Conditions: Multiple Myeloma
Keywords: Newly Diagnosed multiple myeloma multiple myeloma MLN9708 IXAZOMIB Proteasome inhibitor Tourmaline MM2
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 705
Healthy volunteers: no

Brief summary:
The purpose of this study is to provide continued access to ixazomib and/or lenalidomide to participants who are continuing to have clinical benefit and to continue collecting relevant safety data to monitor safety in participants with Newly Diagnosed Multiple Myeloma (NDMM) who are not eligible for stem cell transplant.

Detailed description:

Arms:
arm 1: Participants who were randomly assigned to receive placebo matching capsule single oral dose on Days 1, 8 and 15 along with standard regimen of LenDex (lenalidomide 25 mg capsules orally on Days 1-21 and dexamethasone 40 mg tablets orally on Days 1, 8, 15 and 22) for the first 18 cycles (each cycle was of 28 days). Following Cycle 18, participants received 3.0 mg ixazomib matching placebo capsule as single oral dose on Days 1, 8 and 15 along with lenalidomide 10 mg capsules orally on Days 1-21 in each 28-day cycle until progressive disease or unacceptable toxicity, whichever comes first up to end of study (up to approximately 109 months). arm 2: Participants who were randomly assigned to receive Ixazomib 4.0 mg capsule single oral dose on Days 1, 8 and 15 along with standard regimen of LenDex (lenalidomide 25 mg capsules orally on Days 1-21 and dexamethasone 40 mg tablets orally on Days 1, 8, 15 and 22) for the first 18 cycles (each cycle was of 28 days). Following Cycle 18, participants received 3.0 mg ixazomib capsule as single oral dose on Days 1, 8 and 15 along with lenalidomide 10 mg capsules orally on Days 1-21 in each 28-day cycle until progressive disease or unacceptable toxicity, whichever comes first up to end of study (up to approximately 109 months).

Interventions: intervention 1: Ixazomib intervention 2: Placebo intervention 3: Dexamethasone intervention 4: Lenalidomide
Intervention descriptions: intervention 1: IXAZOMIB capsules. intervention 2: IXAZOMIB matching-placebo capsules. intervention 3: Dexamethasone tablets. intervention 4: Lenalidomide capsules.

Protocol document:
Prot_000.pdf: 



Title: A Phase 3, Randomized, Double-Blind, Multicenter Study Comparing Oral MLN9708 Plus 
Lenalidomide and Dexamethasone Versus Placebo Plus Lenalidomide and Dexamethasone in 
Adult Patients With Newly Diagnosed Multiple Myeloma
NCT Number: NCT01850524
Protocol Approve Date: 09 July 2020
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.


MLN9708
Clinical Study Protocol C16014 Amendment 5, 2013-000326-54, 09 July 2020
1
CLINICAL STUDY PROTOCOL C16014 AMENDMENT 5
MLN9708
A Phase 3, Randomized, Double-Blind, Multicenter Study Comparing Oral MLN9708 
Plus Lenalidomide and Dexamethasone Versus Placebo Plus Lenalidomide and 
Dexamethasone in Adult Patients With Newly Diagnosed Multiple Myeloma
Protocol Number:
C16014
Indication:
Newly Diagnosed Multiple Myeloma
Phase:
3 
Sponsor:
Millennium Pharmaceuticals, Inc.
EudraCT Number:
2013-000326-54
IFM Number
IFM 2013-07
Therapeutic Area:
Oncology
Protocol History
Original
14 February 2013
Amendment 1
22 July 2014
Amendment 1A (for use in South Korea continuation only)
02 February 2016
Amendment 2
30 November 2016
Amendment 2A (for use in South Korea continuation only)
14 March 2017
Amendment 3
10 May 2017
Amendment 4 (substantial)
09 August 2019
Amendment 5 (substantial)
09 July 2020
Millennium Pharmaceuticals, Inc.
40 Landsdowne Street
Cambridge, MA  USA  02139
Telephone: +1 (617) 679-7000
Approved by:
Note: If this document was approved electronically, the electronic approval signatures may 
be found at the end of the document.
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or Non-Commercial Use Only and Subject to the Applicable Terms of Use
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MLN9708
Clinical Study Protocol C16014 Amendment 5, 2013-000326-54, 09 July 2020
2
Rationale for Amendment 5
This document describes the changes to the protocol incorporating Amendment 5. The 
primary rationale for this amendment is to modify the study assessments. The second 
interim analysis (IA) was conducted (data cutoff date 02 December 2019), and the primary 
endpoint of progression-free survival (PFS) did not reach statistical significance. Because 
the primary endpoint was not met, the planned final analysis will not occur and the study is
now unblinded.
Although the primary endpoint was not met, patients in both treatment arms appeared to 
receive benefit. As such, patients deriving clinical benefit may continue their current study 
treatment if there are no other means of accessing the study drugs, until such time as other 
means of accessing the study drugs are arranged. When possible, patients should complete 
an End of Treatment (EOT) visit and transition onto a commercial supply of ixazomib 
and/or lenalidomide, or other standard of care treatment. 
Patients who are receiving ixazomib and lenalidomide will continue to receive ixazomib and 
lenalidomide. Patients who are receiving placebo and lenalidomide will receive 
lenalidomide only; the placebo capsule will no longer be administered and patients receiving 
placebo will not be crossed over to ixazomib in this study.
For patients continuing on study, the majority of study assessments are discontinued to ease 
the burden of protocol-mandated assessments. Upon implementation of Amendment 5, data 
collection requirements will be limited to collection of adverse events (AEs) and serious 
adverse events (SAEs). All other study assessments are no longer required. All central 
laboratory efficacy measures of response and progression are discontinued. Bone marrow 
aspirates for confirmation of complete response (CR) or minimal residual disease (MRD) 
status are no longer required. No further Independent Review Committee (IRC) response or 
progression evaluations will be performed. Radiographic studies and bone density studies
for study purposes are no longer required. Quality of life and health utilization assessments 
and collection of concomitant medications and procedures are discontinued. Patients will not 
be followed for the PFS or overall survival (OS) follow-up periods, as PFS and OS data are 
no longer being collected. Patients should otherwise be treated by the investigator according 
to standard of care. See the updated Schedule of Events—Amendment 5 and Beyond for 
more detailed information.
Descriptions of how to manage study procedures during unavoidable circumstances, such as 
the COVID-19 pandemic, have additionally been added.
Minor grammatical, editorial, formatting, and administrative changes are included for
clarification purposes only. For specific examples of changes in text and where the changes 
are located, see Section 15.19.
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Clinical Study Protocol C16014 Amendment 5, 2013-000326-54, 09 July 2020
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Changes in Amendment 5
1. Updated signatories on Title Page.
2. Added language to clarify ongoing treatment of patients—patients should be moved off 
study and onto commercial supply of ixazomib and/or lenalidomide, if available, and 
otherwise kept on study).
3. Updated Schedule of Events and placed previous Schedule of Events in the Appendix.
4. Revised Study Period Definitions.
5. Added explanatory text to Study Objectives.
6. Added explanatory text to Study Endpoints.
7. Added explanatory text to Overview of Study Design and removed language regarding
the previous Schedule of Events.
8. Revised information regarding the interim analyses in the Overview of Study Design.
9. Revised thrombocytopenia text in Management of Clinical Events.
10. Revised Blinding and Unblinding text.
11. Revised language in Preparation, Reconstitution, and Dispensing. 
12. Added a sentence to Packaging and Labeling.
13. Added language in Storage, Handling, and Accountability.
14. Added language regarding alternative methods for administering study 
procedures/assessments when it is not possible for the patient to come to the study site 
due to extenuating circumstances (eg, due to the COVID-19 pandemic).
15. Removed or revised several study procedures upon implementation of Amendment 5 and
included cross-references to the Full Schedule of Events.
16. Revised language regarding unscheduled visits.
17. Revised language regarding completion of treatment.
18. Revised language regarding completion of study.
19. Revised language regarding discontinuation of treatment with the study drug regimen, 
and patient replacement.
20. Revised language regarding withdrawal of patients from study.
21. Revised language regarding statistical and quantitative analyses.
22. Added language to Independent Review Committee section.
23. Added language to Procedures for Recording and Reporting Adverse Events and Serious 
Adverse Events.
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MLN9708
Clinical Study Protocol C16014 Amendment 5, 2013-000326-54, 09 July 2020
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PROTOCOL SUMMARY
Study Title: A Phase 3, Randomized, Double-Blind, Multicenter Study Comparing Oral MLN9708 
Plus Lenalidomide and Dexamethasone Versus Placebo Plus Lenalidomide and Dexamethasone in 
Adult Patients With Newly Diagnosed Multiple Myeloma
Study Phase: 3
Number of Patients: Approximately 701
Study Objectives
As of this amendment, the objectives are to provide continued access to ixazomib and/or 
lenalidomide to patients who are continuing to have clinical benefit and to continue collecting 
relevant safety data to monitor patient safety. All other study objectives will no longer be assessed. 
However, the complete list of objectives is retained below for reference.
Primary Objective:
To determine whether the addition of oral MLN9708 to lenalidomide and dexamethasone 
improves progression-free survival (PFS) in patients with newly-diagnosed multiple myeloma 
(NDMM) 
Key Secondary Objectives:
To determine whether the addition of oral MLN9708 to lenalidomide and dexamethasone 
improves overall survival (OS)
To determine whether the addition of oral MLN9708 to lenalidomide and dexamethasone 
improves the rate of complete response (CR) 
To determine whether the addition of oral MLN9708 to lenalidomide and dexamethasone 
improves pain response rate, as assessed by the Brief Pain Inventory – Short Form (BPI-SF) 
and analgesic use
Other Secondary Objectives:
To determine overall response rate (ORR), including partial response (PR), very good partial 
response (VGPR), and CR
To determine time to response (TTR), duration of response (DOR), and time to progression 
(TTP)

To determine the effect of the addition of MLN9708 to lenalidomide and dexamethasone on 
progression-free survival 2 (PFS2), defined as the date from randomization to the date of 
second disease progression or death from any cause, whichever comes first 
To determine the safety of the addition of MLN9708 to lenalidomide and dexamethasone 
To assess change in global health status, as measured by the global health status, functioning, 
and symptoms as measured by the patient-reported outcome (PRO) instrument European 
Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC 
QLQ-C30) and MY-20 module 
To determine the PFS and OS in high-risk cytogenetic patient groups defined by the 
following cytogenetic abnormalities: t(4;14), t(14;16), amp(1q21), and del(17p)
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Clinical Study Protocol C16014 Amendment 5, 2013-000326-54, 09 July 2020
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! To evaluate minimal residual disease status (MRD), via flow cytometry, in patients suspected 
to have reached CR at any time during the entire conduct of the study, and at Cycle 18 for 
patients who have maintained CR until that point. The impact of MRD status on TTP, PFS, 
and OS will be assessed. 
! To assess time to pain progression 
! To collect pharmacokinetic (PK) data to contribute to population PK analyses
! To evaluate the frequency of skeletal-related events (SREs) (eg, new fractures [including 
vertebral compression fractures]), irradiation of or surgery on bone, or spinal cord 
compression) from baseline through the last survival assessment
Overview of Study Design: 
This is a phase 3, randomized, double-blind, multicenter study to evaluate the safety and efficacy of
MLN9708 versus placebo when added to lenalidomide and dexamethasone (LenDex) in patients 
with NDMM. Adult patients with a confirmed diagnosis of symptomatic multiple myeloma (MM) 
who have not received previous antimyeloma treatment, who are ineligible for high-dose therapy 
plus stem cell transplantation (HDT-SCT) because of age (ie, ∀65 years) or coexisting conditions 
per investigator judgment, who are candidates for treatment with LenDex as their standard therapy, 
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MLN9708
Clinical Study Protocol C16014 Amendment 5, 2013-000326-54, 09 July 2020
6
and who meet other eligibility criteria detailed in Section 5 will be enrolled in this study.
Following the Screening period, patients to be enrolled will be randomized to receive either 
MLN9708 or placebo in a double-blind fashion in addition to the background therapy of LenDex. 
Eligible patients will be randomized in a 1:1 ratio into those 2 treatment arms, stratified by age 
(75 years vs 75), International Staging System (ISS) (stage 1 or 2 vs stage 3), and BPI-SF worst 
pain score (4 vs 4) at screening.
Patients will receive oral MLN9708 4.0 mg or a matching placebo capsule on Days 1, 8, and 15 plus 
lenalidomide (25 mg) on Days 1 through 21 and dexamethasone (40 mg) on Days 1, 8, 15, and 22 of
a 28-day cycle. Patients over 75 years of age at randomization will receive a reduced dexamethasone 
dose (20 mg). Dose modifications may be made throughout the study based on toxicities. Patients 
with a low creatinine clearance 60 mL/min (or 50 mL/min, according to local label/practice) but 
30 mL/min will receive a reduced lenalidomide dose of 10 mg once daily on Days 1 through 21 of 
a 28-day cycle. The lenalidomide dose may be escalated to 15 mg once daily after 2 cycles if the 
patient is not responding to treatment and is tolerating the treatment. If renal function normalizes 
(ie, creatinine clearance > 60 mL/min or > 50 mL/min, according to local label/practice) and the 
patient continues to tolerate this treatment, lenalidomide may then be escalated to 25 mg once daily.
Patients may continue to receive treatment as outlined previously for 18 cycles (approximately 
18 months), or until progressive disease (PD) or unacceptable toxicity, whichever comes first. After 
18 cycles, patients will continue treatment in the same randomization arm on the same schedule with 
modified dose levels of the study drug and lenalidomide: reduce MLN9708 (or placebo) dose to 
3.0 mg, reduce lenalidomide dose to 10 mg, and no dexamethasone.
The treatment period of the study is defined as any time a patient is receiving any of the study drug 
regimen, and will be comprised of 28-day treatment cycles. Patients will be seen at regular treatment 
cycle intervals while they are participating in the study: weekly for the first 2 cycles, twice a 
treatment cycle during the third cycle, and then once a treatment cycle for the remainder of their 
participation in the treatment period, until they experience disease progression or discontinue for 
alternate reasons. If a patient discontinues treatment with the study regimen before disease 
progression, they will enter the PFS follow-up period of the study.
Patients will be assessed for disease response and progression by the investigator and an independent 
review committee (IRC). Response will be assessed according to the International Myeloma 
Working Group (IMWG) criteria for all patients every cycle during the treatment period until PFS 
significance has been claimed in this study. After the primary endpoint has been met, central efficacy 
and investigator assessments for protocol purposes will be discontinued except for investigator 
assessment of PFS2. For patients who discontinue treatment before disease progression, assessments 
will be made every 4 weeks during the PFS follow-up period until disease progression is confirmed 
or the patient is started on another anticancer therapy, or the PFS significance has been claimed in 
this study. After disease progression or start of another anticancer therapy, all patients will be 
followed for survival in the OS follow-up period. Patients will be contacted every 12 weeks from the 
start of the OS follow-up period until death or termination of the study by the sponsor. All 
subsequent anticancer therapies for MM will be reported as part of the OS follow-up period 
assessments. In addition, patients who receive a subsequent anticancer therapy for MM will be 
assessed by the investigator for disease response (at minimum disease progression) on the second 
line of anticancer therapy to determine PFS2.
As of Amendment 5, however, the second interim analysis has been conducted (data cutoff date of 
02 December 2019), and the primary endpoint of PFS did not reach statistical significance. Thus, the
planned final analysis will not occur and the study is now unblinded. Although the primary endpoint 
was not met, patients in both treatment arms appeared to receive benefit. As such, patients deriving 
clinical benefit may continue their current study treatment until such time as other means of 
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MLN9708
Clinical Study Protocol C16014 Amendment 5, 2013-000326-54, 09 July 2020
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accessing the study drugs are arranged. When possible, patients should complete an End of 
Treatment (EOT) visit and transition onto a commercial supply of ixazomib and/or lenalidomide or 
other standard of care treatment.  
Patients who are receiving ixazomib and lenalidomide will continue to receive ixazomib and 
lenalidomide. Patients who are receiving placebo and lenalidomide will receive lenalidomide only; 
the placebo capsule will no longer be administered and patients receiving placebo will not be crossed 
over to ixazomib in this study. 
For patients continuing on study, the majority of study assessments are discontinued to ease the 
burden of protocol-mandated assessments. Upon implementation of Amendment 5, data collection 
requirements will be limited to collection of adverse events and serious adverse events. All other 
study assessments are no longer required. All central laboratory efficacy measures of response and 
progression are discontinued. Bone marrow aspirates for confirmation of CR or MRD status are no 
longer required. No further IRC response or progression evaluations will be performed. 
Radiographic studies and bone density studies for study purposes are no longer required. Quality of 
life and health utilization assessments and collection of concomitant medications and procedures are 
discontinued. Patients will not be followed for the PFS or OS follow-up periods, as PFS and OS data 
are no longer being collected. Patients should otherwise be treated by the investigator according to 
standard of care.
Study Population: 
Adult patients with a confirmed diagnosis of symptomatic MM, who have not received previous 
antimyeloma treatment, who are not transplant eligible, and who are candidates for treatment with 
LenDex will be enrolled in this study.
Duration of Study:
The duration of the study, including enrollment, treatment, and follow-up, will be approximately 
87 months, including a 27-month enrollment period and an additional 60-month (5-year) follow-up 
from the last patient enrolled.
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MLN9708
Clinical Study Protocol C16014 Amendment 5, 2013-000326-54, 09 July 2020
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STUDY OVERVIEW DIAGRAM
NOTE: Upon implementation of Protocol Amendment 5, follow-up for PFS and OS will no longer occur. The 
full Study Overview Diagram is retained for reference.
a Patients with a low creatinine clearance of 60 mL/min (or 50 mL/min, according to local label/practice) 
but 30 mL/min will receive a reduced lenalidomide dose of 10 mg once daily on Days 1 through 21 of a 
28-day cycle. The lenalidomide dose may be escalated to 15 mg once daily after 2 cycles if the patient is not 
responding to treatment and is tolerating the treatment. If renal function normalizes (ie, creatinine clearance 
> 60 mL/min or > 50 mL/min, according to local label/practice) and the patient continues to tolerate this 
treatment, lenalidomide may then be escalated to 25 mg once daily.
b Patients over 75 years of age at randomization will receive a reduced dexamethasone dose (20 mg).
c If the dose of MLN9708 (or placebo) was reduced to 3.0 or 2.3 mg during the first 18 cycles of treatment,
dose will remain at that reduced level beyond 18 cycles (see Table 4-1).
d If the dose of lenalidomide was reduced to 15 mg or 10 mg during the first 18 cycles of treatment, dose will 
be 10 mg beyond 18 cycles. If the lenalidomide dose was reduced to 5 mg during the first 18 cycles of 
treatment, dose will remain at 5 mg beyond 18 cycles (see Table 4-1).
e Patients who receive a subsequent line of anticancer therapy will be evaluated by the investigator for disease 
response (at minimum disease progression) for determination of PFS2. Disease response on the next line of 
therapy will be recorded every 12 weeks during the OS follow-up period until PFS2 is reported or a new 
(third) line of anticancer therapy is started, whichever comes first.
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MLN9708
Clinical Study Protocol C16014 Amendment 5, 2013-000326-54, 09 July 2020
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SCHEDULE OF EVENTS—AMENDMENT 5 AND BEYOND
As of Amendment 5, the second IA has been conducted (data cutoff date of 
02 December 2019) and the primary endpoint of PFS did not reach statistical significance. 
Thus, the planned final analysis will not occur and the study is now unblinded. Although the 
primary endpoint was not met, patients in both treatment arms appeared to receive benefit. 
As such, patients deriving clinical benefit may continue their current study treatment if there 
are no other means of accessing the study drugs, until such time as other means of accessing 
the study drugs are arranged. When possible, patients should complete an EOT visit and 
transition onto a commercial supply of ixazomib and/or lenalidomide, or other standard of 
care treatment.  
Patients who are receiving ixazomib and lenalidomide will continue to receive ixazomib and 
lenalidomide. Patients who are receiving placebo and lenalidomide will receive 
lenalidomide only; the placebo capsule will no longer be administered and patients receiving 
placebo will not be crossed over to ixazomib in this study. 
For patients continuing on study, the majority of study assessments are discontinued to ease 
the burden of protocol-mandated assessments. For ease of study conduct, the Schedule of 
Events now presented has been simplified to apply to the remainder of the study. Beyond the 
assessments noted here, patients still on study should be treated by the investigator 
according to the local or country-specific standard of care.
The full Schedule of Events and PK Sampling Schedule in effect prior to Amendment 5 
have been moved to Section 15.12.
Study Procedures
Treatment Period
28-Day Cycles
End of
Treatmentb
Cycle
Cycle Xa and Beyond
Day
1
Window
± 7 days
+ 1 week
Informed Consent (Reconsent)
Xc
Complete Physical Examination
Xd
Symptom-Directed Physical Exam
Xd, e
Pregnancy Test f
X
X
Hematology
Xe, g
Xg
Clinical Chemistry
Xe, g
Xg
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Clinical Study Protocol C16014 Amendment 5, 2013-000326-54, 09 July 2020
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Study Procedures
Treatment Period
28-Day Cycles
End of
Treatmentb
Cycle
Cycle Xa and Beyond
Day
1
Window
± 7 days
+ 1 week
Adverse Event Reporting
Recorded from the first dose of drug in the study drug regimen 
through 30 days after last dose of drug in the study drug regimen h
Serious Adverse Event Reporting
Serious adverse events will be collected from signing of the 
informed consent form through 30 days after the last dose of drug 
in the study drug regimen h
Study Drug Administration
MLN9708i
Days 1, 8, and 15 of each cycle
Lenalidomide
Continuous Days 1-21 of each cycle
AE=adverse event; eCRF=electronic case report form; GCP=Good Clinical Practice;
IMiDs=immunomodulatory drugs; IEC=independent ethics committee; IRB=institutional review board; 
SAE=serious adverse event.
a Follow this Schedule of Events at the start of the next full treatment cycle upon implementation of 
Amendment 5.
b Patients who do not continue treatment must complete the End of Treatment assessments, which should 
occur 30 days (+1 week) after the last dose of study drug or prior to the initiation of subsequent 
antineoplastic therapy, whichever comes first.
c Before dosing on Day 1 of the next full treatment cycle upon implementation of Amendment 5, patients 
must be reconsented. Reconsenting should be done in person.  Remote reconsenting is permitted as long as 
the process adheres to site, sponsor, IRB/IEC, regulatory, and GCP standards.
d Patients should be assessed and treated according to standard of care. Collect and record only clinically 
significant findings as AEs in the eCRF.
e Alternative methods for administering study procedures/assessments may be considered when it is not 
possible for the patient to come to the study site due to extenuating circumstances (eg, due to the COVID-19 
pandemic). Alternative methods should be considered for performing the assessments by other means than 
the patient presenting to the clinic (eg, remote assessment, having lab assessment performed at a facility 
closer to the patient’s home, etc.) If any of the following study procedures/assessments is missed because a 
site visit is done remotely, the study procedure/assessment is waived: symptom-directed physical exam, 
hematology, clinical chemistry. 
f
Treatment with IMiDs requires pregnancy testing in female patients of child-bearing age prior to each cycle. 
A serum pregnancy test will be performed at the local laboratory for all women of childbearing potential.
g All central laboratory assessments are discontinued. Patients should be assessed and treated according to 
standard of care using local laboratory evaluations. Abnormal hematology and chemistry data are to be 
collected and recorded in the eCRF only to the extent that they are needed to document or support an AE. 
Laboratory assessments to inform dosing decisions and routinely monitor patients do not need to be 
recorded in the eCRF.
h Patients should be assessed and treated per standard of care. All AEs/SAEs will be recorded in the eCRF 
according to the criteria outlined in Section 10. Patient safety outside the protocol assessments should be 
monitored during the time between on-site visits at the investigator's discretion, per standard of care. At 
minimum, there will be a phone call with an investigator within the specified-visit window timeframe, 
which will include an assessment of AEs/SAEs.  
i
Only for patients who were receiving MLN9708 in combination with lenalidomide. Patients who received 
placebo in combination with lenalidomide will receive lenalidomide but will no longer be administered the 
placebo capsule.
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TABLE OF CONTENTS
LIST OF TABLES.............................................................................................................14
LIST OF FIGURES............................................................................................................15
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS ..........................................16
STUDY PERIOD DEFINITIONS......................................................................................21
1. BACKGROUND AND STUDY RATIONALE..............................................................22
1.1 Scientific Background ..............................................................................................22
1.1.1 Disease Under Treatment...................................................................................22
1.1.2 MLN9708, Millennium’s Next-Generation Proteasome Inhibitor.......................23
1.2 Nonclinical Experience.............................................................................................24
1.3 Clinical Experience ..................................................................................................24
1.3.1 Clinical Trial Experience Using the IV Formulation of MLN9708 .....................24
1.3.2 Clinical Trial Experience Using the Oral Formulation of MLN9708 ..................25
1.4 Pharmacokinetics and Drug Metabolism...................................................................26
1.5 Study Rationale ........................................................................................................28
1.6 Rationale for the Combination of MLN9708, Lenalidomide, and Dexamethasone ....29
1.6.1 Combination of MLN9708, Lenalidomide, and Dexamethasone.........................29
1.6.2 Rationale for MLN9708, Lenalidomide, and Dexamethasone Dose and 
Schedule Selection......................................................................................30
1.6.3 Rationale for the Molecular Analyses.................................................................32
1.6.4 Rationale for the Combination of MLN9708, Lenalidomide, and 
Dexamethasone in Patients with High-Risk Cytogenetic Characteristics......34
1.6.5 Minimal Residual Disease Assessment...............................................................35
1.6.6 Rationale for Bone Disease Assessment.............................................................36
1.6.7 Rationale for Selected Subgroups.......................................................................36
1.7 Potential Risks and Benefits .....................................................................................37
2. STUDY OBJECTIVES ..................................................................................................38
2.1 Primary Objectives ...................................................................................................38
2.2 Secondary Objectives ...............................................................................................38
2.3 Exploratory Objectives .............................................................................................39
3. STUDY ENDPOINTS....................................................................................................40
3.1 Primary Endpoint .....................................................................................................40
3.2 Secondary Endpoints................................................................................................41
3.3 Exploratory Endpoints..............................................................................................42
4. STUDY DESIGN...........................................................................................................43
4.1 Overview of Study Design........................................................................................43
4.2 Number of Patients...................................................................................................47
4.3 Duration of Study.....................................................................................................47
5. STUDY POPULATION.................................................................................................47
5.1 Inclusion Criteria......................................................................................................47
5.2 Exclusion Criteria.....................................................................................................51
6. STUDY DRUG..............................................................................................................53
6.1 Test Article (MLN9708) and Matched Placebo.........................................................53
6.2 Background Therapies..............................................................................................54
6.2.1 Lenalidomide Administration.............................................................................54
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6.2.2 Dexamethasone Administration .........................................................................55
6.3 Dose-Modification Guidelines..................................................................................55
6.4 Criteria for Dose Modification (Delays, Reductions, and Discontinuations)..............56
6.4.1 Dose Adjustments for Hematologic and Nonhematologic Toxicity: Study 
Drug and Lenalidomide...............................................................................56
6.4.2 Study Drug Treatment Modification...................................................................60
6.4.3 Lenalidomide Treatment Modification...............................................................61
6.4.4 Dexamethasone-Related Treatment Modification...............................................62
6.5 Criteria for Toxicity Recovery Before Beginning the Next Cycle of Treatment.........64
6.6 Excluded Concomitant Medications and Procedures.................................................64
6.7 Permitted Concomitant Medications and Procedures.................................................65
6.8 Precautions and Restrictions .....................................................................................66
6.9 Contraception Requirements.....................................................................................66
6.10 Management of Clinical Events..............................................................................68
6.11 Blinding and Unblinding ........................................................................................72
6.12 Description of Investigational Agents .....................................................................73
6.13 Preparation, Reconstitution, and Dispensing ...........................................................74
6.14 Packaging and Labeling..........................................................................................74
6.15 Storage, Handling, and Accountability....................................................................75
6.15.1 Background Therapies .....................................................................................76
6.16 Other Protocol-Specified Materials.........................................................................76
7. STUDY CONDUCT ......................................................................................................77
7.1 Study Personnel and Organizations...........................................................................77
7.2 Arrangements for Recruitment of Patients ................................................................77
7.3 Treatment Group Assignments .................................................................................77
7.4 Study Procedures......................................................................................................77
7.4.1 Informed Consent ..............................................................................................78
7.4.2 Patient Demographics ........................................................................................79
7.4.3 Medical History.................................................................................................79
7.4.4 Physical Examination.........................................................................................79
7.4.5 Vital Signs .........................................................................................................79
7.4.6 Eastern Cooperative Oncology Group Performance Status.................................79
7.4.7 Pregnancy Test ..................................................................................................80
7.4.8 Concomitant Medications and Procedures..........................................................81
7.4.9 Adverse Events..................................................................................................81
7.4.10 Enrollment .......................................................................................................81
7.4.11 Electrocardiogram............................................................................................81
7.4.12 Clinical Laboratory Evaluations.......................................................................82
7.4.13 Health Utilization Data Collection ...................................................................84
7.4.14 Quality of Life Assessment (European Organization for Research and 
Treatment of Cancer) ..................................................................................84
7.4.15 Pain Assessment ..............................................................................................85
7.4.16 Utility Measurement ........................................................................................86
7.4.17 Skeletal Survey................................................................................................86
7.4.18 Skeletal-Related Events....................................................................................87
7.4.19 Bone Mineral Density ......................................................................................87
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7.4.20 Radiographic Disease Assessments ..................................................................87
7.4.21 2-Microglobulin.............................................................................................88
7.4.22 Quantification of M-Protein .............................................................................88
7.4.23 Quantification of Immunoglobulin (Ig) ............................................................88
7.4.24 Serum Free Light Chain Assay.........................................................................89
7.4.25 Immunofixation of Serum and Urine................................................................89
7.4.26 Bone Marrow Evaluation .................................................................................89
7.4.27 Response Assessment ......................................................................................91
7.4.28 Pharmacokinetic Measurements .......................................................................92
7.4.29 Blood Sample for Biomarker Analysis .............................................................93
7.4.30 Treatment Beyond 18 Cycles ...........................................................................93
7.4.31 Follow-up Assessments (PFS, PFS2, and OS) ..................................................94
7.5 Unscheduled Visits...................................................................................................95
7.6 Study Compliance ....................................................................................................95
7.7 Completion of Treatment..........................................................................................95
7.8 Completion of Study.................................................................................................96
7.9 Discontinuation of Treatment With the Study Drug Regimen, and Patient 
Replacement .....................................................................................................96
7.10 Withdrawal of Patients From Study ........................................................................97
8. STATISTICAL AND QUANTITATIVE ANALYSES ..................................................97
8.1 Statistical Methods ...................................................................................................97
8.1.1 Determination of Sample Size............................................................................98
8.1.2 Randomization and Stratification .......................................................................98
8.1.3 Populations for Analysis ....................................................................................99
8.1.4 Procedures for Handling Missing, Unused, and Spurious Data...........................99
8.1.5 Demographic and Baseline Characteristics.......................................................100
8.1.6 Efficacy Analysis.............................................................................................100
8.1.7 Analyses of Patient-Reported Outcomes and Health Economics.......................104
8.1.8 Pharmacokinetics and Biomarkers....................................................................106
8.1.9 Safety Analysis ................................................................................................107
8.1.10 Interim Analysis.............................................................................................109
9. STUDY COMMITTEES..............................................................................................111
9.1 Independent Review Committee.............................................................................111
9.2 Independent Data Monitoring Committee...............................................................111
10. ADVERSE EVENTS .................................................................................................112
10.1 Definitions............................................................................................................112
10.1.1 Pretreatment Event Definition........................................................................112
10.1.2 Adverse Event Definition...............................................................................112
10.1.3 Serious Adverse Event Definition ..................................................................113
10.2 Procedures for Recording and Reporting Adverse Events and Serious 
Adverse Events...............................................................................................114
10.3 Monitoring of Adverse Events and Period of Observation.....................................115
10.4 Procedures for Reporting Drug Exposure During Pregnancy and Birth Events......116
11. ADMINISTRATIVE REQUIREMENTS ...................................................................117
11.1 Good Clinical Practice..........................................................................................117
11.2 Data Quality Assurance ........................................................................................118
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11.3 Electronic Case Report Form Completion.............................................................118
11.4 Study Monitoring .................................................................................................118
11.5 Ethical Considerations..........................................................................................119
11.6 Patient Information and Informed Consent............................................................119
11.7 Patient Confidentiality..........................................................................................119
11.8 Investigator Compliance.......................................................................................119
11.9 On-site Audits ......................................................................................................120
11.10 Investigator and Site Responsibility for Drug Accountability..............................120
11.11 Product Complaints and Medication Errors (Including Overdose).......................120
11.12 Closure of the Study ...........................................................................................121
11.13 Record Retention................................................................................................122
12. INVESTIGATOR AGREEMENT..............................................................................123
13. USE OF INFORMATION..........................................................................................124
14. REFERENCES...........................................................................................................125
15. APPENDICES ...........................................................................................................132
15.1 Eastern Cooperative Oncology Group (ECOG) Scale for Performance Status.......132
15.2 Multiple Myeloma Diagnostic Criteria..................................................................132
15.3 Cockcroft-Gault Equation to Calculate the Creatinine Clearance ..........................133
15.4 ISS Staging Criteria and Durie-Salmon Criteria....................................................134
15.5 Steroid Equivalent Doses......................................................................................135
15.6 World Health Organization Steps of Analgesics and OME Conversions ...............136
15.6.1 Steps of Analgesics........................................................................................136
15.6.2 Oral Morphine Equivalent (OME) Conversions..............................................142
15.7 EQ-5D..................................................................................................................144
15.8 Brief Pain Inventory-Short Form (BPI-SF) ...........................................................147
15.9 QLQ-MY20..........................................................................................................149
15.10 European Organization for Research and Treatment of Cancer 
(EORTC QLQ-C30 (Version 3) ......................................................................151
15.11 Response Criteria [72] ........................................................................................153
15.12 Full Schedule of Events and PK Sampling Schedule (Schedules Prior to 
Implementation of Amendment 5)...................................................................155
15.13 Amendment 1 Rationale and Purposes................................................................163
15.14 Amendment 1A Rationale and Purposes .............................................................166
15.15 Amendment 2 Rationale and Purposes................................................................168
15.16 Amendment 2A Rationale and Purposes .............................................................170
15.17 Amendment 3 Rationale and Purposes................................................................172
15.18 Amendment 4 Rationale and Purposes................................................................173
15.19 Amendment 5 Detailed Summary of Changes.....................................................174
LIST OF TABLES
Table 1-1   
Clinical Trials Using Intravenous MLN9708...............................................25
Table 1-2   
Ongoing Studies of Oral MLN9708.............................................................25
Table 4-1   
Dose Level Changes Beyond 18 Cycles of Treatment..................................44
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Table 6-1   
Study Drug and Lenalidomide Dose Adjustment for Thrombocytopenia .....56
Table 6-2   
Study Drug and Lenalidomide Dose Adjustment for Neutropenia................58
Table 6-3   
Study Drug and Lenalidomide Dose Adjustment for Rash...........................59
Table 6-4   
Dose Reduction Steps for Study Drug .........................................................60
Table 6-5   
Study Drug Treatment Modification (Delays, Reductions, and 
Discontinuations) Due to Adverse Events....................................................60
Table 6-6   
Dose Reduction Steps for Lenalidomide......................................................61
Table 6-7   
Lenalidomide (REVLIMID®) Treatment Modification (Delays, Reductions, 
and Discontinuations) Guidelines Due to Non-Hematologic Adverse 
Events[68]...................................................................................................62
Table 6-8   
Dose Reduction Steps for Dexamethasone...................................................63
Table 6-9   
Dexamethasone–Related Treatment Modification (Delays, Reductions, and 
Discontinuations) Guidelines Due to Adverse Events[69]............................63
Table 6-10   
MLN9708/Placebo Capsules .......................................................................73
Table 7-1   
Response Assessment..................................................................................92
Table 15-1
Pain Medication List Categorized by World Health Organization (WHO) 
Steps I, II, and III......................................................................................136
Table 15-2
Oral and Parenteral Opioid Equivalences and Relative Potency of Drugs as 
Compared With Morphine.........................................................................142
Table 15-3
Recommended Dose Conversion From Other Opioids to Transdermal 
Fentanyl....................................................................................................143
LIST OF FIGURES
Figure 1-1   
No Apparent Relationship Between MLN9708 Clearance and BSA ............32
Figure 8-1
Schematic of Statistical Plan .....................................................................110
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LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS
Abbreviation
Term
5-HT3
5-hydroxytryptamine 3 serotonin receptor
AE
adverse event
AL
systemic light chain
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ASCT
autologous stem cell transplant
AST
aspartate aminotransferase
AUC
area under the plasma concentration versus time curve
BCRP
breast cancer resistance protein
BPI-SF
Brief Pain Inventory – Short Form
BRAF
gene/gene product: human homolog of a murine sarcoma viral oncogene
BSA
body surface area
BUN
blood urea nitrogen
CBC
complete blood count
CHW
Cui-Hung-Wang
CL
clearance
Cmax
maximum (peak) concentration 
CMH
Cochran-Mantel-Haenszel
CO2
carbon dioxide
CR
complete response
CrCl
creatinine clearance
CT
computed tomography
CTCAE
Common Toxicity Criteria for Adverse Events
CYP
cytochrome P450
DDI
drug-drug interaction(s)
DEXA
dual-energy X-ray absorptiometry
DLT
dose-limiting toxicity
DNA
deoxyribonucleic acid
DOR
duration of response
DVT
deep vein thrombosis
ECG
electrocardiogram
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Abbreviation
Term
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EOT
End of Treatment (visit)
EQ-5D
EuroQol 5-Dimensional Health Questionnaire
EQ VAS
EQ visual analogue scale
ESMO
European Society for Medical Oncology
FA
final analysis
FCBP
female of childbearing potential
FDA
United States Food and Drug Administration
GCP
Good Clinical Practice
G-CSF
granulocyte colony stimulating factor
GI
gastrointestinal
GM-CSF
granulocyte macrophage-colony stimulating factor
HDT-ASCT
high-dose therapy followed by autologous stem-cell transplantation
HIV
human immunodeficiency virus
HU
health utilization
IA
interim analysis
IB
Investigator’s Brochure
IC50
concentration producing 50% inhibition
ICF
informed consent form
ICH
International Conference on Harmonisation
IDMC
independent data monitoring committee
IEC
independent ethics committee
IFM
Intergroupe Francophone du Myelome
IG
immunoglobulin
IMiD
immunomodulating drugs
IMMPACT
Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials
IMWG
International Myeloma Working Group
IR
immunophenotypic response
IRB
institutional review board
IRC
independent review committee
ISC
independent statistical center
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Abbreviation
Term
ISS
International Staging System
ITT
intent-to-treat
IUD
intrauterine device
IV
intravenous; intravenously
IXRS
interactive voice/ web response system
K-M
Kaplan Meier
KRAS
gene/gene product: Kirsten rat sarcoma viral oncogene homolog
LDH
lactate dehydrogenase
LenDex
lenalidomide + dexamethasone 
LMWH
low molecular weight heparin
LOCF
last observation carried forward
MDS
myelodysplastic syndrome
MedDRA
Medical Dictionary for Regulatory Activities
MID
minimally important difference
Millennium
Millennium Pharmaceuticals, Inc., and its affiliates
MM
multiple myeloma
MP
melphalan + prednisone 
MPI
Millennium Pharmaceuticals, Inc.
MPR
melphalan + prednisone + Revlimid (lenalidomide)
MPR-R
melphalan + prednisone + Revlimid (lenalidomide) with Revlimid as 
maintenance
MRD
minimal residual disease 
MRI
magnetic resonance imaging
MRP2
multidrug resistance associated protein
MTD
maximum tolerated dose
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NDMM
newly diagnosed multiple myeloma
NRAS
gene/gene product: neuroblastoma rat sarcoma virus oncogene homolog
NSAID
non-steroidal anti-inflammatory drug
OME
oral morphine equivalent
ORR
overall response rate
OS
overall survival
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Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Abbreviation
Term
PD
progressive disease (disease progression)
PET-CT
positron emission tomography-computed tomography
PFS
progression-free survival
PFS2
progression-free survival 2 (from randomization on study to PFS on the next 
line of treatment)
P-gp
P-glycoprotein
PI
package insert 
PK
pharmacokinetic(s)
PN
peripheral neuropathy
PO
per os; by mouth (orally)
POEMS
polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and 
skin changes
PR
partial remission or partial response 
PRO
patient-reported outcome(s)
QD
quaque die; each day; once daily
QOL
quality of life
QTc
rate-corrected QT interval (millisec) of electrocardiograph
RD
Revlimid (lenalidomide) + dexamethasone
RRAL
relapsed and/or refractory systemic light chain amyloidosis
RRMM
relapsed and/or refractory multiple myeloma
SAE
serious adverse event
SAP
statistical analysis plan
sCR
stringent complete response
SCT
stem cell transplant
SD
stable disease
SmPC
Summary of Product Characteristics
SPEP
serum protein electrophoresis
SRE
skeletal-related event
t1/2
terminal disposition half-life
TEAE
treatment-emergent adverse event
TMA
thrombotic microangiopathy
Tmax
time to reach maximum (peak) concentration
TTP
time to (disease) progression
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Abbreviation
Term
TTR
time to response
TW
twice weekly
ULN
upper limit of the normal range
UPEP
urine protein electrophoresis
US
United States
V2
volume of distribution in the central compartment
VGPR
very good partial response
VMP
VELCADE (bortezomib) + melphalan + prednisone 
VRD
VELCADE (bortezomib) + Revlimid (lenalidomide) + dexamethasone
WHO
World Health Organization
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Study Period Definitions
Screening Period
A period of time 1 to 28 days before randomization when a prospective patient is 
screened for eligibility criteria.
Treatment Period
The time during which a patient receives any dose of the study drug regimen, and 
is comprised of 28-day treatment cycles.
End of Treatment (EOT) 
Visit
A visit within 30 days after the last dose of the study drug regimen when certain 
procedures are performed, as outlined in the Schedule of Events.
Progression-free Survival 
Follow-up Period
Visits for patients who stop treatment with the study drug regimen for any reason
other than progressive disease. See Section 15.12 for the full Schedule of Events 
before Amendment 5 was implemented for appropriate assessments. The 
progression-free survival follow-up should occur every 4 weeks until the 
occurrence of disease progression; radiographic disease assessments are to be 
performed every 8 weeks for patients with documented extramedullary disease. 
Note that with the implementation of Amendment 5, patients will not be followed 
for the PFS or OS follow-up periods, as PFS and OS data are no longer being 
collected.
Progression-free Survival
2 Follow-up Period
Patients who receive a subsequent anticancer therapy for MM will be assessed by 
the investigator for disease response (at minimum disease progression) to 
determine PFS2; response assessments should be made using local laboratory 
results, and the frequency will be determined by the investigator (recommended 
every 12 weeks) on the next line of therapy only (as part of the overall survival 
follow-up period [see below]). When a patient experiences disease progression on 
the next line of anticancer therapy or initiates a third line of anticancer therapy, 
whichever comes first, further disease response will no longer be recorded. Note 
that with the implementation of Amendment 5, patients will not be followed for 
the PFS or OS follow-up periods, as PFS and OS data are no longer being 
collected.
Overall Survival 
Follow-up Period
Visits (may be conducted by phone, internet, etc) every 12 weeks to assess 
survival. Depending on response to treatment, patients may enter the OS follow-up 
period at different times:

