to implementation of Amendment 08, 10 patients had been randomized and treated in the 
China Continuation. All patients continuing in the study under Amendment 08 must reconsent. 
o
Patients still on treatment: Patients who were randomized to study drug (ixazomib or placebo) prior to implementation of Amendment 08 and who are 
still on study treatment will complete their current cycle of treatment, following the previous Schedule of Events (see Section 15.13), and be unblinded. 

Patients who are in the placebo arm and who have not yet experienced disease progression will have the opportunity to cross over to ixazomib 
maintenance, based on the investigator’s judgement and the patient’s informed consent. Patients who cross over will follow the “Schedule of 
Events for Crossover Patients” starting at Crossover Cycle 1 Day 1. Patients in the placebo arm who do not cross over should complete an 
EOT visit and discontinue the study. 

Patients who are in the ixazomib arm will continue to receive ixazomib maintenance. Patients who reconsent will follow the “Schedule of 
Events for Patients Randomized to Ixazomib + Newly Enrolled Patients” according to their current cycle of treatment. 
o
Patients in the PFS Follow-up Period: All patients will be unblinded.

Patients in the placebo arm who have discontinued study treatment but who have not yet experienced disease progression or started alternative 
therapy have the opportunity to cross over to ixazomib maintenance. The decision to cross over is based on the investigator’s judgement and 
the patient’s informed consent. Patients who cross over will follow the “Schedule of Events for Crossover Patients” starting at Crossover 
Cycle 1 Day 1. Patients in the placebo arm who do not cross over will discontinue the study.

Patients in the ixazomib arm who reconsent should continue on study and follow the “Schedule of Events for Patients Randomized to 
Ixazomib + Newly Enrolled Patients” according to the PFS Follow-up period schedule. 
o
Patients in the PFS2 or OS Follow-up periods: All patients will be unblinded.

Patients in the placebo arm will discontinue the study. No crossover to the ixazomib arm is permitted in these patients who have experienced 
primary disease progression or who have initiated alternative therapy.

Patients in the ixazomib arm who reconsent will continue on study and follow the “Schedule of Events for Patients Randomized to Ixazomib 
+ Newly Enrolled Patients” according to the OS Follow-up period schedule. Note, the PFS2 Follow-up period has been removed in Protocol 
Amendment 08; patients previously in PFS2 follow-up will be followed in the OS Follow-up period. 
o
Patients Off Study: All these patients will be unblinded.

Patients to be enrolled after implementation of Amendment 08: Approximately 20 additional patients with NDMM who responded to initial treatment will be 
enrolled in the China Continuation, for a total of approximately 30 patients overall. All newly enrolled patients will receive ixazomib maintenance and will 
follow the “Schedule of Events for Patients Randomized to Ixazomib + Newly Enrolled Patients.” For newly enrolled patients, ixazomib must be initiated 
within 5 days of the patient being entered into the IXRS system. 
k A starting dose of 3 mg of ixazomib 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 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, 
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Schedule of Events for Crossover Patients—Amendment 08 and Beyond
Study Procedures
Treatment Period
EOT a
Follow-up b
28-Day Cycles b
PFS
PD
OS
Cycle
Crossover Cycle Number
Every 
4 Wk 
Until PD
Every 
4 Wk 
After PD 
Until 
Next-Line 
Therapy
Every 12 Wk 
After PD on 
Next-Line 
Therapy
Cycle 1
Cycle 2
Cycle 3
Cycles 
4–5
Cycle 
5 c
Cycles 
6-26
Days
1
8
15
1
8
1
1
8
1
Window
±2 days
±1 Wk
+1 Wk
±1 Wk
±1 Wk
±1 Wk
Informed consent 
(reconsent) d, e
X
Complete physical 
examination, including 
for PN 
X f
Symptom-directed 
physical examination, 
including for PN f
X
X
X
X
X
X
X
ECOG Performance 
Status f
X
X
X
X
X
X
X
Frailty status g
Vital signs f
X
X
X
X
X
X
X
X
Height (cm)
Weight (kg) f
X
X
X
X
X
X
12-lead ECG
EORTC QLQ-C30 h
X
X
X
X
X
X
X
X
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Schedule of Events for Crossover Patients—Amendment 08 and Beyond
Study Procedures
Treatment Period
EOT a
Follow-up b
28-Day Cycles b
PFS
PD
OS
Cycle
Crossover Cycle Number
Every 
4 Wk 
Until PD
Every 
4 Wk 
After PD 
Until 
Next-Line 
Therapy
Every 12 Wk 
After PD on 
Next-Line 
Therapy
Cycle 1
Cycle 2
Cycle 3
Cycles 
4–5
Cycle 
5 c
Cycles 
6-26
Days
1
8
15
1
8
1
1
8
1
Window
±2 days
±1 Wk
+1 Wk
±1 Wk
±1 Wk
±1 Wk
Imaging disease 
assessment i
Investigator assessment
of disease 
response/status
X
X
X
X
X
X
Ixazomib j, k
Single dose on Days 1, 8, and 15 of each cycle
Determination of dose 
escalation k
X 
(Cycle 5)
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Schedule of Events for Crossover Patients—Amendment 08 and Beyond
Study Procedures
Treatment Period
EOT a
Follow-up b
28-Day Cycles b
PFS
PD
OS
Cycle
Crossover Cycle Number
Every 
4 Wk 
Until PD
Every 
4 Wk 
After PD 
Until 
Next-Line 
Therapy
Every 12 Wk 
After PD on 
Next-Line 
Therapy
Cycle 1
Cycle 2
Cycle 3
Cycles 
4–5
Cycle 
5 c
Cycles 
6-26
Days
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]) f
X
X
X
X
X
X
X
X
SFLC assay f
X
X
X
X
X
X
X
X
Immunofixation: serum 
and urine f, p
X
X
X
X
X
X
X
X
Quantification of Ig f, q
X
X
X
X
X
X
X
X
Bone marrow aspiration 
(BMA)
Disease assessment 
BMA (local lab) r
Disease assessment BMA specimen is requested when patient has reduction of serum and urine M-protein 
consistent with possible CR or when indicated to investigate suspected PD 
Progressive disease 
BMA (local lab) s
Progressive disease BMA specimen is requested at any time of progressive disease confirmation
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Schedule of Events for Crossover Patients—Amendment 08 and Beyond
Study Procedures
Treatment Period
EOT a
Follow-up b
28-Day Cycles b
PFS
PD
OS
Cycle
Crossover Cycle Number
Every 
4 Wk 
Until PD
Every 
4 Wk 
After PD 
Until 
Next-Line 
Therapy
Every 12 Wk 
After PD on 
Next-Line 
Therapy
Cycle 1
Cycle 2
Cycle 3
Cycles 
4–5
Cycle 
5 c
Cycles 
6-26
Days
1
8
15
1
8
1
1
8
1
Window
±2 days
±1 Wk
+1 Wk
±1 Wk
±1 Wk
±1 Wk
Abbreviations: BMA=bone marrow aspirate; COVID-19: coronavirus disease 2019; CT=computed tomography; EC: ethics committee; 
ECG=electrocardiography; ECOG=Eastern Cooperative Oncology Group; EORTC=European Organization for Research and Treatment of Cancer; 
EOT=End of Treatment; 
; GCP: Good Clinical Practice; 
; Ig=immunoglobulins; IRB: institutional review board; IXRS: interactive voice/web response system; MRD=minimal residual disease; 
MRI=magnetic resonance imaging; N/A=not available; OS=overall survival; PD=progressive disease (disease progression); PET=positron emission 
tomography; PFS=progression-free survival, defined as time from date of first dose to PD or death from any cause; PFS2=progression-free survival 2, 
defined as time from date of first dose 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); 
 
SFLC=serum free light chain; SPEP=serum protein electrophoresis; UPEP=urine protein electrophoresis.
Tests and procedures should be performed on schedule but, unless otherwise specified, occasional changes are allowable within a 2-day window during 
Cycles 1-5 and within a 7-day window during Cycle 6 and beyond for holidays, vacations, and other administrative reasons; a longer window is allowable 
after discussion with the Millennium Pharmaceuticals, Inc. (Millennium) project clinician or designee. If the study schedule is shifted, assessments must be 
shifted to ensure that collection of assessments is completed before dosing. These windows are also 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 Millennium 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 Patients randomized to the placebo arm prior to implementation of Amendment 08 who crossover to receive ixazomib must be reconsented prior to receiving 
the first dose of ixazomib on Crossover Cycle 1 Day 1. 
e Reconsenting should be done in person. Remote reconsenting is permitted as long as the process adheres to site, IRB/EC, and Good Clinical Practice (GCP) 
standards and local regulations. 
f
Patients must present to the study site for all visits shown in the Schedule of Events during Cycles 1-5 to ensure proper safety, efficacy, and PK monitoring. 
Alternative methods for administering study procedures/assessments may be considered for Cycle 6 and beyond 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 
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Schedule of Events for Crossover Patients—Amendment 08 and Beyond
Study Procedures
Treatment Period
EOT a
Follow-up b
28-Day Cycles b
PFS
PD
OS
Cycle
Crossover Cycle Number
Every 
4 Wk 
Until PD
Every 
4 Wk 
After PD 
Until 
Next-Line 
Therapy
Every 12 Wk 
After PD on 
Next-Line 
Therapy
Cycle 1
Cycle 2
Cycle 3
Cycles 
4–5
Cycle 
5 c
Cycles 
6-26
Days
1
8
15
1
8
1
1
8
1
Window
±2 days
±1 Wk
+1 Wk
±1 Wk
±1 Wk
±1 Wk
patient presenting to the clinic (eg, remote assessment, having lab assessment performed at a facility closer to the patient’s home, etc). If an in-clinic visit is 
not possible, the permitted alternatives are as follows. These assessments/procedures may be waived: symptom-directed physical examination, ECOG 
performance status, vital signs, weight, whole blood, 
. These assessments/procedures may be deferred until the next in-
clinic visit: SPEP, UPEP, serum free light-chain assay, immunofixation, quantification of immunoglobulins, BMA, and biopsy. These 
assessments/procedures may be performed locally if possible and, if not, may be deferred until the next in-clinic visit: hematology and chemistry laboratory 
tests.
g 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 [1-3].
h Patient-reported outcomes 
 should be completed before any other study procedures are performed or 
study drug is administered. Patient-reported outcome questionnaires are preferred to be completed by patients in the clinic, but if needed due the COVID-19 
pandemic, the EORTC QLQ-C30 
 questionnaires may be completed at the patient’s home using paper versions of the 
questionnaires. At time points when a clinic visit is not required, or if needed due to the COVID-19 pandemic,
 
.
i
A skeletal survey to assess status of bone disease and extramedullary disease will be done at screening (within 8 weeks before date of first dose) 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.
j
Upon implementation of Amendment 08, all patients will receive open-label oral ixazomib. Patients will receive ixazomib on Days 1, 8, and 15 of every 28-
day cycle.

Patients enrolled prior to implementation of Amendment 08: Prior to implementation of Amendment 08, 10 patients had been randomized and 
treated in the China Continuation. All patients continuing in the study under Amendment 08 must reconsent. 
o
Patients still on treatment: Patients who were randomized to study drug (ixazomib or placebo) prior to implementation of Amendment 08 and 
who are still on study treatment will complete their current cycle of treatment, following the previous Schedule of Events (see Section 15.13),
and be unblinded. 

Patients who are in the placebo arm and who have not yet experienced disease progression will have the opportunity to cross over to 
ixazomib maintenance, based on the investigator’s judgement and the patient’s informed consent. Patients who cross over will follow 
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Schedule of Events for Crossover Patients—Amendment 08 and Beyond
Study Procedures
Treatment Period
EOT a
Follow-up b
28-Day Cycles b
PFS
PD
OS
Cycle
Crossover Cycle Number
Every 
4 Wk 
Until PD
Every 
4 Wk 
After PD 
Until 
Next-Line 
Therapy
Every 12 Wk 
After PD on 
Next-Line 
Therapy
Cycle 1
Cycle 2
Cycle 3
Cycles 
4–5
Cycle 
5 c
Cycles 
6-26
Days
1
8
15
1
8
1
1
8
1
Window
±2 days
±1 Wk
+1 Wk
±1 Wk
±1 Wk
±1 Wk
the “Schedule of Events for Crossover Patients” starting at Crossover Cycle 1 Day 1. Patients in the placebo arm who do not cross 
over should complete an EOT visit and discontinue the study. 

Patients who are in the ixazomib arm will continue to receive ixazomib maintenance. Patients who reconsent will follow the 
“Schedule of Events for Patients Randomized to Ixazomib + Newly Enrolled Patients” according to their current cycle of treatment. 
o
Patients in the PFS Follow-up Period: All patients will be unblinded.

Patients in the placebo arm who have discontinued study treatment but who have not yet experienced disease progression or started 
alternative therapy have the opportunity to cross over to ixazomib maintenance. The decision to cross over is based on the 
investigator’s judgement and the patient’s informed consent. Patients who cross over will follow the “Schedule of Events for 
Crossover Patients” starting at Crossover Cycle 1 Day 1. Patients in the placebo arm who do not cross over will discontinue the 
study.

Patients in the ixazomib arm who reconsent should continue on study and follow the “Schedule of Events for Patients Randomized to 
Ixazomib + Newly Enrolled Patients” according to the PFS Follow-up Period schedule. 
o
Patients in the PFS2 or OS Follow-up Periods: All patients will be unblinded.

Patients in the placebo arm will discontinue the study. No crossover to the ixazomib arm is permitted in these patients who have 
experienced primary disease progression or who have initiated alternative therapy.

Patients in the ixazomib arm who reconsent will continue on study and follow the “Schedule of Events for Patients Randomized to 
Ixazomib + Newly Enrolled Patients” according to the OS Follow-up period schedule. Note, the PFS2 Follow-up period has been 
removed in Protocol Amendment 08; patients previously in PFS2 follow-up will be followed in the OS follow-up period. 
o
Patients Off Study: All these patients will be unblinded.

Patients to be enrolled after implementation of Amendment 08: Approximately 20 additional patients with NDMM who responded to initial treatment 
will be enrolled in the China Continuation, for a total of approximately 30 patients overall. All newly enrolled patients will receive ixazomib 
maintenance and will follow the “Schedule of Events for Patients Randomized to Ixazomib + Newly Enrolled Patients.” For newly enrolled patients, 
ixazomib must be initiated within 5 days of the patient being entered into the IXRS system. 
k A starting dose of 3 mg of ixazomib will be given to all patients through Cycle 4. Upon evaluation of toxicities at Cycle 4, and on the basis of the dose 
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Schedule of Events for Crossover Patients—Amendment 08 and Beyond
Study Procedures
Treatment Period
EOT a
Follow-up b
28-Day Cycles b
PFS
PD
OS
Cycle
Crossover Cycle Number
Every 
4 Wk 
Until PD
Every 
4 Wk 
After PD 
Until 
Next-Line 
Therapy
Every 12 Wk 
After PD on 
Next-Line 
Therapy
Cycle 1
Cycle 2
Cycle 3
Cycles 
4–5
Cycle 
5 c
Cycles 
6-26
Days
1
8
15
1
8
1
1
8
1
Window
±2 days
±1 Wk
+1 Wk
±1 Wk
±1 Wk
±1 Wk
escalation criteria detailed in Section 6.5, the dose will be escalated to 4 mg 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 Millennium project clinician or designee.
l
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.
m 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.
n 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).
 
p 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).
q 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.
r
BMA with local assessment should be performed if the patient has reduction of serum and urine M-protein consistent with possible CR or when indicated to 
investigate suspected PD.
s
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.
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IXAZOMIB PHARMACOKINETIC SAMPLING SCHEDULE
Upon implementation of Amendment 08, PK sampling will be performed only for patients receiving ixazomib. 

Patients who were randomized to ixazomib prior to implementation of Amendment 08 and who are still on study treatment will 
continue to follow this PK sampling schedule according to their current cycle of treatment. 

Patients who were randomized to placebo prior to implementation of Amendment 08 and who cross over to the ixazomib arm 
after their current cycle will follow this PK sampling schedule starting at Crossover Cycle 1 Day 1 (first dose of ixazomib after 
crossover). 

Patients who enroll after implementation of Amendment 08 will follow this PK sampling schedule starting at Cycle 1 Day 1 
(first dose of ixazomib).
Cycle 1
Cycle 2
Cycles 3-5
Cycle 5 a
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)
Predose b
Predose b
Predose b
Predose b
Predose b
Predose b
Predose b
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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TABLE OF CONTENTS
LIST OF TABLES.............................................................................................................30
LIST OF FIGURES............................................................................................................30
1. BACKGROUND AND STUDY RATIONALE..............................................................34
1.1 Scientific Background ..............................................................................................34
1.1.1 Disease Under Treatment...................................................................................34
1.1.2 Ixazomib: Millennium’s Next-Generation Proteasome Inhibitor.........................35
1.2 Nonclinical Experience.............................................................................................36
1.3 Clinical Experience ..................................................................................................36
1.3.1 Ongoing Studies of Ixazomib.............................................................................36
1.3.2 Overall Clinical Experience ...............................................................................39
1.3.3 Pharmacokinetics and Drug Metabolism ............................................................41
1.4 Study Rationale ........................................................................................................42
1.4.1 Rationale for Investigating Maintenance Therapy in Multiple Myeloma.............42
1.4.2 Rationale for Placebo Control as the Original Study Design...............................46
1.4.3 Rationale for Removal of Placebo Control .........................................................46
1.4.4 Rationale for Ixazomib Schedule and Dose ........................................................47
1.4.5 Rationale for Blood-Based Biomarkers 
..............................50
1.5 Potential Risks and Benefits .....................................................................................51
2. STUDY OBJECTIVES ..................................................................................................52
2.1 Primary Objective.....................................................................................................52
2.2 Secondary Objectives ...............................................................................................53
2.3 Exploratory Objectives .............................................................................................53
3. STUDY ENDPOINTS....................................................................................................54
3.1 Primary Endpoint .....................................................................................................54
3.2 Secondary Endpoints................................................................................................54
3.3 Exploratory Endpoints..............................................................................................55
4. STUDY DESIGN...........................................................................................................55
4.1 Overview of Study Design........................................................................................55
4.2 Number of Patients...................................................................................................60
4.3 Duration of Study.....................................................................................................60
5. STUDY POPULATION.................................................................................................60
5.1 Inclusion Criteria......................................................................................................60
5.2 Exclusion Criteria.....................................................................................................62
6. STUDY DRUG..............................................................................................................64
6.1 Study Drug Administration.......................................................................................64
6.2 Study Drug (Ixazomib Capsules) ..............................................................................65
6.3 Dose-Modification Guidelines..................................................................................66
6.4 Criteria for Dose Modification (Delays, Reductions, and Discontinuations)..............66
6.4.1 Dose Adjustment ...............................................................................................66
6.4.2 Criteria for Toxicity Recovery Before Beginning the Next Treatment Cycle ......67
6.4.3 Study Drug Dose Modification for Hematologic Toxicities................................67
6.4.4 Study Drug Dose Modification for Nonhematologic Toxicities ..........................68
6.5 Criteria for Dose Escalation at Cycle 5 .....................................................................70
6.6 Excluded Concomitant Medications and Procedures.................................................70
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6.7 Permitted Concomitant Medications and Procedures.................................................71
6.8 Precautions and Restrictions .....................................................................................71
6.9 Management of Clinical Events................................................................................73
6.10 Blinding and Unblinding ........................................................................................76
6.10.1 Blinding and Unblinding Prior to Implementation of Amendment 08...............76
6.10.2 Blinding and Unblinding Upon Implementation of Amendment 08..................77
6.11 Description of Investigational Agents .....................................................................77
6.12 Preparation, Reconstitution, and Dispensation ........................................................78
6.13 Packaging and Labeling..........................................................................................78
6.14 Storage, Handling, and Accountability....................................................................78
6.15 Other Protocol-Specified Materials.........................................................................80
7. STUDY CONDUCT ......................................................................................................80
7.1 Study Personnel and Organizations...........................................................................80
7.2 Arrangements for Recruitment of Patients ................................................................80
7.3 Treatment Group Assignments .................................................................................80
7.4 Study Procedures......................................................................................................81
7.4.1 Informed Consent ..............................................................................................83
7.4.2 Patient Demographics ........................................................................................83
7.4.3 Medical History.................................................................................................83
7.4.4 Physical Examination.........................................................................................84
7.4.5 Vital Signs, Body Weight, and Height................................................................84
7.4.6 Eastern Cooperative Oncology Group Performance Status.................................84
7.4.7 Frailty Status......................................................................................................84
7.4.8 Pregnancy Test ..................................................................................................85
7.4.9 Concomitant Medications and Procedures..........................................................85
7.4.10 Adverse Events................................................................................................85
7.4.11 Enrollment .......................................................................................................85
7.4.12 Electrocardiogram............................................................................................86
7.4.13 Clinical Laboratory Evaluations.......................................................................86
7.4.14
...................................................................88
7.4.15 Quality of Life Assessments.............................................................................88
7.4.16 Bone Marrow Aspiration..................................................................................90
7.4.17 Imaging Assessments.......................................................................................90
7.4.18 Quantification of M-Protein .............................................................................90
7.4.19 Quantification of Immunoglobulins..................................................................91
7.4.20 Serum Free Light Chain Assay.........................................................................91
7.4.21 Immunofixation of Serum and Urine................................................................91
7.4.22 Disease Response Assessment..........................................................................91
7.4.23 Pharmacokinetic Measurements.......................................................................92
7.4.24 Follow-up Assessment for Progression-Free Survival, Progressive Disease, 
and Overall Survival ...................................................................................92
7.5 Unscheduled Visits...................................................................................................94
7.6 Study Compliance ....................................................................................................94
7.7 Completion of Treatment..........................................................................................94
7.8 Completion of Study.................................................................................................94
7.9 Discontinuation of Treatment With Study Drug........................................................94
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7.10 Withdrawal of Patients from Study.........................................................................95
8. STATISTICAL AND QUANTITATIVE ANALYSES ..................................................96
8.1 Statistical Methods ...................................................................................................96
8.1.1 Determination of Sample Size............................................................................96
8.1.2 Stratification ......................................................................................................96
8.1.3 Populations for Analysis ....................................................................................96
8.1.4 Procedures for Handling Missing, Unused, and Spurious Data...........................98
8.1.5 Demographic and Baseline Characteristics.........................................................98
8.1.6 Safety Analysis ..................................................................................................98
8.1.7 Efficacy Analysis.............................................................................................101
8.1.8 Analyses of Patient-Reported Outcomes 
.......................103
8.1.9 Pharmacokinetics/Pharmacodynamics/Biomarkers...........................................103
8.1.10 Interim and Final Analyses.............................................................................104
9. STUDY COMMITTEES..............................................................................................104
9.1 Steering Committee................................................................................................104
10. ADVERSE EVENTS .................................................................................................104
10.1 Definitions............................................................................................................104
10.1.1 Pretreatment Event Definition........................................................................104
10.1.2 Adverse Event Definition...............................................................................104
10.1.3 Serious Adverse Event Definition ..................................................................105
10.2 Procedures for Recording and Reporting Adverse Events and Serious 
Adverse Events...............................................................................................106
10.3 Monitoring of Adverse Events and Period of Observation.....................................107
10.4 Procedures for Reporting Drug Exposure During Pregnancy and Birth Events......108
11. ADMINISTRATIVE REQUIREMENTS ...................................................................109
11.1 Good Clinical Practice..........................................................................................109
11.2 Data Quality Assurance ........................................................................................109
11.3 Electronic Case Report Form Completion.............................................................109
11.4 Study Monitoring .................................................................................................110
11.5 Ethical Considerations..........................................................................................110
11.6 Patient Information and Informed Consent............................................................110
11.7 Patient Confidentiality..........................................................................................111
11.8 Investigator Compliance.......................................................................................111
11.9 On-site Audits ......................................................................................................111
11.10 Investigator and Site Responsibility for Drug Accountability..............................112
11.11 Product Complaints and Medication Errors (Including Overdoses) .....................112
11.12 Closure of the Study ...........................................................................................112
11.13 Record Retention................................................................................................113
12. USE OF INFORMATION..........................................................................................114
13. INVESTIGATOR AGREEMENT..............................................................................115
14. REFERENCES...........................................................................................................116
15. APPENDICES ...........................................................................................................121
15.1 Multiple Myeloma Diagnostic Criteria..................................................................121
15.2 Eastern Cooperative Oncology Group Scale for Performance Status.....................121
15.3 Cockcroft-Gault Equation.....................................................................................122
15.4 Steroid Equivalent Doses......................................................................................122
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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
ASCT
autologous stem cell transplantation
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
CDE
Center for Drug Evaluation 
Cmax
maximum observed concentration
COVID-19
coronavirus disease 2019
CR
complete response
CT
computed tomography
CYP
cytochrome P450
DDI
drug-drug interaction
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
 
EORTC QLQ-C30
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire Core 30
EOT
End of Treatment (visit)
 
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
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Abbreviation
Term
GIMEMA
Italian Group for Hematologic Diseases in Adults
HRQL
health-related quality of life
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
NGS
next generation sequencing
NMPA
National Medical Products Administration 
OS
overall survival
PAD
bortezomib, Adriamycin, and dexamethasone
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Abbreviation
Term
PD
progressive disease (disease progression)
PET
positron emission tomography
PFS
progression-free survival, defined as the time from date of first dose to 
progressive disease or death from any cause
PFS2
progression-free survival 2, defined as the time from date of first dose 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
SDV
source data verification
Millennium 
Millennium Pharmaceuticals, Inc.
TEAE
treatment-emergent adverse event
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
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1. 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 [4]. In the Americas and Western European countries, approximately 5 to 7 new 
cases of MM are diagnosed per 100,000 people each year [4-6]. 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 [7,8].
Information on cancer incidence in China is rather sparse, with population-based cancer 
registries covering only a small proportion of the total population [9]. The estimated age-
specific MM incidence rates per 100,000 people in China in 2005 are as follows for men 
versus women, respectively: 45 to 54 years, 1.2 vs. 0.5; 55 to 64 years, 1.7 vs. 1.1; 65 to 
74 years, 3.1 vs. 2.4; and 75 years or older, 2.9 vs. 1.1 [9]. The GLOBOCAN 2012 age-
standardized incidence of MM in China is 0.6/100,000 people. The 5-year prevalence of 
MM in China is 1.5/100,000 men and 1.0/100,000 women [10]. Death from MM accounts 
for 0.4% of deaths from cancer in China, and the age-standardized death rate from MM is 
0.5/100,000 deaths [10].
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) [11-15].
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 without 
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 
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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, Millennium 
Pharmaceuticals, Inc. (Millennium) has developed ixazomib, a small molecule 20S 
proteasome inhibitor.
1.1.2
Ixazomib: Millennium’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 Millennium. Building on the 
efficacy seen with bortezomib in MM and other hematologic malignancies, Millennium 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.
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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 multiple myeloma [RRMM] and
Study C16014 in newly diagnosed multiple myeloma [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 
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. 
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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.
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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 
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 
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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 
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.a.
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Table 1.a
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.
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.
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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 [16]. 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 [17]. 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 drug-drug 
interactions (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 (maximum observed 
concentration [Cmax] and AUC0-last) was similar with and without co-administration of 
clarithromycin, a strong CYP3A inhibitor (Study C16009, Arm 5) [18]; hence, no dose 
adjustment is necessary when ixazomib is administered with strong CYP3A inhibitors. 
These findings are explained by the in vitro metabolism data indicating the lack of a 
discernible contribution of CYP-mediated metabolism at clinically relevant ixazomib 
concentrations. As discussed earlier, no CYP isoforms have been identified to contribute 
meaningfully to ixazomib metabolism at clinically relevant concentrations, and CYP3A 
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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 Pgp but not of breast 
cancer resistance protein (BCRP) or multidrug resistance associated protein (MRP2) efflux 
pump transporters. Ixazomib is not an inhibitor of Pgp, BCRP, or MRP2. The potential for 
DDIs with substrates or inhibitors of Pgp, 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 area under the curve (AUC) by 74% (Study C16009, 
Arm 4).[18] 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 
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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) [19]. Initially, trials of 
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 [20], whereas a decrement in OS 
was observed in others [21]. 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 [22,23], and in 1 study, patients experienced a decrement 
in benefit [23].
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 [24-26]. 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 [24].
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The phase 3 HOVON/GMMG study investigated induction therapy leading to autologous 
SCT and subsequent maintenance therapy in patients with MM [25]. 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 [27-29]. 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 [28]. 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 [30]. To understand 
whether ixazomib maintenance therapy affects the incidence of new primary malignancies, 
the proposed trial includes a secondary endpoint assessing the incidence of new primary 
malignancies.
Recent Findings
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 
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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 in the non-ASCT setting 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 
[31,32] 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. Lenalidomide was approved by the 
United States (US) Food and Drug Administration for post-ASCT maintenance therapy in 
2017. 
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 in the non-autologous stem cell transplantation (ASCT) setting [19], and a true standard 
of care has not been adopted. Current US National Comprehensive Cancer Network 
guidelines (version 2.2014) [33] 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 [34] and European 
Society for Medical Oncology (ESMO) guidelines for the treatment of MM [35] 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” [36]. The guidelines also point out that the role of 
other novel agents in this setting is currently under evaluation. The ESMO 2013 guidelines 
for the treatment of MM [35] state that for patients not undergoing SCT, “systematic 
maintenance therapy is [also] not recommended in elderly patients.”
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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 as the Original Study Design
At the time the C16021 global study was initiated, maintenance therapy had 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, provided 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 Removal of Placebo Control
Over the past 6 years, as of the initiation of the C16021 global study, maintenance therapy 
has become more widely utilized. Additionally, the first interim analysis (IA) of the C16021 
global study was conducted (data cut-off date 12 August 2019) and the primary endpoint of 
PFS was found to be both statistically significant and clinically meaningful. No new safety 
concerns were found in patients receiving ixazomib. Given the positive results from the 
C16021 global study and the fact that the C16021 China Continuation is still open to 
enrollment, the sponsor does not believe it is appropriate to continue enrolling patients into a 
randomized, placebo-controlled maintenance study. The Center for Drug Evaluation (CDE) 
National Medical Products Administration (NMPA) acknowledged that it will be difficult to 
continue enrolling patients into the placebo arm of the C16021 China Continuation. The 
CDE suggested that the sponsor amend the study into a single arm study, so as to collect
more efficacy and safety data from Chinese patients receiving ixazomib. 
This amendment describes modifications to the China Continuation study procedures 
specifically for patients who are still on treatment, who are in one of the follow-up periods,
or who will be enrolled after this amendment takes effect.
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1.4.4
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 PD or 
unacceptable toxicity (whichever occurs first). Please see Section 1.4.4.1 and Section 1.4.4.2
below for the rationale for the schedule and dose, respectively. 
1.4.4.1
Schedule Rationale
The balance of benefit and risk is paramount in this 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 [25] and 
the GIMEMA trial in the non-SCT setting [24]. 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 
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 [24]. 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. 
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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 [37]. 
1.4.4.2
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 life. The different cutoffs were used for hematologic and 
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Currently, there are 2 ongoing, phase 3 trials of ixazomib coadministered with lenalidomide 
and dexamethasone in patients with MM (Study C16010 in patients with RRMM and 
Study C16014 in patients with NDMM). Millennium’s phase 3 dose in these 2 pivotal trials 
is 4 mg weekly, which is 1 dose level below the ixazomib MTD of 5.5 mg and was chosen 
to optimize benefit:risk on the basis of results from Study C16004.
As noted previously, the balance of benefit:risk is paramount in the 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.[38].
As shown in Figure 1.a, 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.a) 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.
1.4.5
Rationale for Blood-Based Biomarkers 
1.4.5.1
Single-Nucleotide Polymorphism Analyses
This section is not applicable in this protocol amendment.
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1.4.5.2
 
 
 
 
 
 
 
 
 
1.5
Potential Risks and Benefits
As of 27 March 2014, 1287 patients comprised the oral ixazomib Safety population. Clinical 
safety data included 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) indicated that the AEs reported with ixazomib 
were generally consistent with the class-based effects of proteasome inhibition and were 
similar to what had been previously reported with bortezomib, though the frequencies may 
have slightly differed. 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 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 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 
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AL amyloidosis, and NDMM. Weekly dosing appears to enable delivery of higher ixazomib 
doses for a longer period than twice-weekly dosing.
Emerging data from ixazomib clinical studies and discussions with the CDE NMPA have 
led the sponsor to modify the study design of the China Continuation part of Study C16021. 
The first IA of the C16021 global study was conducted (data cut-off date 12 August 2019) 
and the primary endpoint of PFS was found to be both statistically significant and clinically 
meaningful. Additionally, no new safety concerns were found in patients receiving 
ixazomib. Given the positive results from the C16021 global study and the fact that the 
C16021 China Continuation is still open to enrollment, the sponsor does not believe it is 
appropriate to continue enrolling patients into a randomized, placebo-controlled 
maintenance study. The CDE NMPA acknowledged that it will be difficult to continue 
enrolling patients into the placebo arm of the C16021 China Continuation. CDE suggested 
that the sponsor amend the study into a single arm study, so as to collect more efficacy and 
safety data from Chinese patients receiving ixazomib. 
The China Continuation is now converted to an open-label, single-arm study of ixazomib 
maintenance. Patients who were randomized to the placebo arm are permitted to cross over 
to the ixazomib arm; patients receiving placebo who do not cross over will discontinue the 
study. The study objectives are now focused on long-term tolerability and efficacy of 
ixazomib in patients in China, so as to evaluate the consistency of the safety and efficacy of 
ixazomib maintenance between the China population and the C16021 global study 
population.
This trial will be conducted in compliance with the protocol, the ethical principles that have 
their origin in the Declaration of Helsinki, Good Clinical Practice (GCP), applicable 
regulatory requirements, and International Conference on Harmonisation (ICH) guidelines.
2. STUDY OBJECTIVES
2.1
Primary Objective
The primary objective of this study is:

To determine the long-term safety and tolerability of ixazomib maintenance therapy
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2.2
Secondary Objectives

To determine PFS, defined as the time from date of first dose to PD or death from 
any cause, in patients in China with NDMM who have had a major 
responsedefined as CR, VGPR, or PRto initial therapy and who have not 
undergone SCT.

To determine OS. 

To determine whether response at study entry is improved or maintained.

To determine the TTP. 

To determine the time to next-line therapy (TTNT).

To assess the incidence of new primary malignancy in patients receiving 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.
2.3
Exploratory Objectives
 
 
 
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3. STUDY ENDPOINTS
3.1
Primary Endpoint
The primary endpoint is: 

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. 
3.2
Secondary Endpoints
The secondary endpoints are:

PFS, defined as the time from date of first dose (patient entered into IXRS and 
received first dose of ixazomib) to the first occurrence of PD, as evaluated by the 
investigator, or death from any cause, whichever occurs first. 

Overall survival, measured as the time of date of first dose to the date of death.

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 date of first dose to the date of first 
documented PD.

TTNT, defined as the time from date of first dose to the date of first dose of the next 
line of antineoplastic therapy.

Incidence of new primary malignancies.
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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.
3.3
Exploratory Endpoints 
 
 
 
 
 
4. STUDY DESIGN 
4.1
Overview of Study Design
The China Continuation part of Study C16021 was originally designed as a randomized, 
double-blind, placebo-controlled, multicenter study in patients in China with NDMM who 
have not undergone SCT. Upon implementation of Amendment 08, the China Continuation 
will now be a single-arm, open-label study of ixazomib maintenance for patients in China 
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 enrolled under Amendment 08 will be 
enrolled based on the same eligibility criteria.
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The Study Overview Diagram depicts the study design.
Screening 
The purpose of the study is to evaluate the role of maintenance therapy with ixazomib 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 have received initial therapy for 6 to 
12 months, according to standard of care, and have met all additional inclusion/exclusion 
criteria before study enrollment. The initial therapy permitted is any standard of care MM 
therapy. Upon implementation of Amendment 08, new eligible and consenting patients are 
to be enrolled no later than 60 days after the last dose of initial therapy. For patients who 
were previously randomized to the placebo arm who reconsent and cross over to ixazomib, 
reconsenting more than 60 days after the last dose of initial therapy is permitted. A 
Millennium project clinician or designee will confirm patient eligibility before study 
treatment is initiated; the investigator will ensure that documentation adequately captures the 
reasons for not proceeding to SCT. Upon implementation of Amendment 08, all patients will 
receive open-label ixazomib.
Study Treatment
Prior to implementation of Amendment 08, 10 patients have been randomized and treated in 
the China Continuation part of Study C16021. Patients who were randomized to study drug 
(ixazomib or placebo) prior to implementation of Amendment 08 and who are still on study 
treatment will complete their current cycle of treatment and be unblinded. 

Patients who are in the placebo arm and who have not yet experienced disease 
progression will have the opportunity to cross over to ixazomib maintenance, based 
on the investigator’s judgement and the patient’s informed consent. Patients who 
cross over will follow the “Schedule of Events for Crossover Patients” starting at 
Crossover Cycle 1 Day 1. Patients in the placebo arm who do not cross over should 
complete an EOT visit and discontinue the study. 