Patients who experience disease progression during the treatment period 
enter the OS follow-up period after the EOT visit

Patients who do not experience disease progression during the treatment 
period go on to the PFS follow-up period. They will enter the OS 
follow-up after experiencing disease progression in the PFS follow-up.

Patients who are removed from study treatment prior to disease 
progression (ie, for toxicity) AND immediately continue to receive a 
subsequent line of anticancer therapy will skip the PFS follow-up period 
and enter the OS follow-up period.
Note that with the implementation of Amendment 5, patients will not be followed 
for the PFS or OS follow-up periods, as PFS and OS data are no longer being 
collected.
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1.   
BACKGROUND AND STUDY RATIONALE
1.1   
Scientific Background
1.1.1   
Disease Under Treatment
Multiple myeloma (MM), a B-cell tumor of malignant plasma cells within the bone marrow, 
remains incurable despite advances in novel therapies with proteasome inhibitors, 
immunomodulating drugs (IMiD), and stem cell transplant (SCT) therapy. MM is 
characterized by the accumulation of plasma cells in the bone marrow (and other organs)
and can result in bone marrow failure, bone destruction, hypercalcemia, and renal failure. It 
constitutes approximately 1% of all reported neoplasms and approximately 13% of 
hematologic cancers worldwide.[1] In the Americas, Canada, and Western European 
countries, approximately 5 to 7 new cases of MM are diagnosed per 100,000 people each
year.[1-3] Although less common in Asian countries, incidences of MM have increased 
almost 4-fold in the past 25 years and are characterized by younger onset age, more invasive 
disease, and a less favorable prognosis.[4,5]
MM is sensitive to many cytotoxic drugs including alkylating agents, anthracyclines, and 
corticosteroids for both initial treatment and relapsed disease. Over the past decade, 
significant achievements have been made in expanding treatment options for MM with
novel therapies such as thalidomide, bortezomib, and lenalidomide. These regimens have 
extended PFS and/or time-to-progression (TTP).[6-10] The introduction of novel therapies 
and the increased use of high-dose therapy significantly improved overall survival in 
patients with newly diagnosed myeloma who were eligible for autologous stem cell 
transplant (ASCT).[11-13] For patients with newly diagnosed myeloma who are not eligible 
for ASCT, adding VELCADE to melphalan and prednisone (VMP) significantly extended 
overall survival. Final results of the international, multicenter, phase 3 VISTA trial 
confirmed that after 5 years of follow-up, VMP demonstrated a persistent, significant OS
benefit versus melphalan and prednisone (MP) with a 13.3 median month increase (43.1 vs 
56.4 mo, HR 0.695, p = 0.0004).[14] Palumbo reported that adding Revlimid onto MP 
(MPR) and with Revlimid as maintenance (MPR-R), significantly improved PFS in newly 
diagnosed myeloma patients who were ineligible for ASCT; the median PFS was 
significantly longer with MPR-R (31 months) than with MPR (14 months; hazard ratio, 
0.49; p < 0.001) or MP (13 months; hazard ratio, 0.40; p < 0.001).[15]
Despite more therapeutic options, MM remains incurable, and there is a need for new and 
better agents. Patients who relapse after their initial therapy demonstrate variable responses 
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to subsequent treatments with decreasing likelihood and duration of response (DOR). 
Patients become refractory to approved therapies and ultimately are left with no alternative 
treatment options. In an effort to expand the therapeutic armamentarium against MM with
agents that target the proteasome, Millennium Pharmaceuticals, Inc. (Millennium) has 
developed MLN9708, a small molecule 20S proteasome inhibitor.
1.1.2   
MLN9708, Millennium’s Next-Generation Proteasome Inhibitor
The proteasome was validated as an effective oncology target with the clinical success of 
intravenous and subcutaneous bortezomib (VELCADE®), the first-in-class, small molecule 
proteasome inhibitor developed by Millennium. Building on the efficacy seen with 
bortezomib in MM and other hematologic malignancies, Millennium has subsequently 
developed oral MLN9708 to improve the pharmacology of the agent and provide a more 
convenient mode of drug administration.
Like VELCADE, MLN9708 is a modified peptide boronic acid. MLN9708 is the citrate 
ester of MLN2238, the biologically active form that potently, reversibly, and selectively 
inhibits the proteasome. MLN9708 was formulated to improve the chemical properties of 
MLN2238 for clinical delivery. MLN9708 rapidly hydrolyzes to MLN2238 upon contact 
with either plasma or aqueous solutions. In contrast to bortezomib, MLN9708 demonstrates 
a faster dissociation rate from the proteasome, possibly resulting in enhanced tumor 
penetration, exhibits antitumor activity in a broader range of tumor xenografts, and has more 
prolonged tissue penetration.
MLN2238 preferentially binds the 5 site of the 20S proteasome with a concentration 
producing 50% inhibition (IC50) of 3.4 nM. At higher concentrations, it also inhibits the 
activity of the 1 and 2 sites. MLN2238 was selective for the proteasome when tested 
against a panel of proteases (IC50 values between 20 and 100 M), kinases (IC50 values 
> 10 M), and receptors (IC50 values > 10 M). MLN2238 and bortezomib have different 
5 proteasome dissociation half-lives (t1/2), reflecting differences in their on-off binding 
kinetics (the 5 proteasome dissociation [t1/2] for MLN9708 and bortezomib is 18 and 
110 minutes, respectively). Based on these favorable characteristics, MLN9708 is 
anticipated to be effective against MM.
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1.2   
Nonclinical Experience
Detailed information regarding the nonclinical pharmacology, absorption, distribution, 
metabolism, excretion, pharmacokinetics (PK) and toxicology of MLN9708 may be found in 
the Investigator’s Brochure (IB).
1.3   
Clinical Experience
MLN9708 is the first investigational oral proteasome inhibitor in clinical trials in humans 
with safety, tolerability, PK, pharmacodynamics, and disease response assessed in each 
phase 1 and phase 1/2 study. As of 30 April 2012, 382 patients have been treated with
MLN9708 across 9 enrolling sponsor-led phase 1 or phase 1/2 studies with a twice-weekly 
(TW) and a weekly dosing schedule being evaluated. MLN9708 is available as an 
intravenous and oral formulation. Regardless of the route of administration in the TW
dosing schedule, MLN9708 is given on Days 1, 4, 8, and 11 of a 21-day cycle. In the weekly 
dosing schedule, the drug is given on Days 1, 8, and 15 of a 28-day cycle. 
To date, the development of oral MLN9708 has focused on multiple myeloma (relapsed 
and/or refractory as well as newly diagnosed) and a different yet related plasma cell 
dyscrasia, systemic light chain (AL) amyloidosis. A clinical pharmacology study looking at 
drug-drug interactions, food effect, and bioavailability also uses the oral formulation.
Additionally, patients with nonhematologic malignancies (Study C16001) and patients with 
advanced lymphoma (Study C16002) have been treated with the intravenous (IV) 
formulation of MLN9708.
1.3.1   
Clinical Trial Experience Using the IV Formulation of MLN9708
There are 2 ongoing studies investigating IV MLN9708 in patients with advanced solid 
tumors and advanced lymphomas, a total of 140 patients have been treated in these studies 
as of 30 April 2012. These patients have been treated with different doses of MLN9708 as a 
single-agent treatment. Information regarding the ongoing studies, patient populations, and 
doses investigated are included in Table 1-1.
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Table 1-1   
Clinical Trials Using Intravenous MLN9708
Trial/
Population
Description
Doses Investigated
C16001
Solid tumors
N = 116
IV, TW, single agent 
0.125 to 2.34 mg/m2
MTD: 1.76 mg/m2
DLT: rash, thrombocytopenia, acute renal failure
Enrollment closed
C16002
Lymphoma
N = 24
IV, W, single agent
0.125 to 3.11mg/m2
MTD: TBD
DLT: neutropenia
Abbreviations: DLT = dose-limiting toxicity; IV = intravenous; MTD = maximum tolerated dose; TBD = to 
be determined; TW = twice weekly; W = weekly.
1.3.2   
Clinical Trial Experience Using the Oral Formulation of MLN9708
In the 7 studies actively enrolling patients to investigate oral MLN9708 in patients with 
differing malignancies (multiple myeloma, AL amyloidosis, nonhematologic cancers, and 
lymphoma), a total of 242 patients have been treated as of 30 April 2012. These patients 
have been treated with different doses of MLN9708 either as a single-agent treatment (in 
146 patients) or in combination with currently clinically available treatments (in 
96 patients). Information regarding the ongoing studies, patient populations, and doses 
investigated are included in Table 1-2.
Table 1-2   
Ongoing Studies of Oral MLN9708
Trial/
Population
Description
Doses Investigated
C16003
RRMM
N = 58
PO, TW, single agent
0.24-2.23 mg/m2 TW
MTD: 2.0 mg/m2
DLT: rash, thrombocytopenia
C16004
RRMM
N = 52
PO, W, single agent
0.24-3.95 mg/m2 W
MTD: 2.97 mg/m2
DLT: rash, nausea, vomiting, diarrhea
C16005
NDMM
N = 65
PO, W, combination with LenDex 
28-day cycle
1.68-3.95 mg/m2 W
MTD: 2.97 mg/m2
DLT: nausea, vomiting, diarrhea, syncope
RP2Da: 4.0 mg fixed (switched to fixed dosing in 
phase 2, relevant to 2.23mg/m2)
Closed to enrollment
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Table 1-2   
Ongoing Studies of Oral MLN9708
C16006
NDMM
N = 20
PO, TW (Arm A- 42 day cycle) and W 
(Arm B- 28 day cycle), combination 
with Melphalan and Prednisone
Arm Aa: 3-3.7-mg fixed dose TW
DLT: rash, thrombocytopenia, subileus
Arm Ba: 3-5.5-mg fixed dose, W
DLT: Esophageal ulcer
C16007
RRAL
N = 14
PO, W, single agent
4-5.5-mg fixed dosea W
MTD: 4 mg
DLT: thrombocytopenia, diarrhea, dyspnea, acute 
rise in creatinine, cardiac arrest
C16008
NDMM
N = 11
PO, TW, combination with LenDex 
21-day cycle
3.0-3.7-mg fixed dosea W
MTD: TBD
C16009
Solid 
tumors, 
Lymphomas
N = 22
PO, W, single agent
5.5-mg fixed dosea W
Abbreviations: BSA = body surface area; DLT = dose-limiting toxicity; IV = intravenously; 
LenDex = lenalidomide plus dexamethasone; MTD = maximum tolerated dose; NDMM = newly 
diagnosed multiple myeloma; PO = orally; RP2D= recommended phase 2 dose; RRAL = Relapsed and/or 
refractory Primary systemic light chain (AL) amyloidosis; RRMM = relapsed and/or refractory multiple 
myeloma; TBD = to be determined; TW = twice weekly; W = weekly.
a Approximate BSA and fixed dosing equivalence: 3 mg~ equivalent to 1.68 mg/m2 BSA dosing; 4.0 mg 
~ equivalent to 2.23 mg/m2 BSA dosing; and 5.5 mg~ equivalent to 2.97 mg/m2 BSA dosing.
Further details on planned and ongoing studies are provided in the IB.
1.4   
Pharmacokinetics and Drug Metabolism
Clinical IV and oral PK data show that MLN9708 (measured as the biologically active 
boronic acid form of MLN9708 [MLN2238]) has multi-exponential disposition with a rapid 
initial phase that is largely over by 4 hours. Oral MLN9708 is rapidly absorbed with a
median time to first maximum plasma concentration (Tmax) of approximately 0.5 to 
2.0 hours and terminal t1/2 after multiple dosing of approximately 5 to 7 days. Results of a 
population PK analysis (N = 137) show that there is no relationship between body surface 
area (BSA) or body weight and clearance (CL). Also, based on stochastic simulations for 
fixed dose, exposures are independent of the individual patient’s BSA. Based on these data,
a recommendation was made for fixed dosing in clinical trials. An absolute bioavailability of 
67% was determined for MLN9708 using the population PK analysis. See the IB for 
information on the PK for IV doses of MLN9708. 
Metabolism appears to be the major route of elimination for MLN2238, with negligible 
urinary excretion of the parent drug (< 5% of dose). In vitro studies indicate that MLN2238 
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Clinical Study Protocol C16014 Amendment 5, 2013-000326-54, 09 July 2020
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is metabolized by multiple cytochrome P450 (CYP) enzymes and non-CYP 
enzymes/proteins. At clinically relevant concentrations of MLN2238, in vitro studies using 
human cDNA-expressed CYP isozymes showed that no specific CYP isozyme 
predominantly contributes to MLN2238 clearance. At concentrations exceeding those 
observed clinically (10 µM), MLN2238 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 MLN2238 following oral 
administration of 4 mg MLN2238, non-CYPmediated clearance was observed and seemed 
to play a major role in MLN2238 clearance in vitro. These data indicate that at clinically 
relevant concentrations of MLN2238, minimal CYP-mediated drug-drug interactions (DDIs) 
with selective CYP inhibitors would be expected. In addition, MLN2238 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 MLN2238 (maximum [peak] 
concentration [Cmax] and area under the plasma concentration versus time curve [AUC]) was 
similar with and without co-administration of clarithromycin, a strong CYP3A inhibitor 
(Study C16009, Arm 5) [16]; hence, no dose adjustment is necessary when MLN2238 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 MLN2238 concentrations. As discussed earlier, no CYP 
isoforms have been identified to contribute meaningfully to MLN2238 metabolism at 
clinically relevant concentrations, and CYP3A contribution to total metabolism was highest 
across all CYP isoforms when characterized at a supratherapeutic concentration of 10 µM. 
Therefore, on the basis of the totality of information from the clinical clarithromycin DDI 
study and the in vitro CYP phenotyping data, it can be concluded that MLN2238 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 MLN2238 clearance; 
therefore, no dose adjustment is required for patients receiving strong inhibitors of CYP1A2. 
MLN2238 may be a weak affinity substrate of P-glycoprotein (P-gp), but not of breast 
cancer resistance protein (BCRP) or multidrug resistance associated protein (MRP2) efflux 
pump transporters. MLN2238 is not an inhibitor of P-gp, BCRP, or MRP2. The potential for 
DDIs with substrates or inhibitors of P-gp, BCRP, and MRP2 is, therefore, inferred to be 
low.
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In a recently completed DDI study, co-administration of MLN2238 with rifampin decreased 
MLN2238 Cmax by 54% and AUC by 74% (Study C16009, Arm 4). Accordingly, 
concomitant administration of MLN2238 with strong CYP3A inducers should be avoided.
Additional details on the PK and drug metabolism of MLN9708 are provided in the IB.
1.5   
Study Rationale
The recommended course of treatment for patients with newly diagnosed multiple myeloma 
(NDMM) depends largely on their age and overall health, and thus their ability to tolerate 
toxic combination therapies. For patients under the age of 65 who are in otherwise good 
health, the standard treatment for NDMM is high-dose therapy followed by autologous 
stem-cell transplantation (HDT-ASCT) with or without maintenance.[17,18] On the other 
hand, HDT-ASCT is not a preferred treatment option for most elderly patients. Randomized 
trials that demonstrated the superiority of standard dose versus HDT-ASCT were done in 
patients 65 or younger. Moreover, elderly patients are often not able to tolerate the 
accompanying toxicity. Because of this, improvements in survival seen over the past decade 
in patients with MM have been more pronounced in younger patients than in elderly 
patients.[19] It is hypothesized that the apparent lack in survival progress in these elderly 
patients may be a result of treatment-related toxicity burden and/or the inability to deliver 
efficacious therapy.[19] Furthermore, within the heterogeneous elderly patient population, 
there is a subset of patients who are particularly frail and are especially challenging to 
treat.[18] The median age of diagnosis for patients with multiple myeloma is between 
63 and 70 years, categorizing many newly diagnosed patients as elderly and thus not 
candidates for transplant.[17] This fact, coupled with lagging survival improvements in the 
elderly, highlights the clear medical need to develop novel combination therapies with 
improved efficacy and toxicity profiles. In elderly patients, current treatment options include 
melphalan-containing regimens (declining in use in recent years due to the known risk of 
leukemia and myelodysplastic syndrome with melphalan), or a non-melphalan containing 
regimen such as lenalidomide (an immunomodulatory agent) plus dexamethasone. 
Individually and in combination, the proteasome inhibitors and immunomodulatory 
analogues (IMiDs) have changed the conventional treatment of NDMM. The combination of 
a proteasome inhibitor, IMiD, and dexamethasone have shown significant improvements 
largely in terms of overall response rates and are now recognized by the National 
Comprehensive Cancer Network (NCCN) as induction therapy for both transplant and 
nontransplant eligible patients.[20] Studies of SCT, a standard of care for select patients, 
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were conducted before the availability of bortezomib and the IMiDs. More recently, the high 
response rates reported with these agents in transplant-eligible and -ineligible patients and 
the reports of similar outcomes when such agents are continued after the induction period 
and transplant delayed until disease progression–compared to the usual upfront transplant–
have raised the questions of the utility of early ASCT and of maintenance therapy in 
NDMM.[20-22]
Moreover, despite the current therapeutic options, the disease is characterized by frequent 
relapses and there remains a need for more active, safer, and convenient agents as well as
the challenge of combining currently established agents with contemporary novel ones in an 
attempt to achieve long-term disease control.[23] To examine the feasibility of those 
objectives, this study is proposed based on the results of bortezomib, Millennium’s first 
generation proteasome inhibitor, and MLN9708, a next generation proteasome inhibitor, will 
be administered in combination with lenalidomide and dexamethasone. Further support for 
MLN9708 in this trial is provided by Chauhan and colleagues. Based on their work in 
in vitro model systems, this group reports MLN2238 combined with lenalidomide or 
dexamethasone triggers synergistic anti‒multiple myeloma activity supporting further 
clinical evaluation of MLN9708 in combination with these agents.[24]
The purpose of this study is to evaluate whether the addition of MLN9708 to lenalidomide
and dexamethasone increases efficacy and safety outcomes in patients with NDMM who are 
transplant ineligible.
1.6   
Rationale for the Combination of MLN9708, Lenalidomide, and 
Dexamethasone
1.6.1   
Combination of MLN9708, Lenalidomide, and Dexamethasone
Standard front-line treatment for patients with multiple myeloma consists of either high-dose 
induction antineoplastic therapy (HDT) followed by stem cell transplantation (SCT) or 
antineoplastic therapy alone for those who are not eligible for HDT-SCT.[20,25-28] Oral 
combination of melphalan and prednisone (MP) and MP-based therapies (VELCADE 
[bortezomib] +MP; Thalidomide +MP) have been the standard of treatment recommended 
by the NCCN and European Society for Medical Oncology  and for patients with NDMM 
who are not eligible for HDT-SCT.[17,29,30] The VISTA phase 3 study confirms that the 
addition of VELCADE to MP was more active than MP-alone and produced a higher health-
related quality of life in this population.[31,32] The NCCN guidelines on Multiple Myeloma
and the National Cancer Institute summary of Plasma Cell Neoplasms for Health 
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Professionals recommend combination treatment with a proteasome inhibitor and/or 
lenalidomide plus dexamethasone for the initial treatment of NDMM in patients who are not 
candidates for stem cell transplant. Clinical data from multiple studies support the 
combination of a proteasome inhibitor, an IMiD, and a glucocorticosteroid. The combination 
of bortezomib, lenalidomide, and low-dose dexamethasone, as noted in Section 1.5 and the 
NCCN guidelines, illustrates that this combination is very active and well tolerated in the
NDMM population.[20,33-35] On the other hand, there is also a solid rationale for the 
control arm of lenalidomide-dexamethasone (plus placebo), which has demonstrated activity 
in phase 3 testing in this population.[36,37] Given that MLN9708 has improved binding 
kinetics and pharmacologic profile compared with bortezomib, it is expected that these 
differences will translate into similar, if not improved, efficacy and safety profiles.[38]
Preclinical work by Chauhan and colleagues also supports clinical evaluation of MLN9708 
in combination with lenalidomide and dexamethasone based on their results reporting that 
MLN2238 combined with lenalidomide or dexamethasone triggers synergistic anti‒multiple 
myeloma activity.[24] Though no clinical studies have been completed with the combination 
of MLN9708, lenalidomide, and dexamethasone (Study C16005 and Study C16010 are 
ongoing), the data available with bortezomib forms the foundation for adding the 
proteasome inhibitor in the combination in this study.
In terms of safety, the toxicological profile of MLN2238 in nonclinical studies is generally 
consistent with class-based effects of proteasome inhibition and is similar to what has been 
reported previously in nonclinical studies with bortezomib. The most common treatment-
emergent adverse events (TEAE) of single-agent MLN9708 across all dose level cohorts 
regardless of causality in all phase 1 studies reported to date, as discussed in Section 1.3, 
were anticipated based on preclinical data and previous experience with bortezomib. Given 
the available clinical data in Study C16005, the similar nonclinical toxicity profile between 
MLN2238 and bortezomib, the toxicities demonstrated in studies with lenalidomide and 
dexamethasone, and the low potential for DDI, it is anticipated that any potential for 
overlapping toxicities with a combination of MLN9708, lenalidomide, and dexamethasone 
can be monitored in the clinic with routine clinical observations and clinical pathology 
assessments.
1.6.2   
Rationale for MLN9708, Lenalidomide, and Dexamethasone Dose and 
Schedule Selection
Oral MLN9708 administered weekly on Days 1, 8, and 15 of a 28-day cycle is supported by 
nonclinical data and clinical trial results in which MLN9708 has been given as a single agent 
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and in combination with lenalidomide and dexamethasone. The weekly schedule was well 
tolerated in in vivo toxicology studies and was predicted to allow dosing on a schedule that 
produced maximum antitumor activity in mouse models. These doses are chosen based on 
the Study C16005, which is an open-label, dose escalation, phase 1/2 study of MLN9708 
dosing on a weekly schedule (Days 1, 8, and 15 of a 28-day cycle) in combination with 
lenalidomide and low-dose dexamethasone (LenDex) in adult patients with NDMM. In the 
phase 1 portion of Study C16005, 3 evaluable patients were enrolled in each of the 
following cohorts: Cohort 1 (1.68 mg/m2), Cohort 2 (2.23 mg/m2), Cohort 3 (2.97 mg/m2), 
and Cohort 4 (3.95 mg/m2). While 2.97 mg/m2 was determined to be the maximum tolerated 
dose (MTD), 3 out of 6 patients were not able to receive all of their lenalidomide doses 
during Cycle 1 due to Grade 2 or 3 rash. Given that the dose of MLN9708 at 2.97 mg/m2
significantly compromised the doses of the LenDex background regimen, and that the dose 
of 2.23mg/m2 is very tolerable and clinically active, the sponsor has decided to use 
2.23 mg/m2 as the dose for the phase 2 portion of the C16005 study. Enrollment in 
Study C16005 has been completed with a total of 65 patients (15 in phase 1 and 50 in phase 
2). Final study results are not available, but preliminary data suggests oral MLN9708 given 
weekly plus lenalidomide and dexamethasone in a 28-day cycle appears well tolerated with 
manageable toxicity and encouraging antitumor activity. Encouraging signs of antitumor 
activity were observed with preliminary overall response rates (partial response [PR]) of 
91% and a CR + very good partial response (VGPR) rate of 39% in a setting where patients 
have received a median of 4 cycles of therapy (range 1-15) as of the 30 April 2012 data cut. 
In the MTD cohorts, fatigue was the most common AE reported (38%). Other common AEs 
(at least 15%) reported include nausea (32%); constipation (30%); upper respiratory 
infection (23%); peripheral edema (21%); thrombocytopenia, vomiting, and diarrhea (19% 
each); anemia, fever, and back pain (17% each); and dysgeusia (15%). Skin toxicity, 
primarily erythematous rash, occurred in 62% of patients (of note, rash is an overlapping 
toxicity with MLN9708 and lenalidomide). Peripheral neuropathy was reported in 13% of 
patients; Grade 3 in 1 patient. The data today support further clinical study of MLN9708 in 
combination with LenDex in patients with NDMM.
This recommended starting dose of 2.23 mg/m2 is translated into a fixed dose of 4.0 mg 
based on the results from population PK analysis. A population PK model was built using
data from both the TW and W IV (N = 86) and oral (N = 51) dosing regimens (N = 137).
Population PK analysis showed that MLN9708 PK can be well described by a 
3-compartment model with linear elimination for IV data and with an additional absorption 
compartment (first order absorption) for oral administration (PO) data. Covariate analyses 
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Clinical Study Protocol C16014 Amendment 5, 2013-000326-54, 09 July 2020
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indicate that interpatient variability in BSA and/or body weight did not significantly 
contribute to the variability in CL and volume of distribution in the central compartment 
(V2). CL and V2 are the PK parameters that will affect AUC and Cmax. The lack of a 
discernable relationship between BSA and MLN9708 CL based on data in 137 patients over 
a relatively wide BSA range (1.4-2.6 m2) indicates that total systemic exposure (AUC) 
following fixed dosing should be independent of the individual patient’s BSA (see 
Figure 1-1). Accordingly, the starting dose of MLN9708 in the phase 2 portion of
Study C16005 is a fixed dose of 4.0 mg, based on the recommended dose of 2.23 mg/m2
(using mean patient BSA of 1.86 m2 from the 2208 MM patients in bortezomib clinical trials 
for conversion to fixed dose).
Figure 1-1   
No Apparent Relationship Between MLN9708 Clearance and BSA
BSA (sq m)
Clearance (L/hr) 
1.4
1.6
1.8
2.0
2.2
2.4
2.6
0
1
2
3
4
5
6
1
1
1
1
1
1
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1
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1
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1
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1
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1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
111
1
1
11
1
1
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1
1
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1
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4
4
4
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4
4
4
4
4
4
1
16001
2
16002
3
16003
4
16004
Figure 1-1 provides a plot of individual values of MLN9708 clearance across the range of BSA (1.4-2.6 m2) 
from 4 phase 1 studies (N = 137). Each color identifies each study, and the blue line represents linear 
regression line.
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Clinical Study Protocol C16014 Amendment 5, 2013-000326-54, 09 July 2020
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Additional associations with either the efficacy or safety of MLN9708 
may be examined if there is a reasonable approach to identify myeloma patient populations 
with differential risk to benefit ratios upon treatment with MLN9708.[44,45]
Property of Takeda: For Non
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Clinical Study Protocol C16014 Amendment 5, 2013-000326-54, 09 July 2020
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1.6.4   
Rationale for the Combination of MLN9708, Lenalidomide, and 
Dexamethasone in Patients with High-Risk Cytogenetic Characteristics 
The clinical outcome of multiple myeloma patients is highly variable and can be related to 
specific cytogenetic subtypes. Abnormalities such as t(11;14), t(6;14), and hyperdiploidy are 
associated with neutral or favorable prognosis while t(4;14), t(14;16), deletion of 17p, and 
amplification of 1q21 impart an unfavorable prognosis.[50] Some reports suggest that 
bortezomib treatment, in combination with lenalidomide, is able to overcome the adverse 
effects associated with high-risk cytogenetics, whereas other studies show contradicting 
results. Recently Dimopoulos et al., has described the outcome of these subtypes in the 
context of patients with relapsed and refractory MM treated with lenalidomide and 
dexamethasone (RD) with or without bortezomib.[51] In this study poor risk cytogenetic 
populations were associated with lower response rate, which was significant in the RD arm 
(p = 0.01), but not in the RD with bortezomib (VRD) arm (p = 0.219). The adverse effect of 
del13q, amp(1q21), and t(4;14) were more pronounced mainly for the RD-treated patients.
Despite the responses observed in the high-risk cytogenetics groups with VRD, the PFS and 
OS in these patients, especially the del(17p) group, was significantly worse than standard 
risk patients (p < 0.001 and p = 0.017 respectively). One potential reason the VRD responses 
in del(17p) did not translate into improved time to event could be the difference in length of 
treatment between RD and VRD arms. Patients enrolled in the RD arm were treated until 
progression or until unacceptable toxicity arise. Differently, patients enrolled in the VRD 
arm received the treatment for only 8 cycles, then VELCADE was dropped, and patients 
who did not progress at that time were treated with RD until progression. 
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MLN9708
Clinical Study Protocol C16014 Amendment 5, 2013-000326-54, 09 July 2020
35
The aggressive del(17p) myelomas may require long-term treatment with a proteasome 
inhibitor. This hypothesis is further supported by Neben at al., where it was shown that 
VELCADE based treatment before and after ASCT in NDMM improves outcome in patients 
with del(17p) compared to control therapy.[52] In this phase 3 study, the bortezomib, 
adriamycin, and dexamethasone regimen was compared to vincristine, adriamycin, and 
dexamethasone. PFS and OS were compared in the whole population and specifically in the 
high-risk cytogenetic populations. Median PFS and OS (3 years) rates were at least 
comparable or superior in the bortezomib-containing arm compared to the standard arm. 
However, a statistically significant difference was found only for patients carrying the 
del(17p) abnormality. PFS in del(17p)-positive patients was 26.2 months in the bortezomib 
containing arm, compared to 12 months in the standard arm. Similarly, 3-year OS benefit in 
patients with del(17p) was 69% in the bortezomib-containing regimen vs 17% in the 
standard arm, while it was 80% in the bortezomib arm versus 85% in the standard arm in 
patients without del(17p).
1.6.5   
Minimal Residual Disease Assessment
Complete response remains the optimal objective in front-line treatment of myeloma to 
improve survival. The definition of CR has evolved in recent years from normalization of 
serum protein electrophoresis and bone marrow morphology with negative immunofixation 
to normal serum free light-chain ratio test (stringent CR), and more recently to normal 
immunophenotypic response (IR). Immunophenotyping defines a tumor’s surface marker 
profile via flow cytometry and is highly sensitive to the presence of tumor cells in marrow 
specimens. Patients with tumor cells below the detection threshold (1 MM cell in 
~ 10,000 cells) are considered to be in a flow cytometric remission. Although the long-term 
utility of this approach is still in its early day in MM, several studies have indicated that 
MRD-negative patients experienced longer PFS and OS than flow cytometric-positive 
patients. Recently, Paiva and colleagues from Salamanca, Spain, have investigated the 
impact of IR versus CR and stringent CR in 260 newly diagnosed elderly (65 years) 
patients with multiple myeloma treated with novel agents in the PETHEMA/GEM 05 
trial.[53] In this trial, IR showed significantly increased 3-year rates of PFS and TTP as 
compared with those in stringent CR or CR (90% vs 69% and 60%, and 96% vs 71% and 
68% [p 0.001], respectively). On a multivariate COX regression analysis for PFS, only IR 
status was an independent prognostic factor (relative risk, 4.1; 95% confidence interval [CI], 
1.4-12.0; p 0.01).
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In this study, the assessment of MRD will be done using bone marrow aspirates collected 
when a patient is suspected to have reached CR at any time during the conduct of the entire 
study. A repeat bone marrow aspirate will be obtained at Cycle 18 for only those patients 
who have maintained a CR until that point. This repeat bone marrow aspirate may be 
collected up to 4 weeks after Cycle 18, Day 1 to assess MRD.
If a patient has had MRD testing because of a suspected CR within 2 cycles of Cycle 18, 
then this repeat MRD assessment does not need to be performed. Samples are required to be 
sent to a central lab for analysis. These samples will be processed according to the 
Laboratory Manual.
1.6.6   
Rationale for Bone Disease Assessment
Bone disease is a common feature of MM, occurring in more than 80% of patients, and can 
result in bone pain, fractures, spinal cord compression, and hypercalcemia. There is 
increasing evidence that bortezomib has a positive effect on bone metabolism, and 
MLN9708 may have a similar positive effect. Bortezomib therapy has been associated with
a reduction in bone disease-related myeloma progression events, increases in bone density, 
and favorable changes in bone biomarkers.[54] The phase 3 VISTA trial randomized 
682 patients with NDMM to melphalan/prednisone with or without the addition of 
bortezomib. The bortezomib group had lower rates of disease progression due to worsening 
bone disease (3% vs 11%), lower rates of bisphosphonate use (73% vs 82%), and a lower 
requirement for subsequent radiotherapy (3% vs 8%).[55]
This study will build on the VISTA trial by studying skeletal-related events (SRE), bone 
density, 
 