Patients who are in the ixazomib arm will continue to receive ixazomib maintenance.
Patients who reconsent will follow the “Schedule of Events for Patients Randomized 
to Ixazomib + Newly Enrolled Patients” according to their current cycle of treatment. 
Approximately 20 additional patients with NDMM will be enrolled in the China 
Continuation, for a total of approximately 30 patients overall. All newly enrolled patients 
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will receive ixazomib maintenance and will follow the “Schedule of Events for Patients 
Randomized to Ixazomib + Newly Enrolled Patients.”
Patients will receive ixazomib (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 
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. 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.
Patients will receive ixazomib 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. Note, patients previously randomized to the 
placebo arm who reconsent and cross over to ixazomib may receive up to 24 months 
(26 cycles) of ixazomib treatment. 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.
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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 3 Follow-up periods: PFS, PD, 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.
Progression-Free Survival Follow-up and Progressive Disease Follow-up
If a patient completes 24 months of ixazomib 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 4 weeks until PD occurs. All patients enrolled prior to implementation of 
Amendment 08 will be unblinded. Patients who were previously randomized to the placebo 
arm who have discontinued study treatment but who have not yet experienced disease 
progression or started alternative therapy have the opportunity to cross over to ixazomib 
maintenance. The decision to cross over is based on the investigator’s judgement and the 
patient’s informed consent. Patients who cross over will follow the “Schedule of Events for 
Crossover Patients” starting at Crossover Cycle 1 Day 1. Patients in the placebo arm who do 
not cross over will discontinue the study. Patients in the ixazomib arm who reconsent should 
continue on study and follow the new Schedule of Events. 
After PD occurs during the PFS Follow-up period, the patient enters the PD Follow-up 
period and continues to be followed every 4 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 4 weeks until initiation of 
next-line therapy by the investigator/treating physician. No crossover is permitted after a 
patient experiences PD.
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Overall Survival Follow-up
Patients who start next line therapy (regardless of when) will 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
Upon implementation of Amendment 08, the study objectives are now focused on long-term 
tolerability and efficacy of ixazomib in patients in China, so as to evaluate the consistency 
of the safety and efficacy of ixazomib maintenance between the China population and the 
C16021 global study population. There will be 1 IA for the safety and efficacy endpoints. 
This IA will be the primary analysis for the China Continuation and will be performed 
approximately 12 months after the additional ~20 patients have been enrolled under this 
amendment. The safety and efficacy endpoints will be assessed in the overall Chinese 
patient population (patients from China who were enrolled in the ixazomib arm of the 
C16021 global study, patients in the ixazomib arm of the China Continuation before 
implementation of Amendment 08, all patients enrolled in the China Continuation under 
Amendment 08, and patients who were randomized to the placebo arm before 
implementation of Amendment 08 and who crossed over to the ixazomib arm). The final 
analysis will be performed when all patients in the China Continuation are off study 
treatment and have completed the EOT visit, or upon termination of the study by the 
sponsor, whichever occurs earlier.
The Schedules 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.
For HRQL, the focus is on tolerability 
 
 
 
Eastern Cooperative Oncology Group Performance Status and AEs will be assessed, and 
laboratory values, vital signs, and electrocardiograms 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 [52].
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4.2
Number of Patients
Approximately 30 total patients from China with NDMM who had a major response to 
initial therapy and who have not undergone SCT will be enrolled in the China Continuation 
part of Study C16021. Prior to implementation of Amendment 08, 10 patients have been 
randomized and treated in the China Continuation. An additional ~20 patients are to be 
enrolled upon implementation of Amendment 08.
Enrollment is defined as a patient being entered into the IXRS system and receiving the first 
dose of study drug. 
4.3
Duration of Study
Patients will be treated 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 or 
intolerable toxicity, whichever occurs first. Note, patients previously randomized to the 
placebo arm who reconsent and cross over to ixazomib may receive up to 24 months 
(26 cycles) of ixazomib treatment. 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, HRQL, new primary malignancy, and survival.
The study will last until all patients in the China Continuation are off study treatment and 
have completed the EOT visit, or upon termination of the study by the sponsor, whichever 
occurs earlier.
5. 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).
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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.
6. Availability of complete documentation for

Details of initial disease state, initial therapy, and response
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
Cytogenetic assessment at diagnosis (cytogenetic assessment performed after 
diagnosis must be approved by a Millennium 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 enrollment.

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 Cockroft-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 enrollment.
4. Diagnosed or treated for another malignancy within 5 years before enrollment or 
previously diagnosed with another malignancy with evidence of residual disease. 
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Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not 
excluded if they have undergone complete resection.
5. Female patients who are lactating and breastfeeding or have a positive serum 
pregnancy test during the Screening period. 
6. Major surgery within 14 days before enrollment. 
7. Central nervous system involvement.
8. Infection requiring IV antibiotic therapy or other serious infection within 14 days 
before enrollment.
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 enrollment.
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.
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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 enrollment.
6. 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. 
Prior to implementation of Amendment 08, 10 patients have been randomized and treated in 
the China Continuation part of Study C16021. Patients who are still on study treatment will 
complete their current cycle of treatment and be unblinded. 

Patients who are in the placebo arm and who have not yet experienced disease 
progression will have the opportunity to cross over to ixazomib maintenance, based 
on the investigator’s judgement and the patient’s informed consent. Patients who 
cross over will follow the “Schedule of Events for Crossover Patients” starting at 
Crossover Cycle 1 Day 1. Patients in the placebo arm who do not cross over should 
complete an EOT visit and discontinue the study. 

Patients who are in the ixazomib arm will continue to receive ixazomib maintenance.
Patients who reconsent will follow the “Schedule of Events for Patients Randomized 
to Ixazomib + Newly Enrolled Patients” according to their current cycle of treatment. 
Patients who are in the placebo arm who have discontinued study treatment but who have 
not yet experienced PD or started alternative therapy (ie, in the PFS Follow-up Period) will 
also have the opportunity to cross over to ixazomib maintenance, based on the investigator’s 
judgement and the patient’s informed consent. Patients who cross over will follow the 
“Schedule of Events for Crossover Patients” starting at Crossover Cycle 1 Day 1.
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Approximately 20 additional patients with NDMM will be enrolled in the China 
Continuation and will follow the “Schedule of Events for Patients Randomized to Ixazomib 
+ Newly Enrolled Patients,” for a total of approximately 30 patients overall. 
Patients will receive oral ixazomib 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 Schedules of Events. During the first cycle of treatment, all patients will receive doses of 
ixazomib 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
Study Drug (Ixazomib Capsules)
Ixazomib capsules will be supplied as single capsules containing 0.5, 2.3, 3.0, or 4.0 mg of 
ixazomib. Ixazomib capsules will be provided by the sponsor.
Ixazomib capsules will be hereafter referred to as “study drug.”
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 
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but should resume dosing at the time of the next scheduled dose. Section 6.14 gives 
information about returning unused medication.
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 Schedules of Events. Toxicity will be evaluated according 
to the NCI CTCAE, Version 4.03, effective 14 June 2010 [52]. These criteria are provided in 
the Study Manual. 
Further clarification can be obtained in consultation with the Millennium 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.a. When a 
dose reduction of study drug is required due to toxicity, no dose re-escalation will be 
permitted.
Table 6.a
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.
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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 
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.b 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.a. 
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Table 6.b
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 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.a.
Dose Modifications for Subsequent 
Treatment Cycles 
Delay of 2 weeks at the start of a 
subsequent cycle due to lack of 
toxicity recovery as defined in 
Section 6.4.2: 

ANC<1.0109/L; platelet 
count<75109/L 
(Or other nonhematologic 
toxicities>Grade 1 or not to the 
patient’s baseline condition)
Hold study drug until resolution per criteria.
Reduce study drug by 1 dose level as outlined in Table 6.a.
The maximum delay before treatment should be discontinued will 
be 4 weeks (except in the case of investigator-determined clinical 
benefit and discussion with the project clinician or designee, at 
which time a reduction of 1 or more dose levels should be made).
All hematologic toxicities
For hematologic toxicity that occurs during a cycle but recovers in 
time for the start of the next cycle:

If dose was reduced within the cycle, start the next cycle at that 
same dose.

If 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.d for criteria for re-treatment and cycle delays.
6.4.4
Study Drug Dose Modification for Nonhematologic Toxicities
Please refer to Table 6.c 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.a. 
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Table 6.c
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.a.
Grade 3 signs and symptoms: 
severe symptoms, limiting self-
care activities of daily living, 
assistive device indicated
New or worsening Grade 4 
peripheral neuropathy
Discontinue 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.a.
Note: A dose level reduction will be made either on the basis of within-cycle 
criteria or subsequent cycle criteria but not both for the same cycle.
Grade 4 Nonhematologic 
Toxicities 
Consider permanently discontinuing 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.d for criteria for retreatment and cycle delays. Dose level reductions 
should be made in accordance with those outlined in Table 6.a.
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Table 6.d
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.a when treatment 
resumes.
The maximum delay before treatment should be discontinued will be 4 weeks 
(except in the case of investigator-determined clinical benefit and discussion with 
the project clinician or designee at which time dose reduction by at least 1 dose 
level should be considered).
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 Millennium
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
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
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
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 
electronic case report forms (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 Millennium 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.
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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

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.)
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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.
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 
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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, 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. Thrombotic microangiopathy 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 
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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.
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, which ultimately resolved, 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 while receiving ixazomib, the 
possibility that ixazomib may have contributed to the transverse myelitis cannot be excluded. 
Transverse myelitis should be managed according to standard medical practice.
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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
6.10.1 Blinding and Unblinding Prior to Implementation of Amendment 08
To maintain the blind, all study personnel, including the investigators, site personnel, study 
clinicians, and the sponsor, will be blinded to the treatment assignments for the duration of 
the study. When a patient is discontinued from the study, the investigator may request 
unblinding if it is necessary for determination of the patient’s subsequent anticancer 
treatment. 
Treatment assignments will be obtained through the interactive voice/web response system 
(IXRS) according to the procedures outlined in the Study Manual. Information regarding the 
treatment assignments will be kept securely at Millennium 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, to treat an AE, or to inform decisions for subsequent 
therapy, the investigator will contact the Millennium project clinician or designee (contact 
information is in the Study Manual). A decision to break the blind must be reached by the 
Millennium project clinician or designee and the investigator. The investigator, or designee, 
may break the blind through the IXRS independent of the Millennium project clinician or 
designee only if it is considered to be an emergency by the investigator that requires specific 
knowledge of the blinded study treatment to properly treat the AE/safety issue. If the 
treatment of the AE/safety issue is the same regardless of the study drug assignment, the 
blind should not be broken. The event requiring breaking the blind must be documented in 
the eCRF, including the date the blind was broken. In addition, the patient will be 
discontinued from further study drug administration in this study.
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6.10.2 Blinding and Unblinding Upon Implementation of Amendment 08
Upon implementation of Amendment 08, the China Continuation part of Study C16021 will 
transition from a double-blind, placebo-controlled design to an open-label, single-arm 
design (ixazomib only). Individual treatment assignments are now available in the IXRS. 
Note, the C16021 global study remains blinded.
Prior to implementation of Amendment 08, 10 patients have been randomized and treated in 
the China Continuation part of Study C16021. Patients who are still on study treatment will 
complete their current cycle of treatment and be unblinded. 

Patients who are in the placebo arm and who have not yet experienced disease 
progression will have the opportunity to cross over to ixazomib maintenance, based 
on the investigator’s judgement and the patient’s informed consent. Patients who 
cross over will follow the “Schedule of Events for Crossover Patients” starting at 
Crossover Cycle 1 Day 1. Patients in the placebo arm who do not cross over should 
complete an EOT visit and discontinue the study. 

Patients who are in the ixazomib arm will continue to receive ixazomib maintenance.
Patients who reconsent will follow the “Schedule of Events for Patients Randomized 
to Ixazomib + Newly Enrolled Patients” according to their current cycle of treatment.
Patients who are in the placebo arm who have discontinued study treatment but who have 
not yet experienced PD or started alternative therapy (ie, in the PFS Follow-up Period) will 
also have the opportunity to cross over to ixazomib maintenance, based on the investigator’s 
judgement and the patient’s informed consent. Patients who cross over will follow the 
“Schedule of Events for Crossover Patients” starting at Crossover Cycle 1 Day 1.
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). The dose strengths are differentiated by both capsule size 
and color, as described in the Table 6.e. 
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Table 6.e
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.
6.13
Packaging and Labeling
The study drug will be provided by Millennium. The study drug labels will fulfill all 
requirements specified by governing regulations. 
The capsules are individually packaged using cold form foil-foil blisters that are child 
resistant. There are 3 capsules per package.
6.14
Storage, Handling, and Accountability
On receipt at the investigative site, study drug should remain in the blister pack and carton 
provided until use or dispensation. The container should be stored according to the storage 
conditions that are in the pharmacy manual or equivalent storage guidelines. All excursions 
that occurred at 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 
Millennium. 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. Comprehensive instructions should be provided 
to the patient to ensure compliance with, and understanding of, dosing procedures. Patients 
are permitted to transport study drug from the site to home at room temperature. If 
circumstances due to the coronavirus disease 2019 [COVID-19] pandemic prevent a patient 
from attending the study site, sites may utilize alternative strategies to deliver study drug to 
patients (eg, via courier or site staff), per local standard practice and regulations and with 
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prior approval from the investigator and sponsor’s project clinician/designee. This may 
include planned shipments of the study drug from the central pharmacy (which may be a 
sub-depot), depot, or a clinical site to the patients, referred to as DTP (Direct-to-Patient). 
Patients who are receiving take-home medication should ordinarily 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. Patients should be instructed to store the medication 
according to the storage conditions that are in the pharmacy manual or equivalent storage 
guidelines for the duration of each cycle. 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-19 pandemic prevent a 
patient from attending the study site, drug packs and dosing diaries should be returned at the 
next available on-site clinic visit. Any excursions in temperature should be reported and 
dealt with on a case-by-case basis. 
Ixazomib is an anticancer drug and, as with other potentially toxic compounds, caution 
should be exercised when handling the study drug. Patients should be instructed not to chew, 
break, or open capsules. In case of contact with broken capsules, raising dust should be 
avoided during the clean-up operation. The product may be harmful by inhalation, ingestion, 
or skin absorption. Gloves and protective clothing should be worn during clean-up and 
during return of broken capsules and powder to minimize skin contact. The area should be 
ventilated and the site washed with soap and water after material pick up is complete. The 
material should be disposed of as hazardous medical waste in compliance with federal, state, 
and local regulations. 
In case of contact with the powder (eg, from a broken capsule), skin should be washed 
immediately with soap and copious amounts of water for at least 15 minutes. In case of 
contact with the eyes, copious amounts of water should be used to flush the eyes for at least 
15 minutes. Medical personnel should be notified.
Patients are to be instructed on proper storage, accountability, and administration of study 
drug, including that study drug is to be taken as intact capsules.
Please refer to the Pharmacy Manual for additional instructions.
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6.15
Other Protocol-Specified Materials
No other drugs or ancillary material are supplied for use in this trial.
7. 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: Guideline for Good Clinical Practice.

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 Millennium 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 Millennium project clinician or designee before 
study entry. 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.
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Upon implementation of Amendment 08, the China Continuation part of Study C16021 will 
transition from a double-blind, placebo-controlled design to an open-label, single-arm study 
of ixazomib maintenance. Patients who are still on study treatment will complete their 
current cycle of treatment and be unblinded. 

Patients who are in the placebo arm and who have not yet experienced disease 
progression will have the opportunity to cross over to ixazomib maintenance, based 
on the investigator’s judgement and the patient’s informed consent. Patients who 
cross over will follow the “Schedule of Events for Crossover Patients” starting at 
Crossover Cycle 1 Day 1. Patients in the placebo arm who do not cross over should 
complete an EOT visit and discontinue the study. 

Patients who are in the ixazomib arm will continue to receive ixazomib maintenance.
Patients who reconsent will follow the “Schedule of Events for Patients Randomized 
to Ixazomib + Newly Enrolled Patients” according to their current cycle of treatment.
Patients who are in the placebo arm who have discontinued study treatment but who 
have not yet experienced PD or started alternative therapy (ie, in the PFS Follow-up 
Period) will also have the opportunity to cross over to ixazomib maintenance, based on 
the investigator’s judgement and the patient’s informed consent. Patients who cross over 
will follow the “Schedule of Events for Crossover Patients” starting at Crossover 
Cycle 1 Day 1.
Note, the C16021 global study will remain a double-blind, placebo-controlled design. 
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. Patients must present to the study site for all visits shown in the Schedules of Events 
during Cycles 1-5 to ensure proper safety, efficacy, and PK monitoring. Alternative methods 
for administering study procedures/assessments may be considered for Cycle 6 and beyond 
when it is not possible for the patient to come to the study site due to the COVID-19 
pandemic.
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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 that are impacted by these unavoidable circumstances, any procedures 
not conducted per the study protocol will be documented in the eCRF.
If a patient misses an in-person study visit, the investigator/study team staff will speak 
directly with the patient by telephone or other medium (eg, a computer-based video 
communication) during each visit window to assess subject safety and overall clinical status. 
During this contact with the patient, the study site physician or other qualified site staff 
should at minimum conduct AE collection and an assessment of clinical symptoms. Other 
study assessments may be collected remotely as is feasible and may involve audio or video 
recording. If an in-clinic visit is not possible, the permitted alternatives are as follows. These 
assessments/procedures may be waived: symptom-directed physical examination, ECOG 
performance status, vital signs, weight, whole blood, 
. 
These assessments/procedures may be deferred until the next in-clinic visit: SPEP, UPEP, 
serum free light-chain assay, immunofixation, quantification of immunoglobulins, BMA, 
and biopsy. These assessments/procedures may be performed locally if possible and, if not, 
may be deferred until the next in-clinic visit: hematology and chemistry laboratory tests.
Patients will be evaluated at scheduled visits over 4 study periods: Screening, Treatment, 
EOT, and Follow-up (PFS, PD, and OS). 
Tests and procedures should be performed on schedule but, unless otherwise specified, 
occasional changes are allowable within a 2-day window during Cycles 1-5 and within a 
7-day window during Cycle 6 and beyond for holidays, vacations, and other administrative 
reasons; a longer window is allowable after discussion with the Millennium project clinician 
or designee. If the study schedule is shifted, assessments must be shifted to ensure that 
collection of assessments is completed before dosing. These windows are also permissible 
for study days not specified in the Schedules of Events, including Cycle 2 Day 15 and Day 8 
and Day 15 of Cycle 3 and beyond.
Refer to the Schedules of Events for timing of assessments. Additional details are provided 
as necessary in the sections that follow.
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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. 
For patients enrolled prior to implementation of Amendment 08 and still on study treatment, 
all patients must be reconsented before dosing on Day 1 of the next full treatment cycle. 
Patients enrolled prior to implementation of Amendment 08 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/EC, 
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.

Cytogenetic evaluation should be performed at diagnosis (or after diagnosis, only 
with approval from the Millennium 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 
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
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 
enrollment for symptomatic bone lesion or >5 years before enrollment for another 
malignancy), and the patient’s current smoking status.
Refer to the Schedules 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 
Schedules 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 
Schedules 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 Schedules of Events. 
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).
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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 [1,2].
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 Schedules 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 Schedules of Events. Refer to Section 10 for details regarding definitions, 
documentation, and reporting of pretreatment events, AEs, and SAEs. 
7.4.11 Enrollment
Prior to implementation of Amendment 08, a patient was considered to be enrolled in the 
study when the patient had been randomized to study treatment. Upon implementation of 
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Amendment 08, a patient will be considered to be enrolled when they meet all eligibility 
criteria, are entered into IXRS, and receive their first dose of ixazomib. For newly enrolled 
patients under Amendment 08, ixazomib must be initiated within 5 days of the patient being 
entered into the IXRS system. 
Procedures for completing the enrollment information are described in the Study Manual.
7.4.12 Electrocardiogram
A 12-lead electrocardiogram 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 enrollment, local laboratory results may be used as long as 
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samples are also sent to the central laboratory before the patient is enrolled. 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 Millennium project clinician or designee. The Millennium 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 Millennium 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 Millennium 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.
Clinical Chemistry, Hematology, Urinalysis, 
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 Schedules of 
Events.
Hematology

Hemoglobin

Hematocrit

Platelet (count)

Leukocytes with differential

Neutrophils (absolute neutrophil count [ANC])
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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
7.4.14
 
 
 
 
 
7.4.15 Quality of Life Assessments 
The HRQL assessments (EORTC QLQ-C30 
; see Sections 15.9
and 15.10) will be completed by the patient as specified in the Schedules of Events. The 
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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 items 
(dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). 
 