 using blood samples.
1.6.7   
Rationale for Selected Subgroups
If the test for PFS in the intent-to-treat (ITT) population is not statistically significant at the 
first IA, PFS will be tested at IA2 in both the ITT population and in 3 prespecified 
subgroups: 1) patients with baseline creatinine clearance (CrCl) > 60 mL/min; 2) patients 
aged < 75 years; and 3) patients harboring high-risk cytogenetic abnormalities defined as 
del(17p), t(4;14), t(14;16), and amp(1q21). These subgroups were selected on the basis of
recent data suggesting the potential for treatment benefit in these patients:
!
Worse outcomes following treatment with continuous lenalidomide/dexamethasone 
have been observed in patients with CrCl ≤60 mL/min and patients aged ≥75 years 
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18,8,
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[56-59]. Therefore, it could be clinically plausible that in a renally impaired (CrCl 
≤60 mL/min) or older (≥75 years) subpopulation, the already higher risk/benefit 
ratio (less tolerability with less efficacy) is further affected by the addition of a third 
agent.

In addition, the International Myeloma Working Group consensus has recently 
identified cytogenetic abnormalities as conferring poor prognosis [60,61]. However, 
patients harboring high-risk cytogenetic abnormalities may derive particular benefit 
in this trial on the basis of data showing improved treatment outcomes in patients 
with relapsed and/or refractory multiple myeloma treated with ixazomib (MLN9708) 
in combination with lenalidomide/dexamethasone in Study C16010 and in patients 
with newly diagnosed multiple myeloma treated with another proteasome inhibitor 
(bortezomib) [62-65].
1.7   
Potential Risks and Benefits
As of the clinical cutoff date of 30 April 2012, 382 patients across 9 ongoing sponsor-led 
studies have been treated with MLN9708. Clinical safety data includes experience from 
patients who received multiple cycles followed by treatment-free periods and from patients 
who reduced or discontinued treatment. The emerging safety profile indicates that the AEs 
reported with MLN9708 are consistent with the known effects of proteasome inhibition and 
are similar to what has been previously reported with VELCADE, though the frequency and 
severity may slightly differ. While some of these potential toxicities may be severe, they can 
be managed by clinical monitoring and standard medical intervention. It is possible that 
MLN9708 will have toxicities that were not predicted from its evaluation in nonclinical 
studies or previously observed in ongoing clinical studies. To mitigate the inherent risks in 
clinical studies of MLN9708, patients are monitored closely for anticipated toxicities. 
Guidance for the management of AEs and procedures for reducing doses are provided in the 
protocols, and drug dosage can be reduced by either reducing the dose administered or by 
interruption of the scheduled treatment within a cycle. 
MLN9708 shows early signs of antitumor activity as evidenced by at least a 50% reduction 
in disease burden in some patients and prolonged disease stabilization in others across all 
ongoing trials. To date, antitumor activity has been seen with single-agent MLN9708, when 
combined with established therapies, and across all malignancies studied (advanced solid 
tumors, non-Hodgkin lymphoma, RRMM, relapsed and/or refractory systemic light chain 
amyloidosis [RRAL], and newly diagnosed multiple myeloma [NDMM]). Though 
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additional data are needed to characterize the clinical benefit of this drug, the emerging data 
supports the ongoing development of MLN9708. 
Further information can be found in the MLN9708 IB.
2.   
STUDY OBJECTIVES
As of this amendment, the objectives are to provide continued access to MLN9708 and/or 
lenalidomide to patients who are continuing to have clinical benefit and to continue 
collecting relevant safety data to monitor patient safety. All other study objectives will no 
longer be assessed. However, the complete list of objectives is retained below for reference.
2.1   
Primary Objectives
The primary objective of this study is:

To determine whether the addition of oral MLN9708 to lenalidomide and 
dexamethasone improves PFS in patients with NDMM
2.2   
Secondary Objectives
The key secondary objectives are:

To determine whether the addition of oral MLN9708 to lenalidomide and 
dexamethasone improves OS

To determine whether the addition of oral MLN9708 to lenalidomide and 
dexamethasone improves the rate of CR 

To determine whether the addition of oral MLN9708 to lenalidomide and 
dexamethasone improves pain response rate, as assessed by the Brief Pain Inventory-
Short Form (BPI-SF) and analgesic use
Other secondary objectives include:

To determine overall response rate (ORR), including PR, VGPR, and CR

To determine time to response (TTR), DOR, and TTP
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!
To determine the effect of the addition of MLN9708 to lenalidomide and 
dexamethasone on progression-free survival 2 (PFS2), defined as the date from 
randomization to the date of second disease progression or death from any cause, 
whichever comes first 
!
To determine the safety of the addition of MLN9708 to lenalidomide and 
dexamethasone 
!
To assess change in global health status, as measured by the global health status, 
functioning, and symptoms as measured by the patient-reported outcome (PRO) 
instrument European Organization for Research and Treatment of Cancer Quality of 
Life Questionnaire (EORTC QLQ-C30) and MY-20 module 
!
To determine the PFS and OS in high-risk cytogenetic patient groups defined by the 
following cytogenetic abnormalities: t(4;14), t(14;16), amp(1q21), and del(17p)
!
To evaluate minimal residual disease status (MRD), via flow cytometry, in patients 
suspected to have reached CR at any time during the entire conduct of the study, and 
at Cycle 18 for patients who have maintained a CR until that point. The impact of 
MRD status on TTP, PFS, and OS will be assessed.
!
To assess time to pain progression 
!
To collect PK data to contribute to population PK analyses
!
To evaluate the frequency of SREs (eg, new fractures [including vertebral 
compression fractures], irradiation of or surgery on bone, or spinal cord 
compression) from baseline through the last survival assessment
2.3   
Exploratory Objectives
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3.  
STUDY ENDPOINTS
As of this amendment, evaluation of the safety profile of MLN9708 and/or lenalidomide is 
the only endpoint being assessed. All other study endpoints will no longer be assessed. 
However, the complete list of endpoints is retained below for reference.
3.1   
Primary Endpoint
The primary endpoint is:
!
PFS, defined as the time from the date of randomization to the date of first 
documentation of disease progression based on central laboratory results and 
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international myeloma working group (IMWG) criteria as evaluated by an IRC, or 
death due to any cause, whichever occurs first
3.2   
Secondary Endpoints
The key secondary endpoints are:

OS, measured as the time from the date of randomization to the date of death

CR rate 

Pain response rate, measured by the proportion of pain responders, as determined by 
the BPI-SF and analgesic use
Other secondary endpoints are:

Overall response rate (CR + VGPR + PR) 

Time to response, measured as the time from randomization to the date of first 
documented objective response

Duration of response, measured as the time from the date of first documentation of 
response to the date of first documented progression

Time to progression, measured as the time from randomization to the date of first 
documented progression

PFS2, defined as the time from the date of randomization to the date of second 
documentation of disease progression (on subsequent line of anticancer therapy), as 
assessed by the investigator in accordance with IMWG criteria, or death due to any 
cause, whichever comes first

Eastern Cooperative Oncology Group (ECOG) performance scores, AEs, SAEs, and 
assessments of clinical laboratory values

Comparison of change in global health status between baseline and each postbaseline 
assessment, as measured by the global health scale, functioning, and symptoms of 
the EORTC QLQ-C30 and MY-20
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!
OS and PFS in high-risk population carrying del(17p), amp(1q21), t(4;14), or 
t(14;16)
!
Estimate the frequency of detection of MRD via flow cytometry in patients assessed 
at suspected CR at any time during the entire conduct of the study and in patients 
who have maintained CR until Cycle 18, and its impact on TTP, PFS, and OS
!
Time to pain progression, as assessed by the time from randomization to the date of
initial progression classification
!
Plasma concentration-time data to contribute to future population PK analysis
!
Development of new or worsening of existing SREs, defined as new fractures 
(including vertebral compression fractures), irradiation of or surgery on bone, or 
spinal cord compression
3.3   
Exploratory Endpoints
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4.   
STUDY DESIGN 
4.1   
Overview of Study Design
This is a phase 3, randomized, double-blind, multicenter study in patients with NDMM to 
evaluate the safety and efficacy of oral MLN9708 versus placebo when added to 
lenalidomide and dexamethasone. Adult patients with a confirmed diagnosis of symptomatic 
MM who have not received previous antimyeloma treatment, who are ineligible for 
high-dose therapy plus stem cell transplantation (HDT-SCT) because of age (ie, ∀65 years) 
or coexisting conditions per investigator judgment, who are candidates for treatment with 
LenDex as their standard therapy, and who meet all other eligibility criteria (see Section 5) 
will be enrolled in this study. Approximately 701 patients will be enrolled in the study.
The following describes the study design before Amendment 5 was implemented.
General eligibility criteria may be assessed prior to the formal Screening period if it is part 
of standard clinical practice. However, formal screening will occur during the Screening 
period, which may last for up to 28 days prior to randomization. A Millennium
Pharmaceuticals, Inc. (MPI)/designee clinician will confirm patient eligibility prior to 
randomization by the investigator.
Following the Screening period, patients to be enrolled will be randomized to receive 
MLN9708 or placebo in a double-blind fashion, in addition to the background therapy of 
LenDex. Eligible patients will be randomized in a 1:1 ratio into those 2 treatment arms, 
stratified by age (# 75 years vs ∀75), International Staging System (ISS) (stage 1 or 2 vs 
stage 3), and BPI-SF worst pain score (# 4 vs ∀4) at screening.
Patients will receive study drug (MLN9708 4.0 mg or matching placebo capsule) on Days 1, 
8, and 15 plus lenalidomide (25 mg) on Days 1 through 21 and dexamethasone (40 mg) on 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applic
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Clinical Study Protocol C16014 Amendment 5, 2013-000326-54, 09 July 2020
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Days 1, 8, 15, and 22 of a 28-day cycle. Patients over 75 years of age at randomization will 
receive reduced dexamethasone dose (20 mg). Patients with a low creatinine clearance of 
60 mL/min (or 50 mL/min, according to local label/practice) but 30 mL/min will 
receive a reduced lenalidomide dose of 10 mg once daily (QD) on Days 1 through 21 of a 
28-day cycle. The lenalidomide dose may be escalated to 15 mg QD after 2 cycles if the 
patient is not responding to treatment and is tolerating the treatment. If renal function 
normalizes (ie, creatinine clearance > 60 mL/min or > 50 mL/min, according to local 
label/practice) and the patient continues to tolerate this treatment, lenalidomide may then be 
escalated to 25 mg QD. Dose modifications may be made throughout the study based on 
toxicities.
Patients may continue to receive treatment as detailed previously for 18 cycles, or until 
progressive disease (PD) or unacceptable toxicity, whichever comes first. After 18 cycles, 
patients remaining on treatment will continue the study drug regimen in the same 
randomization arm on the same schedule with modified dose levels of study drug and 
lenalidomide until disease progression or unacceptable toxicity (see Table 4-1). Dose 
modifications should be made based on prior dose modifications during the first 18 cycles of 
treatment.
Table 4-1   
Dose Level Changes Beyond 18 Cycles of Treatment
Drug
Dose (18 Cycles)
Dose (18 Cycles)
MLN9708/Placebo
4.0 mg
3.0 mg
3.0 mga
3.0 mg
2.3 mga
2.3 mg
Lenalidomide
25 mgb
10 mg
15 mga
10 mg
10 mga
10 mg
5 mga
5 mg
Dexamethasone
40 mgc
none
a Dose reduction within first 18 cycles of treatment due to toxicity.
b Patients with a low creatinine clearance of 60 mL/min (or 50 mL/min, according to local 
label/practice) but 30 mL/min will receive a reduced lenalidomide dose of 10 mg QD on Days 1 
through 21 of a 28-day cycle. The lenalidomide dose may be escalated to 15 mg QD after 2 cycles if the 
patient is not responding to treatment and is tolerating the treatment. If renal function normalizes (ie, 
creatinine clearance > 60 mL/min or > 50 mL/min, according to local label/practice) and the patient 
continues to tolerate this treatment, lenalidomide may then be escalated to 25 mg QD.
c Patients over 75 years of age at randomization will receive a reduced dexamethasone dose (20 mg).
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The treatment period of the study is defined as any time a patient is receiving any of the 
study drug regimen and will be comprised of 28-day treatment cycles. Patients will be seen 
at regular treatment cycle intervals while they are participating in the study: weekly for the 
first 2 cycles, twice a treatment cycle during the third cycle, and then once a treatment cycle 
for the remainder of their participation in the treatment period, until they experience disease
progression or discontinue for alternate reasons. Patients will then enter either the PFS 
follow-up period (for patients who discontinue before disease progression) or the OS 
follow-up period (for patients who have disease progression during the treatment period).
Patients will be assessed for disease response and progression by the investigator and an 
IRC. Response will be assessed according to the IMWG uniform response criteria 
(Section 15.11) for all patients every cycle during the treatment period. For patients who 
discontinue treatment before disease progression, response will also be assessed in 
accordance with the IMWG uniform response criteria every 4 weeks during the PFS 
follow-up period until disease progression is confirmed or the patients are started on another 
anticancer therapy; radiographic disease assessments are to be performed every 8 weeks for 
patients with documented extramedullary disease. Following disease progression or start of 
another anticancer therapy, patients will enter the OS follow-up period and will be contacted 
every 12 weeks until death or termination of the study by the sponsor. All subsequent 
anticancer therapies for MM will be reported as part of the OS follow-up period 
assessments. In addition, patients who receive a subsequent anticancer therapy for MM will 
be assessed by the investigator (according to the IMWG uniform response criteria 
[Section 15.11]) for disease response (at minimum, disease progression) to determine PFS2 
on the next line of therapy. Response assessments should be made using local laboratory 
results, and the frequency will be determined by the investigator (recommended every 
12 weeks). Results will be recorded in the electronic case report form (eCRF) every 
12 weeks until PFS2 is reported or a new (third) line of anticancer therapy is started, 
whichever comes first.
Pain evaluation (using the BPI-SF) will include quantified assessments of intensity, 
frequency and duration, degree of discomfort, location, and likely relationship to MM 
(versus comorbidities). Time to pain progression will be based on pain assessments using 
the worst pain item on the BPI-SF rated on a scale from 0 to 10, collected as outlined in the 
Full Schedule of Events. Health-related quality of life (QOL) will also be evaluated through 
patient self-reported instruments including the EORTC QLQ-C30, MY-20, and the EQ-5D 
generic health status measure. In addition to assessing selected symptoms, these instruments 
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elucidate the effects of disease on physical, social, psychological/emotional, and cognitive 
functioning.
ECOG performance score and AEs will be assessed, and laboratory values, vital signs, and 
electrocardiograms (ECGs) will be obtained to evaluate the safety and tolerability of 
MLN9708. Toxicity will be evaluated according to National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03, effective date
14 June 2010.
Unscheduled visits may occur between treatment cycles as required. For example, 
symptomatic pain progression should result in an interim unscheduled visit, as would 
ongoing Grade 3 or worse AEs.
Patients will attend an EOT visit 30 days (+1 week) after receiving their last dose of the 
study drug regimen 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. Patients will continue to be followed for other follow-up assessments specified in 
the Full Schedule of Events.
An independent data monitoring committee (IDMC) reviewed safety and efficacy data at the 
2 planned IAs. See Section 9.2 for more information. 
As of Amendment 5, the 2 planned IAs have been conducted (data cutoff date of 
15 February 2018 for the first IA and data cutoff date of 02 December 2019 for the second 
IA). However, in the second IA, the primary endpoint of PFS did not reach statistical 
significance. Thus, the planned final analysis will not occur and the study is now unblinded.
Although the primary endpoint was not met, patients in both treatment arms appeared to 
receive benefit. As such, patients deriving clinical benefit may continue their current study 
treatment if there are no other means of accessing the study drugs, until such time as other 
means of accessing the study drugs are arranged.  When possible, patients should complete 
an EOT visit and transition onto a commercial supply of ixazomib and/or lenalidomide or 
other standard of care treatment.  
Patients who are receiving ixazomib and lenalidomide will continue to receive ixazomib and 
lenalidomide. Patients who are receiving placebo and lenalidomide will receive 
lenalidomide only; the placebo capsule will no longer be administered and patients receiving
placebo will not be crossed over to ixazomib in this study. 
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For patients continuing on study, the majority of study assessments are discontinued to ease 
the burden of protocol-mandated assessments. Upon implementation of Amendment 5, data 
collection requirements will be limited to collection of AEs and SAEs. All other study 
assessments are no longer required. All central laboratory efficacy measures of response and 
progression are discontinued. Bone marrow aspirates for confirmation of CR or MRD status 
are no longer required. No further IRC response or progression evaluations will be 
performed. Radiographic studies and bone density studies for study purposes are no longer 
required. Quality of life and health utilization assessments and collection of concomitant 
medications and procedures are discontinued. Patients will not be followed for the PFS or
OS follow-up periods, as PFS and OS data are no longer being collected. Patients may 
choose to stay in the study if the investigator believes that the patient is continuing to benefit 
from the treatment. Alternatively, the patient may discontinue from the study and be treated 
by their physician according to standard of care. See the updated Schedule of Events—
Amendment 5 and Beyond for more detailed information.
4.2   
Number of Patients
Approximately 701 patients will be enrolled in this study from approximately 150 study 
centers in North America, Europe, Russia, New Zealand, and Asia. Enrollment is defined as 
being randomized to treatment in the study.
4.3   
Duration of Study
It is anticipated that this study will last for approximately 87 months, including a 27-month 
randomization period and an additional 60-month (5-year) follow-up from the last patient 
enrolled.
5.   
STUDY POPULATION
Adult patients age 18 or older with a confirmed diagnosis of symptomatic MM who have 
received no prior antimyeloma treatment and who are ineligible for HDT-SCT due to age 
(65 years) or comorbidities will be enrolled in this study.
5.1   
Inclusion Criteria
Each patient must meet all of the following inclusion criteria to be randomized to treatment:
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1. Adult male or female patients 18 years old and above with a confirmed diagnosis of 
symptomatic multiple myeloma according to IMWG criteria (see Section 15.2) who 
have not received prior treatment for multiple myeloma
2. Patients for whom lenalidomide and dexamethasone treatment is appropriate and 
who are not eligible for HDT-SCT for 1 or more of the following reasons: 

The patient is 65 years of age or older

The patient is less than 65 years of age but has significant comorbid 
condition(s) that are, in the opinion of the investigator, likely to have a
negative impact on tolerability of HDT-SCT
3. Patients must have measurable disease defined by at least 1 of the following 
3 measurements:

Serum M-protein 1 g/dL (10 g/L)

Urine M-protein 200 mg/24 hours

Serum free light chain assay: involved free light chain level 10 mg/dL 
(100 mg/L), provided that the serum free light chain ratio is abnormal
4. Patients must meet the following clinical laboratory criteria:

Absolute neutrophil count (ANC) 1,000/mm3 and platelet count 75,000/mm3. 
Platelet transfusions to help patients meet eligibility criteria are not allowed 
within 3 days prior to randomization

Total bilirubin 1.5 the upper limit of the normal range (ULN).

Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 
3 ULN.

Calculated creatinine clearance 30 mL/min, as calculated using the Cockcroft-
Gault Equation (Section 15.3).
NOTE: Patients with a low creatinine clearance 60 mL/min (or 50 mL/min, 
according to local label/practice) but 30 mL/min will receive a reduced 
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lenalidomide dose of 10 mg QD on Days 1 through 21 of a 28-day cycle; patients 
with a creatinine clearance 30 mL/min are not permitted to be enrolled into the 
study. The lenalidomide dose may be escalated to 15 mg once daily after 2 cycles 
if the patient is not responding to treatment and is tolerating the treatment. If 
renal function normalizes (ie, creatinine clearance > 60 mL/min or > 50 mL/min, 
according to local label/practice) and the patient continues to tolerate this 
treatment, lenalidomide may then be escalated to 25 mg QD.
5. ECOG performance status of 0, 1, or 2.
6. Female patients who:

Are postmenopausal for at least 24 months before the Screening visit, OR

Are surgically sterile, OR

Females of childbearing potential ([FCBP] – see Section 6.9 for definition) must: 
a.
All countries except Canada: Have TWO medically-supervised negative 
pregnancy tests (serum or urine with sensitivity of at least 25 mIU/mL), even 
if continuous abstinence is the chosen method of contraception. One test must 
be obtained within 10 to 14 days and the other test must be obtained within 
24 hours prior to administering the first dose of the study drug regimen at 
Cycle 1, Day 1. The dates and results of pregnancy tests must be documented
b. Canada: Have TWO medically supervised negative serum pregnancy tests 
with a sensitivity of at least 25 mIU/mL prior to the first dose of the study 
drug regimen, even if continuous abstinence is the chosen method of 
contraception. One test must be obtained within 7 to 14 days and the second 
within 24 hours prior to administering the first dose of the study drug 
regimen at Cycle 1, Day 1. The dates and results of pregnancy tests must be 
documented
c.
Either agree to practice true abstinence, when this is in line with the preferred 
and usual lifestyle of the patient (periodic abstinence [eg, calendar, ovulation, 
symptothermal, post-ovulation methods] and withdrawal are not acceptable 
methods of contraception) OR begin TWO reliable methods of birth control: 
1 highly effective method and 1 additional effective method AT THE SAME 
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TIME (refer to Section 6.9), at least 28 days before starting the study drug 
regimen through 90 days after the last dose of study treatment
d. Agree to ongoing pregnancy testing
e.
Adhere to the guidelines of the Revlimid REMS(formerly known as 
RevAssist®) program (United States [US] participants), RevAid® program 
(Canadian participants), or The Lenalidomide Pregnancy Risk Minimisation 
Plan as outlined in the Study Manual (all other participants who are not using 
commercial Revlimid supplies). The counseling must be documented.
Male patients, even if surgically sterilized (ie, status postvasectomy), must:

Agree to practice true abstinence, when this is in line with the preferred and 
usual lifestyle of the patient (periodic abstinence [eg, calendar, ovulation, 
symptothermal, post-ovulation methods] and withdrawal are not acceptable 
methods of contraception) OR

Agree to practice effective barrier contraception during the entire study 
treatment period and through 90 days after the last dose of study treatment if 
their partner is of childbearing potential, even if they have had a successful 
vasectomy, AND

Adhere to the guidelines of the Revlimid REMS(formerly known as 
RevAssist®) program (US participants), RevAid® program (Canadian 
participants), or The Lenalidomide Pregnancy Risk Minimisation Plan as 
outlined in the Study Manual (all other participants who are not using 
commercial Revlimid supplies). The counseling must be documented.
7. Suitable venous access for the study-required blood sampling 
8. Must be able to take concurrent aspirin 70 to 325 mg daily (or equivalent dose per 
country product label [package insert (PI) or Summary of Product Characteristics 
(SmPC)]) or enoxaparin 40 mg subcutaneously daily (or its equivalent) if allergic to 
aspirin, per published standard or institutional standard of care, as prophylactic 
anticoagulation prior to randomization.
NOTE: For patients with prior history of deep vein thrombosis (DVT), low 
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molecular weight heparin (LMWH) is mandatory. (See Section 6.10 for 
thromboembolism prophylaxis.)
9. Voluntary written consent must be given before performance of any study-related 
procedure not part of standard medical care, with the understanding that consent may
be withdrawn by the patient at any time without prejudice to future medical care.
10. Patient is willing and able to adhere to the study visit schedule and other protocol 
requirements.
5.2   
Exclusion Criteria
Patients meeting any of the following exclusion criteria are not to be randomized to 
treatment:
1. Prior treatment for multiple myeloma with either standard of care treatment or 
investigational regimen
NOTE: Prior treatment with corticosteroids or localized radiotherapy is permitted as 
long as it is below a therapeutic level (maximum dose of corticosteroids should not 
exceed the equivalent of 160 mg of dexamethasone over a 2-week period [see 
Table 15-3]) 
2. Localized radiotherapy within 14 days before randomization 
3. Diagnosed and treated for another malignancy within 5 years before randomization 
or previously diagnosed with another malignancy and have any evidence of residual 
disease  
Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not 
excluded if they have undergone histologically confirmed complete surgical 
resection
4. Inability or unwillingness to receive thromboembolism prophylaxis
5. Female patients who are lactating and breastfeeding or have a positive pregnancy test 
during the Screening period
6. Major surgery within 14 days before randomization.
NOTE: Kyphoplasty or vertebroplasty is not considered major surgery
7. Central nervous system involvement
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8. Infection requiring systemic antibiotic therapy or other serious infection within 
14 days before randomization
9. Diagnosis of Waldenstrom’s macroglobulinemia, polyneuropathy, organomegaly, 
endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome, 
plasma cell leukemia, primary amyloidosis, myelodysplastic syndrome, or 
myeloproliferative syndrome
10. Evidence of current uncontrolled cardiovascular conditions within 6 months prior to 
randomization, including:

Uncontrolled hypertension, cardiac arrhythmias, or congestive heart failure

Unstable angina, or

Myocardial infarction 
11. Systemic treatment with strong inhibitors of CYP1A2 (fluvoxamine, enoxacin, 
ciprofloxacin), strong inhibitors of CYP3A (clarithromycin, telithromycin, 
itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole) or strong 
CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, 
phenobarbital), or use of Ginkgo biloba or St. John’s wort within 14 days before 
randomization in the study
12. Ongoing or active infection, or active hepatitis B or C infection, or known human 
immunodeficiency virus positive
13. Comorbid systemic illnesses or other severe concurrent disease which, in the 
judgment of the investigator, would make the patient inappropriate for entry into this 
study or interfere significantly with the proper assessment of safety and toxicity of 
the prescribed regimens (eg, peripheral neuropathy that is Grade 1 with pain or 
Grade 2 or higher of any cause)
14. Psychiatric illness/social situation that would limit compliance with study 
requirements
15. Known allergy to any of the study medications, their analogues, or excipients in the 
various formulations of any agent
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16. Inability to swallow oral medication, inability or unwillingness to comply with the 
drug administration requirements, or gastrointestinal (GI) procedure that could 
interfere with the oral absorption or tolerance of treatment
17. Treatment with any investigational products within 60 days before randomization
6.   
STUDY DRUG
All protocol eligibility criteria must be met before randomization and documented in the 
eCRF before study drug regimen administration. The study drug regimen will be 
administered only to randomized patients under the supervision of the investigator or 
identified subinvestigator(s). Patients should be monitored for toxicity as necessary and 
doses of the appropriate drug should be modified as needed to accommodate patient 
tolerance to treatment; this may include symptomatic treatment, dose interruptions, and 
adjustments of dose.
All doses must be taken as outlined in the Schedule of Events. Eligible patients may take the 
study drug regimen at home as directed. Refer to the Study Manual for additional 
instructions regarding study drug administration.
6.1   
Test Article (MLN9708) and Matched Placebo
MLN9708 capsules and matching placebo capsules will be subsequently referred to as study 
drug. Study drug in combination with lenalidomide and dexamethasone will be referred to as 
study drug regimen.
This is a double-blind, placebo-controlled study, and study drug will contain either 
MLN9708 or placebo. MLN9708 active capsules will be supplied as single capsules at 
3 different dose strengths, containing 4.0, 3.0, and 2.3 mg of MLN9708. Placebo capsules 
will be identical in shape, size, and color to the MLN9708 active capsules. Both the active 
and placebo capsules will be provided by the sponsor.
During the first 18 cycles of treatment, study drug will be given as a single, oral dose of 
4.0 mg weekly (Days 1, 8, and 15) for 3 weeks, followed by 1 week without study drug in a 
28-day cycle. After 18 cycles of treatment, if the patient is still receiving the study drug 
regimen, study drug will be given as a single, oral dose of 3.0 mg weekly on the same 
schedule as above. If the dose of study drug was reduced to 2.3 mg during the first 18 cycles 
of treatment, the patient will remain on 2.3 mg after 18 cycles of treatment (see Table 4-1).
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Patients should be instructed to swallow 1 capsule of study drug whole with water and not to 
break, chew, or open the capsules. Study drug should be taken on an empty stomach, at least 
1 hour before or no sooner than 2 hours after a meal. The capsule should be swallowed with 
water. A total of approximately 240 mL of water should be taken with the capsules. 
Missed doses can be taken as soon as the patient remembers as long as the next scheduled 
dose is 72 hours or more away. A double dose should not be taken to make up for a missed 
dose. If the patient vomits after taking a dose, the patient should not repeat the dose but 
should resume dosing at the time of the next scheduled dose.
6.2   
Background Therapies
6.2.1   
Lenalidomide Administration
During the first 18 cycles of treatment, lenalidomide will be given as a single, daily, oral 
dose of 25 mg for a total of 21 days out of a 28-day cycle. Patients with a low creatinine 
clearance 60 mL/min (or 50 mL/min, according to local label/practice) but 30 mL/min 
will receive a reduced lenalidomide dose of 10 mg QD on Days 1 through 21 of a 28-day 
cycle. The lenalidomide dose may be escalated to 15 mg QD after 2 cycles if the patient is 
not responding to treatment and is tolerating the treatment. If renal function normalizes 
(ie, creatinine clearance > 60 mL/min or > 50 mL/min, according to local label/practice) and 
the patient continues to tolerate this treatment, lenalidomide may then be escalated to 25 mg 
QD. 
After 18 cycles of treatment, if the patient is still receiving the study drug regimen, a 
reduced lenalidomide oral dose of 10 mg daily will be given as on the same schedule as 
above. If the dose of lenalidomide was reduced to 5 mg during the first 18 cycles of 
treatment, the patient will remain on the 5 mg dose after 18 cycles of treatment (see 
Table 4-1).
Administration of lenalidomide will be at approximately the same time each day, and may 
be with or without food. Patients should be instructed to swallow lenalidomide capsules 
whole with water and not to break, chew, or open the capsules. 
If a patient misses a dose of lenalidomide, he/she may still take it up to 12 hours after the 
time they would normally take it. If more than 12 hours have elapsed, they should be 
instructed to skip the dose for that day. The next day, they should take lenalidomide at the 
usual time. A patient should not take 2 doses of lenalidomide to make up for the one that 
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they missed. If the patient vomits after taking a dose, the patient should not repeat the dose 
but should resume dosing at the time of the next scheduled dose.
Patients who take more than the prescribed dose of lenalidomide should be instructed to 
seek emergency medical care if needed and contact study staff immediately. 
Upon implementation of this amendment, lenalidomide may be administered as commercial 
REVLIMID or as generic lenalidomide through clinical trial material.
6.2.2   
Dexamethasone Administration
During the first 18 cycles of treatment, dexamethasone will be given as a single, oral dose of 
40 mg/day weekly on Days 1, 8, 15, and 22 of a 28-day cycle. Patients over 75 years old (at 
randomization) will receive a reduced dose of dexamethasone (20 mg, same schedule).
After 18 cycles of treatment, if the patient is still receiving the study drug regimen, 
dexamethasone will be discontinued.
Dexamethasone should be taken at approximately the same time each day. Each dose of 
dexamethasone should be taken with food or liquid (ie, milk) to avoid stomach irritation,
according to the local label/practice. 
If a dose of dexamethasone is missed, the dose should be taken as soon as the patient 
remembers as long as the next scheduled dose is 72 hours or more away. A double dose 
should not be taken to make up for a missed dose. If the patient vomits after taking a dose, 
the patient should not repeat the dose but should resume dosing at the time of the next 
scheduled dose.
6.3   
Dose-Modification Guidelines
The patient will be evaluated for possible toxicities that may have occurred after the 
previous dose(s) according to the Schedule of Events. Toxicities are to be assessed 
according to the NCI Common Terminology Criteria for Adverse Events (CTCAE), 
version 4.03. Each adverse event should be attributed to a specific drug, if possible, so that 
the dose modifications can be made accordingly. Reduction or discontinuation of 1 agent 
and not the other is appropriate if the toxicity is suspected to be related primarily to 1 of the 
agents; however, dose reduction of multiple agents is permitted for overlapping toxicities 
after consultation with the Millennium clinician/study clinician designee. Prior to beginning 
the next cycle of treatment, refer to the guidelines in Section 6.5.
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Further clarification can be obtained in consultation with the Millennium clinician/study 
clinician designee. If multiple toxicities are noted, the dose adjustments and/or delays should 
be made according to the highest CTCAE toxicity grade.
Alternative dose modifications may be recommended after discussion with the investigator 
and MPI clinician/designee to maximize exposure of study treatment while protecting 
patient safety. After initiation of lenalidomide and dexamethasone, dose modification of 
those drugs should be based on individual patient treatment tolerance, as described in the 
PI/SmPC.
6.4   
Criteria for Dose Modification (Delays, Reductions, and Discontinuations)
Sections 6.4.1 through 6.4.4 detail within cycle dose modifications for toxicity. See 
Section 6.5 for information on criteria for toxicity recovery before beginning the next cycle 
of treatment.
6.4.1   
Dose Adjustments for Hematologic and Nonhematologic Toxicity: Study 
Drug and Lenalidomide
A decision regarding dose reduction of study drug and/or lenalidomide will be dependent 
upon the toxicity, its onset, and time course. Alternative dose modifications may be 
recommended after discussion with the investigator and Millennium clinician/study clinician 
designee to maximize exposure of study treatment while protecting patient safety given that 
there may be overlapping dose-limiting toxicities (eg, thrombocytopenia, neutropenia, rash, 
and peripheral neuropathy (see Table 6-1, Table 6-2, Table 6-3, and Table 6-5 respectively).
Table 6-1   
Study Drug and Lenalidomide Dose Adjustment for 
Thrombocytopenia
Platelet Count
Action on  Study Drug 
(MLN9708/Placebo)
Action on 
Lenalidomide[68]
Action
First fall to 
< 30,000/mm3
Interrupt treatment
Interrupt treatment
Follow complete blood 
count (CBC) weekly
Return to
≥30,000/mm3 within 
the same cycle
Resume and maintain
dose level
Resume lenalidomide 
at next lower dose level
Eg, if lenalidomide dose 
was 25 mg, reduce to 15 mg
Second fall to 
< 30,000/mm3
Interrupt treatment
Interrupt treatment
Follow CBC weekly
Return to 
≥30,000/mm3 within 
the same cycle
Resume study drug at 
next lower dose level
Resume and maintain
dose level
Eg, if study drug dose was 
4 mg, reduce to 3 mg
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Table 6-1   
Study Drug and Lenalidomide Dose Adjustment for 
Thrombocytopenia
Platelet Count
Action on  Study Drug 
(MLN9708/Placebo)
Action on 
Lenalidomide[68]
Action
Third fall to 
< 30,000/mm3
Interrupt treatment
Interrupt treatment
Follow CBC weekly
Return to 
≥30,000/mm3 within 
the same cycle
Resume and maintain
dose level
Resume lenalidomide 
at next lower dose level
Eg, if lenalidomide dose 
was 15 mg, reduce to 10 mg
Fourth fall to 
< 30,000/mm3
Interrupt treatment
Interrupt treatment
Follow CBC weekly
Return to 
≥30,000/mm3 within 
the same cycle
Resume study drug at 
next lower dose level
Resume and maintain
dose level
Eg, if study drug dose was 
3 mg, reduce to 2.3 mg
Discontinue study drug if 
the 2.3 mg dose is not 
tolerated
Fifth fall to 
< 30,000/mm3
Interrupt treatment
Interrupt treatment
Follow CBC weekly
Return to 
≥30,000/mm3 within 
the same cycle
Resume and maintain
dose level
Resume lenalidomide 
at next lower dose level
Eg, if lenalidomide dose 
was 10 mg, reduce to 5 mg
Discontinue lenalidomide if 
the 5 mg dose is not 
tolerated
Abbreviations: CBC = complete blood count; mg = milligram; mm3 = cubic millimeter. 
Please refer to Section 6.5 for the required platelet count before initiating the next cycle of treatment.
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Table 6-2   
Study Drug and Lenalidomide Dose Adjustment for Neutropenia
Absolute Neutrophil 
Count
Action on Study 
Drug 
(MLN9708/Placebo)
Action on 
Lenalidomide[68]
Action
First fall to < 0.5 109/L
Interrupt treatment
Interrupt treatment
Follow CBC weekly; see 
Section 6.7 for myeloid 
growth factor 
recommendations 
Return to ≥0.5 109/L
within the same cycle
Resume and 
maintain dose level
Resume 
lenalidomide at 
next lower dose 
level
Eg, if lenalidomide dose was 
25 mg, reduce to 15 mg
Second fall to < 0.5 
109/L
Interrupt treatment
Interrupt treatment
Follow CBC weekly; see 
Section 6.7 for myeloid 
growth factor 
recommendations
Return to ≥0.5 109/L
within the same cycle
Resume study drug 
at next lower dose 
level
Resume and 
maintain dose level
Eg, if study drug dose was 
4 mg, reduce to 3 mg
Third fall to < 0.5 109/L
Interrupt treatment
Interrupt treatment
Follow CBC weekly; see 
Section 6.7 for myeloid 
growth factor 
recommendations
Return to ≥0.5 109/L
within the same cycle
Resume and 
maintain dose level 
lower
Resume 
lenalidomide at 
next lower dose 
level
Eg, if lenalidomide dose was 
15 mg, reduce to 10 mg
Fourth fall to < 0.5 
109/L
Interrupt treatment
Interrupt treatment
Follow CBC weekly; see 
Section 6.7 for myeloid 
growth factor 
recommendations
Return to ≥0.5 109/L
within the same cycle
Resume study drug 
at next lower dose 
level
Resume and 
maintain dose level
Eg, if study drug dose was 
3 mg, reduce to 2.3 mg
Discontinue study drug if the 
2.3 mg dose is not tolerated.
Fifth fall to < 0.5 109/L
Interrupt treatment
Interrupt treatment
Follow CBC weekly; see 
Section 6.7 for myeloid 
growth factor 
recommendations.
Return to ≥0.5 109/L
within the same cycle
Resume and 
maintain dose level 
lower
Resume
lenalidomide at 
next lower dose 
level
Eg, if lenalidomide dose was 
10 mg, reduce to 5 mg
Discontinue lenalidomide if 
the 5 mg dose is not tolerated.
Abbreviations: ANC = absolute neutrophil count; CBC = complete blood count; G-CSF = granulocyte 
colony-stimulating factor; L = liter; mg = milligram.
Please refer to Section 6.5 for the required ANC values before initiating the next cycle of treatment.
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Table 6-3   
Study Drug and Lenalidomide Dose Adjustment for Rash
CTCAE Grade
Action on Study Drug 
(MLN9708/Placebo)
Action on 
Lenalidomide[68]
Actiona
First occurrence  
Grade 2 or 3
Interrupt treatment
Interrupt treatment
Symptomatic recommendations 
noted in Section 6.10
Return to < Grade 2 
within the same cycle
Resume and maintain
dose level
Resume lenalidomide 
at next lower dose 
level[68]
Eg, if lenalidomide dose was 
25 mg, reduce to 15 mg
Second occurrence
Grade 2 or 3
Interrupt treatment
Interrupt treatment
Symptomatic recommendations, 
including prophylactic 
treatment, in Section 6.10
Eg, if study drug dose was 
4 mg, reduce to 3mg
Return to < Grade 2 
within the same cycle
For Grade 2, resume 
and maintain dose 
level
For Grade 3, resume 
study drug at next 
lower dose level
For Grade 2, resume 
and maintain dose 
level
For Grade 3, resume 
and maintain dose 
level
Third occurrence 
Grade 2 or 3
Interrupt treatment
Interrupt treatment
Symptomatic recommendations, 
including prophylactic 
treatment, noted in Section 6.10
Return to < Grade 2 
within the same cycle
Resume and maintain
dose level
Resume lenalidomide 
at next lower dose
level
Eg, if lenalidomide dose was 
15 mg, reduce to 10 mg
Fourth occurrence 
Grade 2 or 3
Interrupt treatment
Interrupt treatment
Symptomatic recommendations, 
including prophylactic 
treatment, noted in Section 6.10
Return to < Grade 2 
within the same cycle
For Grade 2, resume 
and maintain dose 
level
For Grade 3, resume 
study drug at next 
lower dose level
For Grade 2, resume
and maintain dose 
level
For Grade 3, resume 
and maintain dose 
level
Eg, if study drug dose was 
3 mg, reduce to 2.3 mg
Discontinue study drug if the 
2.3 mg dose is not tolerated
Fifth occurrence 
Grade 2 or 3
Interrupt treatment
Interrupt treatment
Symptomatic recommendations, 
including prophylactic 
treatment, noted in Section 6.10
Return to < Grade 2 
within the same cycle
Resume and maintain
dose level
Resume lenalidomide 
at next lower dose 
level
Eg, if lenalidomide dose was 
10 mg, reduce to 5 mg
Discontinue lenalidomide if the 
5 mg dose is not tolerated
In some severe situations, both lenalidomide and study drug may be interrupted if needed or alternative dose 
modification management implemented based on discussion between the treating physician and 
Millennium clinician/study clinician designee. Angioedema and Grade 4 rash have been reported with 
lenalidomide and should result in lenalidomide discontinuation.[68]
a Please refer to Table 6-7 for additional information on lenalidomide treatment modification for rash.
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6.4.2   
Study Drug Treatment Modification
Dose adjustments are allowed based on clinical and laboratory findings. Sequential dose 
reductions of study drug from the starting dose of 4.0 mg daily are recommended for 
toxicity as indicated in Table 6-4. Treatment modifications due to study drug-related AEs 
are outlined in Table 6-5.
Table 6-4   
Dose Reduction Steps for Study Drug
Starting Dose
First Dose
Reduction
Second Dose Reduction
Third Dose Reduction
4.0 mg
3.0 mg
2.3 mg
Discontinue study drug
Table 6-5   
Study Drug Treatment Modification (Delays, Reductions, and 
Discontinuations) Due to Adverse Events
Adverse Event (Severity)
Action on Study Drug/Placebo
CTC Definitions/ Further 
Considerations
Peripheral Neuropathy
Grade 1 peripheral neuropathy 
No action
Grade 1 signs & symptoms: 
asymptomatic, without pain 
or loss of function, clinical 
or diagnostic observations 
only[68]
Grade 1 peripheral neuropathy with 
pain or Grade 2
Hold study drug until resolution 
to Grade ≤1 without pain or 
baseline
Grade 2 signs & symptoms: 
moderate symptoms, 
limiting instrumental 
activities of daily living 
(ADL)[68]
Grade 2 peripheral neuropathy with 
pain or Grade 3
Hold study drug until resolution 
to Grade ≤ 1 without pain or 
baseline
Reduce study drug to next lower 
dose upon recovery
Grade 3 signs & symptoms: 
severe symptoms, limiting 
self care ADL, assistive 
device indicated[68]
Grade 4 peripheral neuropathy
Discontinue study drug
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Table 6-5   
Study Drug Treatment Modification (Delays, Reductions, and 
Discontinuations) Due to Adverse Events
Adverse Event (Severity)
Action on Study Drug/Placebo
CTC Definitions/ Further 
Considerations
Nonhematologic Toxicity
Grade 3 nonhematologic toxicity 
judged to be related to study drug
Hold study drug until resolution 
to Grade 1 or baseline  
Symptomatic 
recommendations noted in 
Section 6.10
If does not recover to < Grade 1 
or baseline within 4 weeks
Reduce study drug 1 to next lower 
dose upon return to Grade 1 or 
baseline
Subsequent recurrence Grade 3 
that does not recover to < Grade 
1 or baseline within 4 weeks
Hold study drug until resolution 
to Grade 1 or baseline
Reduce study drug to next lower 
dose 
Monitor closely, take 
appropriate medical 
precautions, and provide 
appropriate symptomatic 
care
Grade 4 nonhematologic toxicities 
judged to be related to study drug
Consider permanently 
discontinuing study drug
Exception, in a case where 
the investigator determines 
the patient is obtaining a 
clinical benefit and has 
discussed this with the 
MPI/designee clinician
Abbreviations: ADL = activities of daily living; MPI = Millennium Pharmaceuticals, Inc.
6.4.3   
Lenalidomide Treatment Modification
Dose adjustments are allowed based on clinical and laboratory findings. Sequential dose 
reductions from the starting dose of 25 mg daily are recommended for toxicity as indicated 
in Table 6-6. Treatment modifications due to lenalidomide-related AEs are outlined in 
Table 6-7. Alternative dose modifications may be recommended after discussion with the 
investigator and Millennium project clinician/designee to maximize exposure of study 
treatment while protecting patient safety.
Table 6-6   
Dose Reduction Steps for Lenalidomide
Starting Dose
First Dose 
Reduction
Second Dose 
Reduction
Third Dose 
Reduction
Fourth Dose 
Reduction
25 mg QD
15 mg QD
10 mg QD
5 mg QD
Discontinue 
lenalidomide
Abbreviations: QD = once daily.
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Table 6-7   
Lenalidomide (REVLIMID®) Treatment Modification (Delays, 
Reductions, and Discontinuations) Guidelines Due to Non-Hematologic 
Adverse Events[68]
Adverse Event (Severity)
Action on Lenalidomide
Further Considerations
Grade 3/4 toxicities judged to be 
related to lenalidomide
Hold lenalidomide treatment, and restart at 
the next lower dose level when toxicity has 
resolved to Grade 2 during a treatment 
cycle[68] or to Grade 1 or patient’s 
baseline condition before initiating the next 
cycle.
Discontinue lenalidomide if 
the 5 mg dose is not tolerated
Renal impairment
Dose reduce per lenalidomide package 
insert/SmPC for impaired renal function
Care should be taken in the 
elderly as they are more likely 
to have renal impairment. 
Monitor renal function 
regularly in elderly patients 
and/or patients with renal
impairment.
Grade 2 thrombosis/embolism
Hold lenalidomide and start anticoagulation 
therapy; restart at investigator’s discretion 
after adequate anticoagulation; maintain 
dose level
See Section 6.10 for 
anticoagulation 
recommendations
Angioedema, Stevens-Johnson 
Syndrome (SJS), and Toxic 
Epidermal Necrolysis (TEN)
Permanently discontinue lenalidomide per 
package insert/SmPC[68]
Grade 2/3 skin rash
Hold or discontinue lenalidomide per 
package insert/SmPC[68]
Grade 4 exfoliative or bullous 
rash 
Permanently discontinue lenalidomide per 
package insert/SmPC[68]
Abbreviations: SmPC = Summary of Product Characteristics.
6.4.4   
Dexamethasone-Related Treatment Modification
Dosage adjustments for dexamethasone are outlined in Table 6-8. Treatment modifications 
due to dexamethasone-related AEs are outlined in Table 6-9. Alternative dose modifications 
may be recommended after discussion with the investigator and Millennium project 
clinician/designee to maximize exposure of study treatment while protecting patient safety.
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Table 6-8   
Dose Reduction Steps for Dexamethasone
Starting Dose
First Dose 
Reduction
Second Dose Reduction
Third Dose Reduction
40 mg
20 mg
8 mg
Discontinue 
dexamethasone
Table 6-9   
Dexamethasone–Related Treatment Modification (Delays, Reductions, 
and Discontinuations) Guidelines Due to Adverse Events[69]
Adverse Event (Severity)
Action on Dexamethasone
Gastrointestinal
Dyspepsia, gastric, or duodenal ulcer,
gastritis Grade 1-2 (requiring medical 
management)
Treat with histamine-H2 receptor blockers, 
sucralfate, or omeprazole. If symptoms 
persist despite these measures, decrease 
dexamethasone by 1 dose level.
Grade 3 (or any grade requiring 
hospitalization or surgery)
Hold dexamethasone until symptoms 
adequately controlled. Restart and decrease 
1 dose level of current dose along with 
concurrent therapy with histamine-H2 
receptor blockers, sucralfate, or 
omeprazole. If symptoms persist despite 
these measures, discontinue 
dexamethasone and do not resume.
Acute pancreatitis
Permanently discontinue dexamethasone.
Cardiovascular
Edema Grade 2 (limiting function and 
unresponsive to therapy or anasarca)
Intervention indicated (eg, diuretics) as 
needed and decrease dexamethasone by 
1 dose level. If edema persists despite these 
measures, decrease dose another level. 
Discontinue dexamethasone and do not 
resume if symptoms persist despite second 
reduction.
Neurological
Confusion or mood alteration Grade 2 
Hold dexamethasone until symptoms 
resolve. Restart with 1 dose level 
reduction. If symptoms persist despite 
these measures, permanently discontinue 
dexamethasone.
Musculoskeletal
Generalized muscle weakness Grade 2
Decrease dexamethasone dose by 1 dose 
level. If weakness persists despite these 
measures, decrease dose further by 1 dose 
level. Permanently discontinue 
dexamethasone if symptoms persist. 
Metabolic
Hyperglycemia 
Treatment with insulin or oral 
hypoglycemics as needed. If uncontrolled 
despite these measures, decrease dose by 
1 dose level until blood glucose levels are 
satisfactory.
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6.5   
Criteria for Toxicity Recovery Before Beginning the Next Cycle of Treatment
The criteria for toxicity recovery before the patient can begin the next cycle of treatment are 
as follows:

ANC 1,000/mm3

Platelet count 75,000/mm3, and 

Other clinically significant nonhematologic toxicities ≤Grade 1 (or to the patient’s 
baseline condition)
Based on attribution of toxicity to a particular drug in the study drug regimen (see 
Section 6.4), hold the study drug until resolution of toxicity. A patient is to then be restarted 
on the study drug at the next lower dose. If a patient fails to meet the criteria above for 
beginning the next cycle of treatment, initiation of the next cycle should be delayed for 
1 week. At the end of that time, the patient should be re-evaluated to determine whether the 
criteria for retreatment have been met.
The maximum delay allowed before treatment should be permanently discontinued (except 
in the case of investigator determined clinical benefit and discussion with the MPI/designee 
clinician) will be 3 weeks.
6.6   
Excluded Concomitant Medications and Procedures
The following medications and procedures are prohibited while the patient is on the study 
drug regimen. Note that the excluded concomitant medication information has been updated 
to reflect the available in vitro metabolism and clinical drug-drug interaction information as 
of Amendment 2. Please refer to Section 1.4 and the IB for additional details.
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, MLN2238 exposure 
would be decreased.)