 
 
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
 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.
These patient-reported outcome questionnaires are preferred to be completed by patients in 
the clinic but, if needed due the COVID-19 pandemic, the questionnaires may be completed 
at the patient’s home using mailed paper versions of the questionnaires. In the case of paper-
based questionnaires, only copies of questionnaires supplied by Millennium or ordered from 
the publisher may be used. 
 
 
 
 
 
 
 
 
 
Note that signs and symptoms assessed with the patient-reported outcome questionnaires 
will not be considered AEs unless entered as such into the eCRF.
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7.4.16 Bone Marrow Aspiration
7.4.16.1 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. 
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.
An additional, optional BMA may be collected from patients at any time that PD is 
suspected or before the patient starts a new therapy. This BMA specimen will be evaluated 
locally. 
7.4.17 Imaging Assessments
Skeletal survey of disease will be performed at screening (within 8 weeks before enrollment
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.
7.4.18 Quantification of M-Protein
A blood sample and urine sample will be obtained at screening and at the time points 
specified in the Schedules of Events. 
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7.4.19 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 Schedules 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). 
7.4.20 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 Schedules of Events.
7.4.21 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 Schedules of Events. Undetectable M-protein by 
protein electrophoresis in both serum and urine will lead the central laboratory to perform 
immunofixation testing in both serum and urine.
7.4.22 Disease Response Assessment
Patients will be assessed for disease response according to the IMWG uniform response 
criteria, version 2011 (see Section 15.12) [53]. 
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 Schedules of Events). 
Before an investigator discontinues a patient from treatment for PD, the pertinent data must 
be confirmed by a Millennium project clinician or designee. 
Patients will be assessed for disease response by the investigator.  
Response categories are as follows in Table 7.a:
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Table 7.a
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.
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).
7.4.23 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. 
7.4.24 Follow-up Assessment for Progression-Free Survival, Progressive Disease, and 
Overall Survival
At EOT, patients will enter a Follow-up period for PFS, PD, and/or OS. See the Schedules 
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 3 Follow-up periods.
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7.4.24.1 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 4 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 4 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 4 weeks until initiation of 
next-line therapy by the investigator/treating physician.
In both the PFS and PD Follow-up periods, the EORTC QLQ-C30 
 
questionnaires 
 will be administered every 4 weeks. 
 
 
7.4.24.2 Overall Survival Follow-up
After patients have PD, they enter into the OS Follow-up period (Note: Upon 
implementation of Amendment 08, the PFS2 Follow-up period is removed from the study.) 
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 by accessing publicly-available information. 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 Millennium 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 
Millennium Department of Pharmacovigilance or designee. 
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Refer to Section 10 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 Millennium 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 Schedules of Events. Also refer 
to the Schedules 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 when all 
patients in the China Continuation are off study treatment and have completed the EOT visit, 
or upon termination of the study by the sponsor, whichever occurs earlier.
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: 
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
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 Schedules of Events. The primary reason for study drug 
discontinuation will be recorded on the eCRF.
In addition, upon implementation of Amendment 08, patients previously randomized to the 
placebo arm who do not cross over to ixazomib will complete an EOT visit and discontinue 
the study. 
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
In addition, upon implementation of Amendment 08, patients previously randomized to the 
placebo arm who do not cross over to ixazomib will complete an EOT visit and discontinue 
the study. 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. STATISTICAL AND QUANTITATIVE ANALYSES
8.1
Statistical Methods
In general, summary tabulations will be presented 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% CIs for time-to-event data. 
Details for the statistical analysis will be provided in the statistical analysis plan (SAP).   
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 the China Continuation is to allow the continued evaluation of any 
emerging safety signals and efficacy trends in patients in China. Prior to implementation of 
Amendment 08, 10 patients have been randomized and treated in the China Continuation. 
An additional ~20 patients are to be enrolled upon implementation of Amendment 08 for a 
total of approximately 30 patients overall.
With 30 patients, if the true rate for an AE is 10%, the probability of observing at least one 
patient with that AE is more than 95%. Similarly, if the true rate for an AE is 5%, the 
probability of observing at least one patient with that AE is more than 79%. Thus, the 
sample size is enough to give a large probability of observing AEs that are expected to 
commonly occur (ie, 5% or more) in this population. 
8.1.2
Stratification
Upon implementation of Amendment 08, there will be no randomization or stratification of 
patients. All patients will receive open-label ixazomib.
8.1.3
Populations for Analysis
All analyses will be performed on the Overall Chinese Patient Population, defined as 
follows: 
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Overall Chinese Patient Population:

Patients from China who were enrolled in the ixazomib arm of the C16021 global 
study, PLUS

Patients in the ixazomib arm of the China Continuation before implementation of 
Amendment 08, PLUS

All patients enrolled in the China Continuation under Amendment 08

Patients who were randomized to the placebo arm before implementation of 
Amendment 08 and who crossed over to the ixazomib arm.
All Chinese patients listed in the above bullets constitute the population of interest for this 
study. Subsets from this population of interest will be derived and used for analysis, as 
follows:
Ixazomib Safety population: The Ixazomib Safety population is defined as all patients who 
receive at least 1 dose of ixazomib. Patients will be analyzed according to the treatment they 
actually received; patients who were randomized to the placebo arm prior to implementation 
of Amendment 08 and who cross over to the ixazomib arm will contribute safety data from 
the time they initiate ixazomib onward. The primary analysis of safety will focus on the 
Ixazomib Safety population.
Placebo Safety population: The Placebo Safety population is defined as all patients who 
receive at least 1 dose of placebo. Patients will be analyzed according to the treatment they 
actually received; patients who were randomized to the placebo arm prior to implementation 
of Amendment 08 and who cross over to the ixazomib arm will contribute safety data to this 
population only during the time they receive placebo. Adverse event data from this patient 
population will be listed.
Efficacy population: The Efficacy population is defined as all patients who receive 
ixazomib treatment for the duration of their study participation. Patients who were 
randomized to the placebo arm and crossed over to the ixazomib arm upon implementation 
of Amendment 08 will not be included in the Efficacy population.
Per-Protocol population: The Per-Protocol population is a subset of the Efficacy 
population and consists of all patients who do not have major protocol violations. The 
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definition of major protocol violations will follow the definitions used in the C16021 global 
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
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 
Ixazomib 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
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
Grade 3 or higher drug-related TEAEs

The most commonly reported TEAEs (ie, those reported by both 5% and 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.
8.1.6.1
New Primary Malignancy
Two types of incidence rates will be calculated for the Ixazomib Safety population based on 
the new primary malignancy assessment:
1. Incidence proportions, defined as the percentage of the subjects reporting any new 
primary malignancy in the Ixazomib Safety population with available information
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2. Incidence rates, defined as the number of the subjects reporting any new primary 
malignancy divided by the total duration of follow-up in the Ixazomib Safety 
population with available information up to the onset of new primary malignancies
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.
8.1.6.2
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.
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8.1.7
Efficacy Analysis
8.1.7.1
Analyses for PFS
The analysis of PFS will be based on the Efficacy population using investigator-assessed 
progression data.
Progression-free survival is defined as the time from date of first dose to 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 descriptively using Kaplan-Meier K-M) method. The K-M 
survival curves and medians (if estimable), along with their 2-sided 95% CIs, will be 
provided. The K-M estimates along with 95% CI will be provided by 6-month intervals at 
6 months, 12 months, 18 months, and so on.
The analysis of PFS will be conducted at the time of the IA, approximately 12 months after 
the additional ~20 patients have been enrolled under this amendment. The analysis will be 
performed on the overall Chinese patient population (patients from China who were enrolled 
in the ixazomib arm of the C16021 global study, patients in the ixazomib arm of the China 
Continuation before implementation of Amendment 08, all patients enrolled in the China 
Continuation under Amendment 08, and patients who were randomized to the placebo arm 
before implementation of Amendment 08 and who crossed over to the ixazomib arm). The 
final analysis (FA) will be performed when all patients in the China Continuation are off 
treatment and have completed the EOT visit, or upon termination of the study by the 
sponsor, which occurs earlier. Descriptive statistics will be used to summarize patient data 
collected after the IA. A sensitivity analysis of PFS, as assessed by the investigator, in the 
Per-Protocol population may also be conducted.
Progression-free survival assessed by the investigator using different censoring mechanisms 
(eg, not censoring for patients who discontinue treatment and go on alternative 
antineoplastic therapy) will be analyzed in the Efficacy population. Details of different 
censoring approaches will be included in the SAP.
Subgroup analyses may be performed for PFS, as appropriate.  
8.1.7.2
Analyses of OS
OS will be analyzed on the basis of the Efficacy population and is defined as the time from 
the date of the first dose of study drug to the date of death. Patients without documentation 
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of death at the time of analysis will be censored at the date last known to be alive. OS will 
be analyzed descriptively using K-M method. The K-M survival curves and medians (if 
estimable), along with their 2-sided 95% CIs, will be provided. The K-M estimates along 
with 95% CI will be provided by 6-month interval at 6 months, 12 months, 18 months, and 
so on.
Subgroup analyses for OS may be performed as appropriate. 
8.1.7.3
Analyses of Other Secondary Efficacy Endpoints
Disease responserelated endpoints will be analyzed using investigator-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. 
Duration of Complete Response
Duration of CR is defined as the time from the date of the first dose (for those who had a CR 
at study entry) 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 the first dose 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 Efficacy population using methods similar to those used for PFS.
Time to Next-Line Therapy
TTNT is defined as the time from date of first dose to date of first dose of next-line 
antineoplastic therapy. TTNT will be analyzed on the basis of the Efficacy population. 
Patients who have not started next-line therapy will be censored at the last known contact 
date. 
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Correlation Between Frailty Status and Progression-Free Survival and Overall 
Survival
The K-M survival curves and K-M median PFS or OS (if estimable), along with their 2-
sided 95% CIs, will be provided for each frailty status.
8.1.8
Analyses of Patient-Reported Outcomes 
 
Analyses of patient-reported outcomes 
 will be performed using the 
Efficacy population.
8.1.8.1
Patient-Reported Outcomes Analysis
The actual value and change from baseline of the subscale scores for the EORTC QLQ-C30 
will be summarized using descriptive statistics and plotted over 
time. 
The number and percentage of patients with a meaningful change from baseline in subscale 
scores will be summarized 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.
The change from baseline in subscale scores will be presented using cumulative distribution 
function figures.
8.1.8.2
 
 
 
8.1.9
Pharmacokinetics/Pharmacodynamics/Biomarkers
8.1.9.1
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. 
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8.1.10 Interim and Final Analyses
The primary analysis for safety and efficacy will be performed at the time of the first IA, 
approximately 12 months after the additional ~20 patients have been enrolled under this 
amendment. The safety and efficacy endpoints will be assessed in the overall Chinese 
patient population (patients in China enrolled to the ixazomib arm of the C16021 global 
study, patients from the ixazomib arm of the China Continuation before implementation of 
Amendment 08, and all patients enrolled under Amendment 08). The final analysis will be 
performed when all patients in the China Continuation part of Study C16021 are off 
treatment and have completed an EOT visit, or upon termination of the study by the sponsor, 
which occurs earlier.
9. STUDY COMMITTEES
9.1
Steering Committee
A steering committee that includes a subset of investigators in this study and representatives 
from Millennium will be formed to provide advice on the conduct of the study and 
publications.
10. 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 require 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.
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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 
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 [52]. Clarification should be 
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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 
Millennium 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 Millennium, will be 
provided to each clinical study site. A sample of the SAE Form may be found in the Study 
Manual. Follow-up information on the SAE or serious pretreatment event may be requested 
by Millennium. SAE report information must be consistent with the data provided on the 
eCRF.
The paper SAE forms should be submitted via fax (see fax numbers below) within 24 hours 
of awareness. In case of fax, site personnel must confirm successful transmission of all 
pages and include an e-mail address on the fax cover sheet so that an acknowledgment of 
receipt can be returned via e-mail within 1 business day. E-mail 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 e-mail, site personnel must confirm 
successful transmission by awaiting an acknowledgment of the receipt via e-mail within 1 
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business day. If SAEs are reported via fax or by e-mail, the EDC application must be 
updated as soon as possible with the appropriate information.
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 [52]. 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 
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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 Millennium Department of 
Pharmacovigilance or designee from the time of the signing of the ICF up to first 
dose of study drug but will not be recorded in the eCRF.

Related and unrelated SAEs will be reported to the Millennium Department of 
Pharmacovigilance or designee from the first dose of study drug through 30 days 
after administration of the last dose of study drug 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 Millennium 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. 
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 
Millennium 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 Millennium 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. ADMINISTRATIVE REQUIREMENTS
11.1
Good Clinical Practice
The study will be conducted in accordance with the ICH-GCP and the appropriate regulatory 
requirement(s). The investigator will be thoroughly familiar with the appropriate use of the 
study drug as described in the protocol and the IB.
11.2
Data Quality Assurance
The investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each study 
patient. Study data will be entered into an eCRF by site personnel using a secure, validated, 
web-based electronic data capture (EDC) application. Millennium 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
Millennium 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.
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Millennium, 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 Millennium will be followed 
to comply with GCP guidelines.
All information recorded on the eCRFs for this study must be consistent with the patient’s 
source documentation. During the course of the study, the study monitor will make study 
site visits to review protocol compliance, verify eCRFs against source documentation, assess 
drug accountability, and ensure that the study is being conducted according to pertinent 
regulatory requirements. The review of medical records will be performed in a manner that 
ensures that patient confidentiality is maintained. 
In the event a monitor cannot visit the site in a timely manner due to the COVID-19 
pandemic, alternative monitoring approaches such as remote source data verification (SDV) 
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. For 
patients enrolled prior to implementation of Amendment 08 and still on study treatment, all 
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patients must be reconsented before dosing on Day 1 of the next full treatment cycle. 
Patients enrolled prior to implementation of Amendment 08 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 
Millennium 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 Millennium. Changes to the protocol will require 
written IRB/IEC approval/favorable opinion before implementation, except when the 
modification is needed to eliminate an immediate hazard or hazards to patients. Millennium, 
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 Millennium, 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 Millennium 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.
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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 Millennium, or a designee (or disposal of 
the drug, if approved by Millennium) will be maintained by the clinical site. Millennium 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 Millennium 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 to 
ctmcomplaint@takeda.com.
11.12
Closure of the Study
Within 90 days of the end of the study, the sponsor will notify the competent authorities and 
the IECs in all member states where the study is being carried out that the study has ended.
Within 1 year 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 Millennium, there is sufficient reasonable cause. Written 
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notification documenting the reason for study termination will be provided to the 
investigator or Millennium by the terminating party.
Circumstances that may warrant termination include, but are not limited to:

Determination of unexpected, significant, or unacceptable risk to patients

Failure to enter patients at an acceptable rate

Insufficient adherence to protocol requirements

Insufficient, incomplete, and/or unevaluable data

Determination of efficacy based on 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 Millennium once the site’s participation in the study has concluded.
Within 15 days after premature closure, Millennium must notify the competent authorities 
and IECs of any member state where the study is being conducted, providing the reasons for 
study closure. 
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 
Millennium notified. 
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12. USE OF INFORMATION
All information regarding ixazomib supplied by Millennium 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 Millennium. It is 
understood that there is an obligation to provide Millennium 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 Millennium, 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 Millennium 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 Millennium.
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13. INVESTIGATOR AGREEMENT
I have read Protocol C16021 Amendment 10: China Continuation: A Single-Arm, Open-
Label 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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Mateos MV, Richardson PG, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg 
O, et al. Bortezomib plus melphalan and prednisone compared with melphalan and 
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Gay F, Larocca A, Petrucci M. Achievement of Complete Remission is a Strong 
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multiple myeloma. Leukemia 2009;23(11):2147-52.
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Analysis of Data From Four Phase 1 Monotherapy Studies. Blood 
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NINLARO® (ixazomib) capsules, for oral use [prescribing information]. Cambridge, 
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Ludwig H, Durie BG, McCarthy P, Palumbo A, San Miguel J, Barlogie B, et al. 
IMWG consensus on maintenance therapy in multiple myeloma. Blood 
2012;119(13):3003-15.
20.
Spencer A, Prince HM, Roberts AW, Prosser IW, Bradstock KF, Coyle L, et al. 
Consolidation therapy with low-dose thalidomide and prednisolone prolongs the 
survival of multiple myeloma patients undergoing a single autologous stem-cell 
transplantation procedure. J Clin Oncol 2009;27(11):1788-93.
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phase 3 trial of thalidomide and prednisone as maintenance therapy after ASCT in 
patients with MM with a quality-of-life assessment: the National Cancer Institute of 
Canada Clinicals Trials Group Myeloma 10 Trial. Blood 2013;121(9):1517-23.
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Attal M, Harousseau JL, Leyvraz S, Doyen C, Hulin C, Benboubker L, et al. 
Maintenance therapy with thalidomide improves survival in patients with multiple 
myeloma. Blood 2006;108(10):3289-94.
23.
Morgan GJ, Gregory WM, Davies FE, Bell SE, Szubert AJ, Brown JM, et al. The 
role of maintenance thalidomide therapy in multiple myeloma: MRC Myeloma IX 
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multiple myeloma: a randomized controlled trial. J Clin Oncol 2010;28(34):5101-9.
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Sonneveld P, Schmidt-Wolf IG, van der Holt B, El Jarari L, Bertsch U, Salwender H, 
et al. Bortezomib induction and maintenance treatment in patients with newly 
diagnosed multiple myeloma: results of the randomized phase III HOVON-65/ 
GMMG-HD4 trial. J Clin Oncol 2012;30(24):2946-55.
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Mateos M-V, Oriol A, Teruel A-I, Bengoechea E, Pérez M, López J, et al. 
Maintenance Therapy with Bortezomib Plus Thalidomide (VT) or Bortezomib Plus 
Prednisone (VP) In Elderly Myeloma Patients Included In the GEM2005MAS65 
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Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N 
Engl J Med 2012;366(19):1782-91.
28.
McCarthy PL, Owzar K, Hofmeister CC, Hurd DD, Hassoun H, Richardson PG, et 
al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med 
2012;366(19):1770-81.
29.
Palumbo A, Hajek R, Delforge M, Kropff M, Petrucci MT, Catalano J, et al. 
Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J 
Med 2012;366(19):1759-69.
30.
Revlimid (Lenalidomide) European Public Assessment Report. European Medicines 
Agency Committee for Medicinal Products for Human Use. 21 June 2012. 
Publication No. EMA/432817/2012.
31.
Kantar Health. Treatment Architecture: Western Europe Multiple Myeloma. 
CancerMPact® Western Europe 2012.
32.
Kantar Health. Treatment Architecture: United States Multiple Myeloma. 
CancerMPact® United States 2012.
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NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Multiple 
Myeloma.  Version 2.2014  National Comprehensive Cancer Network. 2014.
34.
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International myeloma working group consensus statement for the management, 
treatment, and supportive care of patients with myeloma not eligible for standard 
autologous stem-cell transplantation. J Clin Oncol 2014;32(6):587-600.
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Moreau P, San Miguel J, Ludwig H, Schouten H, Mohty M, Dimopoulos M, et al. 
Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and 
follow-up. Ann Oncol 2013;24 Suppl 6:vi133-7.
36.
Ludwig H, Miguel JS, Dimopoulos MA, Palumbo A, Garcia Sanz R, Powles R, et al. 
International Myeloma Working Group recommendations for global myeloma care. 
Leukemia 2013.
37.
Badros AZ. Lenalidomide in myeloma--a high-maintenance friend. N Engl J Med 
2012;366(19):1836-8.
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Gupta N, Labotka R, Liu G, Hui AM, Venkatakrishnan K. Exposure-safety-efficacy 
analysis of single-agent ixazomib, an oral proteasome inhibitor, in 
relapsed/refractory multiple myeloma: dose selection for a phase 3 maintenance 
study. Invest New Drugs 2016;34(3):338-46.
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Bruggemann M, Pott C, Ritgen M, Kneba M. Significance of minimal residual 
disease in lymphoid malignancies. Acta Haematol 2004;112(1-2):111-9.
40.
Foroni L, Coyle LA, Papaioannou M, Yaxley JC, Sinclair MF, Chim JS, et al. 
Molecular detection of minimal residual disease in adult and childhood acute 
lymphoblastic leukaemia reveals differences in treatment response. Leukemia 
1997;11(10):1732-41.
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Eradication of minimal residual disease in B-cell chronic lymphocytic leukemia after 
alemtuzumab therapy is associated with prolonged survival. J Clin Oncol 
2005;23(13):2971-9.
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Mortuza FY, Papaioannou M, Moreira IM, Coyle LA, Gameiro P, Gandini D, et al. 
Minimal residual disease tests provide an independent predictor of clinical outcome 
in adult acute lymphoblastic leukemia. J Clin Oncol 2002;20(4):1094-104.
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Pott C, Hoster E, Delfau-Larue MH, Beldjord K, Bottcher S, Asnafi V, et al. 
Molecular remission is an independent predictor of clinical outcome in patients with 
mantle cell lymphoma after combined immunochemotherapy: a European MCL 
intergroup study. Blood 2010;115(16):3215-23.
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Liu H, Johnson JL, Koval G, Malnassy G, Sher D, Damon LE, et al. Detection of 
minimal residual disease following induction immunochemotherapy predicts 
progression free survival in mantle cell lymphoma: final results of CALGB 59909. 
Haematologica 2012;97(4):579-85.
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Andersen NS, Pedersen LB, Laurell A, Elonen E, Kolstad A, Boesen AM, et al. Pre-
emptive treatment with rituximab of molecular relapse after autologous stem cell 
transplantation in mantle cell lymphoma. J Clin Oncol 2009;27(26):4365-70.
46.
Geisler CH, Kolstad A, Laurell A, Andersen NS, Pedersen LB, Jerkeman M, et al. 
Long-term progression-free survival of mantle cell lymphoma after intensive front-
line immunochemotherapy with in vivo-purged stem cell rescue: a nonrandomized 
phase 2 multicenter study by the Nordic Lymphoma Group. Blood 
2008;112(7):2687-93.
47.
Pott C. Minimal residual disease detection in mantle cell lymphoma: technical 
aspects and clinical relevance. Semin Hematol 2011;48(3):172-84.
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Paiva B, Vidriales MB, Cervero J, Mateo G, Perez JJ, Montalban MA, et al. 
Multiparameter flow cytometric remission is the most relevant prognostic factor for 
multiple myeloma patients who undergo autologous stem cell transplantation. Blood 
2008;112(10):4017-23.
49.
Sarasquete ME, Garcia-Sanz R, Gonzalez D, Martinez J, Mateo G, Martinez P, et al. 
Minimal residual disease monitoring in multiple myeloma: a comparison between 
allelic-specific oligonucleotide real-time quantitative polymerase chain reaction and 
flow cytometry. Haematologica 2005;90(10):1365-72.
50.
Martinez-Sanchez P, Montejano L, Sarasquete ME, Garcia-Sanz R, Fernandez-
Redondo E, Ayala R, et al. Evaluation of minimal residual disease in multiple 
myeloma patients by fluorescent-polymerase chain reaction: the prognostic impact of 
achieving molecular response. Br J Haematol 2008;142(5):766-74.
51.
Paiva B, Martinez-Lopez J, Vidriales MB, Mateos MV, Montalban MA, Fernandez-
Redondo E, et al. Comparison of immunofixation, serum free light chain, and 
immunophenotyping for response evaluation and prognostication in multiple 
myeloma. J Clin Oncol 2011;29(12):1627-33.
52.
Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03. U.S. 
Department of Health and Human Services National Cancer Institute. 14 June 2010.
53.
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.
54.
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.
55.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. 
Nephron 1976;16(1):31-41.
56.
Knoben J, Anderson P. Handbook of Clinical Drug Data, 6th ed.: Drug Intelligence 
Pub, Inc.; 1988.
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57.
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.
58.
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.
59.
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. 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 [54].
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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 [55].
15.4
Steroid Equivalent Doses
Approximate equivalent doses:
Steroid
Glucocorticoid
Anti-inflammatory
(mg)
Mineralicorticoid
(mg)
Half-life
(hours)
Cortisone
100
100
812
Hydrocortisone
80
80
812
Prednisone
20
100
1236
Prednisolone
20
100
1236
Methylprednisolone
16
no effect
1236
Dexamethasone
2
no effect
3672
Source: Knoben JE, Anderson PO. Handbook of Clinical Drug Data, 6th ed. Drug Intelligence Pub, Inc. 
1988 [56].
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 [57].
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.
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15.6
Charlson Comorbidity Scoring System Without Age Weighting
Source: Charlson et al., 1987.[3]
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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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© Copyright 1995 EORTC Quality of Life Study Group.  All rights reserved.  Version 3.0
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15.12
Response Criteria
Source: Rajkumar SV, et al. 2011 [58]. (adapted from Durie et al. [53] and Kyle et al. [59] with permission).
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15.13
Schedule of Events Prior to Implementation of Amendment 08
Study 
Procedures
Screening
Treatment Period
EOTa
Follow-upb
28-Day Cyclesb
PFS
PD
PFS2
OS
Cycle
Cycle 1
Cycle 2
Cycle 
3
Cycles 
4–5
Cycle 
5c
Cycles 
6-26
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
12-lead ECG
X
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Study 
Procedures
Screening
Treatment Period
EOTa
Follow-upb
28-Day Cyclesb
PFS
PD
PFS2
OS
Cycle
Cycle 1
Cycle 2
Cycle 
3
Cycles 
4–5
Cycle 
5c
Cycles 
6-26
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 (Cycle 
13)
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
Cycle 1
Cycle 2
Cycle 
3
Cycles 
4–5
Cycle 
5c
Cycles 
6-26
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 lab)t
Progressive disease BMA specimen is requested at any time of progressive disease confirmation
Abbreviations: BMA=bone marrow aspirate; CT=computed tomography; ECG=electrocardiography; ECOG=Eastern Cooperative Oncology Group; EORTC=European 
Organization for Research and Treatment of Cancer; EOT=End of Treatment; 
 
; 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); 
 
 SFLC=serum free light chain; SPEP=serum protein electrophoresis; UPEP=urine protein electrophoresis.
Tests and procedures should be performed on schedule, but unless otherwise specified, occasional changes are allowable within a 2-day window for holidays, vacations, 
and other administrative reasons or a longer window after discussion with the Millennium Pharmaceuticals, Inc. (Millennium) project clinician or designee. If the 
study schedule is shifted, assessments must be shifted to ensure that collection of assessments is completed before dosing. 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 Millennium 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 Millennium 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 [1-3].
f
Patient-reported outcomes 
 should be completed before any other study procedures are performed or study 
drug is administered. During the PFS2 Follow-up period only, assessments should be done twice—ideally once approximately 8-12 weeks after the start of next-line 
therapy and again 8-12 weeks later—and are preferred to be administered in the clinic, but if needed, the QLQ-C30 
 questionnaires may be completed 
at home. At time points when a clinic visit is not required, 
.
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 
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Study 
Procedures
Screening
Treatment Period
EOTa
Follow-upb
28-Day Cyclesb
PFS
PD
PFS2
OS
Cycle
Cycle 1
Cycle 2
Cycle 
3
Cycles 
4–5
Cycle 
5c
Cycles 
6-26
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
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 Millennium 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). 
 
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 
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Study 
Procedures
Screening
Treatment Period
EOTa
Follow-upb
28-Day Cyclesb
PFS
PD
PFS2
OS
Cycle
Cycle 1
Cycle 2
Cycle 
3
Cycles 
4–5
Cycle 
5c
Cycles 
6-26
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
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, and 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.
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
Clarify details about disease response assessment.

Clarify the purposes of the interim and final analyses.

Clarify the definition of the safety population.

Clarify the definition and analysis of time to end of next-line therapy.

Clarify the definition and analysis of duration of next-line therapy.

Specify details about medical history compilation.

Clarify details about bone marrow aspiration.

Clarify details about MRD assessments in the Schedule of Events.

Clarify details of the MRD analyses.

Correct the reference citations in Section 1.4.1.1, History of Maintenance Therapy in 
Multiple Myeloma, and Section 1.4.4.2, Rationale for Mutational Analyses.

Add the citation of newly published reference supporting dose selection.

Clarify physical examination procedures.

Clarify imaging procedures.

Clarify that respiratory rate should be measured as clinically indicated.

Clarify when central laboratory results must be reviewed before initiating the next 
treatment cycle.

Clarify the local laboratory data that must be entered into the electronic case report form.

Allow for more frequent pregnancy testing in compliance with local regulations.

Correct a dose reduction detail.

Clarify the circumstances under which dose escalation can occur.

Clarify that the end-of-treatment (EOT) window is +1 week, rather than ±1 week.

Clarify an exception to the EOT visit 30 days (+1 week) after last dose of study drug.

Clarify details about storage and transport of study drug.

Update Section 6.9, Management of Clinical Events, to align with ixazomib clinical 
development program language. 

Clarify details around monitoring of adverse events.

Update the product complaint and medication error reporting contact information.

Clarify that study drug treatment may be discontinued permanently if the patient is 
withdrawn by the investigator.

Correct the unit of serum calcium used to determine calcium elevation for the diagnosis 
of myeloma.

Remove mention of the Safety Management Attachment, which is no longer relevant.

Use the term “next-line therapy” consistently.

Correct typographical errors, punctuation, grammar, and formatting.
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15.16 Amendment 03 (China) Rationale and Purposes
Rationale for Amendment 03
The primary rationale for the changes in the global Amendment 2, which are incorporated in 
this China-specific Amendment 3, is to extend the follow-up period in which health-related 
quality of life (HRQL) measurements are obtained, update the description of the HRQL 
analyses, and update the HRQL statistical analysis methods; remove the exclusion of 
cytochrome P450 (CYP) inhibitors; and change the Charlson Comorbidity Scoring System 
from one that is weighted for age to the original scoring system, which is not weighted for 
age. Other purposes for the amendment are the addition of a secondary endpoint and 
numerous administrative changes. Additional changes in Amendment 3 include the 
assessment of minimum residual disease (MRD) by next generation sequencing (NGS), not 
flow cytometry, and clarification that the ixazomib storage conditions are provided in the 
pharmacy manual or equivalent.   
Purposes for Amendment 03
The purposes of this amendment are to:

Update the cover page with current signatories.

Extend the duration of HRQL data collection into the period of next-line therapy and 
update the description of HRQL analyses.

Update HRQL statistical analysis methods. 

Update the pharmacokinetics (PK) and concomitant medication information to reflect 
recent population PK analyses and drug-drug interaction study results from Study 
C16009 demonstrating that CYP inhibitors do not affect ixazomib PK.

Remove Ginkgo biloba use as an exclusion criterion.

Change the Charlson Comorbidity Scoring System in use, which is weighted for age, to 
the original scoring system, which is not weighted for age.

Clarify details around the window for study procedures.

Update the Schedule of Events to include inadvertently missing information.

Add a new secondary objective pertaining to the effect of ixazomib maintenance 
therapy on the time to next-line therapy (TTNT).

Add a new secondary endpoint to measure the TTNT. 

Add methods of statistical analysis for the new secondary endpoint.

Clarify the wording of certain secondary endpoints.

Reclassify certain exploratory endpoints as secondary, and reword them.

Clarify inclusion criterion 6.

Clarify exclusion criterion 4.

Reflect the completion of Study C16009.

Clarify the criteria for beginning a treatment cycle.

Remove waveforms as a type of electrocardiogram data that may be obtained.
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
Clarify details about disease response assessment.

Clarify the purposes of the interim and final analyses.

Clarify the definition of the safety population.

Clarify the definition and analysis of time to end of next-line therapy.

Clarify the definition and analysis of duration of next-line therapy.

Specify details about medical history compilation.

Clarify details about bone marrow aspiration.

Clarify details about MRD assessments in the Schedule of Events.

Clarify details of the MRD analyses.

Correct the reference citations in Section 1.4.1.1, History of Maintenance Therapy in 
Multiple Myeloma.

Add the citation of newly published reference supporting dose selection.

Clarify physical examination procedures.

Clarify imaging procedures.

Clarify that respiratory rate should be measured as clinically indicated.

Clarify when central laboratory results must be reviewed before initiating the next 
treatment cycle.

Clarify the local laboratory data that must be entered into the electronic case report 
form.

Allow for more frequent pregnancy testing in compliance with local regulations.

Correct a dose reduction detail.

Clarify the circumstances under which dose escalation can occur.

Clarify that the end-of-treatment (EOT) window is +1 week, rather than ±1 week.

Clarify an exception to the EOT visit 30 days (+1 week) after last dose of study drug.

Clarify details about storage and transport of study drug.

Update Section 6.9, Management of Clinical Events, to align with ixazomib clinical 
development program language. 

Clarify details around monitoring of adverse events.

Update the product complaint and medication error reporting contact information.

Clarify that study drug treatment may be discontinued permanently if the patient is 
withdrawn by the investigator.

Correct the unit of serum calcium used to determine calcium elevation for the diagnosis 
of myeloma.

Remove mention of the Safety Management Attachment, which is no longer relevant.

Use the term “next-line therapy” consistently.

Clarify that MRD assessment will be by NGS.

Correct typographical errors, punctuation, grammar, and formatting.
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15.17
Amendment 04 (China Continuation Study) Rationale and Purposes
Rationale for Amendment 04
The primary rationale for this amendment is to establish a China continuation of the global 
Study C16021. This amendment describes modifications to the global study procedures 
specifically for those patients who enroll in the China continuation. Approximately 105 
patients with newly diagnosed multiple myeloma will be enrolled in China.   
The China continuation is an extension of the global study that will continue to assess the 
primary objective of progression-free survival (PFS) and the key secondary objective of 
overall survival (OS). PFS will be assessed when a total of approximately 58 PFS events 
have been reported in China (pooled from patients enrolled in the global study from the most 
recent interim analysis and the China continuation). The final analysis for OS will be 
performed when a total of approximately 60 death events have been reported for patients in 
China (pooled between the events among the China patients in the global study from the 
most recent interim analysis or final analysis and events among patients in the China 
continuation), or when the final analysis of OS in the global study has been conducted, 
whichever occurs later, or termination of the study by the sponsor.
Minor grammatical, editorial, and formatting changes are included for clarification purposes 
only.
Purposes for Amendment 04
The purposes of this amendment are to:
1. Update the number of patients to reflect that approximately 105 patients from China will 
be enrolled.  
2. Emphasize that the primary objective is for patients in China.  
3. Update the Endpoint and Follow-up Period Diagram to include the time to start of next-
line therapy endpoint. 
4. Provide the number of events required for the primary analysis of PFS for the China 
continuation, and define the primary and final analyses for patients in China.
5. Provide the number of death events required for the final analysis for OS and clarify the 
duration of the study.
6. Provide the approaches for the statistical analysis of endpoints (PFS and OS) in the 
China continuation.
7. Clarify the statistical methods and subgroup analyses for key secondary efficacy 
analyses.
8. Clarify the analysis of average scores from the EORTC QLQ-C30 global quality of life 
domain.
10. Clarify the planned safety and efficacy review by the IDMC.
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15.18
Amendment 05 (Global, Substantial) Rationale and Purposes
Rationale for Amendment 05
This document describes the changes to the protocol incorporating Amendment 05. The 
primary rationale for this amendment is fourfold: to reduce the sample size, to include 
subgroup analyses of progression-free survival (PFS), to update the PFS assumptions and 
type I error allocation, and to adopt an adaptive design for the final analysis for overall 
survival (OS). Details are provided below. 

Reduce the sample size. The enrollment for this study is slower than originally 
expected, resulting in the timing of the first interim analysis (IA) (which is the final 
analysis [FA] for the primary endpoint, PFS) being very close to the timing of the 
completion of enrollment. As such, later-enrolled patients will not have a follow-up 
period that is long enough to ascertain their PFS at the time of the first IA, resulting in 
potential bias of the analysis results. To allow for reasonable follow-up for all enrolled 
patients, the sample size will be reduced from the original plan for 761 patients to 700 
patients, and the timing of the first IA will be changed to approximately 10 months after 
the last patient has been enrolled or approximately 392 PFS events have been observed, 
whichever occurs later. 

Include a subgroup analysis approach focusing on patients who may derive 
particular benefit from ixazomib. A subgroup analysis is prospectively planned for the 
first IA, in parallel with the PFS analysis, in the intent-to-treat (ITT) population. The 
addition of this subgroup analysis will serve to determine whether the ixazomib group 
shows superiority over the placebo group with regard to PFS in 3 prespecified subgroups 
using the Hochberg procedure for multiplicity correction: patients ≥75 years of age, 
patients who have International Staging System (ISS) stage III disease before initial 
therapy, and patients with a best response of complete response (CR) or very good 
partial response (VGPR) to initial therapy, as assessed during screening.

With this subgroup analysis approach, the type I error is divided and reallocated for 2 
statistical tests: an alpha level of 0.04 is used for the primary PFS analysis in the ITT 
population, and an alpha level of 0.01 is used for the subgroup analysis.

Three subgroups were selected for the subgroup analysis: 1) patients with ISS stage 
III disease at diagnosis, 2) patients aged ≥75 years; and 3) patients with a response of 
CR or VGPR at study entry. These subgroups were selected on the basis of recent 
data suggesting the potential for preferential benefit of maintenance therapy in these 
patients, as follows. 

Patients with MM who have ISS stage III have historically worse outcomes 
following initial therapy [1]; thus, maintenance therapy may preferentially 
improve outcomes in this subgroup, particularly because the lenalidomide 
maintenance benefit is less than in other patients [2].

Older patients generally receive less intense induction therapy and have poorer 
outcomes [3,4], such that maintenance therapy may provide a preferential benefit 
in this subgroup as well—particularly because lenalidomide maintenance therapy 
did not provide a meaningful clinical benefit in patients >75 years of age [5].
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
Finally, patients with CR or VGPR at study entry may benefit preferentially from 
maintenance therapy, as they have less residual disease at the start of 
maintenance therapy than other patients and may experience further reduction of 
the tumor cell mass during the study [6].  

Update the PFS assumptions and the type I error allocation. The sponsor believes an 
assumption of median PFS of 11 months for the control (placebo) arm is more 
reasonable than the original assumption of 15 months, on the basis of data from other 
relevant clinical trials, including the MM-15 and MM-20 studies of lenalidomide and the 
VISTA study of bortezomib. The target number of PFS events assessed by the 
independent review committee (IRC) will not change from 392, and statistical power 
will remain at 90% with a 2-sided alpha = 0.04 and a hazard ratio (HR) of 0.71 (median 
PFS, 15.5 months with ixazomib vs 11 months with placebo). 