Strong CYP3A inducers: rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, 
and phenobarbital
Excluded medicinal products include St. John’s wort.
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The following procedures are prohibited while the patient is on the study drug regimen:

Any antineoplastic treatment other than study drug regimen

Radiotherapy (note that, in general, the requirement for local radiotherapy indicates 
disease progression). Palliative local radiotherapy for pain control in a preexisting 
lesion at baseline may be considered after agreement with the Millennium/designee 
clinician

Platelet transfusions to help patients meet eligibility criteria are not allowed
6.7   
Permitted Concomitant Medications and Procedures
All necessary supportive care consistent with optimal patient care will be available to 
patients, as necessary. All blood products and concomitant medications received from first 
dose of the study drug regimen until 30 days after the final dose will be recorded in the 
eCRFs.
The following medications and procedures are permitted while the patient is receiving the 
study drug regimen: 

Myeloid growth factors (eg, granulocyte colony stimulating factor [G-CSF], 
granulocyte macrophage-colony stimulating factor [GM-CSF]) are permitted. Their 
use should follow the product label, published guidelines and/or institutional 
practice.

Erythropoietin will be allowed in this study, but given the potential increased risk of 
DVT when erythropoietin is administered concurrent with lenalidomide, the use of 
erythropoietin should be minimized as much as possible.

Patients should be transfused with red cells and platelets as clinically indicated.

Concomitant treatment with bisphosphonates will be encouraged for all patients with 
evidence of lytic destruction of bone or with osteopenia, 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 prior to the study start, it should be initiated 
as soon as clinically indicated.
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
Supportive measures consistent with optimal patient care may be given throughout 
the study.
6.8   
Precautions and Restrictions

When digoxin was co-administered with lenalidomide, the digoxin AUC was not 
significantly different; however, the digoxin Cmax was increased by 14%. Periodic 
monitoring of digoxin plasma levels in accordance with clinical judgment and based 
on standard clinical practice in patients receiving this medication is recommended 
during administration of lenalidomide.

Fluid deficit should be corrected before initiation of treatment and during treatment.

Nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided with impaired 
renal function given reported NSAID-induced renal failure in patients with decreased 
renal function.
6.9   
Contraception Requirements
It is not known what effects MLN9708 has on human pregnancy or development of the 
embryo or fetus. Lenalidomide is structurally related to thalidomide. Thalidomide is a 
known human teratogenic active substance that causes severe life-threatening birth defects. 
Therefore, female patients participating in this study should avoid becoming pregnant, and 
male patients should avoid impregnating a female partner. Female patients of childbearing 
potential (FCBP) and male patients should use effective methods of contraception through 
defined periods during and after study treatment as specified below. 
Definition of FCBP

All countries except Canada: This protocol defines a FCBP as a sexually mature 
woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy or 
2) has not been naturally postmenopausal (amenorrhea following cancer therapy 
does not rule out childbearing potential) for at least 24 consecutive months (ie, has 
had menses at any time in the preceding 24 consecutive months).

Canada: This protocol defines a FCBP as a sexually mature woman who: 1) has not 
undergone previous bilateral salpingo-oophorectomy or hysterectomy or 2) has not 
been naturally amenorrheic (amenorrhea following cancer therapy does not rule out 
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childbearing potential) for at least 12 consecutive months (ie, has had menses at any 
time in the preceding 12 consecutive months)
All females of childbearing potential must either:

Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the patient, for at least 28 days before starting the study drug regimen 
through 90 days after the last dose of study treatment (periodic abstinence 
[eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are 
not acceptable methods of contraception) OR

Agree to use 2 reliable methods of contraception, at the same time, for at least 
28 days before starting the study drug regimen through 90 days after the last dose of 
study treatment
o
The 2 methods of reliable contraception must include 1 highly effective method 
and 1 additional effective (barrier) method. FCBP must be referred to a qualified 
provider of contraceptive methods if needed. The following are examples of 
highly effective and additional effective methods of contraception:
Highly effective methods:

Intrauterine device (IUD)

Tubal ligation

Partner’s vasectomy
Additional effective methods:

Condom

Diaphragm + spermicide 

Cervical Cap + spermicide 

Must also adhere to the guidelines of the Revlimid REMS(formerly known as 
RevAssist®) program (US participants), RevAid® program (Canadian participants), 
or The Lenalidomide Pregnancy Risk Minimisation Plan as outlined in the Study 
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Manual (all other participants who are not using commercial Revlimid supplies). The 
counseling must be documented.

Because of the increased risk of venous thromboembolism in patients with multiple 
myeloma taking lenalidomide and dexamethasone, combined oral contraceptive pills 
are not recommended. If a patient is currently using combined oral contraception, the 
patient should switch to 1 of the effective methods listed above. The risk of venous 
thromboembolism continues for 4 to 6 weeks after discontinuing combined oral 
contraception. The efficacy of contraceptive steroids may be reduced during 
co-treatment with dexamethasone.
Male patients, even if surgically sterilized (ie, status postvasectomy), must either:

Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the patient (periodic abstinence [eg, calendar, ovulation, symptothermal, 
post-ovulation methods] and withdrawal are not acceptable methods of 
contraception) OR

Agree to use effective barrier contraception during the entire study treatment period 
and through 90 days after the last dose of study treatment if their partner is of 
childbearing potential, even if they have had a successful vasectomy, AND

Must also adhere to the guidelines of the Revlimid REMS(formerly known as 
RevAssist®) program (US participants), RevAid® program (Canadian participants), 
or The Lenalidomide Pregnancy Risk Minimisation Plan as outlined in the Study 
Manual (all other participants who are not using commercial Revlimid supplies). The 
counseling must be documented.
6.10   
Management of Clinical Events
Prophylaxis Against Risk of Infection
Patients may be at an increased risk of infection including reactivation of herpes zoster and 
herpes simplex viruses. Antiviral therapy such as acyclovir or valacyclovir may be initiated 
as clinically indicated.
Hypotension
Symptomatic hypotension and orthostatic hypotension with or without syncope have been 
reported with MLN9708. 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 
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concomitant symptoms such as nausea, vomiting, diarrhea, or decreased appetite. Patients 
taking medications and/or diuretics to manage their blood pressure (for either hypo- or 
hypertension) should be managed according to standard clinical practice, including 
considerations for dose adjustments of their concomitant medications during the course of 
the trial. Fluid deficit should be corrected before initiation of any drug in the study drug 
regimen and as needed during treatment to avoid dehydration.
Thromboembolism Prophylaxis
While on lenalidomide, patients should be on routine thromboprophylaxis.[6] Prophylactic 
therapy with aspirin (70 - 325 mg PO QD, or equivalent dose per country product label [PI 
or SmPC]) or LMWH (equivalent to enoxaparin 40 mg subcutaneous [SQ] per day) per 
published standard or institutional standard of care is required for all patients to prevent 
thromboembolic complications that may occur with lenalidomide-based regimens in 
combination with dexamethasone (see Section 5.1, inclusion criterion 8 for details on the 
mandatory use of LMWH).
Nausea and/or Vomiting
Standard antiemetics including 5-hydroxytryptamine 3 serotonin receptor (5-HT3) 
antagonists are recommended for emesis if it occurs once treatment is initiated; prophylactic 
antiemetics may also be considered at the physician’s discretion. Dexamethasone should not 
be administered as an antiemetic. Fluid deficit should be corrected before initiation of any 
drug in the study drug regimen, 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 any drug in the study drug regimen, and 
during treatment.
Erythematous Rash With or Without Pruritus
Rash has been reported with both lenalidomide and MLN9708. The lenalidomide-induced 
rash is characterized as generalized, maculopapular, morbilliform, urticarial, papular, often 
with pruritus, and is noted as a warning/precaution in the lenalidomide PI.[68,70,71] Serious 
skin reactions such as Stevens-Johnson Syndrome, toxic epidermal necrolysis, and erythema 
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multiforme have been reported. Lenalidomide interruption or discontinuation should be 
considered as described in the PI/SmPC.[68]
Rash may range from some erythematous areas, macular and/or small papular bumps that 
may or may not be pruritic over a few areas of the body, to a more generalized eruption that 
is predominately on the trunk or extremities. Rash has been most commonly characterized as 
maculopapular or macular. To date, when it does occur, rash is most commonly reported 
within the first 3 cycles of therapy. The rash is often transient and self-limiting, and is 
typically Grade 1 to 2 in severity. As in any other oncology trial, rash may occur in patients 
receiving placebo and in patients receiving MLN9708. If rash occurs, consideration should 
be given to alternate causes of the rash such as concomitant medications, infections, etc.
Symptomatic measures such as antihistamines or corticosteroids (oral or topical) have been 
successfully used to manage rash and have been used prophylactically in subsequent cycles. 
The use of a topical, IV, or oral steroid (eg, prednisone ≤ 10 mg per day or equivalent [see 
Section 15.5]) is permitted. Management of a Grade 3 rash may require IV antihistamines or 
corticosteroids. Administration of MLN9708 (and/or other causative agent if given in 
combination) should be modified per protocol and re-initiated at a reduced level from where 
rash was noted (also per protocol) (see Table 6-3).
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, drug reaction with 
eosinophilia and systemic symptoms (DRESS syndrome), and pemphigus vulgaris have 
been reported in oncology studies when MLN9708 (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.
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Thrombocytopenia
Blood counts should be monitored regularly as outlined in the protocol with additional 
testing obtained according to standard clinical practice. Thrombocytopenia may be severe 
but has been manageable with platelet transfusions according to standard clinical practice. 
Lenalidomide or study drug administration should be modified as noted as per dose 
modification recommendations in the protocol when thrombocytopenia occurs (see 
Table 6-1). Therapy can be reinitiated at a reduced level upon recovery of platelet counts.
Thrombotic microangiopathy (TMA), including thrombotic thrombocytopenia purpura and 
hemolytic uremic syndrome, are rare, serious blood disorders that cause low levels of 
platelets and red blood cells and result in blood clots in small blood vessels. Symptoms may 
include fatigue, fever, bruising, nose bleeds, and decreased urination. These disorders can 
occasionally be fatal. TMA should be managed symptomatically according to standard 
medical practice.
Neutropenia
Blood counts should be monitored regularly as outlined in the protocol with additional 
testing obtained according to standard clinical practice. Neutropenia may be severe but has 
been manageable. Growth factor support is not required but may be considered according to 
standard clinical practice. Lenalidomide or study drug administration should be modified as 
noted as per dose modification recommendations in the protocol when neutropenia occurs 
(see Table 6-2). Therapy can be reinitiated at a reduced level upon recovery of absolute 
neutrophil counts.
Fluid Deficit
Dehydration should be avoided since lenalidomide is substantially excreted by kidney, and 
MLN9708 may cause vomiting, diarrhea, and dehydration. Acute renal failure has been 
reported in patients treated with MLN9708, commonly in the setting of the above-noted GI 
toxicities and dehydration. Fluid deficit should be corrected before initiation of any drug in 
the study drug regimen and during treatment to avoid dehydration (see Section 6.8).
Posterior Reversible Encephalopathy Syndrome
One case of posterior reversible encephalopathy syndrome, which ultimately resolved, has 
been reported with MLN9708. This condition is characterized by headache, seizures, and 
visual loss, as well as abrupt increase in blood pressure. Diagnosis may be confirmed by 
magnetic resonance imaging (MRI) or computed tomography (CT). If the syndrome is 
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diagnosed or suspected, symptom-directed treatment should be maintained until the 
condition is reversed by control of hypertension or other instigating factors. 
Transverse Myelitis
One case of transverse myelitis has been reported with MLN9708. It is not known whether 
MLN9708 causes transverse myelitis; however, because it happened to a patient receiving 
MLN9708, the possibility that MLN9708 may have contributed to transverse myelitis 
cannot be excluded. Transverse myelitis should be managed according to standard medical 
practice.
Overdose
An overdose is defined as a known deliberate or accidental administration of investigational 
drug, to or by a study subject, at a dose above that which is assigned to that individual 
subject according to the study protocol. If overdose occurs, consider close observation 
including hospitalization for hemodynamic support. Gastric lavage may be considered if 
instituted within 1 hour of ingestion of MLN9708 overdose.
6.11   
Blinding and Unblinding
To maintain the blind, all study personnel including the investigators, site personnel, study 
clinicians, and the sponsor will be blinded to the treatment assignments for the duration of 
the study. When a patient is discontinued from the study drug regimen, the investigator can 
request to know the patient’s actual study drug assignment upon approval from the 
Millennium clinician/ study clinician designee (contact information is in the Study Manual). 
The investigator will provide a justification for the request (eg, why knowing the study drug 
assignment will aid decision making as to the patient’s subsequent anticancer treatment or 
why this information is required to investigate and treat a suspected study drug-related 
toxicity).
Treatment assignments will be obtained through the interactive voice/ web response system 
(IXRS) according to the procedures outlines 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 each drug in the study drug regimen was dispensed, 
and the treatment assignment will be maintained by the study site. If the treatment 
assignment must be revealed for the safety of the patient or to treat an AE, the investigator 
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will contact the Millennium clinician/ study clinician designee. A decision to break the blind 
must be reached by the Millennium clinician/study clinician designee and the investigator. 
The investigator, or designee, may break the blind through the IXRS independent of the 
Millennium clinician/ study clinician designee if it is considered to be an emergency by the 
investigator that requires specific knowledge of the blinded study treatment in order to 
properly treat the AE/safety issue. If the treatment of the AE/ safety issue is the same 
regardless of the study drug assignment, the blind should not be broken. In addition, the 
patient will be discontinued from further study drug administration in this study.
As of Amendment 5, the second IA has been conducted and the primary endpoint of PFS did 
not reach statistical significance. The study is now unblinded globally. Individual patient 
treatment assignments are now available in the IXRS. Patients deriving clinical benefit may 
continue their current study treatment if there are no other means of accessing the study 
drugs, until such time as other means of accessing the study drugs are arranged.  When 
possible, patients should complete an EOT visit and transition onto a commercial supply of 
ixazomib and/or lenalidomide or other standard of care treatment.  
Patients who are receiving ixazomib and lenalidomide will continue to receive ixazomib and 
lenalidomide. Patients who are receiving placebo and lenalidomide will receive 
lenalidomide only; the placebo capsule will no longer be administered and patients receiving 
placebo will not be crossed over to ixazomib in this study.
For patients continuing on study, the majority of study assessments are discontinued to ease 
the burden of protocol-mandated assessments. Discontinued patients will be treated by their 
physician per standard of care.
6.12   
Description of Investigational Agents
MLN9708 and matching placebo capsules are manufactured by Millennium. The MLN9708 
drug product is provided in strengths of 4.0-, 3.0-, and 2.3-mg capsules as the active boronic 
acid. Matched placebo will correspond to each dose strength of MLN9708 and will be 
identical in size, shape, and color to the corresponding MLN9708 capsule.
The 3 different dose strengths are differentiated by both capsule size and color:
Table 6-10   MLN9708/Placebo Capsules
Dose Strengtha
Capsule Size
Capsule Color
4.0 mg
Size 3
Ivory
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3.0 mg
Size 4
Light Gray
2.3 mg
Size 4
Flesh
a Dose strength for MLN9708. The placebo capsules contain microcrystalline cellulose, talc, and 
magnesium stearate and are identical in color and size to the corresponding active dose.
For additional details, please see the MLN9708 IB and Pharmacy Manual.
6.13   
Preparation, Reconstitution, and Dispensing
Study drug dispensed to the patient for take-home dosing should remain in the blister 
packaging and carton until the point of use. Refer to the Pharmacy Manual or equivalent 
storage guidelines. In case of extenuating circumstances that prevent a patient from 
attending the study site (eg, the 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. Comprehensive instructions should be provided to the patient to 
ensure compliance with dosing procedures. Patients who are receiving take-home 
medication should be given only 1 cycle of medication at a time. More than 1 cycle of 
medication may be dispensed on a case-by-case basis for holidays, travel, or other 
circumstances upon discussion with the investigator and sponsor’s project clinician/designee
(Note: patients in France are only permitted to receive 1 cycle of medication at a time).
Should more than 1 cycle of medication be dispensed, the investigator and/or health care 
provider must review the proper dosing instructions with the patient to avoid the potential 
for incorrect self-administration or overdose of medication.
Patients should be instructed to store the medication according to the storage conditions that 
are outlined in the Pharmacy Manual or equivalent storage guidelines for the duration of 
each cycle. Patients should be instructed to return their empty cartons to the investigative 
site, rather than discarding them, as permitted by site policy. Reconciliation will occur 
accordingly when the patient returns for their next cycle of take-home medication. 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 extreme in temperature should be reported as an excursion 
and should be dealt with on a case-by-case basis. 
6.14   
Packaging and Labeling
For the finished drug product, the capsules are packaged in cold form foil-foil blisters in a 
child-resistant carton.
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The MLN9708 capsules and placebo capsules will be provided by Millennium. The study 
drug labels will fulfill all requirements specified by governing regulations. The formulation 
consists of 2.3-, 3.0-, and 4.0-mg capsules for oral administration. 
The capsules are individually packaged using cold form foil-foil blisters that are in a 
child-resistant carton. There are 3 capsules in each wallet/carton. See the Pharmacy Manual 
for more information.
6.15   
Storage, Handling, and Accountability
On receipt at the investigative site, study drug should remain in the blister and carton 
provided until use or dispensation. All excursions that occur during the site storage or during 
transportation from depot to the site should immediately be brought to the sponsor’s 
attention for assessment and authorization for continued use. Ensure that the drug is used 
before the retest expiry date provided by Millennium. Expiry extensions will be 
communicated accordingly with updated documentation to support the extended shelf life.
Because MLN9708 is an anticancer drug, 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 contract. 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 country, 
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, including, but not limited to 
study drug shipping and storage guidelines.
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6.15.1   
Background Therapies
6.15.1.1   Lenalidomide
Lenalidomide may be supplied by the site or from commercial sources, depending on 
regional availability as follows:

US: Subjects will receive lenalidomide through the Revlimid REMS(formerly 
known as RevAssist®) program. Patients in the US must be enrolled into the 
Revlimid REMSprogram for the procurement of lenalidomide, details for which 
may be found in the separate Study Manual.

Canada: Subjects will receive lenalidomide through the RevAid® program. Patients 
in Canada must be enrolled into the RevAid® program for the procurement of 
lenalidomide, details for which may be found in the separate Study Manual.

All other countries: Subjects will receive lenalidomide from the site through supply 
provided by sponsor. These patients must follow the guidelines for the Lenalidomide 
Pregnancy Risk Minimisation Plan as outlined in the Study Manual.
Additional details are provided in the PI/SmPC.[68]
Lenalidomide capsules should be stored at temperatures in accordance with the instructions 
provided in the manufacturer’s PI/SmPC.
6.15.1.2   Dexamethasone
Dexamethasone may be supplied by the site from commercial sources or from the sponsor, 
depending on regional availability. Additional details are provided in the PI.[69]
Dexamethasone tablets should be stored according to the instructions provided in the 
manufacturer’s PI or on the drug label (if supplied by the sponsor).
6.16   
Other Protocol-Specified Materials
No other drugs or ancillary material are supplied for use in this trial.
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7.   
STUDY CONDUCT
This trial will be conducted in compliance with the protocol, good clinical practice (GCP), 
applicable regulatory requirements, and International Conference on Harmonisation (ICH) 
guidelines.
7.1   
Study Personnel and Organizations
The contact information for the Millennium clinician/ study clinician designee, the central 
laboratory, any additional clinical laboratories, or vendors participating on 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 IXRS.
Patient eligibility will be confirmed by an MPI/designee clinician before randomization by 
the investigator into the study. A centralized randomization using IXRS will be used. 
Patients will be randomized strictly sequentially at a center as they become eligible for 
randomization. If a patient discontinues from the study, that randomization code will not be 
reused, and the patient will not be allowed to re-enter the study.
7.4   
Study Procedures
In acknowledgement of hospital, local, state or national government restrictions, or other 
site-related factors caused by unavoidable circumstances (eg, the COVID-19 pandemic) that 
may prevent investigators from conducting the study according to the Schedule of Events at 
the clinical study site, investigators may continue patients in the study despite departure 
from the Schedule of Events. Investigators are expected to evaluate the impact to the safety 
of the study participants and site personnel for patients to continue. In evaluating such 
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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: any 
procedures not conducted per the original study plan will be documented in the study 
records.  
If a patient misses an in-person study visit, the investigator/study team staff will speak 
directly with the patient by telephone or other medium (eg, a computer-based video
communication) during each visit window to assess subject safety and overall clinical status. 
During this contact with the patient, the study site physician or other qualified site staff 
should at minimum conduct AE collection and an assessment of clinical symptoms. Other 
study assessments may be collected remotely as is feasible and may involve audio or video 
recording. Assessments/procedures that cannot be completed during the protocol-specified 
window because a site visit is done remotely (ie, symptom-directed physical exam, 
hematology, clinical chemistry) are waived.
Patients will be evaluated at scheduled visits over 4 study periods: Screening, Treatment, 
EOT, and Follow-Up (PFS and OS [including assessment of PFS2 during OS follow-up]). 
Note that upon implementation of Amendment 5, patients will not be followed for the PFS 
or OS follow-up periods, as PFS and OS data are no longer being collected. Tests and 
procedures during the Treatment Period should be performed on schedule, but occasional 
changes are allowable (± 7 days or a longer window after discussion with the Millennium 
project clinician or designee) for holidays, vacations, and other administrative reasons. If the 
study schedule is shifted, assessments must be shifted to ensure that collection of 
assessments is completed before dosing.
Refer to the Schedule of Events—Amendment 5 and Beyond for timing of assessments. For 
the timing of assessments performed before implementation of Amendment 5, please refer to
the Full Schedule of Events and MLN9708 Pharmacokinetic Sampling Schedule in 
Section 15.12. Additional details are provided as necessary in the sections that follow.
7.4.1   
Informed Consent
Informed consent may be obtained prior to the 28-day Screening period. 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.
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As of Amendment 5, patients remaining on study treatment will need to be reconsented.
Reconsenting should be done in person.  Remote reconsenting is permitted as long as the 
process adheres to site, sponsor, IRB/EC, regulatory and GCP standards.
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 all current medications, prior radiation, and the patient’s current smoking status.
In addition, IMWG diagnostic criteria (Section 15.2) and current ISS staging (Section 15.4) 
of MM will be determined based on clinical exam and laboratory results.
7.4.4   
Physical Examination
Upon implementation of Amendment 5, a physical examination will be completed per 
standard of care at the times specified in the Schedule of Events—Amendment 5 and 
Beyond. Please refer to the Full Schedule of Events for the timing of assessments before 
implementation of Amendment 5. Symptom-directed examinations should include 
examination of organ systems related to patient symptoms to document potential AEs, AE 
severity, or AE resolutions. A baseline (pretreatment) evaluation of PN will be conducted as 
part of the visit. If PN is present at baseline and within the permitted criteria for study 
participation (see Section 5.2), the grade must be reported in the eCRF.
7.4.5   
Vital Signs
Measurement of vital signs, including temperature, blood pressure, heart rate, respiratory 
rate, and body weight will be done at the time points specified in the Full Schedule of 
Events (before implementation of Amendment 5). Height will only be measured at the 
Screening visit.
Upon implementation of Amendment 5, vital signs and body weight will no longer be 
collected.
7.4.6   
Eastern Cooperative Oncology Group Performance Status
Performance status will be assessed using the ECOG performance scale at the time points 
specified in the Full Schedule of Events (before implementation of Amendment 5).
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Upon implementation of Amendment 5, ECOG performance status assessments will no 
longer be collected.
7.4.7   
Pregnancy Test
Screening
All countries except Canada: FCBP are required to have TWO medically-supervised 
negative serum and/or urine pregnancy tests with a sensitivity of at least 25 mIU/mL, even if 
continuous abstinence is the chosen method of contraception, prior to the first dose of 
lenalidomide. One test must be obtained within 10 to 14 days and 1 test within 24 hours 
prior to the start of the study drug regimen at Cycle 1, Day 1. The dates and results of 
pregnancy tests must be documented.
Canada: FCBP are required to have TWO medically-supervised negative serum pregnancy 
tests with a sensitivity of at least 25 mIU/mL, even if continuous abstinence is the chosen 
method of contraception, prior to the first dose of lenalidomide. One test must be obtained 
within 7 to 14 days, the second within 24 hours prior to the start of the study drug regimen 
on Cycle 1, Day 1. The dates and results of pregnancy tests must be documented.
Refer to Section 6.9 for definition of FCBP.
On Treatment
FCBP with regular or no menstruation must have a serum or urine pregnancy test weekly, as 
defined regionally, for the first 28 days and then every 28 days while on treatment 
(including breaks in therapy), at discontinuation of study treatment, and at Day 28 after the 
last dose of the study drug regimen. Females with irregular menstruation must have a 
pregnancy test weekly for the first 28 days and then every 14 days while on study (including 
breaks in therapy), at discontinuation of treatment, and at Days 14 and 28 after the last dose 
of treatment. The dates and results of all pregnancy tests must be documented. All patients 
must follow the lenalidomide PI while on therapy and be counseled about pregnancy 
precautions, risks of fetal exposure, and other risks in accordance with the Revlimid 
REMS(formerly known as RevAssist®) program (US participants), RevAid® program 
(Canadian participants), or the Lenalidomide Pregnancy Risk Minimisation Plan as outlined 
in the Study Manual (all other participants who are not using commercial supplies).
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The Cycle 1, Day 1 pregnancy test may be collected up to 24 hours before dosing. The 
results must be available and negative before the first dose of the study drug regimen is 
administered. The date and results must be documented.
Pregnancy tests may also be repeated during the study as per request of IEC/IRBs or if 
required by local regulations. The dates and results of these additional pregnancy tests must 
be documented.
7.4.8   
Concomitant Medications and Procedures
Concomitant medications and therapy will be recorded from the first dose of drug in the 
study drug regimen through 30 days after last dose of drug in the study drug regimen, with 
the exception of narcotics and other analgesics, which will be recorded from first dose of 
study drug until progressive disease (see the Full Schedule of Events [before implementation 
of Amendment 5]). 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.
Upon implementation of Amendment 5, concomitant medications and procedures data will 
no longer be collected.
7.4.9   
Adverse Events
Monitoring of AEs, serious and nonserious, will be conducted throughout the study as 
specified in the Schedule of Events—Amendment 5 and Beyond (upon implementation of 
Amendment 5). Please refer to the Full Schedule of Events for the timing of assessments 
before implementation of Amendment 5. Refer to Section 10 for details regarding 
definitions, documentation, and reporting of pretreatment events, AEs, and SAEs.
7.4.10   
Enrollment
A patient is considered to be enrolled in the study when he/she has been randomized to 
study treatment.
Procedures for completion of the enrollment information are described in the Study Manual.
7.4.11   
Electrocardiogram
A 12-lead electrocardiogram (ECG) will be conducted at screening and at the times outlined 
in the Full Schedule of Events (before implementation of Amendment 5). It may be repeated 
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as clinically indicated during the study at the discretion of the investigator. ECG data to be 
obtained include PR interval, QRS interval, QT interval, QTc interval, and waveforms.
Upon implementation of Amendment 5, electrocardiogram data will no longer be collected.
7.4.12   
Clinical Laboratory Evaluations
Clinical laboratory evaluations will be performed by a central laboratory. For on study 
treatment dosing decisions, local hematology and chemistry laboratory results may be used; 
however, samples must still be sent to the central laboratory in parallel. The central 
laboratory results will be used for determination of eligibility criteria. Patients may have 
central laboratory assessments repeated when discrepant results between the central and 
local laboratories are observed. Hematology and chemistry panels may be collected up to 
3 days before Day 1 dosing and 24 hours before Days 8, 15, and 22 dosing, where required. 
Local laboratory evaluations may be done more frequently at the investigator’s discretion, 
ie, for acute management of TEAEs. Handling and shipment of central clinical laboratory 
samples are outlined in the Study Manual.
Please consult your central laboratory manual for the turnaround times in obtaining the 
central laboratory results. The site must allow an adequate amount of time for these samples 
to be processed and include this in the planning during the Screening period. If the samples 
have been submitted to the central laboratory but were unable to be processed for technical 
reasons and the end of the screening window is approaching, the site may submit local 
laboratory results for consideration by the MPI project clinician or designee. These samples 
should be repeated and dispatched to the central laboratory before the patient receives their 
first dose of study treatment. However, when approved by the MPI project clinician or 
designee, the central laboratory results do not need to be available if the MPI project 
clinician or designee has approved eligibility based upon local laboratory results.
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.
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2. It is required per your local practice to have safety labs reviewed before starting the 
next cycle of treatment.
Upon implementation of Amendment 5, centralized clinical laboratory evaluations of 
efficacy and safety are no longer required and local laboratories are to be utilized. Local 
laboratory evaluations should be entered into the eCRF only if required to understand a 
TEAE. For dosing decisions and all other safety assessments for the patient, local 
hematology and chemistry laboratory results should be used and do not need to be entered 
into the eCRF. Local laboratory evaluations may be done more frequently at the 
investigator’s discretion (ie, for acute management of TEAEs), per the investigator’s 
judgement of standard of care.
Clinical Chemistry, Hematology, and Urinalysis
Blood and urine samples for analysis of the following clinical chemistry and hematological 
parameters will be obtained as specified in the Schedule of Events—Amendment 5 and 
Beyond. Blood samples should be collected prior to administration of any study drugs.
Hematology

Hemoglobin

Hematocrit

Platelet (count)

Leukocytes with differential

Neutrophils (ANC)
Serum Chemistry

Blood urea nitrogen 
(BUN)

Creatinine*

Bilirubin (total)

Urate

Lactate 
dehydrogenase 

Phosphate

Albumin

Alkaline phosphatase 
(ALP)

AST

ALT

Glucose 

Sodium

Potassium

Calcium

Chloride

Carbon dioxide 
(CO2)

Magnesium

Thyroid stimulating 
hormone (TSH)
* Creatinine clearance should be determined by using the Cockcroft-Gault Equation (see Section 15.3).
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Urinalysis