Implement an adaptive design to test OS, the key secondary endpoint, at the second 
IA. The sponsor has observed that blinded OS events are accumulating at a rate slower 
than estimated initially. To allow for greater maturity of data and reasonable timing of 
analyses, the second IA for OS will be updated to occur when 206 deaths have occurred 
(approximately 70% of 295 death events, the minimal number of events for the OS final 
analysis). At this time, an adaptive approach will also be implemented to determine the 
number of OS events needed for the final analysis—which could range from 295 events 
to approximately 393 events, according to the unblinded event re-estimation adaptation 
rule. In addition, the O’Brien-Fleming alpha spending function (the Lan-DeMets 
method) will be used to calculate the significant boundary for OS analyses instead of the 
gamma method with gamma = -1.
Changes in Amendment 05
The purposes of this amendment are to:
1. Reduce the number of patients to be enrolled from 761 to 700.
2. Modify the statistical design to change the timing of the first IA, allocate statistical 
power to a subgroup analysis, and update the PFS assumptions and type I error 
allocation.
3. Modify the statistical design to adopt an adaptive design to test OS at the second IA.
4. Clarify the timing of discontinuation of sample collection and stopping of the study 
relative to the timing of PFS analyses. 
5. Move the details of analysis of the secondary endpoint, duration of the next line of 
therapy, to the correct section. 
6. Clarify a detail about sensitivity analyses for PFS. 
7. Describe how adjustment for potential effects of subsequent therapy used after study 
discontinuation may be analyzed. 
8. Change the duration of the study to accommodate other changes to the statistical design. 
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
Three subgroups were selected for the subgroup analysis: 1) patients with ISS stage 
III disease at diagnosis, 2) patients aged ≥75 years; and 3) patients with a response of 
CR or VGPR at study entry. These subgroups were selected on the basis of recent 
data suggesting the potential for preferential benefit of maintenance therapy in these 
patients, as follows. 

Patients with MM who have ISS stage III have historically worse outcomes 
following initial therapy [1]; thus, maintenance therapy may preferentially 
improve outcomes in this subgroup, particularly because the lenalidomide 
maintenance benefit is less than in other patients [2].

Older patients generally receive less intense induction therapy and have poorer 
outcomes [3,4], such that maintenance therapy may provide a preferential benefit 
in this subgroup as well—particularly because lenalidomide maintenance therapy 
did not provide a meaningful clinical benefit in patients >75 years of age [5].

Finally, patients with CR or VGPR at study entry may benefit preferentially from 
maintenance therapy, as they have less residual disease at the start of 
maintenance therapy than other patients and may experience further reduction of 
the tumor cell mass during the study [6].  

Update the PFS assumptions and the type I error allocation. The sponsor believes an 
assumption of median PFS of 11 months for the control (placebo) arm is more 
reasonable than the original assumption of 15 months, on the basis of data from other 
relevant clinical trials, including the MM-15 and MM-20 studies of lenalidomide and the 
VISTA study of bortezomib. The target number of PFS events assessed by the 
independent review committee (IRC) will not change from 392, and statistical power 
will remain at 90% with a 2-sided alpha = 0.04 and a hazard ratio (HR) of 0.71 (median 
PFS, 15.5 months with ixazomib vs 11 months with placebo). 

Implement an adaptive design to test OS, the key secondary endpoint, at the second 
IA. The sponsor has observed that blinded OS events are accumulating at a rate slower 
than estimated initially. To allow for greater maturity of data and reasonable timing of 
analyses, the second IA for OS will be updated to occur when 206 deaths have occurred 
(approximately 70% of 295 death events, the minimal number of events for the OS final 
analysis). At this time, an adaptive approach will also be implemented to determine the 
number of OS events needed for the final analysis—which could range from 295 events 
to approximately 393 events, according to the unblinded event re-estimation adaptation 
rule. In addition, the O’Brien-Fleming alpha spending function (the Lan-DeMets 
method) will be used to calculate the significant boundary for OS analyses instead of the 
gamma method with gamma = -1.
Changes in Amendment 06
1. Reduce the number of patients to be enrolled from 761 to 700.
2. Modify the statistical design to change the timing of the first IA, allocate statistical 
power to a subgroup analysis, and update the PFS assumptions and type I error 
allocation.
3. Modify the statistical design to adopt an adaptive design to test OS at the second IA.
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to assess disease response/progression according to International Myeloma Working Group 
(IMWG) criteria (including use of local efficacy laboratory measures) for documentation of 
initial disease progression (PD) 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 End of 
Treatment 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 anticancer therapies 
(see the Schedule of Events). Patients will be contacted every 12 weeks until death or 
termination of the study by the sponsor.
Additionally, this amendment clarifies other elements of the study design and procedures. 
Descriptions of how to manage study procedures during unavoidable circumstances, such as 
the coronavirus disease 2019 (COVID-19) pandemic, have additionally been added. 
Language regarding a new adverse drug reaction of thrombotic microangiopathy has been 
added to the management of clinical events. Procedures for unblinding patients at the time of 
PD and subsequent therapy are clarified. Paper-based serious adverse event (SAE) reporting 
procedures are additionally clarified. 
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 07
The purposes of this amendment are to:
1. Clarify the study objectives as of Amendment 07.
2. Clarify the study endpoints as of Amendment 07.
3. Discontinue a number of efficacy response assessments, including central laboratory 
assessments of efficacy for protocol purposes and IRC evaluations, and clarify safety 
laboratory evaluation.
4. Update the estimated study duration.
5. Clarify the frequency of PFS Follow-up and PD Follow-up visits.
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6. Update language about the management of clinical events in patients receiving 
ixazomib.
7. Clarify the unblinding procedures for patients during the Treatment period and in the 
Follow-up periods.
8. Require all patients to reconsent. 
9. Clarify that pharmacokinetic assessments are complete for all patients.
10. Clarify the duration of evaluation for new primary malignancies. 
11. Clarify details about ixazomib dispensing.
12. Clarify that additional packaging information can be found in the Pharmacy Manual. 
13. Clarify the procedures for storage, handling, and accountability. 
14. Clarify ethical principles that are to be considered for patients in the study.
15. Add flexibility in study conduct in unavoidable circumstances (eg, the COVID-19 
pandemic).
16. Clarify the schedule, collection procedures, and analyses for 
 
patient-reported outcomes. 
17. Clarify that the first IA has been conducted but all statistical and quantitative 
analyses details are retained for reference. 
18. Update the procedures for SAE reporting.
19. Add information about alternative monitoring approaches, such as remote source 
data verification, in the event a monitor cannot visit the site in a timely manner due 
to the COVID-19 pandemic.
For specific examples of changes in text and where the changes are located, see 
Section 15.14
15.21
Amendment 08 (China Continuation Study) Rationale and Purposes
Rationale for Amendment 08
This document describes the changes to the protocol incorporating Amendment 08. The 
primary rationale for this amendment is to convert the China Continuation part of Study 
C16021 (herein referred to as the C16021 China Continuation) from a double-blind, 
placebo-controlled design to an open-label, single-arm design (ixazomib only). Two factors 
led to the change in design:
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
The first interim analysis (IA) of the C16021 global study has been conducted (data 
cut-off date 12 August 2019) and the primary endpoint of progression-free survival 
(PFS) was found to be statistically significant and clinically meaningful. 
Additionally, no new safety concerns were found in patients receiving ixazomib.

Recently available treatment options for patients with multiple myeloma (MM) have 
contributed to enrollment challenges in the C16021 China Continuation; to date, only 
10 patients have been randomized. 
Given the positive results from the C16021 global study and the fact that the C16021 China 
Continuation is still open to enrollment, the sponsor does not believe it is appropriate to 
continue enrolling patients into a randomized, placebo-controlled maintenance study. The 
Center for Drug Evaluation (CDE), National Medical Products Administration 
acknowledged that it will be difficult to continue enrolling patients into the placebo arm of 
the C16021 China Continuation. The CDE suggested that the sponsor amend the study into a 
single arm study, so as to collect more efficacy and safety data from Chinese patients 
receiving ixazomib. 
This amendment describes modifications to the C16021 China Continuation procedures for 
patients who are still on treatment, who are in 1 of the follow-up periods, or who will be 
enrolled after this amendment takes effect.  

Patients enrolled prior to implementation of Amendment 08: Prior to 
implementation of Amendment 08, 10 patients had been randomized and treated in 
the China Continuation. All patients continuing in the study under Amendment 08 
must be reconsented. 
o
Patients still on treatment: Patients who were randomized to study drug 
(ixazomib or placebo) prior to implementation of Amendment 08 and who 
are still on study treatment will complete their current cycle of treatment and 
be unblinded. 

Patients who are in the placebo arm and who have not yet experienced 
disease progression will have the opportunity to cross over to 
ixazomib maintenance, based on the investigator’s judgement and the 
patient’s informed consent. Patients who cross over will follow the 
“Schedule of Events for Crossover Patients” starting at Crossover 
Cycle 1 Day 1. Patients in the placebo arm who do not cross over 
should complete an End of Treatment (EOT) visit and discontinue the 
study. 

Patients who are in the ixazomib arm will continue to receive 
ixazomib maintenance. Patients who reconsent will follow the 
“Schedule of Events for Patients Randomized to Ixazomib + Newly 
Enrolled Patients” according to their current cycle of treatment.
o
Patients in the PFS Follow-up period: All patients will be unblinded.

Patients in the placebo arm who have discontinued study treatment 
but who have not yet experienced disease progression or started 
alternative therapy have the opportunity to cross over to ixazomib 
maintenance. The decision to cross over is based on the investigator’s 
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judgement and the patient’s informed consent. Patients who cross 
over will follow the “Schedule of Events for Crossover Patients” 
starting at Crossover Cycle 1 Day 1. Patients in the placebo arm who 
do not cross over will discontinue the study.

Patients in the ixazomib arm who reconsent should continue on study 
and follow the “Schedule of Events for Patients Randomized to 
Ixazomib + Newly Enrolled Patients” according to the PFS Follow-up 
period schedule. 
o
Patients in the progression-free survival (PFS2) or overall survival (OS) 
Follow-up periods: All patients will be unblinded.

Patients in the placebo arm will discontinue the study. No crossover 
to the ixazomib arm is permitted in these patients who have 
experienced primary disease progression or who have initiated 
alternative therapy.

Patients in the ixazomib arm who reconsent will continue on study 
and follow the “Schedule of Events for Patients Randomized to 
Ixazomib + Newly Enrolled Patients” according to the OS Follow-up 
period schedule. Note, the PFS2 Follow-up period has been removed 
in Protocol Amendment 08; patients previously in PFS2 follow-up 
will be followed in the OS Follow-up period. 

Patients to be enrolled after implementation of Amendment 08: Approximately 
20 additional patients with newly diagnosed multiple myeloma who responded to 
initial treatment will be enrolled in the China Continuation, for a total of 
approximately 30 patients overall. All newly enrolled patients will receive ixazomib 
maintenance and will follow the “Schedule of Events for Patients Randomized to 
Ixazomib + Newly Enrolled Patients.”
As the primary endpoint of PFS has been met in the C16021 global study, upon 
implementation of Amendment 08 for the China Continuation and the change to an open-
label, single-arm design of ixazomib maintenance, the primary study objective will be safety. 
PFS and OS will become secondary objectives. The primary analysis will be performed 
approximately 12 months after the additional ~20 patients have been enrolled under this 
amendment. Safety and efficacy endpoints will be assessed in the overall Chinese patient 
population (patients from China who were enrolled in the ixazomib arm of the C16021 
global study, patients in the ixazomib arm of the China Continuation before implementation 
of Amendment 08, and all patients enrolled in the China Continuation under Amendment 
08). The final analysis will be performed when all patients in the China Continuation are off 
study treatment and have completed the EOT visit, or upon termination of the study by the 
sponsor, whichever occurs earlier. 
Additionally, this amendment clarifies other elements of the study design and procedures. 
Descriptions of how to manage study procedures during unavoidable circumstances, such as 
the coronavirus disease 2019 (COVID-19) pandemic, have additionally been added. 
Language regarding a new adverse drug reaction of thrombotic microangiopathy was added 
to the management of clinical events. Paper-based serious adverse event (SAE) reporting 
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procedures were additionally clarified. See the purposes below for a list of all changes 
included in this amendment. 
Purposes for Amendment 08
The purposes of this amendment are to: 
1. Update the study design from a double-blind, placebo-controlled study to an open-
label single-arm study of ixazomib maintenance in all patients. Patients who were 
previously randomized to the placebo arm are permitted to cross over to ixazomib. 
2. Modify the existing Schedule of Events table to apply only to patients who were 
previously randomized to the ixazomib arm or to patients who will be enrolled under 
Amendment 08, and to create a new Schedule of Events table for patients who were 
previously randomized to the placebo arm and who will cross over to ixazomib.
3. Modify the primary objective to be long-term safety and tolerability of ixazomib 
maintenance therapy for patients in the C16021 China Continuation.  
4. Remove the key secondary objective because there will be no alpha-controlled 
secondary objective, and to update the list of secondary objectives to align with the 
new study design. 
5. Update the study endpoints for alignment with the new study design and study 
objectives.
6. Update the number of patients to be enrolled in the C16021 China Continuation.  
7. Update the duration of study definition.
8. Indicate that, given the changes in the current amendment, patients enrolled prior to 
implementation of Amendment 08 remaining on study will need to be reconsented.
9. Add flexibility in study conduct in unavoidable circumstances (eg, the COVID-19 
pandemic).
10. Clarify the Pharmacokinetic Sampling schedule for patients enrolled prior to 
implementation of Amendment 08 and for newly enrolled patients under 
Amendment 08. 
11. Update the definition of study enrollment.
12. Clarify the schedule, collection procedures, and analyses 
 
patient-reported outcomes.
13. Remove minimal residual disease and biomarker assessments from the study 
analyses, as they are no longer informative endpoints given the changes in the study 
design.
14. Remove the PFS2 Follow-up period, as it is no longer an informative follow-up 
period given the changes in the study design. 
15. Update the text on the use of maintenance therapy in MM to reflect the new 
treatment landscape.
16. Update the Study Rationale section to reflect the new study design. 
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17. Update the number of events required for the IA of PFS for the C16021 China 
continuation, and to clarify the interim and final efficacy analyses for patients in 
China.
18. Clarify that review of disease response data will be done by the investigator and that 
independent review committee review is optional. 
19. Remove the independent data monitoring committee (IDMC) review now that the 
study is an open-label study of ixazomib maintenance. 
20. Update language about management of clinical events in patients receiving 
ixazomib.
21. Clarify details about ixazomib dispensing. 
22. Clarify details about ixazomib packaging, handling, and storage guidelines.
23. Clarify ethical principles that are to be considered for patients in the study. 
24. Update the study populations for analysis.
25. Clarify the safety analyses. 
26. Add information about submitting SAE reports.
27. Clarify the time period for assessing new primary malignancies. 
28. Add information about alternative monitoring approaches, such as remote source 
data verification, in the event a monitor cannot visit the site in a timely manner due 
to the COVID-19 pandemic. 
Minor grammatical, editorial, formatting, and administrative changes not affecting the 
conduct of the study are included for clarification and administrative purposes only. 
15.22
Amendment 09 (Global, Substantial) Rationale and Purposes
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.
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Minor grammatical, editorial, formatting, and administrative changes not affecting the 
conduct of the study are included for clarification and administrative purposes only. 
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 COVID-19 pandemic.
4. Clarify local laboratory assessment recordings.
15.23
Amendment 10 Detailed Summary of Changes
The primary section(s) of the protocol affected by the changes in Amendment No. 10 are 
indicated. The corresponding text has been revised throughout the protocol. 
Change 1: Remove the references to randomization throughout the protocol.
The primary change occurs in the 3.2 Secondary Endpoints: 
Initial 
wording:
Overall survival, measured as the time of randomization to the date of death
Amended or 
new wording:
Overall survival, measured as the time of randomizationdate of first dose to 
the date of death
Rationale for Change: Replaced "randomization" with "date of first dose" or "enrollment," 
depending on context, to align with changes incorporated in Protocol Amendment 08.
The following sections also contain this change:

Protocol Summary.

Study Overview Diagram.

Study Endpoint and Follow-up Period Diagram.

Schedules of Events.

List of Abbreviations.

Section 2.2 Secondary Objectives.

Section 3.2 Secondary Endpoints.

Section 5.1 Inclusion Criteria.

Section 5.2 Exclusion Criteria.

Section 7.4.3 Medical History.

Section 7.4.13 Clinical Laboratory Evaluations.
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
Section 7.4.17 Imaging Assessments.

Section 8.1.7.1 Analyses for PFS.
Change 2: Remove reference to second progressive disease (PD2) throughout the protocol.
The primary change occurs in Study Endpoint and Follow-up Period Diagram. 
Description 
of change:
Removed "PD2=second PD (on second line therapy)" from abbreviations.
Rationale for Change: The PD2 endpoint was removed in Protocol Amendment 08.
The following sections also contain this change:

Schedules of Events.

List of Abbreviations.
Change 3: Clarify "vital signs" with a footnote in the Schedules of Events.
The primary change occurs in Schedules of Events: 
Description 
of change:
Added footnote "f" to vital signs.
Rationale for Change: Added footnote to clarify the proper assessment of vital signs.
Change 4: Clarify unblinding of patients off study. 
The primary change occurs in Schedules of Events:
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Added text:

Patients enrolled prior to implementation of Amendment 08: Prior to 
implementation of Amendment 08, 10 patients had been randomized 
and treated in the China Continuation. All patients continuing in the 
study under Amendment 08 must be reconsented.
...
o
Patients in the PFS2 or Overall Survival (OS) Follow-up 
Periods: All patients will be unblinded.

Patients in the placebo arm will discontinue the study. 
No crossover to the ixazomib arm is permitted in these 
patients who have experienced primary disease 
progression or who have initiated alternative therapy.

Patients in the ixazomib arm who reconsent will 
continue on study and follow the “Schedule of Events 
for Patients Randomized to Ixazomib + Newly Enrolled 
Patients” according to the OS Follow-up Period 
schedule. Note, the PFS2 Follow-up period has been 
removed in Protocol Amendment 08; patients 
previously in PFS2 follow-up will be followed in the 
OS follow-up period. 
o
Patients Off Study: All these patients will be unblinded.
Rationale for Change: Clarified that patients off study will be unblinded if they were 
enrolled before implementation of Amendment 08.
Change 5: Clarify language regarding procedures for reporting product complaints or 
medication errors.
The primary change occurs in Section 11.11 Product Complaints and Medication Errors 
(Including Overdoses): 
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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)
E-mail: GlobalOncologyMedinfo@takeda.com
FAX: 1-800-881-6092
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).
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Amended or 
new wording:
A product complaint is a verbal, written, or electronic expression that implies 
dissatisfaction regarding the identity, strength, purity, quality, or stability of a 
drug product. Individuals who identify a potential product complaint situation 
should immediately contact Dohmen Life Sciences (see below) and report the 
event to ctmcomplaint@takeda.com. Whenever possible, the associated 
product should be maintained in accordance with the label instructions 
pending further guidance from a Takeda Quality representative.
Product complaints in and of themselves are not AEs. If a product 
complaint is associated with an SAE, a Millennium 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)
E mail: GlobalOncologyMedinfo@takeda.com
FAX: 1 800 881 6092
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 6: Clarify language in study conduct regarding the coronavirus disease 2019 
(COVID-19) pandemic.
The primary change occurs in Section 6.14 Storage, Handling, and Accountability:
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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. Comprehensive instructions 
should be provided to the patient to ensure compliance with, and 
understanding of, dosing procedures. 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 utilize 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. Patients who are 
receiving take-home medication should ordinarily 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. Patients should 
be instructed to store the medication according to the storage conditions that 
are in the pharmacy manual or equivalent storage guidelines for the duration 
of each cycle. 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 and dealt with on a case-by-case basis. 
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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. Comprehensive instructions 
should be provided to the patient to ensure compliance with, and 
understanding of, dosing procedures. Patients are permitted to transport study 
drug from the site to home at room temperature. In case of extenuating If 
circumstances due to the coronavirus disease 2019 [COVID-19] 
pandemicthat prevent a patient from attending the study site (eg, the 
coronavirus disease 2019 [COVID 19] pandemic), sites may utilize 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. This may include 
planned shipments of the study drug from the central pharmacy (which 
may be a sub-depot), depot, or a clinical site to the patients, referred to as 
DTP (Direct-to-Patient). Patients who are receiving take-home medication 
should ordinarily 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. Patients should be instructed to store the 
medication according to the storage conditions that are in the pharmacy 
manual or equivalent storage guidelines for the duration of each cycle. 
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 extenuatingIf circumstances due to 
the COVID-19 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 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.
The following sections also contain this change:

Schedules of Events.

Section 7.4 Study Procedures.

Section 7.4.14

Section 7.4.15 Quality of Life Assessments.
Change 7: Clarify definitions of some of the populations for analysis. 
The primary change occurs in Section 8.1.3 Populations for Analysis:
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Added text:
Overall Chinese Patient Population:

Patients from China who were enrolled in the ixazomib arm of the C16021 
global study, PLUS

Patients in the ixazomib arm of the China Continuation before 
implementation of Amendment 08, PLUS

All patients enrolled in the China Continuation under Amendment 08

Patients who were randomized to the placebo arm before 
implementation of Amendment 08 and who crossed over to the 
ixazomib arm.
Initial 
wording:
Ixazomib Safety population: The Ixazomib Safety population is defined as 
all patients who receive at least 1 dose of ixazomib. Patients will be analyzed 
according to the treatment they actually received; patients who were 
randomized to the placebo arm prior to implementation of Amendment 08 and 
who cross over to the ixazomib arm will contribute safety data from the time 
they initiate ixazomib onward. The primary analysis of safety will focus on 
this patient population.
Placebo Safety population: The Placebo Safety population is defined as all 
patients who receive at least 1 dose of placebo. Patients will be analyzed 
according to the treatment they actually received; patients who were 
randomized to the placebo arm prior to implementation of Amendment 08 and 
who cross over to the ixazomib arm will contribute safety data to this 
population only during the time they receive placebo. Data from this patient 
population will be briefly summarized using descriptive statistics.
Amended or 
new wording:
Ixazomib Safety population: The Ixazomib Safety population is defined as 
all patients who receive at least 1 dose of ixazomib. Patients will be analyzed 
according to the treatment they actually received; patients who were 
randomized to the placebo arm prior to implementation of Amendment 08 and 
who cross over to the ixazomib arm will contribute safety data from the time 
they initiate ixazomib onward. The primary analysis of safety will focus on 
theis Ixazomib Safety patient population.
Placebo Safety population: The Placebo Safety population is defined as all 
patients who receive at least 1 dose of placebo. Patients will be analyzed 
according to the treatment they actually received; patients who were 
randomized to the placebo arm prior to implementation of Amendment 08 and 
who cross over to the ixazomib arm will contribute safety data to this 
population only during the time they receive placebo. Adverse event Ddata 
from this patient population will be briefly summarized using descriptive 
statisticslisted.
Rationale for Change: Clarified that patients in the placebo arm who crossed over to 
ixazomib contribute to the Overall Chinese Patient Population and other aspects of the study 
populations.
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The following sections also contain this change:

Protocol Summary.

Section 4.1 Overview of Study Design.

Section 8.1.6 Safety Analysis.

Section 8.1.6.1 New Primary Malignancy.

Section 8.1.7.1 Analyses for PFS.
Change 8: Remove the Independent Review Committee section.
The primary change occurs in Section 9.2:
Deleted text: 9.2 
Independent Review Committee
The sponsor may choose to use an IRC review to independently establish PFS. 
If so, the IRC will review all disease evaluation data from the study and 
determine disease status (response and progression, including in the PFS 
follow up period).  
Rationale for Change: The Independent Review Committee is no longer needed.
The following sections also contain this change:

Section 3.2 Secondary Endpoints.

Section 7.4.22 Disease Response Assessment.

Section 8.1.7.1 Analyses for PFS.

Section 8.1.7.3 Analyses of Other Secondary Efficacy Endpoints.
Change 9: Update the management of transverse myelitis for ixazomib to reflect evolving 
data.
The primary change occurs in Section 6.9 Management of Clinical Events:
Initial 
wording:
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.
Amended or 
new wording:
Transverse Myelitis
Transverse myelitis has been reported with ixazomib. It is not known whether 
ixazomib causes transverse myelitis; however, because it happened to a 
patientwhile 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.
Rationale for Change: Removed reference to 1 patient for transverse myelitis.
Change 10: Clarify reporting of patient-reported outcome questionnaires. 
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The primary changes occur in Section 7.4.15 Quality of Life Assessments and 8.1.8.1
Patient-Reported Outcomes Analysis:
Added text:
Section 7.4.15
Note that signs and symptoms assessed with the patient-reported outcome 
questionnaires will not be considered AEs unless entered as such into the 
eCRF.
Deleted text: Section 8.1.8.1
The actual value and change from baseline of the subscale scores for the 
EORTC QLQ-C30 
will be summarized using 
descriptive statistics and plotted over time. 
The number and percentage of patients with a meaningful change from 
baseline in subscale scores will be summarized 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.
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.
Rationale for Change: Clarified that signs and symptoms will not be considered AEs 
unless recorded as such and clarified analysis of subscale scores.
Change 11: Clarify the wording of some secondary and exploratory study objectives.
The primary change occurs in Section 2.2 Secondary Objectives and Section 2.3 Exploratory
Objectives:
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Rationale for Change: Reflect that this study is now single arm (ixazomib maintenance 
therapy), with no comparator regimen.
The following section also contains this change:

Protocol Summary.
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SAP_001.pdf: 
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4.11.5 Eastern Cooperative Oncology Group Performance Status ...............................32
4.11.6 Other Safety Assessments ................................................................................32
5. CHANGES TO PLANNED ANALYSES FROM PROTOCOL .....................................32
6. PROGRAMMING CONSIDERATIONS .......................................................................32
6.1 Statistical Software...................................................................................................32
6.2 Rules and Definitions ...............................................................................................32
7. REFERENCES...............................................................................................................33
LIST OF TABLES
Table 4-1   
Handling of Missing Assessments and Censoring for PFS Primary 
Analysis Based on FDA Guidance ..............................................................21
Table 4-2   
Handling of Missing Assessments and Censoring for PFS Sensitivity 
Analysis Based on EMA guidance ..............................................................22
Table 4-3   
Definition of Subscale Scores of EORTC QLQ-C30 ...................................25
Table 4-4   
................................26
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LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS
Abbreviation
Term
AE
adverse event
ALC
absolute lymphocyte count
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical
AUC
area under the curve
BMA
bone marrow aspirate
CDF
cumulative distribution function
CI
confidence interval
CO2
carbon dioxide
CR
complete response 
CT
computed tomography
del
deletion
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
 
EORTC QLQ-C30
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire Core 30
EOT
End of Treatment (visit)
FA
final analysis
GGT
gamma glutamyl transferase
HDT
high-dose therapy
HRQOL
health related quality of life
IA
interim analysis
IDMC
independent data monitoring committee
IRC
independent review committee
ISC
independent statistical center
ISS
International Staging System
ITT
intent-to-treat
IXRS
interactive web/voice response system
K-M
Kaplan-Meier
LDH
lactate dehydrogenase
MedDRA
Medical Dictionary for Regulatory Activities
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Abbreviation
Term
MID
minimally important difference
MM
multiple myeloma
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NDMM
newly diagnosed multiple myeloma
NEC
not elsewhere classified
NGS
generation sequencing
NK
natural killer (cells)
NPM
new primary malignancy
OS
overall survival
PD
progressive disease 
PET
positron emission tomography
PFS
progression-free survival
PK
pharmacokinetic(s)
PN
PP
peripheral neuropathy
per-protocol
PR
partial response 
PRO
patient-reported outcome
SAE
serious adverse event
SAP 
statistical analysis plan
SCT
stem cell transplant/therapy
SD
TTNT
stable disease
time to next-line therapy
TTP
time to progression
VGPR
very good partial response
WBC
white blood cell (count)
WHO
World Health Organization
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1.   
INTRODUCTION
In general, the purpose of the statistical analysis plan (SAP) is to provide a framework that 
addresses the protocol objectives in a statistically rigorous fashion, with minimized bias 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
The China Continuation part of Study C16021 was originally designed as a randomized, 
double-blind, placebo-controlled, multicenter study in patients in China with NDMM who 
have not undergone SCT. Upon implementation of Amendment 08, the China Continuation 
will now be a single-arm, open-label study of ixazomib maintenance for patients in China 
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 enrolled under Amendment 08 will be 
enrolled based on the same eligibility criteria.
The purpose of the study is to evaluate the role of maintenance therapy with ixazomib 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 have received initial therapy for 6 to 
12 months, according to standard of care, and have met all additional inclusion/exclusion 
criteria before study enrollment. The initial therapy permitted is any standard of care MM 
therapy. Upon implementation of Amendment 08, new eligible and consenting patients are 
to be enrolled no later than 60 days after the last dose of initial therapy. For patients who 
were previously randomized to the placebo arm who reconsent and cross over to ixazomib, 
reconsenting more than 60 days after the last dose of initial therapy is permitted. Upon 
implementation of Amendment 08, all patients received open-label ixazomib.
The Treatment period of the study is defined as the interval during which any enrolled 
patient is receiving ixazomib; 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), 
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twice during the second cycle (Days 1 and 8), and then once per treatment cycle for the 
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).
Prior to implementation of Amendment 08, 10 patients have been randomized and treated in 
the China Continuation part of Study C16021. Patients who were randomized to study drug 
(ixazomib or placebo) prior to implementation of Amendment 08 and who are still on study 
treatment will complete their current cycle of treatment and be unblinded. 
Upon implementation of Amendment 08, the study objectives are now focused on long-term 
tolerability and efficacy of ixazomib in patients in China, so as to evaluate the consistency 
of the safety and efficacy of ixazomib maintenance between the China population and the 
C16021 global study population. There will be 1 IA for the safety and efficacy endpoints. 
This IA will be the primary analysis for the China Continuation and will be performed 
approximately 12 months after the additional ~20 patients have been enrolled under this 
amendment. The safety and efficacy endpoints will be assessed in the overall Chinese 
patient population (patients from China who were enrolled in the ixazomib arm of the 
C16021 global study, patients in the ixazomib arm of the China Continuation before 
implementation of Amendment 08, all patients enrolled in the China Continuation under 
Amendment 08, and patients who were randomized to the placebo arm before 
implementation of Amendment 08 and who crossed over to the ixazomib arm). The final 
analysis will be performed when all patients in the China Continuation are off study 
treatment and have completed the EOT visit, or upon termination of the study by the 
sponsor, whichever occurs earlier.
1.2   
Study Objectives
The primary objective is:

To determine the long-term safety and tolerability of ixazomib maintenance therapy
The secondary objectives are:

To determine the progression-free survival (PFS), defined as the time from date of 
the first dose to PD or death from any cause, in patients in China with NDMM who 
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have had a major responsedefined as CR, VGPR, or PRto initial therapy and 
who have not undergone SCT

To determine overall survival (OS)

To determine whether response at study entry is improved or maintained

To determine the time to progression (TTP)

To determine the time to next-line therapy (TTNT)

To assess the incidence of new primary malignancy in patients receiving ixazomib 
maintenance therapy

To assess health-related quality of life (HRQOL) as measured by the Global Health 
Status/Quality of Life (QOL) 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
The exploratory objectives are:
 
 
 
 
 
 
 
 
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2.   
POPULATIONS FOR ANALYSIS
All analyses will be performed on the Overall Chinese Patient Population, defined as 
follows: 

Patients from China who were enrolled in the ixazomib arm of the C16021 global 
study, PLUS

Patients in the ixazomib arm of the China Continuation before implementation of 
Amendment 08, PLUS

All patients enrolled in the China Continuation under Amendment 08.

Patients who were randomized to the placebo arm prior to implementation of 
Amendment 08 and who cross over to the ixazomib arm
All Chinese patients listed in the above bullets constitute the population of interest for this 
study. Subsets from this population of interest will be derived and used for analysis, as 
follows:
2.1   
Efficacy Population
The Efficacy population is defined as all patients who receive ixazomib treatment for the 
duration of their study participation. Patients who were randomized to the placebo arm and 
crossed over to the ixazomib arm upon implementation of Amendment 08 will not be 
included in the Efficacy population. The Efficacy population will be used for the efficacy 
analyses, 
 and patient-reported outcome (PRO) analyses.
Moreover, PRO assessments using the EORTC QLQ-C30 
 will 
be analyzed using patients with PRO measurements at study entry and at least one post study 
entry measurement in the Efficacy population.
2.2   
Safety Population
Ixazomib Safety population: The Ixazomib Safety population is defined as all patients who 
receive at least 1 dose of ixazomib. Patients will be analyzed according to the treatment they 
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actually received; patients who were randomized to the placebo arm prior to implementation 
of Amendment 08 and who cross over to the ixazomib arm will contribute safety data from 
the time they initiate ixazomib onward. The primary analysis of safety will focus on the 
Ixazomib Safety population.
Placebo Safety population: The Placebo Safety population is defined as all patients who 
receive at least 1 dose of placebo. Patients will be analyzed according to the treatment they 
actually received; patients who were randomized to the placebo arm prior to implementation 
of Amendment 08 and who cross over to the ixazomib arm will contribute safety data to this 
population only during the time they receive placebo. Adverse events data from this patient 
population will be listed.
The Ixazomib Safety population will be used for all safety-related analyses such as adverse 
events (AE), concomitant medications, laboratory tests, and vital signs.
2.3   
Per-Protocol Population
The Per-Protocol (PP) population is a subset of the Efficacy population and consists of all 
patients who do not have major protocol violations.
The PP population will be used as a sensitivity analysis of the Efficacy population for the 
efficacy endpoint, PFS.  
2.4   
Response-Evaluable Population
The Response-Evaluable population is a subset of the Efficacy population and consists of all 
patients who have a baseline and at least 1 post-baseline response assessment. The 
Response-Evaluable population is used for the analyses of disease response related 
endpoints. 
   
3.   
HYPOTHESES AND DECISION RULES
Although there will be no formal statistical hypothesis testing performed, this study will be 
practice-informing, and hence, summary statistics will be employed.
4.   
STATISTICAL METHODOLOGY
In general, summary tabulations will be displayed by the number of observations, mean, and 
standard deviation, median, minimum, and maximum for continuous variables, and the 
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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.
4.1   
Sample Size Justification
The primary objective of the China Continuation is to allow the continued evaluation of any 
emerging safety signals and efficacy trends in patients in China. Prior to implementation of 
Amendment 08, 10 patients had been randomized and treated in the China Continuation. An 
additional ~20 patients are to be enrolled upon implementation of Amendment 08 for a total 
of approximately 30 patients overall.
With 30 patients, if the true rate for an AE is 10%, the probability of observing at least one 
patient with that AE is more than 95%. Similarly, if the true rate for an AE is 5%, the 
probability of observing at least one patient with that AE is more than 79%. Thus, the 
sample size is enough to give a large probability of observing AEs that are expected to 
commonly occur (ie, 5% or more) in this population.
4.2   
Randomization and Stratification 
Upon implementation of Amendment 08, there will be no randomization or stratification of 
patients. All patients will receive open-label ixazomib.
4.3   
Blinding and Unblinding
Upon implementation of Amendment 08, the China Continuation part of Study C16021 will 
transition from a double-blind, placebo-controlled design to an open-label, single-arm 
design (ixazomib only). Individual treatment assignments are now available in the IXRS.
4.4   
Data Handling
4.4.1   
Methods for Handling Missing Data
All available efficacy and safety data will be included in data listings and tabulations. Data
that are potentially spurious or erroneous will be examined according to standard data
management operating procedures.
In general, missing data will be treated as missing, and no data imputation will be applied, 
unless otherwise specified. For PRO data, handling of missing data will be based on 
published instrument specific methods and guidelines.
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4.4.1.1   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. 
4.4.1.2   Missing/Partial Dates in Adverse Events/Concomitant Therapies/Subsequent 
Therapies
4.4.1.2.1
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. 
4.4.1.2.2
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
a.
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) 
a.
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.
4.4.1.2.3
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, 
a.
If the onset month and year are the same as the month and year of last dose 
with study drug, the day of last dose + 1 will be imputed.
b. If the onset month and year are not the same as the month and year of last 
dose with study drug, the first day of the month is imputed. 