Turbidity and Color

pH

Specific gravity

Protein

Ketones

Bilirubin

Occult Blood

Nitrite

Urobilinogen

Glucose

Leukocytes

Microscopic 
analysis
7.4.13   
Health Utilization Data Collection
During the treatment and the follow-up periods indicated in the Full Schedule of Events
(before implementation of Amendment 5), all medical care encounters since the previous 
collection will be collected from all patients, regardless of the reason for the medical care 
encounter. Examples of data to be collected are number and duration of medical care 
encounters, such as inpatient/outpatient admissions, homecare, and time of work loss.
Upon implementation of Amendment 5, health utilization assessments will no longer be 
collected.
7.4.14   
Quality of Life Assessment (European Organization for Research and 
Treatment of Cancer)
The QOL assessments (EORTC-QLQ-C30 and MY-20; see Sections 15.9 and 15.10) will be 
completed by the patient as specified in the Full Schedule of Events (before implementation 
of Amendment 5). The EORTC QLQ-30 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).
The MY-20 multiple myeloma module (20-items) has 4 independent subscales, 2 functional 
subscales (body image, future perspective), and 2 symptoms scales (disease symptoms and 
side-effects of treatment). This will be administered subsequent to the EORTC QLQ-C30.
These are reliable and valid measures of health-related QOL in patients with cancer and 
takes about 15 minutes to administer. The instruments consist of a total of 50 items and have 
been validated and used in many countries. 
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These QOL assessments must be completed before other assessments are performed or any 
drug in the study drug regimen is administered.
Upon implementation of Amendment 5, quality of life assessments will no longer be 
collected.
7.4.15   
Pain Assessment
Pain assessments will be performed at study visits as described in the Full Schedule of 
Events (before implementation of Amendment 5). Patients who experience new or 
worsening pain between scheduled visits should be seen at an unscheduled visit, if 
necessary, or when the next scheduled visit is more than 4 weeks in the future. At the 
unscheduled visits, pain assessments should be completed and appropriate management 
instituted. In addition, patients who report new or worsening pain at either a regularly 
scheduled visit or are seen for pain at an unscheduled visit should have a follow-up visit 3 to 
5 weeks later for confirmation of the pain progression and for appropriate pain management.
The Brief Pain Inventory-Short Form (BPI-SF) will be the principal pain assessment tool for 
this study. The BPI-SF contains 15 items designed to capture the pain severity (“worst,” 
“least,” “average,” and “now” [current pain]), pain location, medication to relieve the pain, 
and the interference of pain with various daily activities including general activity, mood, 
walking activity, normal work, relations with other people, sleep, and enjoyment of life.
The questionnaire employs a 24-hour recall period. The pain severity items are rated on a 0 
to 10 scale, with 0 = no pain and 10 = pain as bad as you can imagine. The PRO key 
secondary endpoint will be “pain response rate” as measured by the worst pain item (Item 3) 
in the BPI-SF or analgesic use. The use of the single item, worst pain, is supported by the
Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) 
recommendations for assessing pain in clinical trials and by the European Medicines 
Agency 2003 Guidance on Clinical Investigation of Medicinal Products for Nociceptive 
Pain issued by the Committee for Proprietary Medicinal Products. In addition, the newly 
released Food and Drug Administration (FDA) Guidance uses the following example while 
discussing conceptual frameworks: “The conceptual framework of a PRO instrument may be 
straightforward if a single item is a reliable and valid measure of the concept of interest 
(eg, pain intensity).”
At the time of each pain assessment including unscheduled visits, the patient will be queried 
regarding concomitant use of analgesics, if any, as specified in the Full Schedule of Events
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(before implementation of Amendment 5). The patient-recalled amount of analgesic use
during the 24 hours prior to pain assessment will be recorded on both the 24-hour analgesic 
form and concomitant medication eCRFs.
A full BPI-SF instrument will be administered at each of the visits as specified in the Full 
Schedule of Events (before implementation of Amendment 5) to collect the pain severity, 
location, and interference information with a 24-hour recall period. This must be completed 
prior to other assessments or study drug regimen being administered.
Patients will complete the BPI-SF at each visit as specified in the Full Schedule of Events
(before implementation of Amendment 5). Thus, for patients who discontinue study drug 
before disease progression, the scheduled collection of pain assessment should continue
until disease progression.
Upon implementation of Amendment 5, pain assessments will no longer be collected.
7.4.16   
Utility Measurement
The EQ-5D consists of 2 pages: the EQ-5D descriptive system and the EQ visual analogue 
scale (EQ VAS). The descriptive system comprises 5 dimensions (mobility, self care, usual 
activities, pain/discomfort, and anxiety/depression). The EQ VAS records the respondent’s 
self-rated health on a 20-cm vertical, visual analogue scale ranging from 0 (worst 
imaginable health state) to 100 (best imaginable health state). The EQ-5D will be 
administered as specified in the Full Schedule of Events (before implementation of 
Amendment 5).
Upon implementation of Amendment 5, utility measurement data will no longer be 
collected.
7.4.17   
Skeletal Survey
A complete skeletal survey, using roentgenography, will be performed at screening (within 
8 weeks prior to randomization) and a minimum of every 12 months from randomization 
until disease progression in all patients until PFS significance has been claimed in this study. 
If at any time the physician believes there are symptoms or signs that suggest increased or 
new bone lesions, a repeat of the skeletal survey should be performed. For imaging of 
symptomatic sites, plain films may be obtained for additional clarity.
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At the discretion of the investigator and where regionally permitted, computed tomography 
(CT) scan, a positron emission tomography-computed tomography (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.
Upon implementation of Amendment 5, skeletal survey data will no longer be collected.
7.4.18   
Skeletal-Related Events
SREs, defined as new fractures (including vertebral compression fractures), irradiation of or 
surgery on bone, or spinal cord compression, will be captured from the start of the study 
treatment through death at the time points listed in the Full Schedule of Events (before 
implementation of Amendment 5) until PFS significance has been claimed in this study.
Upon implementation of Amendment 5, skeletal-related events data will no longer be 
collected.
7.4.19   
Bone Mineral Density
DEXA scans will be done of the lumbar spine and femoral neck at screening (the DEXA 
scan does not need to be repeated if already performed within 8 weeks of randomization), 
6 months, 1 year, and then annually (4 weeks at the corresponding study visit to 
approximately 6 or every 12 months of treatment) until progressive disease, as indicated in 
the Full Schedule of Events (before implementation of Amendment 5).
Upon implementation of Amendment 5, bone mineral density data will no longer be 
collected.
7.4.20   
Radiographic Disease Assessments 
For patients with documented extramedullary disease, other assessments and scans such as a 
CT, PET-CT or MRI scan may be required to better delineate the sites and measurements of 
extramedullary disease. Follow-up scans should use the same imaging modality used at 
screening (within 8 weeks of randomization) at the time points specified in the Full 
Schedule of Events (before implementation of Amendment 5), until PFS significance has 
been claimed in this study. 
All follow-up scans should use the same imaging modality used at screening.
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Radiographs will be analyzed locally and reports maintained with the patient record for 
review during monitoring visits.
Upon implementation of Amendment 5, radiographic disease assessments will no longer be 
collected.
7.4.21   
2-Microglobulin
A blood sample will be collected at screening for serum 2-microglobulin testing. A sample 
for the central laboratory is required. A sample may additionally be collected by the local
laboratory. Stratification by ISS stage 1 or 2 vs 3 will be conducted using central laboratory 
results. These results must be available prior to randomization.
7.4.22   
Quantification of M-Protein
A blood sample and urine sample will be obtained at screening and at the time points 
specified in the Full Schedule of Events (before implementation of Amendment 5) until PFS 
significance has been claimed in this study. If the screening test was performed more than
14 days before the first dose, the test will be repeated at baseline in the central laboratory.
Central laboratory results must be utilized for eligibility assessments, per guidance noted in 
Section 7.4.12.
Upon implementation of Amendment 5, all central laboratory assessments of response and 
progression are discontinued.
7.4.23   
Quantification of Immunoglobulin (Ig)
Blood samples for quantification of immunoglobulins (IgM, IgG, IgA) will be obtained as 
specified in the Full Schedule of Events (before implementation of Amendment 5) until PFS 
significance has been claimed in this study. Quantitative IgD and IgE will be done at 
screening (and baseline if necessary) only for all patients. For the rare patient with IgD or 
IgE multiple myeloma, the quantitative test for that antibody will be followed at the same 
time points throughout the treatment period and PFS follow-up period as quantitative Igs (in 
addition to quantitative IgM, IgG, and IgA).
Central laboratory results must be utilized for eligibility assessments, per guidance noted in 
Section 7.4.12.
Upon implementation of Amendment 5, this sample will no longer be collected.
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7.4.24   
Serum Free Light Chain Assay
A blood sample for serum free light chain assay will be obtained at the time points specified 
in the Full Schedule of Events (before implementation of Amendment 5). Central laboratory 
results must be utilized for eligibility assessments, per guidance noted in Section 7.4.12.
Upon implementation of Amendment 5, all central laboratory assessments of response and 
progression are discontinued.
7.4.25   
Immunofixation of Serum and Urine
Serum and urine samples will be obtained at the time points specified in the Full Schedule of 
Events (before implementation of Amendment 5). Central laboratory results must be utilized 
for eligibility assessments, per guidance noted in Section 7.4.12.
Upon implementation of Amendment 5, all central laboratory assessments of response and 
progression are discontinued.
7.4.26  
Bone Marrow Evaluation
Central Lab Evaluation
Molecular Analyses, Cytogenetics, and Minimal Residual Disease
The sample of the bone marrow aspirate obtained at screening (within 8 weeks of 
randomization) will be used for molecular analyses and for evaluation of cytogenetics that 
will cover a panel of high-risk abnormalities including the following: amp(1q21), t(4;14), 
t(14;16), and del(17p). 
 
 
. This sample 
will be submitted to a central laboratory (See Study Laboratory Manual for sample handling 
and shipping instructions). The first or second pull of the bone marrow aspirate is the 
preferred specimen to be sent to the central lab for this analysis.
A bone marrow aspirate will be collected for assessment of MRD in all patients suspected to 
have reached CR anytime during the entire conduct of the study. In addition, a second bone 
marrow aspirate for MRD assessment will be collected at Cycle 18 for only patients who 
have maintained a CR until that point (this sample can be collected up to 4 weeks after 
Cycle 18). If a patient has had MRD testing because of a suspected CR within 2 cycles of 
Cycle 18, then this repeat MRD assessment does not need to be performed.
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Upon implementation of Amendment 5, bone marrow aspirate is not required for central 
laboratory assessment of CR or for MRD for protocol purposes. Investigators may continue 
to take bone marrow aspirate per standard of care for response assessment.
Samples are required to be sent to a central lab for analysis. These samples will be processed 
according to the Laboratory Manual.
An optional aspirate for molecular analysis will also be collected at the time of disease 
relapse only if the patient had previously responded to study drug regimen and consents to 
this procedure. This sample may be collected at the time of PD confirmation, at the End of 
Treatment visit, or prior to starting a new therapy and will be sent to the central laboratory 
for analysis.
Local Lab Evaluations
Disease Assessment
A bone marrow aspirate will be obtained at screening (within 8 weeks of randomization) to 
assess the patient’s eligibility in accordance with the IMWG diagnostic criteria 
(Section 15.2). During the study, a bone marrow aspirate sample should be obtained to 
confirm a CR when the patient has negative immunofixation serum and urine and/or 
disappearance of any soft tissue plasmacytoma. To confirm a stringent CR, the bone marrow 
evaluation must demonstrate the absence of clonal PCs by immunohistochemistry or 2- to 
4-color flow cytometry. These samples will be analyzed by the local laboratory.
A bone marrow biopsy can additionally be performed per local standards for disease 
assessments.
Upon implementation of Amendment 5, a bone marrow aspirate sample for evaluation of 
MRD is no longer required. Investigators should follow local standard of care for bone 
marrow aspirate samples.
Cytogenetics
A bone marrow aspirate sample must be submitted to a central laboratory for analysis of 
cytogenetics, including amp(1q21), t(4;14), t(14;16), and del(17p). An optional bone
marrow aspirate or bone marrow sample may also be submitted for cytogenetics to be 
analyzed locally, including amp(1q21), t(4;14), t(14;16), and del(17p), according to local 
standards, if the site has capability to perform analysis and there is sufficient sample 
available. The central laboratory cytogenetic results will be utilized for study analysis, 
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whereas local laboratory cytogenetic results (where available) will only be utilized in 
instances when central laboratory results are not available.
7.4.27   
Response Assessment
Patients will be assessed for disease response according to the IMWG uniform response 
criteria, version 2011 (see Section 15.11).[72]
Response assessments are made on the basis of central laboratory data and should occur 
every cycle during the treatment period (until disease progression is confirmed) until PFS 
significance has been claimed for this study. At that time, central efficacy and investigator 
assessments for protocol purposes will be stopped except for investigator assessment of 
PFS2. For patients who discontinue treatment before disease progression, disease response 
should occur every 4 weeks during the PFS follow-up period until disease progression is 
confirmed or the patient is started on another anticancer therapy (see the Full Schedule of 
Events [before implementation of Amendment 5]), or until PFS significance has been 
claimed for the study.
The MPI/designee clinician will confirm the investigator assessment of PD prior to the 
investigator taking the patient off treatment. A treatment discontinuation form must be 
submitted and approved prior to removing a patient from study treatment for disease 
progression, toxicity, or any other reason.
Patients who go on to receive a subsequent line of anticancer therapy will be further 
evaluated for disease response (at minimum disease progression) to confirm disease 
progression for determination of PFS2. Response assessments will be made using local 
laboratory results, and the frequency will be determined by the investigator (recommended 
every 12 weeks). Response assessments, including the treatment received and date of second 
disease progression, should be reported in the eCRF every 12 weeks as part of the OS 
follow-up period assessments.
Upon implementation of Amendment 5, all central laboratory assessments of response and 
progression are no longer required.
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Response categories are as follows:
Table 7-1   
Response Assessment
Complete response
CR
Subcategory: stringent complete response
sCR
Partial response
PR
Subcategory: Very good partial response
VGPR
Stable disease
SD
Progressive disease
PD
CR must be confirmed with follow-up assessments 4 weeks (1 cycle) following the first 
observation of CR of serum protein electrophoresis (SPEP), urine protein electrophoresis 
(UPEP), immunofixation of blood and urine, serum free light chains, and radiological 
assessment of soft tissue plasmacytoma if applicable, as outlined in Section 15.11. One bone 
marrow assessment has to occur to document CR; no second bone marrow confirmation is 
needed.
Please note that in order to determine a response of sCR, bone marrow 
immunohistochemistry or 2- to 4- color flow cytometry for kappa/lambda ratio should be 
performed for all patients suspected to be in CR to meet this response category’s 
requirements.
Patients with measurable disease in either SPEP or UPEP or both will be assessed for 
response only based on these 2 tests and not by the free light chain assay. Free light chain 
response criteria are only applicable to patients without measurable disease in the serum or 
urine, and to fulfill the requirements of the category of stringent CR.
7.4.28   
Pharmacokinetic Measurements
Plasma concentrations of the complete hydrolysis product of MLN9708 (MLN2238) will be 
measured using a validated LC/MS/MS assay.
Details regarding the preparation, handling, and shipping of the pharmacokinetic samples 
are provided in the Study Manual. Blood samples (3 mL) for the determination of plasma 
concentrations of MLN2238 (the complete hydrolysis product of MLN9708) will be 
collected during Cycles 1 through 12. Samples are to be collected at the time points
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specified in the MLN9708 Pharmacokinetic Sampling Schedule immediately following the 
Full Schedule of Events (before implementation of Amendment 5).
Upon implementation of Amendment 5, no further PK sample collection will be performed. 
The MLN9708 Pharmacokinetic Sampling Schedule has been moved to Section 15.12 for 
reference.
7.4.29   
Blood Sample for Biomarker Analysis
7.4.30
Treatment Beyond 18 Cycles
Patients may continue to receive the study drug regimen of 4.0-mg study drug + LenDex for 
18 cycles (approximately 18 months), or until PD or unacceptable toxicity, whichever comes 
first. After 18 cycles, patients will continue treatment in the same randomization arm on the 
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same schedule with modified dose levels of study drug and lenalidomide until disease 
progression to mitigate toxicities (see Table 4-1). Dose modifications should be made based 
on prior dose modifications during the first 18 cycles of treatment (see Table 6-4, Table 6-6, 
and Table 6-8). 
7.4.31   
Follow-up Assessments (PFS, PFS2, and OS)
Patients who stop treatment for any reason other than progressive disease will continue to 
have PFS follow-up visits. See the Full Schedule of Events (before implementation of 
Amendment 5) for appropriate assessments. The PFS follow-up should occur every 4 weeks 
until disease progression is confirmed or the patient is started on another anticancer therapy, 
whichever comes first.
Patients who stop treatment due to progressive disease will subsequently start OS follow-up 
assessments/visits. The OS follow-up should be conducted every 12 weeks after documented 
progressive disease until death or termination of the study by the sponsor. All subsequent 
antineoplastic therapies will be recorded until the patient dies. Patients who go on to receive 
a subsequent (second) line of anticancer therapy will be evaluated for disease response (at 
minimum disease progression) to confirm disease progression for determination of PFS2. 
Response assessments will be made using local laboratory results, and the frequency will be 
determined by the investigator (recommended every 12 weeks). The treatment received and 
date of second disease progression should be reported in the eCRF every 12 weeks as part of 
the OS follow-up period assessments.
During the OS follow-up, assessments can be made over the phone and do not require a 
clinic visit. Data may be collected by methods that include but are not limited to telephone, 
e-mail, mail, and social security indexes.
Information for new primary malignancy should be collected during the study, including the 
PFS and OS follow-up periods.
Upon implementation of Amendment 5, patients will no longer be followed during any of 
the follow-up periods, as PFS and OS data are not being collected.
NOTE: 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 the posttreatment follow-up. In addition, new primary malignancies that occur 
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during the follow-up periods, irrespective of causality to study drug regimen, must be 
reported to the Millennium Department of Pharmacovigilance or designee.
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. At unscheduled visits 
before implementation of Amendment 5, the BPI-SF and 
 should be 
captured. Upon implementation of Amendment 5, pain assessments and health utilization 
data will no longer be collected. Other assessments may be performed as clinically indicated 
at the discretion of the investigator.
7.6   
Study Compliance
Each drug in the study drug regimen 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.
Tests and procedures should be performed on schedule, but, unless otherwise specified, 
occasional changes are allowable within a 2-day window for holidays, vacations, and other 
administrative reasons. If the study schedule is shifted, assessments must be shifted to 
ensure that collection of assessments is completed before dosing.
7.7   
Completion of Treatment
Prior to implementation of Amendment 5, patients were considered to have completed study 
treatment if they received the study drug regimen until disease progression or until
discontinuation for unacceptable toxicity, withdrawal of consent, or death. Quality Review 
by a MPI/designee clinician was required prior to discontinuing a patient from treatment or 
stopping disease assessments for progressive disease. A treatment discontinuation form had 
to have been submitted and approved prior to removing a patient from study treatment for 
disease progression, toxicity, or any other reason. 
Upon implementation of Amendment 5, only patients who are demonstrating clinical benefit 
and are unable to access a commercial supply of ixazomib and/or lenalidomide will remain 
in the study, until such time as other means of accessing the study drugs are arranged. 
Completion of study treatment will occur when patients discontinue study drugs provided by 
the sponsor in this clinical trial setting, or when the patient experiences disease progression, 
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unacceptable toxicity, withdrawal of consent, or death. The reason for treatment 
discontinuation must be recorded in the eCRF but no approval is required.   
Patients will attend an EOT visit 30 days (+1 week) after receiving their last dose of the 
study drug regimen 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. Refer to the Schedule of Events—Amendment 5 and Beyond for End of Treatment 
visit assessments.
7.8   
Completion of Study
Prior to implementation of Amendment 5, patients were considered to have completed the 
study if they were followed until death or until the sponsor terminated the study. Upon
implementation of Amendment 5, patients will no longer be followed during any of the 
follow-up periods, as PFS and OS data are not being collected. Patients will be considered to 
have completed the study if they completed study treatment (see Section 7.7).
7.9   
Discontinuation of Treatment With the Study Drug Regimen, and Patient 
Replacement
Treatment with the study drug regimen must be discontinued for pregnancy. Treatment with 
the study drug regimen may be discontinued for any of the following reasons: 

Adverse event (including SAE)

Protocol violation

Study terminated by sponsor

Withdrawal by subject 

Lost to follow-up

Pregnancy (patient must be discontinued)

Other
Once the study drug regimen has been discontinued, all study procedures outlined for the 
EOT visit will be completed as specified in the Schedule of Events—Amendment 5 and 
Beyond. The primary reason for study drug discontinuation will be recorded on the eCRF.
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7.10   
Withdrawal of Patients From Study
A patient may be withdrawn from the study for any of the following reasons:

Study terminated by sponsor

Withdrawal by patient

Lost to follow-up

Other
Upon implementation of Amendment 5, PFS and OS follow-up will no longer be performed. 
Patients will now complete the study immediately following the end of treatment visit. The 
consequence of study withdrawal is that no new information will be collected from the 
withdrawn patient and added to the existing data or any database.
8.   
STATISTICAL AND QUANTITATIVE ANALYSES
The second IA has been performed (data cutoff date of 02 December 2019) and the primary 
endpoint of PFS did not reach statistical significance. Therefore, no subsequent formal 
inferential statistical analyses will be conducted. The primary analysis of efficacy and safety 
was performed on data from the second IA and will be presented in a clinical study report 
(CSR). Minimal descriptive analyses will be performed on patient data collected after the 
second IA and will be presented in a future CSR addendum. The description of the statistical 
methods presented below reflects the original design and the planned analysis for the study,
reflecting the statistical considerations up to the second IA.
8.1   
Statistical Methods
In general, summary tabulations will be presented by treatment arm and will display the 
number of observations, mean, standard deviation, median, minimum, and maximum for 
continuous variables, and the number and percent per category for categorical data. The 
Kaplan-Meier survival curves and 25th, 50th (median), and 75th percentiles will be provided 
along with their 2-sided 95% CIs for time-to-event data.
Details for the analyses will be provided in the statistical analysis plan (SAP). The SAP will 
be written by Millennium and will be finalized prior to the formal IA.
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Deviations from the statistical analyses outlined in this protocol will be indicated in the 
SAP; any further modifications will be noted in the final clinical study report.
8.1.1   
Determination of Sample Size
The primary objective of this study is to determine if MLN9708 plus lenalidomide and 
dexamethasone improves PFS compared with placebo plus lenalidomide and dexamethasone 
in patients with newly diagnosed MM. The study will not be stopped after the PFS analysis, 
however, even if a significant PFS is observed, in order to obtain an adequate statistical 
power for OS. 
The total sample size of approximately 701 patients was calculated based on maintaining 
80% power to test the OS. The study is also adequately powered to test PFS. There are 
2 planned IAs and 1 FA.
Assuming a hazard ratio of 0.70 (median PFS of 25 months in control arm versus 
35.8 months in treatment arm), 370 PFS events will be needed (92% power and 2-sided 
alpha of 0.04) with up to 2 planned PFS analyses conducted at the first IA and potentially 
second IA of this study using the Gamma(-1) alpha-spending function.
The sample size adaptation rule is a prespecified stepwise function to avoid the back 
calculation problem resulting from one sample size corresponding to either barely promising 
or highly promising interim results. The sample size adaptation rule was designed by the 
sponsor’s independent design statistician and approved by the sponsor’s head of 
biostatistics. Neither the independent design statistician nor the head of biostatistics is 
involved in the study conduct.
The adaptation rules were outlined in a separate document and will not be accessible to the 
sponsor’s study team until completion of the study. The rules are available only to the 
sponsor’s independent design statistician, the sponsor’s head of biostatistics, the IDMC, and 
the statistics representative on the sponsor’s executive committee (if different from the 
sponsor’s head of biostatistics).
8.1.2   
Randomization and Stratification
Randomization scheme will be generated by an independent statistician at Millennium who
is not on the study team. Prior to dosing, a randomization number will be assigned to each 
patient. The randomization assignment will be implemented by an IXRS.
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Eligible patients will be randomized in a 1:1 ratio into those 2 treatment arms, stratified by: 
age (75 years vs 75), ISS (stage 1 or 2 vs stage 3), and BPI-SF worst pain score (4 vs 
4) at screening.
8.1.3   
Populations for Analysis
The populations used for analysis will include the following:
Safety population: The safety population is defined as all patients who receive at least 
1 dose of any study drug. Patients will be analyzed according to the treatment actually 
received. That is, those patients who are randomized to the active arm but receive the 
regimen in the control arm will be included in the control arm; those patients who are 
randomized to the control arm but receive the regimen in the active arm will be included in 
the active arm for safety analyses.
Intent-to-Treat (ITT) population: The ITT population is defined as all patients who are 
randomized. Patients will be analyzed according to the treatment they are randomized to 
receive, regardless of any errors of dosing. 
Per-Protocol (PP) population: The PP population is a subset of the ITT population. The PP 
population consists of all patients who do not have major protocol violations, as determined 
by the study clinician, who is blinded to study drug assignment. All decisions to exclude 
patients from the PP population will be made before the unblinding of the study.
Response-Evaluable population: The response-evaluable population is defined as patients 
who have measurable disease at baseline, who receive at least 1 dose of any study drug, and 
have at least 1 postbaseline response assessed by an IRC.
8.1.4   
Procedures for Handling Missing, Unused, and Spurious Data
All available efficacy and safety data will be included in data listings and tabulations. Data 
that are potentially spurious or erroneous will be examined according to standard data 
management operating procedures.
In general, missing data will be treated as missing and no data imputation will be applied, 
unless otherwise specified. For patient reported outcomes data, primarily missing data 
imputation will be based on published instrument specific methods. Other missing data 
imputation methods, such as last observation carry forward and multiple imputation 
methods, may be explored as sensitivity analyses for patient reported outcomes data.
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For the key secondary endpoints CR rate, missing value is defined as no post-baseline 
response assessment either due to lost to follow-up or withdrawal by patient. In the primary 
analysis, if the response assessment in either arm is missing on comparing response rates, it 
will be counted as a failure (non-responder) instead of a missing value. The procedure to 
deal with missing data in the primary analysis for the pain response rate will be using the 
same method as CR rate.
8.1.5   
Demographic and Baseline Characteristics
The demographic and baseline characteristics will be summarized in a descriptive fashion. 
Data to be evaluated will include age, gender, race, weight, baseline disease characteristics, 
and other parameters, as appropriate.
8.1.6   
Efficacy Analysis
A closed sequential testing procedure will be used to test the primary endpoints and all 3 key
secondary endpoints with the following testing order:
1. PFS (primary endpoint) in the ITT population at the first or both IAs (see 
Section 8.1.1) and PFS at IA2 in 3 prespecified subgroups: 1) patients with baseline 
CrCl > 60 mL/min; 2) patients aged < 75 years; and 3) patients harboring high-risk 
cytogenetic abnormalities defined as del(17p), t(4;14), t(14;16), and amp(1q21); 
2. OS (first key secondary endpoint) at the IAs or FA; 
3. CR rate (second key secondary endpoint) at the IAs or FA; and 
4. pain response rate (third key secondary endpoint) at the IAs or FA. 
OS will be tested at the IAs or FA at the significance level determined by the O’Brien-
Fleming alpha spending function (the Lan-DeMets method). CR rate will be tested at the
same alpha level as that for OS whenever OS reaches statistical significance. Pain response 
rate will be tested at the same alpha level as that for CR rate whenever CR rate reaches 
statistical significance. Due to the closed sequential testing property, the family-wise type I 
error is strongly controlled for both the primary endpoint and key secondary endpoints (see 
Section 8.1.10).
All other efficacy endpoints will be tested at a 2-sided alpha level of 0.05.
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8.1.6.1  
Analyses for Primary Efficacy Endpoints
The analysis of primary endpoint, PFS, will be based on the IRC-assessed progression data. 
PFS is defined as the time from the date of randomization to the date of first documentation 
of PD or death due to any cause, whichever occurs first. Patients without documentation of 
PD will be censored at the date of last response assessment that is stable disease (SD) or 
better. 
A 2-sided, stratified log-rank test will be used to compare the treatment groups with respect
to PFS. In addition, an unadjusted stratified Cox model will be used to estimate the hazard 
ratio and its 95% CIs for the treatment effect using the stratification factors. The Kaplan 
Meier (K-M) survival curves and K-M medians (if estimable), along with their 2-sided 
95% CIs, will also be provided for each treatment group. 
Sensitivity analyses for PFS include:
1. PFS assessed by investigator will be analyzed in the ITT population
2. PFS assessed by IRC will be analyzed in the per protocol population
PFS assessed by IRC using different censoring mechanisms will be analyzed in the ITT 
population, for example, not censoring for patients who discontinue treatment and go on 
alternative antineoplastic therapy. Details of different censoring approaches will be included 
in the SAP.
Subgroup analyses will be performed for PFS relative to baseline stratification factors, 
demographic data, such as sex, race, and age, and disease characteristics, such as type of 
prior regimen.
8.1.6.2   Analyses of Key Secondary Efficacy
In addition to the primary comparison of PFS, there are 3 key secondary endpoints, which 
will be tested sequentially.
Overall Survival
OS is defined as the time from the date of randomization to the date of death. Patients 
without documentation of death at the time of analysis will be censored at the date last 
known to be alive. OS will be analyzed based on the ITT population.
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A 2-sided, stratified log-rank test will be used to compare the treatment groups with respect 
to OS in IAs, and Cui-Hung-Wang (CHW) test statistics will be used in FA testing to control 
the Type I error. The test significance level at the IAs and FA is decided by the O’Brien-
Fleming alpha spending function (the Lan-DeMets method). In addition, an unadjusted 
stratified Cox model will be used to estimate the hazard ratio and its 95% CIs for the 
treatment effect using the stratification factors. The K-M survival curves and K-M medians 
(if estimable), along with their 2-sided 95% CIs, will also be provided for each treatment 
group.
Subgroup analyses will be performed for OS relative to baseline stratification factors, 
demographic data such as sex, race, age, and disease characteristics such as type of prior 
regimen. 
CR Rate
The CR rate is defined as the proportion of patients who achieve CR assessed by an IRC 
relative to the ITT population during the treatment period. If the response assessment in 
either arm is missing on comparing CR rates, it will be counted as a failure (non-responder) 
instead of a missing value.
Stratified Cochran-Mantel-Haenszel (CMH) test will be used to compare CR rates between 
the 2 treatment arms. A logistic regression model will be used to estimate the treatment 
effect in terms of odds ratio. The odds ratio and its associated 95% CIs will be presented.
Pain Response Rate 
Pain response is defined as the occurrence of at least a 30% reduction from baseline in 
BPI-SF worst pain score over the last 24 hours without an increase in analgesic use for 
2 consecutive measurements 28 days apart.
Pain response rate will be analyzed in patients with baseline worst pain score ≥4 in the ITT 
population. Pain response rate is the proportion of patients who have a pain response and 
will be summarized by treatment groups. If the pain assessment in either arm is missing on 
comparing pain response rates, it will be counted as a failure (non-responder) instead of a 
missing value. The stratified CMH test will be used to compare the 2 treatment arms. In 
addition, the absolute treatment difference in pain response rate will be provided, along with
95% CI.
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8.1.6.3   Analyses of Other Secondary Efficacy Endpoints
Other secondary efficacy parameters include overall response rate (ORR), TTR, time to 
progression, duration of response, PFS2, and OS and PFS in high-risk population defined by 
del(17p), amp(1q21), and translocation t(4;14) and t(14;16).
Disease response-related endpoints will be analyzed using IRC-assessed response rate.
ORR
ORR is defined as the proportion of patients who achieved PR or better relative to the ITT 
population. ORR will be analyzed based on the ITT population using the method similar to 
that used in the CR rate analysis.
Time to Response
Time to response is defined as the time from randomization to the first documentation of PR 
or better. Time to response for responders will be summarized descriptively.
Time to Progression
TTP is defined as the time from the date of randomization to the date of first documentation 
of PD. Patients without documentation of PD at the time of analysis will be censored at the 
date of last response assessment that is SD or better. TTP will be analyzed based on the ITT 
population using the similar method as PFS.
Duration of Response
DOR is defined as the time from the date of first documentation of a PR or better to the date 
of first documentation of PD for responders. Responders without documentation of PD will 
be censored at the date of last response assessment that is SD or better. DOR will be 
summarized descriptively using the Kaplan-Meier method.
Progression-free Survival 2
PFS2 is defined as the time from the date of randomization to the date of second 
documentation of PD or death due to any cause, whichever occurs first. The second PD 
should occur during or after the second line of antineoplastic therapy following study 
treatment but before the third line of therapy. Patients who do not have documented PD will 
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be censored at the date of last response assessment which is SD or better. PFS2 will be 
analyzed by the treating physician/ investigator using the IMWG response criteria, based on 
the ITT population using the similar method as PFS.
OS and PFS in High-Risk Population
OS and PFS in a high-risk population, defined as patients carrying del(17p), amp(1q21), 
translocation t(4;14), or t(14;16) will be analyzed using the similar method as PFS and OS in 
ITT population.
8.1.7   
Analyses of Patient-Reported Outcomes and Health Economics
8.1.7.1   
Patient-Reported Outcomes Analysis
PRO assessments using the EORTC QLQ-C30 and the MY-20 will be analyzed using the 
ITT population. The analysis will be performed on summary scores as well as on subscales 
and individual symptoms.
Differences between treatment groups in the EORTC QLQ-C30 and MY-20 scores will be 
evaluated using published minimally important difference (MID) values. Specific interest 
centers on physical functioning, global quality of life summary scores, and individual item 
scores for fatigue, nausea/vomiting, pain, dyspnea, appetite loss, and constipation/diarrhea. 
The main endpoint for the PRO analysis will be the global health status/quality of life 
subscale of the EORTC QLQ-C30 and MY-20. The change in PRO scores between baseline 
and each postbaseline assessment will be described overall and according to the response to 
treatment. The other PRO endpoints include the remaining EORTC QLQ-C30 and MY-20 
subscale and individual item scores. The change in scores will be presented using 
cumulative frequency distribution figures. 
The analysis of PRO scores will be performed as a repeated-measures analysis using all 
available time points. The analysis will use mixed model analysis of variance.
8.1.7.2   
Health Economics Analysis Using Medical Resource Utilization and Utility
EQ-5D scores will be summarized in descriptive statistics for treatment arms. 
Health utilization data will be summarized in descriptive statistics of medical encounters 
(length of stay, inpatient, outpatient, and reason), number of missing days from work or 
other activities by patient and care-giver for treatment arms.
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8.1.7.3   
Pain
Additional analyses on pain beyond the key secondary endpoint of pain response rate 
include:

Time to pain response, as assessed by the time from randomization to initial response 
classification

Time to pain progression, as assessed by the time from randomization to initial pain 
progression

Duration of pain response, measured as the time from the first documented pain 
response to the first documented pain progression classification
Time to pain progression and duration of pain response will be compared using the stratified 
log-rank test between the 2 treatment groups. An unadjusted stratified Cox model will be 
used to estimate the hazard ratio and its 95% CIs for the treatment effect using the 
stratification factors. The K-M survival curves and K-M medians (if estimable), along with 
their 2-sided 95% CIs, will also be provided for each treatment arm. Time to pain response 
will be summarized descriptively for pain responders.
Pain progression is defined as the occurrence of 1 of the following and confirmed by 
2 consecutive evaluations (To qualify as progression, the patient must have a BPI-SF worst 
pain score 4 during pain progression):

A ≥ 2 point and 30% increase from baseline in BPI-SF worst pain score without an 
increase in analgesic use, or

A 25% or more increase in analgesic use from baseline without a decrease in BPI-SF 
worst pain score from baseline
Analgesic use change can be increased, stable or decreased, as specified in the SAP. 
A sensitivity analysis will be conducted on pain progression without confirmation by 
2 consecutive assessments. Confirmation is not required if surgical treatment for pain, 
palliative radiation for pain, or subsequent antineoplastic therapy has been receive prior to a 
confirmatory assessment (refer to Table 15-2 for a list of Step II and III analgesics). In 
addition, the pain scores will be summarized by treatment group.
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8.1.8   
Pharmacokinetics and Biomarkers
8.1.8.1   
Pharmacokinetic Analysis
PK data collected in this study will contribute to population PK analyses. These analyses 
may include data from other MLN9708 clinical studies and the analysis plan for the 
population PK analysis will be separately developed and reported.
8.1.8.2   
Biomarker Analysis
8.1.8.3   
Minimal Residual Disease Analysis
The absence of minimal residual disease (MRD negativity) will be tested in all patients who 
achieve a CR, using bone marrow aspirates. The frequency of MRD negativity, in each 
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treatment arm, will be determined, and its association with TTP, PFS, and OS will be 
evaluated.
8.1.9   
Safety Analysis
Safety will be evaluated by the incidence of AEs, severity and type of AEs, and by changes 
from baseline in the patient’s vital signs, weight, and clinical laboratory results using the 
safety population. Exposure to the study drug regimen and reasons for discontinuation will 
be tabulated.
Treatment-emergent AEs that occur after administration of the first dose of study drug 
regimen and through 30 days after the last dose of study drug regimen will be tabulated. 
AEs will be tabulated according to the Medical Dictionary for Regulatory Activities 
(MedDRA) and will include the following categories: 

Treatment-emergent AEs

Drug-related treatment-emergent AEs

Grade 3 or higher treatment-emergent AEs

Grade 3 or higher drug-related treatment-emergent AEs

The most commonly reported treatment-emergent AEs (ie, those events reported by 
10% of all patients)

SAEs
A listing of treatment-emergent AEs resulting in study drug regimen discontinuation will be 
provided.
Development of new or worsening of existing SREs (eg, new fractures [including vertebral 
compression fractures], irradiation of or surgery on bone, or spinal cord compression) from 
baseline through the development of PD will be summarized and presented.
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.
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Descriptive statistics for the actual values (and/or the changes from baseline) of vital signs 
and weight will be tabulated by scheduled time point. ECOG performance scores will be 
summarized using a shift table.
Shift tables for laboratory parameters will be generated based on changes in NCI CTCAE 
grade from baseline to the worst postbaseline value. Graphical displays of key safety 
parameters, such as scatter plots of baseline versus worst postbaseline values, may be used 
to understand the MLN9708 safety profile.
All concomitant medications collected from screening through the study period will be 
classified to preferred terms according to the World Health Organization (WHO) drug 
dictionary.
Two types of incidence rates will be calculated for the safety population based on the new 
primary malignancy assessment:

Incidence proportions, defined as the percentage of the subjects reporting any new 
primary malignancy in the safety population with available information

Incidence rates, defined by the number of the subjects reporting any new primary 
malignancy divided by the total duration of follow-up (patient-years = pt-yrs) in the 
safety population with available information up to the onset of new primary 
malignancies
For incidence proportions, the relative risks, defined as the ratio of incidence proportions 
between the 2 randomized treatment groups, were provided along with their 95% CIs. For 
incidence rates, the relative risks, along with their 95% CIs, will be calculated using an 
exponential regression model for lifetime data (assuming constant hazards). 
Due to the distinct nature of hematologic and nonhematologic neoplasms, as well as the 
emerging signals of new primary malignancies for immunomodulating agents, analyses of 
new primary malignancies may be performed separately for hematologic and non-
hematologic malignancies.
Additional safety analyses may be performed to most clearly enumerate rates of toxicities 
and to further define the safety profile of MLN9708.
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8.1.9.1   
Time to Resolution and Improvement of Peripheral Neuropathy Events
Peripheral neuropathy is defined as the treatment emergent adverse event in the high-level 
term of peripheral neuropathies NEC according to MedDRA.
A PN event is considered as resolved if its final outcome is resolved with no subsequent PN 
event of the same preferred term occurring on the resolution date or the day before and after. 
A PN event is considered as improved if the event improves from the maximum grade. That 
is, all the grades recorded after the maximum grade is less than the maximum grade.
Time to resolution and time to improvement are to be defined for each PN event. Time to 
resolution is defined as the time from the initial onset date (inclusive) to the resolution date 
for resolved events. Time to improvement is defined as the time from the initial onset date 
(inclusive) of the maximum grade to the first onset date that the toxicity grade is below the 
maximum grade with no higher grade thereafter, or the resolution date, whichever occurs 
first.
Time to improvement and time to resolution of PN events will be summarized by outcome 
(improvement or resolution) using the Kaplan-Meier method. The K-M survival curve and 
K-M medians (if estimable), along with their 2-sided 95% CIs, will be presented. This 
analysis is event based, thus 1 subject could contribute multiple observations if the subject 
has more than 1 PN event.
The analysis may be conducted for patients with any PN events or those with ≥2 PN events 
or those ≥3 PN events, respectively, if data permits.
8.1.10   
Interim Analysis
There were 2 planned IAs. The first IA was performed when 328 PFS events had occurred. 
The data cutoff date for this IA was 15 February 2018. The test for PFS in the ITT 
population was not statistically significant at the first IA. The second IA was conducted 
when 378 PFS events had occurred. Because the test for PFS did not reach statistical 
significance at the first IA in the ITT population, in the second IA PFS was tested in both the 
ITT population and in 3 prespecified subgroups, as described below.
The subgroup testing strategy approach included 2 major components: a) preservation of the 
ability to detect the overall treatment effect using a reduced overall significance level of 
1 = 0.04, which was used for the ITT population, and b) test of treatment effect for the 
3 prespecified subgroups: 1) patients with baseline CrCl > 60 mL/min; 2) patients aged 
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< 75 years; and 3) patients harboring high-risk cytogenetic abnormalities defined as 
del(17p), t(4;14), t(14;16), and amp(1q21). Subgroup testing was conducted using the 
remaining ,2 = 0.01 and the Hochberg procedure for multiplicity correction (refer to the 
appendix in the SAP for proof of strong control of the Type I error rate). Because the size of 
the treatment effect could be substantially greater in a prespecified subgroup than in the 
overall study population, analysis of patients in each subgroup at a stringent significance 
level could still provide a statistically significant outcome. The detailed statistical design 
schema is presented in Figure 8-1.
Figure 8-1
Schematic of Statistical Plan
For the testing of PFS in the ITT population, the Gamma(-1) alpha spending function was
used to calculate the significance boundary based on the observed number of PFS events 
with total alpha=0.04. The first IA was performed when 328 PFS events had occurred. This 
was the first analysis for PFS for statistical testing purposes.
Because the test for ITT PFS was not statistically significant at the first IA, response 
assessments continued, and PFS testing in the ITT and subgroup populations was conducted 
in parallel at the second IA, when 378 PFS events had occurred; this was the FA of PFS for 
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statistical testing purposes. If the test for PFS had been significant at the second IA, OS 
would have been tested, and determination of whether the final number of OS events would 
be increased from 320 to up to 400 would have occurred. Because the test for PFS in the 
second IA was not statistically significant in any population (the ITT or any of the 
3 subgroups), the study was stopped and this amendment implemented.
The IAs were conducted by the independent statistical center (ISC) and presented for review 
to the IDMC.
9.   
STUDY COMMITTEES
9.1   
Independent Review Committee
An IRC will review all disease evaluation data from the study and determine disease status 
(response and progression, including PFS follow-up period but does not apply to PFS2 
assessment). Data from the IRC will not be provided back to the investigator during the 
conduct of the study.
Upon implementation of Amendment 5, IRC review of response data will no longer be 
performed.
9.2   
Independent Data Monitoring Committee
An IDMC supported by an independent statistician will review safety and efficacy data at 
1 planned interim analysis. The IDMC will provide a recommendation regarding study 
continuation based on the safety and efficacy parameters. In the event that the study is 
terminated early based on the IDMC recommendation, Millennium will notify the 
appropriate regulatory authorities. In addition, the IDMC will periodically review safety data 
at regularly scheduled meetings prespecified in the IDMC charter. As part of the IDMC 
safety monitoring, this committee will receive reports of all cases of new primary 
malignancies occurring during the trial.
The first formal safety review will occur after approximately 60 subjects (30 in each arm) 
have been randomized and receive at least 1 cycle of study treatment. Subsequently, periodic 
safety reviews will also occur as prespecified in the IDMC charter.
Study accrual will not be interrupted due to the scheduled safety reviews. The IDMC or 
MLN9708 study team may request an ad hoc meeting for any reason, including a significant 
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unexpected safety event, unplanned unblinding of study results, follow-up of an observation 
during a planned IDMC meeting, or a report external to the study, such as publication of 
study results from a competing product. At each review, subject incidence rates of AEs 
(including all serious AEs, treatment-related AEs, serious treatment-related events, and 
events requiring the discontinuation of study drug) will be tabulated by System Organ Class,
preferred term, and severity grade. Listings and/or narratives of “on-study” deaths and other 
serious and significant AEs, including any early withdrawals due to AEs, will be provided. 
Records of all meetings will be archived. The IDMC will communicate major safety 
concerns and recommendations regarding study modification or termination to Millennium. 
Further details will be provided in the IDMC charter.
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 have to have a causal relationship with study 
participation.
10.1.2   
Adverse Event Definition
Adverse event (AE) means any untoward medical occurrence in a patient or subject 
administered a pharmaceutical product; the untoward medical occurrence does not 
necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product whether 
or not it is related to the medicinal product. This includes any newly occurring event, or a 
previous condition that has increased in severity or frequency since the administration of 
study drug.
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is 
considered by the investigator to be a clinically significant change from baseline.
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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.
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.[79] Clarification should be 
made between a serious AE (SAE) and an AE that is considered severe in intensity (Grade 3 
or 4), because the terms serious and severe are NOT synonymous. The general term severe
is often used to describe the intensity (severity) of a specific event; the event itself, however, 
may be of relatively minor medical significance (such as a Grade 3 headache). This is NOT 
the same as serious, which is based on patient/event outcome or action criteria described 
above, and is usually associated with events that pose a threat to a patient’s life or ability to 
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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 need to 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 need to confirm 
successful transmission by awaiting an acknowledgment of the receipt via e-mail within 
1 business day. If SAEs are reported via fax or by e-mail, electronic data capture 
(EDC)/RAVE must be updated as soon as possible with the appropriate information.
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SAE Reporting Contact Information
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.[79] 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
AEs, both nonserious and serious, will be monitored throughout the study as follows:
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!
AEs will be reported from the first dose of study drug through 30 days after 
administration of the last dose of study drug and recorded in the eCRFs. AEs should 
be monitored until they are resolved or are clearly determined to be due to a patient’s 
stable or chronic condition or intercurrent illness(es).
!
Serious pretreatment events will be reported to the Millennium Department of 
Pharmacovigilance or designee from the time of the signing of the informed consent 
form (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. All SAEs 
should be monitored until they are resolved or are clearly determined to be due to a 
patient’s stable or chronic condition or intercurrent illness(es). In addition, all cases 
of new primary malignancy that occur during the follow-up periods must be 
immediately reported to the Millennium Department of Pharmacovigilance or 
designee, irrespective of causality to the study drug regimen, from the first dose of 
the study drug regimen through death or until termination of the study by the 
sponsor, whichever comes first. The IDMC will also receive reports of all cases of 
new primary malignancies occurring during the trial.
10.4   
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of 
age or disease state) of a female patient occurring while the patient is on study drug or 
within 90 days of the patient’s last dose of study drug are considered immediately reportable 
events. Study drug is to be discontinued immediately. The sponsor must also be contacted 
immediately by emailing or faxing a completed Pregnancy Form to the Millennium 
Department of Pharmacovigilance or designee (see Section 10.2). The pregnancy must be 
followed for the final pregnancy outcome. The pregnancy, suspected pregnancy, or positive 
pregnancy test must be reported to 
 (see Section 10.2) 
immediately by facsimile or other appropriate method, using the Pregnancy Initial Report 
Form or approved equivalent form. The female patient should be referred to an obstetrician-
gynecologist, preferably one experienced in reproductive toxicity for further evaluation and 
counseling. The pregnancy must be followed for the final pregnancy outcome. 
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The investigator will follow the female subject until completion of the pregnancy and must 
notify MPI/Cognizant/BI Medical immediately about the outcome of the pregnancy (either 
normal or abnormal outcome) using the Pregnancy Follow-up Report Form or approved 
equivalent form. 
If the outcome of the pregnancy was abnormal (eg, spontaneous or therapeutic abortion), the 
investigator should report the abnormal outcome as an AE. If the abnormal outcome meets 
any of the serious criteria, it must be reported as an SAE to 
 
immediately by facsimile or other appropriate method within 24 hours of the investigator’s 
knowledge of the event using the SAE Report Form or approved equivalent form.
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs. In addition, any infant death after 28 days that the investigator suspects 
is related to the in utero exposure to the investigational product should also be reported to 
 immediately by facsimile or other appropriate method within 24 
hours of the investigator’s knowledge of the event using the SAE Report Form or approved 
equivalent form. 
Male Subjects
If a female partner of a male subject taking investigational product becomes pregnant, the 
male subject taking study drug must notify the investigator, and the pregnant female partner 
should be advised to call her healthcare provider immediately. The sponsor must also be 
contacted immediately by 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.
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.
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11.2   
Data Quality Assurance
The investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each study 
patient. Study data will be entered into an eCRF by site personnel using a secure, validated, 
web-based EDC application. 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.
eCRFs will be completed for each study patient. It is the investigator’s responsibility to 
ensure the accuracy, completeness, clarity, and timeliness of the data reported in the
patient’s eCRF.
The investigator, or designated representative, should complete the eCRF as soon as 
possible after information is collected.
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.
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 (CD) or other electronic media will 
be placed in the investigator’s study file.
11.4   
Study Monitoring
Monitoring and auditing procedures developed or approved by Millennium will be followed 
to comply with GCP guidelines.
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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.
11.5   
Ethical Considerations
The study will be conducted in accordance with applicable regulatory requirement(s) and 
will adhere to GCP standards. The IRB/IEC will review all appropriate study documentation 
to safeguard the rights, safety, and well-being of the patients. The study will be conducted 
only at sites where IRB/IEC approval has been obtained. The protocol, IB, ICF, 
advertisements (if applicable), written information given to the patients (including diary 
cards), safety updates, annual progress reports, and any revisions to these documents will be 
provided to the IRB/IEC by the investigator or the sponsor, as allowed by local regulations.
11.6   
Patient Information and Informed Consent
After the study has been fully explained, written informed consent will be obtained from 
either the patient or his/her guardian or legal representative before study participation. The 
method of obtaining and documenting the informed consent and the contents of the consent 
must comply with the ICH-GCP and all applicable regulatory requirements.
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, 
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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.
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 Overdose)
A product complaint is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product. Individuals 
who identify a potential product complaint situation should immediately 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 
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who identify a potential medication error situation should immediately report this via the 
phone number or email address provided below.
For Prod
MLN9708
Product complaints or medication errors in and of themselves are not AEs. If a product 
complaint or a medication error results in an SAE, an SAE form should be completed and 
sent to 
 (refer to Section 10.2).
11.12   Closure of the Study
Within 90 days of the end of the study, the sponsor will notify the competent authorities and 
the IECs in all member states where the study is being carried out that the study has ended.
Within 1 year of the end of the study, a summary of the clinical trial results will be 
submitted to the competent authorities and IECs in all member states involved in the study.
Study participation by individual sites or the entire study may be prematurely terminated if, 
in the opinion of the investigator or Millennium, there is sufficient reasonable cause. Written 
notification documenting the reason for study termination will be provided to the 
investigator or Millennium by the terminating party.
Circumstances that may warrant termination include, but are not limited to:
!
Determination of unexpected, significant, or unacceptable risk to patients
!
Failure to enter patients at an acceptable rate
!
Insufficient adherence to protocol requirements
!
Insufficient, incomplete, and/or unevaluable data
!
Determination of efficacy based on interim analysis
!
Plans to modify, suspend or discontinue the development of the study drug
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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 of 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.   
INVESTIGATOR AGREEMENT
I have read Protocol C16014 Amendment 5: A Phase 3, Randomized, Double-Blind, 
Multicenter Study Comparing Oral MLN9708 Plus Lenalidomide and Dexamethasone 
Versus Placebo Plus Lenalidomide and Dexamethasone in Adult Patients With Newly 
Diagnosed Multiple Myeloma
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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13.   
USE OF INFORMATION
All information regarding MLN9708 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 MLN9708 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.
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14.   
REFERENCES
1.
Palumbo A, Anderson K. Multiple myeloma. N Engl J Med 2011;364(11):1046-60.
2.
Landgren O, Weiss BM. Patterns of monoclonal gammopathy of undetermined 
significance and multiple myeloma in various ethnic/racial groups: support for 
genetic factors in pathogenesis. Leukemia 2009;23(10):1691-7.
3.
Harousseau JL, Dreyling M, Group EGW. Multiple myeloma: ESMO clinical 
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15.   
APPENDICES
15.1   
Eastern Cooperative Oncology Group (ECOG) Scale for Performance Status
Grade
Description
0
Normal activity. Fully active, able to carry on all predisease performance without restriction
1
Symptoms but ambulatory. Restricted in physically strenuous activity, but ambulatory and 
able to carry out work of a light or sedentary nature (eg, light housework, office work)
2
In bed < 50% of the time. Ambulatory and capable of all self-care, but unable to carry out 
any work activities. Up and about more than 50% of waking hours.
3
In bed > 50% of the time. Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to 
bed or chair
5
Dead
Source: Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET al. Toxicity and response 
criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5(6):649-55.[80]
15.2   
Multiple Myeloma Diagnostic Criteria
IMWG Criteria for the Diagnosis of Myeloma
Diagnosis
Diagnostic Criteria: All Three Required
Symptomatic multiple myelomaa

Monoclonal plasma cells in the bone marrow 10% and/or 
presence of a biopsy-proven plasmacytoma

Monoclonal protein present in the serum and/or urineb

Myeloma-related organ dysfunction (1)c
[C] Calcium elevation in the blood (serum calcium 
> 10.5 mg/l 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 (non-secretory disease), then 30% monoclonal bone marrow plasma 
cells and/or a biopsy-proven plasmacytoma required.
c
A variety of other types of end-organ dysfunctions can occasionally occur and lead to a need for therapy. 
Such dysfunction is sufficient to support classification as myeloma if proven to be myeloma related.
d If a solitary (biopsy-proven) plasmacytoma or osteoporosis alone (without fractures) is the sole defining 
criteria, then 30% plasma cells are required in the bone marrow.
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15.3   
Cockcroft-Gault Equation to Calculate the Creatinine Clearance
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.[81]
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15.4   
ISS Staging Criteria and Durie-Salmon Criteria
International Staging System
Stage
Criteria
Stage I
Serum 2-microglobulin < 3.5 mg/L
Serum albumin 3.5 g/dL
Stage II
Neither Stage I or Stage IIIa
Stage III
Serum 2-microglobulin 5.5 mg/L 
Source: Durie BG, Salmon SE. A clinical staging system for multiple myeloma. Correlation of measured 
myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer 
1975;36(3):842-54.[82]
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.
Durie-Salmon Criteria
Stage
Criteria
I
All of the following:

Hemoglobin value > 10 g/dL 

Serum calcium value normal or 12 mg/dL 

Bone x-ray, normal bone structure (scale 0) 
or solitary bone plasmacytoma only 

Low M component production rate
o
IgG value < 5 g/dL; IgA value 
< 3 g/dL 
Bence Jones protein < 4 g/24 h
II
Neither stage I nor stage III
III
1 or more of the following:

Hemoglobin value < 8.5 g/dL 

Serum calcium value > 12 mg/dL 

Advanced lytic bone lesions (scale 3) 