When only a year is present, 
a.
If the onset year is the same as the year of last dose with study drug, the date 
of last dose + 1 will be imputed.
b. If the onset year is not the same as the year of last dose with study drug, the 
first day of the year is imputed. 
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
If no components of the onset date are present the date of last dose + 1 will be 
imputed.
4.4.2   
Definition of Baseline Values
The baseline for disease 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).
For subjects that crossed over, baseline for safety data will be defined as the last data 
collected prior to receiving ixazomib.
4.4.3   
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).  
4.4.4   
Justification of Pooling
All data from all sites will be pooled.  
4.4.5   
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 4.8.
4.5   
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 discontinued from the 
study, and primary reason to discontinue from the study.  All percentages will be based on 
the number of patients in the Efficacy population.  
A listing will present data concerning patient disposition.
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4.6   
Demographics and Baseline Disease Characteristics
4.6.1   
Disease Status at Study Entry
Study entry disease characteristics including but not limited to (Eastern Cooperative 
Oncology Group [ECOG]) performance status, type of myeloma, ISS stage, serum M-
protein, urine M-protein, 
-microglobin by category (ie, < 3.5, 3.5-5.5, > 5.5 mg/L), 
serum creatinine and its category (≤ 2, >2 mg/dL), creatinine clearance by category (ie, < 60, 
>=60 mL/min and/or , <50, >=50 mL/min ), serum albumin by category (ie, < 3.5, ≥3.5 
g/dL), corrected calcium, hemoglobin, Lytic bone lesions, extramedullary disease will be 
summarized using Efficacy population.  
A patient’s type of myeloma is determined by the combination of heavy chain type (IgG, 
IgA, IgM, IgD, IgE, biclonal, and other) and light chain type (kappa, lambda, and biclonal).  
Creatinine clearance is to be calculated using the Cockcroft-Gault formulas as follows:
For male patients: 
For female patients:
Months from diagnosis to the date of first dose is calculated by 
first dose date - date of diagnosis  
365.25/12
Extent of Disease at Baseline
The following categories of extent of disease at baseline will be summarized:  number of 
patients with bone marrow aspirate, bone marrow aspirate results (percentage of plasma 
cells), number of patients with bone marrow biopsy, bone marrow biopsy results (percentage 
of plasma cells, percentage of cellularity, type of cellularity, kappa/lambda ratio performed), 
skeletal survey results and imaging including magnetic resonance imaging/computed 
2

[mg/dL])
creatinine
(serum
72
weight[kg]
)
Age[years]
(140
clearance
creatinine




[mg/dL])
creatinine
(serum
72
weight[kg]
)
Age[years]
(140
85
.0
clearance
creatinine





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tomography (CT)/positron emission tomography (PET)-CT results (normal, abnormal not 
clinically significant, abnormal clinically significant, and not done), number and percentage 
of present lytic bone lesions, number of extramedullary plasmacytoma, and type of 
extramedullary plasmacytoma. 
Percentage for all categorical summarizations for bone marrow biopsy and aspirate is based 
on patients from the Efficacy population with an adequate sample for the specified test.
4.6.2   
Demographics
Demographics will be summarized in a descriptive fashion in the Efficacy population.  
Baseline demographic data to be evaluated will include age, sex, weight, and other 
parameters as appropriate.  
4.6.3   
Medical History
General medical history and prior medications will be listed for all patients.
Medical history will be summarized (frequency and percentage) by the disease categories 
recorded in the database. A patient is counted only once within a category. Percentages are 
based on the number of patients in the Ixazomib Safety population.
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 using descriptive statistics.
4.6.4   
Disease Status at Initial Diagnosis 
Efficacy data including serum M-protein (g/L), urine M-protein (g/24h), and FLC will be 
summarized using Efficacy population. Other characteristics at initial diagnosis include 
-
microglobin, Durie-Salmon stage, ISS stage, Lytic bone, extramedullary disease, type of 
myeloma. 
4.6.5  
Bone Marrow Cytogenetics
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 
2

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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.
4.7   
Treatments and Medications
4.7.1   
Concomitant Medications
Concomitant medications will be coded by preferred term using the World Health 
Organization (WHO) Drug Dictionary.  The number and percentage of patients taking 
concomitant medications from the first dose through the end of the on-treatment period will 
be tabulated by Anatomical Therapeutic Chemical (ATC) classification pharmacological 
subgroup and WHO drug preferred term in the Ixazomib 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.
Concomitant procedures will not be coded but will be presented in a data listing for the 
Ixazomib Safety population.
4.7.2   
Study Treatments
Following the Screening period, eligible patients will be enrolled and receive ixazomib.
Patients will receive ixazomib capsules (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, 
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 study drug 
dose will be escalated to 4 mg beginning with Cycle 5 Day 1. Patients who have had any
dose reductions will not dose escalate. If dose escalation was inadvertently missed at Cycle 
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5, escalation at a later cycle may be performed with permission from the Takeda project 
clinician or designee.
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. 
4.7.2.1   
Duration of Follow-up
The duration of follow-up is defined as time from the date of first dose to the death or last 
known visit. If a subject dies, the duration equal to date of death minus date of first dose + 1 
and treated as censored for follow up. If a subject is alive, the duration equal to the date 
subject last known to be alive minus date of first dose + 1 and treated as event for follow 
up. 
4.7.2.2   Extent of Exposure
An overall summary of drug exposure will be presented including number of treated cycles, 
numbers and percentages of patients who had ≥1, ≥2, …, and ≥26 treated cycles, in the 
Ixazomib Safety population.  An aggregate summary of numbers and percentages of patients 
who had 1 to 4, 5 to 8, 9 to 12, 13 to 16, 17 to 20, 21 to 24, and ≥25 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.
Additionally, exposure to ixazomib will be characterized by total amount of dose taken in 
mg, total number of dose taken, number of treated cycles, numbers and percentages of 
patients who had ≥1, ≥2, …, and ≥26 treated cycles, and relative dose intensity (%) in the 
Ixazomib Safety population. 
A treated cycle is defined as a cycle in which the patient received any amount of any study 
drug. 
relative dose intensity (%) =  100 ×
total dose received 
sum of prescribed dose over treated cycles 
Sum prescribed dose over 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 
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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. The number of patients with 100% relative dose intensity, 80% 
to <= 100%, 50% to < =80%, and < =50% will be summarized using Safety population. 
Dosing data will also be presented in a by-patient listing.
4.7.2.3   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 in the Ixazomib 
Safety population. Action on drug will be summarized using similar manner. 
4.8   
Efficacy Analyses
All efficacy evaluations will be conducted using the Efficacy population unless otherwise 
specified.
Secondary efficacy parameters include PFS, OS, best response achieved or maintained prior 
to PD or subsequent therapy, duration of CR, TTP, TTNT, time to end of next-line therapy, 
duration of the next line of therapy, OS and PFS in high-risk cytogenetic patient groups 
characterized by individual or multiple cytogenetic abnormalities, including but not limited 
to del(17) and translocations t(4;14) ort(14;16), and correlation between frailty status and 
PFS and OS.  
Progression-free survival
Progression-free survival , PFS, is defined as the time from the date of first dose 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 their last adequate assessment.
The details regarding the handling of missing assessments and censoring for PFS analysis 
are presented in Table 4-1.
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Table 4-1   
Handling of Missing Assessments and Censoring for PFS Primary 
Analysis Based on FDA Guidance
Situation
Date of Progression or Censoring
Outcome
No baseline and/or no postbaseline assessment
Date of first dose
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, withdrawal of consent before any 
documented death or disease progression  
Date of last adequate assessment*
Censored 
Death or progression after more than 1 missed visit 
Date of last adequate assessment*
Censored
Alternate antineoplastic therapy including HDT-SCT
started before disease progression 
Date of last adequate assessment 
before starting alternate antineoplastic 
therapy including HDT-SCT
Censored
Death before first assessment
Date of death
Event 
Death between adequate assessment visits
Date of death
Event 
Abbreviations:  HDT-SCT = high-dose therapy/stem cell transplant; PFS = progression-free survival.
* Adequate disease assessment is defined as there are sufficient data to evaluate a patient’s disease status.
Progression-free survival will be analyzed using PFS events reported in China (pooled from 
patients enrolled in the global study and the China continuation). A sensitivity analysis of 
PFS, as assessed by the investigator, in the Per-Protocol population may also be conducted.
The Kaplan-Meier (K-M) survival curve and K-M median (if estimable), along with their 2-
sided 95% CIs, will be provided. The K-M estimates along with 95% CI will be provided by 
6-month interval at 6 months, 12 months, 18 months, and so on. The final analysis (FA) will 
be performed when all patients in the China Continuation are off treatment and have 
completed the EOT visit, or upon termination of the study by the sponsor, whichever occurs 
earlier. Descriptive statistics will be used to summarize patient data collected after the IA.
PFS assessed by investigator using different censoring mechanisms will be analyzed in the 
Efficacy population, for example, not censoring for patients who discontinue treatment and 
go on transplant or alternative antineoplastic therapy. The other details of the handling of 
missing assessment and censoring for additional sensitivity analyses are presented in Table 
4-2. 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. 
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Table 4-2   
Handling of Missing Assessments and Censoring for PFS Sensitivity 
Analysis Based on EMA guidance 
Situation
Date of Progression or Censoring
Outcome
Alternate antineoplastic therapy including 
HDT-SCT started before disease progression
Date of documented disease progression 
event
Death or disease progression after more than 1
missed visit
Date of death or disease progression 
event
Abbreviations:  HDT-SCT = high-dose therapy/stem cell transplant; PFS = progression-free survival.
The subgroup analysis will be based on baseline factors: initial therapy (proteasome-
inhibitor–containing or not); International Staging System (ISS) stage before initial therapy 
(stage I or II vs stage III); age (< 75 vs ≥ 75 years); and response to initial therapy, as 
measured during screening (CR or VGPR vs PR), demographic data such as sex and age, 
and other factors, as appropriate depending on the number of PFS events in a subgroup.
Overall Survival
Overall survival (OS) is defined as the time from the date of first 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. Patients who withdraw, drop out, or are lost to follow-up are 
censored at the date of last visit. Overall survival will be analyzed based on the Efficacy
population.
The K-M survival curve and K-M median (if estimable), along with their 2-sided 95% CIs, 
will also be provided. The K-M estimates along with 95% CI will be provided by 6-month 
interval at 6 months, 12 months, 18 months, and so on.
The subgroup analysis will be based on baseline factors: initial therapy (proteasome-
inhibitor–containing or not); International Staging System (ISS) stage before initial therapy 
(stage I or II vs stage III); age (< 75 vs ≥ 75 years); and response to initial therapy, as 
measured during screening (CR or VGPR vs PR), demographic data such as sex and age, 
and other factors, as appropriate depending on the number of OS events in a subgroup.
Best Response achieved or maintained prior to PD or subsequent therapy
The percentage of each response category (PR, VGPR, and CR) will be determined relative 
to the Response-Evaluable population. In addition, the improvement of response for 
patients who enroll in the study at PR or VGPR will be analyzed.  
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Duration of Complete Response
Duration of CR is defined as the time from the date of first dose for those who had a CR at 
study entry 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 last assessed CR.  Duration of CR will be summarized 
descriptively using the K-M method.
Time to Progression
Time to progression (TTP) is defined as the time from the date of first dose to the date of 
first documentation of PD. Patients without documentation of PD at the time of analysis 
will be censored at the date of last response assessment that is SD or better. Patients who 
take alternative antineoplastic therapy, or initiation of ASCT, or die during treatment will 
also be censored at the date of last response assessment. TTP will be analyzed based on the 
Efficacy population using similar method as PFS.
Time to Start of Next-Line Therapy
Time to start of the next line of therapy is defined as the time from the date of first dose 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 Efficacy 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 first dose to the date 
of last dose of next antineoplastic therapy following study treatment or death due to any 
cause, whichever occurs first. 
Time to end of next-line therapy will be analyzed based on the Efficacy 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 discontinuation of next antineoplastic therapy following study 
treatment or death due to any cause, whichever occurs first.  
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Duration of next-line therapy will be analyzed in those patients who actually received next-
line therapy following the study treatment using the Efficacy population. Patients who are 
still on treatment on the next line of therapy will be censored at their last visit. Duration of 
next-line therapy will be summarized descriptively using the K-M method.
Correlation Between Frailty Status and Progression-Free Survival and Overall 
Survival
The K-M survival curves and K-M median PFS or OS (if estimable), along with their 2-
sided 95% CIs, will be provided for each frailty status. An unadjusted Cox model including 
frailty status (fit, unfit, or frail) will be used to estimate the hazard ratio and 95% CIs for the
frailty for both PFS and OS, if data permit. A status of fit will be compared with a status of 
unfit or frail. The analysis will be based on the Efficacy population.
4.9   
Pharmacokinetic
4.9.1   
Pharmacokinetic Analyses
Plasma ixazomib concentration-time data may be presented in listings.  Pharmacokinetic
data will be used to perform population PK analysis using a nonlinear mixed effects 
modeling approach and to assess the effect of various covariates on ixazomib PK, and may 
include data from other studies as appropriate.  The analysis plan for the population PK 
analysis will be separately defined, and the results of these analyses will be reported 
separately.
Further exploratory analyses may be carried out based on emerging scientific knowledge.
4.10   Analyses of Patient-Reported Outcomes 
4.10.1   Patient-Reported Outcomes
Descriptive Statistics 
Patient-reported outcome assessments using the EORTC QLQ-C30 
will be analyzed using patients with PRO measurements at study entry and at least 
one post study entry measurement in the Efficacy population.
Descriptive statistics of actual values and change from baseline in the subscale scores and 
summary score of the EORTC QLQ-C30 
will 
be summarized over time.  
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The EORTC QLQ-C30 contains 30 items across 5 functional subscales (physical 
functioning, role functioning, emotional functioning, cognitive functioning, and social 
functioning), 1 global health status/QoL subscale, and 9 symptom subscales (fatigue, nausea 
and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial 
difficulties). 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.  The summary score of 
EORTC QLQ-C30 is calculated from the mean of 13 of the 15 EORTC QLQ-C30 scales 
(the Global Health Status/QOL and the Financial Impact scale are not included).
 
 The recall period for both 
instruments is 1 week. All subscales were linearly transformed to a 0–100 scale based on 
EORTC scoring manuals. High scores for the global health status/QoL and functional 
subscales indicate higher QoL or functioning, while high scores on the symptom subscales 
indicate higher levels of symptomatology or problems. The subscales of the EORTC QLQ-
C30 
are defined as shown in Table 4-3 and Table 4-4.
Table 4-3   
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
Global Health Status/QOL
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.
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4.11   Safety Analyses
Safety will be evaluated by the incidence of adverse events (AEs), severity and type of AEs, 
and by changes from baseline in the patient’s vital signs, weight, and clinical laboratory 
results using the Ixazomib Safety population. Exposure to the study drug regimen and 
reasons for discontinuation will be tabulated.
4.11.1   Adverse Events
4.11.1.1   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 are 
AEs that occur after administration of the first dose of study drug (Ixazomib for Ixazomib 
Safety population, placebo for placebo safety population) and through 30 days after the last 
dose of any study drug. Safety summaries will be provided for Ixazomib Safety population.  
Listings of all the AE’s for the placebo subjects and for the AE’s that occurred prior to crossover 
will be provided.
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)
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
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 Ixazomib Safety population) 

SAEs
Patients with the same AE more than once will have that event counted only once within 
each body system, once within each High Level Term, and once within each Preferred Term.
Drug-related treatment-emergent AEs will also be summarized by the National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. 
Given that this study involves an initial therapy followed by ixazomib, if a treatment-
emergent AE is related to study drug, it will be considered drug related. 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 Ixazomib Safety population) 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 1 AE, drug-related AE, Grade 3 or higher AE (also Grade 3 and 4 AEs), Grade 3 or 
higher drug-related AE (also Grade 3 and 4 drug-related AEs), SAE, drug-related SAE, AE 
resulting in discontinuation, and on-study death.  On-study death is defined as a death that 
occurs between the first dose of any study drug and within 30 days of the last dose of study 
drug.  
Additional safety analyses may be performed to most clearly enumerate rates of toxicities
and to further define the safety profile of ixazomib.
Additionally, summary tables and by-patient listings of the AEs of clinical importance will 
be presented including rash, PN, thrombocytopenia, and gastrointestinal disorders if 
appropriate.
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Incidence of New Primary Malignancies 
Two types of incidence rates will be calculated for the Ixazomib 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 Ixazomib 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 
Ixazomib Safety population with available information up to the onset of NPMs
Due to the distinct nature of hematologic and nonhematologic neoplasms, and the emerging 
signals of NPMs for immunomodulating agents, analyses of NPMs may be performed
separately for hematologic and nonhematologic malignancies.
Time to Resolution and Improvement of Peripheral Neuropathy Events
Peripheral neuropathy is defined as the treatment emergent AE in the High Level Term of 
Peripheral neuropathies NEC (not elsewhere classified) according to MedDRA.
A PN event is considered as resolved if its final outcome is resolved with no subsequent PN 
event of the same Preferred Term occurring on the resolution date or the day before and 
after. A PN event is considered as improved if the event improves from the maximum 
grade; that is, all the grades recorded after the maximum grade 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. Subjects with a PN event without a resolution will be censored at the time of last visit. 
Subjects with a PN event without an improvement will be censored at the time of last visit.
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 curves and K-M 
medians (if estimable), along with their 2-sided 95% CIs, will be presented. This analysis is 
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event based; thus, 1 subject could contribute multiple observations if the subject has more 
than 1 PN event.
The analysis may be conducted for patients with any PN events or those with ≥2 PN events 
or those ≥3 PN events, respectively, if data permit.
4.11.1.2   Serious Adverse Events
The number and percentage of patients experiencing at least 1 treatment-emergent serious 
AE (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).
4.11.1.3   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). 
4.11.1.4   Adverse Events Resulting in Discontinuation of Study Drug
A by-patient listing of treatment-emergent AEs resulting in discontinuation of study drug 
will be presented.
4.11.2   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. Laboratory test 
results from the central laboratory will be used when they are available.  Laboratory test 
results from local laboratories will be used only when no central laboratory test results exist 
at the same scheduled sample collection time point.
If a patient has repeated laboratory values for a given time point, the value from the last 
evaluation will be used.
Laboratory test results will be summarized according to the scheduled sample collection 
time point.  Change from baseline will also be presented. Unscheduled laboratory test 
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results will be listed and included in laboratory shift tables.  The parameters to be analyzed 
are as follows:

Hematology:  hemoglobin, hematocrit, absolute neutrophil count (ANC), absolute 
lymphocyte count (ALC), monocytes, eosinophils, basophils, platelets, and white 
blood cell (WBC) count

Serum chemistry:  blood urea nitrogen, creatinine, total bilirubin, urate, lactate 
dehydrogenase (LDH), albumin, alkaline phosphatase, aspartate aminotransferase 
(AST), alanine aminotransferase (ALT), glucose, calcium, sodium, potassium, 
chloride, carbon dioxide (CO2), magnesium, phosphate, and gamma glutamyl 
transferase (GGT)
 
 
Shift tables will be constructed for laboratory parameters to tabulate changes in NCI 
CTCAE for toxicity (version 4.03) from baseline to postbaseline worst CTCAE grade.  
Parameters to be tabulated will include:

Hematology: ALC, ANC, hemoglobin, platelets, WBC

Serum chemistry: ALT, AST, alkaline phosphatase, creatinine, total bilirubin, 
calcium, magnesium, potassium, sodium, and phosphate
Mean laboratory values and box plots over time for key lab parameters will be produced, 
including but not limited to ANC, platelets, and liver function tests (ALT, AST, alkaline 
phosphatase, and total bilirubin).
By-patient listings to be presented include hematology, serum chemistry,
 
 urinalysis, urine total protein, and urine creatinine.
4.11.3   Electrocardiograms
Descriptive statistics for the actual in electrocardiograms (ECGs) will be listed.
Corrected QT interval (QTc) will be calculated, if necessary.  
Electrocardiogram abnormalities will be presented in a data listing.
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4.11.4   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.  Change from baseline will 
also be presented.  
A by-patient listing will also be presented.
4.11.5  Eastern Cooperative Oncology Group Performance Status
Eastern Cooperative Oncology Group Performance Status and shifts from baseline to 
postbaseline assessment over time, and ECOG score frequency tables over time will be 
summarized.  Shifts from baseline to the worst postbaseline score will be tabulated.
4.11.6   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.
5.   
CHANGES TO PLANNED ANALYSES FROM PROTOCOL
Reference materials for this statistical plan include Clinical Study Protocol C16021
Amendment 10 (Protocol dated 15 June 2022).
6.   
PROGRAMMING CONSIDERATIONS
6.1   
Statistical Software 
SAS version 9.2 (or higher) will be used for all analyses.  
6.2   
Rules and Definitions
Patient populations are defined in Section 2.
Baseline values are defined in Section 4.4.2.
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7.   
REFERENCES
1. Osoba D, Rodrigues G, Myles J, Zee B, Pater J. Interpreting the significance of 
changes in health-related quality-of-life scores. J Clin Oncol 1998;16:139–44.
2. Cella D, Pickard AS, Duh MS, et al. Health-related quality of life in patients with 
advanced renal cell carcinoma receiving pazopanib or placebo in a randomized phase 
III trial. Eur J Cancer. 2012 Feb;48(3):311-23.
 
 
.
4.
Stewart AK, Dimopoulos MA, Masszi T, et al. Health-Related Quality-of-Life 
Results From the Open-Label, Randomized, Phase III ASPIRE Trial Evaluating 
Carfilzomib,  Lenalidomide, and Dexamethasone Versus Lenalidomide and 
Dexamethasone in Patients With Relapsed Multiple Myeloma. J Clin Oncol. 2016 
Nov 10;34(32):3921-3930.
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