High M component production rate
o
IgG value > 7 g/dL; IgA value > 5 
g/dL
o
Bence Jones protein >12 g/24 h
Durie-Salmon sub classifications (either A or B). 
A: Relatively normal renal function (serum creatinine value < 2.0 mg/dL)
B: Abnormal renal function (serum creatinine value 2.0 mg/dL)
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15.5   
Steroid Equivalent Doses
Approximately 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.[83]
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15.6   
World Health Organization Steps of Analgesics and OME Conversions
15.6.1   
Steps of Analgesics
Table 15-1
Pain Medication List Categorized by World Health Organization 
(WHO) Steps I, II, and III
WHO Step I
ACETAMINOPHEN & ASPIRIN
ACETAMINOPHEN & ASPIRIN & CAFFEINE
ACETAMINOPHEN & BUTALBITAL
ACETAMINOPHEN & BUTALBITAL & CAFFEINE
ACETAMINOPHEN & CAFFEINE
ACETAMINOPHEN CAP 500 MG
ACETAMINOPHEN CHEW TAB 80, 160 MG
ACETAMINOPHEN ELIXIR 80, 120 or 160 MG/5ML
ACETAMINOPHEN SOLN 100 MG/ML, 120 MG/2.5ML, 130 MG/5 ML, 160 MG/5ML
ACETAMINOPHEN SUPPOS 120 MG, 325 MG, 650 MG
ACETAMINOPHEN SUSP 80, 160 MG/5ML
ACETAMINOPHEN TAB 160, 325, 500, 650 MG
ACETAMINOPHEN TAB CR 650 MG
ACETAMINOPHEN W/ CALCIUM CARBONATE TAB 500-250 MG
ACETAMINOPHEN-BUTALBITAL CAP 650-50 MG
ACETAMINOPHEN-BUTALBITAL TAB 325-50 MG
ACETAMINOPHEN-BUTALBITAL TAB 650-50 MG
ACETAMINOPHEN-CAFFEINE-BUTALBITAL CAP 325-40-50 MG; 325-40-50 MG; 500-4-50 MG
ALUMINUM GLYCOLATE & ASPIRIN & MAGNESIUM CARBONATE
ALUMINUM HYDROXIDE & ASPIRIN & MAGNESIUM HYDROXIDE
ASPIRIN & BUTALBITAL & CAFFEINE
ASPIRIN & BUTALBITAL & CAFFEINE & PHENACETIN
ASPIRIN & CAFFEINE
ASPIRIN & CAFFEINE & PHENACETIN
ASPIRIN & PHENOBARBITAL
ASPIRIN BUFFERED (MG CARBONATE-AL GLYCINATE) TAB 325 MG
ASPIRIN BUFFERED (MG CARBONATE-AL GLYCINATE) TAB 500 MG
ASPIRIN BUFFERED TAB 325 MG; 500 MG
ASPIRIN CHEW TAB 75 MG
ASPIRIN EC TAB 81; 165; 325; 500;650;975 MG
ASPIRIN TAB 325; 500; 650 MG
ASPIRIN TAB CR 800 MG
ASPIRIN-ACETAMINOPHEN TAB 325-325 MG
ASPIRIN-ACETAMINOPHEN-CAFFEINE POWDER 260-130-16 MG
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Table 15-1
Pain Medication List Categorized by World Health Organization 
(WHO) Steps I, II, and III
ASPIRIN-ACETAMINOPHEN-CAFFEINE TAB 230-125-30 MG;240-125-32 MG
ASPIRIN-ACETAMINOPHEN-CAFFEINE TAB 250-250-65 MG
ASPIRIN-AL HYDRO-MG HYDRO-CA CARB TAB 325-50-50-87 MG; 325-75-75-71 MG; 500-80-80-
71 MG
ASPIRIN-AL HYDROXIDE-MG HYDROXIDE TAB 325-150-150 MG
ASPIRIN-AL HYDROXIDE-MG HYDROXIDE TAB 325-75-75 MG
ASPIRIN-APAP-CAFFEINE-CALCIUM GLUCONATE TAB 230-160-33-60 MG
ASPIRIN-BUTALBITAL TAB 650-50 MG
ASPIRIN-CAFFEINE TAB 400-30 MG; 500-30 MG
ASPIRIN-CAFFEINE-BUTALBITAL CAP 200-40-50 MG; 325-40-50 MG; 200-4-50 MG; 325-40-50 MG
ASPIRIN-CAL CARB-MAG OXIDE TAB 325-158-34-63 MG
ASPIRIN & PHENYLTOLOXAMINE CITRATE & SALSALATE
ASPIRIN EFFER TAB 325, 500 MG
ASPIRIN GUM 210 MG
ASPIRIN SUPPOS 125; 325; 650 MG
APC TAB 260-130-15 MG
BENOXAPROFEN
CHOLINE & MAGNESIUM SALICYLATES LIQ 500 MG/5ML
CHOLINE & MAGNESIUM SALICYLATES TAB 500, 750, 1000 MG
CHOLINE MAGNESIUM TRISALICYLATE
CHOLINE SALICYLATE
CINNAMEDRINE
DICLOFENAC POTASSIUM TAB 50 MG
DICLOFENAC SODIUM EC TAB 25, 50, 75 MG
DIFLUNISAL TAB 250, 500 MG
DIHYDROXYALUMINUM AMINOACETATE
ETHOHEPTAZINE CITRATE
ETODOLAC CAP 200, 300, 400 MG
FENOPROFEN CALCIUM CAP 200, 300, 600 MG
FLURBIPROFEN TAB 50, 100 MG
IBUPROFEN CHEW TAB 100 MG
IBUPROFEN POWDER
IBUPROFEN SUSP 100 MG/5ML
IBUPROFEN SUSP 40 MG/ML
IBUPROFEN TAB 100,200,300,400,600,800 MG
INDOMETHACIN CAP 25,50, 75 MG
INDOMETHACIN SODIUM IV FOR SOLN 1 MG
INDOMETHACIN SUPPOS 50 MG
INDOMETHACIN SUSP 25 MG/5ML
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Table 15-1
Pain Medication List Categorized by World Health Organization 
(WHO) Steps I, II, and III
KETOPROFEN CAP 12.5, 25, 50, 75 MG
KETOPROFEN CAP CR 100, 150,200 MG
KETOROLAC TROMETHAMINE IM INJ 15, 30 MG/ML
KETOROLAC TROMETHAMINE TAB 10 MG
MAGNESIUM SALICYLATE TAB 500, 545, 600 MG
MAGNESIUM TRISILICATE
MECLOFENAMATE SODIUM CAP 50, 100 MG
MEFENAMIC ACID CAP 250 MG
MEPROBAMATE
METHOTRIMEPRAZINE HYDROCHLORIDE
NABUMETONE TAB 500, 750 MG
NAPROXEN SODIUM TAB 220, 275,550 MG
NAPROXEN SUSP 125 MG/5ML
NAPROXEN TAB 250, 375,500 MG
OXYPHENBUTAZONE
OXAPROZIN TAB 600 MG
PAMABROM
PHENYLBUTAZONE
PHENYLTOLOXAMINE
PHENYLTOLOXAMINE CITRATE
PIROXICAM CAP 10, 20 MG
PYRILAMINE
PYRILAMINE MALEATE
SALICYLAMIDE
SALSALATE TAB 500, 750 MG
SODIUM SALICYLATE TAB 325, 650 MG
SODIUM THIOSALICYLATE
SODIUM THIOSALICYLATE INJ 50 MG/ML
SULINDAC TAB 150, 200 MG
SUPROFEN
TOLMETIN SODIUM TAB 200, 400, 600 MG
ZOMEPIRAC SODIUM
WHO Step II
ACETAMINOPHEN & BUTALBITAL & CAFFEINE & CODEINE PHOSPHATE
ACETAMINOPHEN & HYDROCODONE BITARTRATE
ACETAMINOPHEN & OXYCODONE HYDROCHLORIDE
ACETAMINOPHEN & PROPOXYPHENE HYDROCHLORIDE
ACETAMINOPHEN & PROPOXYPHENE NAPSYLATE
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Table 15-1
Pain Medication List Categorized by World Health Organization 
(WHO) Steps I, II, and III
ACETAMINOPHEN W/ CODEINE CAP 300-30 MG
ACETAMINOPHEN W/ CODEINE ELIXIR 120-12 MG/5ML
ACETAMINOPHEN W/ CODEINE TAB 300-15 MG; 300-30 MG; 300-60 MG; 300-7.5 MG; 650-30 MG
ACETAMINOPHEN W/ HYDROCODONE CAP 500-5 MG
ACETAMINOPHEN W/ HYDROCODONE ELIXIR 167-2.5 MG/5ML; 120-2.5 MG/5ML
ACETAMINOPHEN W/ HYDROCODONE TAB 500-2.5 MG;500-5 MG; 500-7.5 MG; 650-10 MG; 650-
7.5 MG; 750-7.5 MG
ACETAMINOPHEN-CAFF-BUTALBITAL W/ COD CAP 325-40-50-30 MG
ACETAMINOPHEN-CAFFEINE-DIHYDROCODEINE CAP 356.4-30-16 MG
AL. HYDROXIDE & ASPIRIN & CODEINE PHOSPHATE & MG. HYDROXIDE
ASPIRIN & BUTALBITAL & CAFFEINE & CODEINE
ASPIRIN & BUTA & CAFF & CODEINE PHOSPHATE & PHENACETIN
ASPIRIN & CAFFEINE & CODEINE PHOSPHATE & PHENACETIN
ASPIRIN & CAFFEINE & HYDROCODONE BITARTRATE
ASPIRIN & CAFFEINE & PHENACETIN & PROPOXYPHENE HYDROCHLORIDE
ASPIRIN & CAFFEINE & PROPOXYPHENE HYDROCHLORIDE
ASPIRIN & CODEINE PHOSPHATE
ASPIRIN & PROPOXYPHENE HYDROCHLORIDE
ASPIRIN & PROPOXYPHENE NAPSYLATE
ASPIRIN W/ CODEINE TAB 325-15 MG; 325-30 MG; 325-60 MG
ASPIRIN W/ HYDROCODONE TAB 500-5 MG
ASPIRIN-CAFF-BUTALBITAL W/ CODEINE CAP 325-40-50-30 MG
ATROPINE SULFATE & MEPERIDINE HYDROCHLORIDE
ATROPINE SULFATE & MORPHINE SULFATE
BUPRENORPHINE HCL INJ 0.324 MG/ML
BUPRENORPHINE HYDROCHLORIDE
BUTORPHANOL TARTRATE INJ 1 MG/ML; 2 MG/ML
BUTORPHANOL TARTRATE NASAL SOLN 10 MG/ML
DEZOCINE INJ 10, 15 MG/ML
DIHYDROCODEINE COMPOUND CAP
MEPERIDINE W/ APAP TAB 50-300 MG
MEPERIDINE W/ ATROPINE INJ 50-0.4 MG/ML; 75-0.4 MG/ML
NALBUPHINE HCL INJ 10, 20 MG/ML
NALOXONE
NALTREXONE HCL TAB 50 MG
OXYCODONE W/ ACETAMINOPHEN SOLN 5-500 MG/5ML
OXYCODONE W/ ACETAMINOPHEN 5-325; 5-500 MG
OXYCODONE W/ ASPIRIN TAB FULL/half STRENGTH
OXYCODONE TEREPHTHALATE
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Table 15-1
Pain Medication List Categorized by World Health Organization 
(WHO) Steps I, II, and III
PENTAZOCINE LACTATE INJ 30 MG/ML
PENTAZOCINE W/ APAP TAB 25-650 MG;12.5-325 MG
PROMAZINE HCL
PROMETHAZINE HCL (CAP & INJ)
PROPOXYPHENE COMPOUND CAP 65 MG
PROPOXYPHENE HCL W/ APAP TAB 65-650 MG;100-650 MG; 50-325 MG
WHO Step III
ALFENTANIL INJ 500 MCG/ML
CODEINE PHOSPHATE INJ 30, 60 MG/ML
CODEINE PHOSPHATE SOLN 15 MG/5ML
CODEINE PHOSPHATE SOLUBLE TAB 30, 60 MG
CODEINE SULFATE
CODEINE SULFATE TAB 30, 60 MG
FENTANYL CITRATE INJ 0.05 MG/ML
FENTANYL CITRATE POWDER
FENTANYL TD SYS 25, 50, 75, 100 MCG/HR
HYDROCODONE BITARTRATE
HYDROMORPHONE HCL INJ 1,2,3,4, 10 MG/ML
HYDROMORPHONE HCL LIQD 1 MG/ML
HYDROMORPHONE HCL POWDER
HYDROMORPHONE HCL SUPPOS 3 MG
HYDROMORPHONE HCL TAB 2,3,4,8 MG
LEVOMETHADYL ACETATE HCL SOLN 10 MG/ML
LEVORPHANOL TARTRATE INJ 2 MG/ML
LEVORPHANOL TARTRATE TAB 2 MG
MEPERIDINE HCL INJ 25, 50, 75, 100 MG/ML
MEPERIDINE HCL SYRUP 50 MG/5ML
MEPERIDINE HCL TAB 50, 100 MG
METHADONE HCL CONC 10 MG/ML
METHADONE HCL SOLN 5, 10 MG/5ML
METHADONE HCL TAB 5, 10, 40 MG
METHADONE HYDROCHLORIDE
MORPHINE SULFATE CAP 15, 30 MG
MORPHINE SULFATE IN DEXTROSE INJ 0.2 MG/ML
MORPHINE SULFATE IN DEXTROSE INJ 1 MG/ML
MORPHINE SULFATE INJ 1,2,3,4,5,8, 10,15,25,50 MG/ML
MORPHINE SULFATE INJ PF 0.5, 1 MG/ML
MORPHINE SULFATE ORAL SOLN 10, 20 MG/5ML; 20 MG/ML
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Table 15-1
Pain Medication List Categorized by World Health Organization 
(WHO) Steps I, II, and III
MORPHINE SULFATE SUPPOS 5, 10, 20, 30 MG
MORPHINE SULFATE TAB 10, 15, 30 MG
MORPHINE SULFATE TAB CR 15, 20,60,100,200 MG
OXYCODONE HCL CONC 20 MG/ML
OXYCODONE HCL SOLN 5 MG/5ML
OXYCODONE HCL TAB 5 MG
OXYCODONE HYDROCHLORIDE
OXYMORPHONE HCL INJ 1 MG/ML
OXYMORPHONE HCL SUPPOS 5 MG
OXYMORPHONE HYDROCHLORIDE
PROPOXYPHENE HCL CAP 65 MG
PROPOXYPHENE NAPSYLATE SUSP 50 MG/5ML
PROPOXYPHENE NAPSYLATE TAB 100 MG
SUFENTANIL CITRATE INJ 50 MCG/ML
TRAMADOL HCL TAB 50 MG
Source: World Health Organization. Cancer Pain Relief. Geneva: World Health Organization, 1986.[84]
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15.6.2   
Oral Morphine Equivalent (OME) Conversions
Table 15-2
Oral and Parenteral Opioid Equivalences and Relative Potency of 
Drugs as Compared With Morphine
Opioid Agonistsa
Oral Dose
(mg)
Parenteral Dose
(mg)
Factor
(IV to PO)
Morphineb
30b
10
3
Codeine
200
130
1.5
Fentanylc
0.1 (100 g)
Hydrocodone
30 to 200
Hydromorphone
7.5
1.5
5
Levorphanol
4
2
2
Oxycodone
15 to 20
Oxymorphone
10
1
10
Tramadold
50 to 100
Source: Adapted from the National Comprehensive Cancer Network (NCCN) Practice Guidelines in 
Oncology, Adult Cancer Pain, V.1.2010.[85]
a Opioid drugs NOT recommended include meperidine, methadone, propoxyphene, partial agonists 
(buprenorphine), and mixed agonist-antagonists (pentazocine, nalbuphine, butorphanol, dezocine).
b Oral morphine equivalent (OME) score is based on an oral morphine dose of 30 mg; the conversion
factor listed is for chronic dosing. Avoid using morphine in renal failure.
c Available in transdermal system for extended dosing. See the calculation below for dose conversion from 
other opioids to transdermal fentanyl.
d Weak opioid receptor agonist with some antidepressant activity; for mild to moderate pain. 
Recommended dose of 100 mg 4 times daily (maximum daily dose of 400 mg) to avoid central nervous 
system toxicity. At maximum dose, tramadol is less potent than other opioid analgesics.
Oral Morphine Equivalence Conversion Calculation
To calculate the OME score of an opioid in Table 15-2:
X dose of an opioid equivalent to an oral morphine dose of 30 mg
Y dose of that opioid consumed by the patient in the last 24 hours
OME of that opioid consumed in the last 24 hours Y / X 30
Example: A patient consumed 100 mg of oral codeine in the last 24 hours. The OME 
calculation is:
X 200 mg
Y 100 mg
OME of oral codeine 100 / 200 30 15 mg
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Table 15-3
Recommended Dose Conversion From Other Opioids to Transdermal 
Fentanyl
Transdermal
Fentanyl
(g/d)
Morphine
Oxycodone
Hydromorphone
Codeine
Orala
(mg/d)
IV/SubQb
(mg/d)
Oral
(mg/d)
IV/Sub
Q
(mg/d)
Oral
(mg/d)
IV/Sub
Q
(mg/d)
Oral
(mg/d)
IV/Sub
Q
(mg/d)
25
60
20
30
15
7.5
1.5
200
130
50
120
40
60
30
15
3.0
400
260
75
180
60
90
45
22.5
4.5
600
390
100
240
80
120
60
30.0
6.0
800
520
Source: Adapted from the National Comprehensive Cancer Network (NCCN) Practice Guidelines in 
Oncology, Adult Cancer Pain, V.1.2010.[85]
Due to patient variability the recommended doses are estimates; clinical judgment should be used to titrate 
to the desired response. 
a Oral morphine equivalent (OME) score is based on an oral morphine dose of 60 mg (as adapted from 
Foley KM. The treatment of cancer pain. NEJM 1985; 313:84-95 [86]).
b Parenteral dosing such as intravenous or subcutaneous.
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15.7   
EQ-5D
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15.8   
Brief Pain Inventory-Short Form (BPI-SF)
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15.9   
QLQ-MY20
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15.10   European Organization for Research and Treatment of Cancer 
(EORTC QLQ-C30 (Version 3)
Please go on to the next page
EORTC QLQ-C30 (version 3)
We are interested in some things about you and your health. Please answer all of the questions
yourself by circling the number that best applies to you. There are no "right" or "wrong"
answers. The information that you provide will remain strictly confidential.
Please fill in your initials:
Your birthdate (Day, Month, Year):
Today's date (Day, Month, Year): 
Not at
A
Quite Very
all
little
a bit much
1.
Do you have any trouble doing strenuous activities,
like carrying a heavy shopping bag or a suitcase?
1
2
3
4
2.
Do you have any trouble taking a long walk?
1
2
3
4
3.
Do you have any trouble taking a shortwalk outside
of the house?
1
2
3
4
4.
Do you need to stay in bed or a chair during the day?
1
2
3
4
5. Do you need help with eating, dressing, washing
yourself or using the toilet?
1
2
3
4
During the past week:
Not at
A
Quite Very
All
little
a bit much
6. Were you limited in doing either your work or other
daily activities?
1
2
3
4
7. Were you limited in pursuing your hobbies or other
leisure time activities?
1
2
3
4
8. Were you short of breath?
1
2
3
4
9. Have you had pain?
1
2
3
4
10. Did you need to rest?
1
2
3
4
11. Have you had trouble sleeping?
1
2
3
4
12. Have you felt weak?
1
2
3
4
13. Have you lacked appetite?
1
2
3
4
14. Have you felt nauseated?
1
2
3
4
15. Have you vomited?
1
2
3
4
16. Have you been constipated?
1
2
3
4
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© Copyright 1995 EORTC Quality of Life Study Group.  All rights reserved.  Version 3.0
During the past week:
Not at
A
Quite
Very
all
little
a bit
much
17. Have you had diarrhea?
1
2
3
4
18. Were you tired?
1
2
3
4
19. Did pain interfere with your daily activities?
1
2
3
4
20. Have you had difficulty in concentrating on things,
like reading a newspaper or watching television?
1
2
3
4
21. Did you feel tense?
1
2
3
4
22. Did you worry?
1
2
3
4
23. Did you feel irritable?
1
2
3
4
24. Did you feel depressed?
1
2
3
4
25. Have you had difficulty remembering things?
1
2
3
4
26. Has your physical condition or medical treatment
interfered with your family life?
1
2
3
4
27. Has your physical condition or medical treatment
interfered with your social activities?
1
2
3
4
28. Has your physical condition or medical treatment
caused you financial difficulties?
1
2
3
4
For the following questions please circle the number between 1 and 7 that
best applies to you
29. How would you rate your overall health during the past week?
1
2
3
4
5
6
7
 Very poor
         Excellent
30. How would you rate your overall quality of life during the past week?
1
2
3
4
5
6
7
 Very poor
         Excellent
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15.11   Response Criteria [72]
Patients will be assessed for disease response according to the IMWG criteria below, 
version 2011.
For VGPR: Disappearance of any soft tissue plasmacytomas present at baseline and no new plasmacytomas.
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International Myeloma Working Group Uniform Response Criteria: Disease 
Progression and Relapse [72]
Relapse Subcategory
Relapse Criteria
PDa
To be used for calculation of 
time to progression and PFS 
endpoints for all subjects, 
including those in CR (includes 
primary progressive disease 
and disease progression on or 
off therapy)
PD: requires any 1 or more of the following:
Increase of 25% from nadir in
Serum M-component and/or (the absolute increase must be 
0.5 g/dL)b
Urine M-component and/or (the absolute increase must be 
200 mg/24 h
Only in subjects without measurable serum and urine M-protein 
levels: the difference between involved and uninvolved FLC levels. 
The absolute increase must be > 10 mg/dL
Bone marrow plasma cell percentage: the absolute % must be 10%
Definite development of new bone lesions or soft tissue 
plasmacytomas or definite increase in the size of existing bone lesions 
or soft tissue plasmacytomas
Development of hypercalcemia (corrected serum calcium 
> 11.5 mg/dL or 2.85 mmol/L) that can be attributed solely to the 
plasma cell proliferative disorder
Abbreviations: CR = complete response; PFS= progression-free survival.
a All relapse categories require 2 consecutive assessments made at any time before classification as relapse 
or disease progression and/or the institution of any new therapy.
b For progressive disease, serum M-component increases of 1 g/dL are sufficient to define relapse if 
starting M-component is 5 g/dL.
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15.12   Full Schedule of Events and PK Sampling Schedule (Schedules Prior to Implementation of Amendment 5)
SCHEDULE OF EVENTS
Study Procedures
Screening
Treatment Period
End of Treatmenta
Follow-up
28-Day Cycles
PFS
OS
Cycle
C1
C1
C1
C1
C2
C2
C2
C2
C3
C3
C4 
Through 
12
C13 
and 
Beyond
Every 
4 weeks
Every 
12 weeks
Days
-28 to -1
1
7
14
21
1
7
14
21
1
14
1
1
Window
± 2 days
+1 wk
± 1 wk
± 1 wk
Informed Consent
Xb
Inclusion/Exclusion Criteriac
X
Demographics
X
Complete Medical History 
and Disease Staging
X
Complete Physical Exam
X
X
Symptom-Directed Physical 
Exam
X
X
X
X
X
X
ECOG Performance Status
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
Height (cm)
X
Weight (kg)
X
X
X
Xd
Xd
X
X
Pregnancy Teste
X
X
X
X
X
X
X
X
X
X
12-lead ECG 
X
X
Hematology Panelf
X
X
Xg
X
X g
X
X g
X
X g
X
X
X
X
X
Chemistry Panelf
X
X
X
X
X
X
X
Thyroid Function Testing
X
Xh
Xh
X
Urinalysis
X
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MLN9708
Clinical Study Protocol C16014 Amendment 5, 2013-000326-54, 09 July 2020
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Study Procedures
Screening
Treatment Period
End of Treatmenta
Follow-up
28-Day Cycles
PFS
OS
Cycle
C1
C1
C1
C1
C2
C2
C2
C2
C3
C3
C4 
Through 
12
C13 
and 
Beyond
Every 
4 weeks
Every 
12 weeks
Days
-28 to -1
1
7
14
21
1
7
14
21
1
14
1
1
Window
± 2 days
+1 wk
± 1 wk
± 1 wk
EORTC-QLQ-C30 and 
MY-20i
X
X
X
Xj
Xj
X
X
EQ-5Di
X
X
X
X
X
X
X
X
Xk
Pain Assessment: BPI-SF & 
24-hour analgesic form (also
for unscheduled visit)i
X
X
X
X
X
X
X
X
HU Assessment (also for 
unscheduled visits)i
X
X
X
X
X
X
X
Xk
Bone Mineral Density 
(DEXA) scan
Xl
Xl
Xl
Xl
Skeletal Survey
X
Xm
Xm
Radiographic Disease 
Assessmentn
X
X
X
X
X
X
2-microglobulin
X
M-protein Measurements 
(SPEP)p
X
Xo
X
X
X
X
X
X
M-protein Measurements 
(UPEP [24hr Urine 
collection])p
X
Xo
X
X
X
X
X
X
Serum Free Light Chain
Assay p
X
Xo
X
X
X
X
X
X
Immunofixation - serum and 
urinep
X
Xo
X
X
X
X
X
X
Quantification of Igq
X
Xo
X
X
X
X
X
X
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MLN9708
Clinical Study Protocol C16014 Amendment 5, 2013-000326-54, 09 July 2020
Confidential
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Study Procedures
Screening
Treatment Period
End of Treatmenta
Follow-up
28-Day Cycles
PFS
OS
Cycle
C1
C1
C1
C1
C2
C2
C2
C2
C3
C3
C4 
Through 
12
C13 
and 
Beyond
Every 
4 weeks
Every 
12 weeks
Days
-28 to -1
1
7
14
21
1
7
14
21
1
14
1
1
Window
± 2 days
+1 wk
± 1 wk
± 1 wk
Bone Marrow Aspiration
Disease Assessment
Xr
Xr
Xr
Xr
Xr
Xr
Xr
Molecular Analysis and 
Cytogenetics 
Xs, t
Xs
Minimal Residual Disease
To be done at any time if CR is suspectedu
Xu
Adverse Event Reporting
Recorded from the first dose of drug in the study drug regimen through 30 days after last dose of 
drug in the study drug regimenw
Serious adverse events and serious pretreatment events will be collected from signing of the 
informed consent form through 30 days after the last dose of drug in the study drug regimen
Concomitant 
Medications/Procedures
Recorded from the first dose of drug in the study drug regimen through 30 days after last dose of 
drug in the study drug regimen
Skeletal-related Events
Continuous from the start of study drug regimen administration until death or termination of the study by the sponsor
Narcotic and Other Analgesic 
Use
Recorded from the first dose of study drug regimen until confirmed progressive disease
New Primary Malignancy 
Reporting
Continuous from the start of study drug regimen administration until death or termination of the study by the sponsor
Property
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inform
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CCI
CCI


MLN9708
Clinical Study Protocol C16014 Amendment 5, 2013-000326-54, 09 July 2020
Confidential
158
Study Procedures
Screening
Treatment Period
End of Treatmenta
Follow-up
28-Day Cycles
PFS
OS
Cycle
C1
C1
C1
C1
C2
C2
C2
C2
C3
C3
C4 
Through 
12
C13 
and 
Beyond
Every 
4 weeks
Every 
12 weeks
Days
-28 to -1
1
7
14
21
1
7
14
21
1
14
1
1
Window
± 2 days
+1 wk
± 1 wk
± 1 wk
Subsequent Therapy/ Disease 
Statusx
X
Survival
X
Study Drug Regimen Administrationy
MLN9708/Placebo
Days 1, 8, and 15 of each cycle
Lenalidomide
Continuous Days 1-21 of each cycle
Dexamethasone
Days 1, 8, 15, and 22 of each cycle
Abbreviations: D = study day; del = deletion; ECOG = Eastern Cooperative Oncology Group; OS = overall survival; PFS = progression-free survival; SPEP = serum 
protein electrophoresis; t = translocation; UPEP = urine protein electrophoresis; wk = week;
Tests and procedures should be performed on schedule, but occasional changes may be allowed (± 2 days or a longer window after discussion with the Millennium 
project clinician or designee) for holidays, vacations, and other administrative reasons. If the study schedule is shifted, assessments must be shifted to ensure that 
collection of assessments is completed prior to dosing. 
a Quality Review by MPI/designee clinician required prior to discontinuing patient from treatment for progressive disease. A treatment discontinuation form must be 
submitted and approved prior to removing a patient from study treatment for disease progression, toxicity, or any other reason. 
b Informed consent may be obtained before the 28-day Screening period and must be documented before initiating any screening procedures. 
c Confirmation of patient eligibility by MPI/designee clinician required prior to randomization.
d Weight to be taken Day 1 of each cycle.
e Pregnancy tests:

Screening for all countries except Canada: Females of childbearing potential (FCBP) are required to have TWO medically supervised negative pregnancy tests 
(serum or urine with sensitivity of at least 25 mIU/mL), even if continuous abstinence is the chosen method of contraception, prior to the first dose of 
lenalidomide. One test must be obtained within 10-14 days and the other test must be obtained within 24 hours prior to the start of the study drug regimen at 
Cycle 1, Day 1.

Screening for Canada: FCBP are required to have TWO medically supervised negative serum pregnancy tests with sensitivity of at least 25 mIU/mL, even if 
continuous abstinence is the chosen method of contraception, prior to the first dose of lenalidomide. One test must be obtained within 7–14 days and the other 
test within 24 hours prior to the start of the study drug regimen at Cycle 1, Day 1.
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MLN9708
Clinical Study Protocol C16014 Amendment 5, 2013-000326-54, 09 July 2020
Confidential
159
Study Procedures
Screening
Treatment Period
End of Treatmenta
Follow-up
28-Day Cycles
PFS
OS
Cycle
C1
C1
C1
C1
C2
C2
C2
C2
C3
C3
C4 
Through 
12
C13 
and 
Beyond
Every 
4 weeks
Every 
12 weeks
Days
-28 to -1
1
7
14
21
1
7
14
21
1
14
1
1
Window
± 2 days
+1 wk
± 1 wk
± 1 wk

On Treatment: Pregnancy tests for FCBP to be collected weekly during Cycle 1 and then within 24 hours of beginning each subsequent cycle. Lenalidomide 
package insert must be followed while patients remain on therapy. If menstrual cycles are irregular, the pregnancy testing must occur weekly for the first 28 days 
and then every 14 days while on therapy. For Canada: all pregnancy tests must be performed using serum with a sensitivity of at least 25 mIU/mL.

End of Treatment: Pregnancy for FCBP to be collected at treatment discontinuation and at Day 28 following drug discontinuation (± 1 wk window for other end 
of treatment assessments does NOT apply). If menstrual cycles are irregular, the pregnancy testing must occur at drug discontinuation and at Days 14 and 28 
following drug discontinuation. For Canada: all pregnancy tests must be performed using serum with a sensitivity of at least 25 mIU/mL.
f
Clinical laboratory evaluations will be performed by a central laboratory. For on study treatment dosing decisions, local hematology and chemistry laboratory results 
may be used; however, samples must still be sent to the central laboratory in parallel. The central laboratory results will be used for determination of eligibility 
criteria. Patients may have central laboratory assessments repeated when discrepant results between the central and local laboratories are observed. Hematology and 
chemistry panels may be collected up to 3 days before Day 1 dosing and 24 hours before Days 8, 15, and 22 dosing, where required. Local laboratory evaluations
may be done more frequently at the investigators discretion, ie for acute management of treatment-emergent adverse events. 
g Patients who live a far distance from the study center or who have other logistical difficulties may have the Cycles 1 and 2, Days 7 and 21 CBC blood draw done by 
a local laboratory, upon consultation and approval with the investigator.
h Thyroid function testing required every 4 cycles on treatment.
i
Patient-reported outcomes and HU assessment (ie, number of medical encounters) should be completed before any other study procedures are performed or study 
drug regimen is administered. 
j
Required every other cycle after Cycle 2 (ie, Cycles 1, 2, 4, 6, etc.) during the treatment period.
k During the OS follow-up, assessments can be made over the phone and do not require a clinic visit. 
l
Dual-energy X-ray absorptiometry (DEXA) scans will be done of the lumbar spine and femoral neck at screening (the DEXA scan does not need to be repeated if 
already performed within 8 weeks of randomization), 6 months, 1 year, and then annually until progressive disease (4 weeks at the corresponding study visit to 
approximately 6 or every 12 months of treatment).
m Skeletal survey will be performed at screening (within 8 weeks prior to randomization) and a minimum of every 12 months from randomization until disease 
progression for all patients. More frequent radiological assessments can be done at the discretion of the investigator (ie, for suspected increased or new bone lesions).
n Patients with documented extramedullary disease must have radiographic disease assessments (CT/PET-CT/MRI) performed at screening, every other cycle during 
treatment until PD, and every 8 weeks during the PFS follow-up period until PD for patients who permanently discontinue study drug regimen before PD. Modality 
should be kept consistent throughout. Screening evaluations may be performed within 8 weeks prior to randomization.
o If the screening test was performed more than 14 days prior to the first dose, the test will be repeated at baseline.
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MLN9708
Clinical Study Protocol C16014 Amendment 5, 2013-000326-54, 09 July 2020
Confidential
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Study Procedures
Screening
Treatment Period
End of Treatmenta
Follow-up
28-Day Cycles
PFS
OS
Cycle
C1
C1
C1
C1
C2
C2
C2
C2
C3
C3
C4 
Through 
12
C13 
and 
Beyond
Every 
4 weeks
Every 
12 weeks
Days
-28 to -1
1
7
14
21
1
7
14
21
1
14
1
1
Window
± 2 days
+1 wk
± 1 wk
± 1 wk
p SPEP, UPEP, serum free light chain assay, and immunofixation to be done on Day 1 of every cycle and at the End of Treatment visit until PFS significance has been 
claimed for this study. At that time, central efficacy and investigator assessments for protocol purposes will be stopped and not recorded in the eCRF, except for 
investigator assessment of PFS2. For patients who discontinue study treatment prior to PD, assessments will be done every 4 weeks during the PFS follow-up period 
until PD, the start of another anticancer therapy, or PFS significance has been claimed for this study.
q Blood samples for quantification of immunoglobulins (IgM, IgG, IgA) will be obtained throughout the study at the time points specified until PFS significance has 
been claimed for this study. Quantitative IgD and IgE will be done at screening (and baseline if needed) only. For the rare patient with IgD or IgE multiple myeloma, 
the quantitative test for that antibody will be followed at the same time points as quantitative Igs (in addition to IgM, IgG, and IgA).
r
To be performed at local lab to assess disease status within 8 weeks of randomization. Only to be repeated if patient is considered to possibly have resolution of 
serum and urine M-protein consistent with CR or to investigate suspected PD if applicable.
s Bone marrow aspirate (first or second pull preferred) for molecular analysis and cytogenetics are required to be collected and sent to the central lab within 8 weeks 
of randomization. An additional bone marrow aspirate at relapse, only for patients who initially respond and then relapse, should be collected. This additional sample 
is optional, but highly recommended.
t
Additional cytogenetics may also be done locally (optional) if the site has the capability to perform analysis and sufficient specimen available. Assessment of the 
following should be obtained if possible: amp(1q21), translocations t(4;14) and t(14;16), and del(17p).
u
Bone marrow aspirate to be collected for assessment of MRD in all patients suspected to have reached CR anytime during the entire conduct of the study. In 
addition, a repeat bone marrow aspirate for MRD assessment will be collected at Cycle 18 for only the patients who have maintained a CR until that point (this
sample can be collected up to 4 weeks after Cycle 18). If a patient has had MRD testing because of a suspected CR within 2 cycles of Cycle 18, then this repeat 
MRD assessment does not need to be performed. Samples are required to be sent to central lab for analysis.
v
w If peripheral neuropathy is present at baseline, the Common Toxicity Criteria for Adverse Events (CTCAE) grade must be reported in the patient’s medical history.
When PN occurs during active treatment on study, each subsequent monthly evaluation will record the CTCAE grade of peripheral neuropathy at that visit. (This is 
in contrast to other AEs where only increases in grade are recorded until the maximum grade is reached and then followed at that grade until complete resolution or 
return to baseline.)  Peripheral neuropathy will be followed every 4 weeks until 1) resolution of peripheral neuropathy, 2) the start of a second-line alternative 
antineoplastic treatment, or 3) 6 months after disease progression has occurred, whichever occurs first.
Property o
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CCI


MLN9708
Clinical Study Protocol C16014 Amendment 5, 2013-000326-54, 09 July 2020
Confidential
161
Study Procedures
Screening
Treatment Period
End of Treatmenta
Follow-up
28-Day Cycles
PFS
OS
Cycle
C1
C1
C1
C1
C2
C2
C2
C2
C3
C3
C4 
Through 
12
C13 
and 
Beyond
Every 
4 weeks
Every 
12 weeks
Days
-28 to -1
1
7
14
21
1
7
14
21
1
14
1
1
Window
± 2 days
+1 wk
± 1 wk
± 1 wk
x All subsequent anticancer therapies for MM will be reported every 12 weeks. Patients who receive a subsequent anticancer therapy for MM will be assessed by the 
investigator for disease response (at minimum disease progression) to determine PFS2; response assessments should be made using local laboratory results, and the 
frequency will be determined by the investigator (recommended every 12 weeks) on the next line of therapy only. When a patient experiences disease progression on 
the next line of anticancer therapy or initiates a subsequent line of anticancer therapy, whichever comes first, further disease response will no longer be recorded. 
y The study drug regimen must be initiated within 5 days of randomization on study. 
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MLN9708
Clinical Study Protocol C16014 Amendment 5, 2013-000326-54, 09 July 2020
Confidential
162
MLN9708 PHARMACOKINETIC SAMPLING SCHEDULE
Cycle 1
Cycle 2-3
Cycles 4-12
Day 1
Day 14
Day 1
Day 14
Day 1
Postdose 1 hour 
(0.25)
Postdose 4 hour 
(0.75)
Predosea,b
Predoseb,c
Predosea,b
Predoseb,c
X
X
X
X
X
X
a If PK sample is taken on a dosing day (due to allowable 2-day window of visits), PK sample must be taken within 2 hours prior to dose of any study drug. If PK 
sample is taken on a non-dosing day, ie, sample on Day 14 and dose on Day 15, PK sample can be taken at any time during the visit.
b 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 distinctive visits should be done as per the protocol.
c Day 1 predose PK assessments should occur within 4 hours of dosing.
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MLN9708
Clinical Study Protocol C16014 Amendment 5, 2013-000326-54, 09 July 2020
163
15.13   Amendment 1 Rationale and Purposes
Rationale for Amendment 1
The primary rationale for this amendment is to add a study objective evaluating progression-
free survival 2 (PFS2), defined as the date from randomization to the date of second disease 
progression or death from any cause, whichever comes first. Procedures and assessments 
required for evaluation of PFS2 have been added throughout the protocol. 
In addition, a second assessment of MRD was added for patients who have an initial 
confirmed complete response.
Directions for administration of lenalidomide and dexamethasone were clarified to align
more closely with the package insert and the SmPC. 
Instructions for dose modifications were additionally clarified based on the evolving 
understanding of MLN9708 and its overlapping toxicities with lenalidomide and
dexamethasone. In addition, Section 6.10, Management of Clinical Events, has been updated 
to reflect the most recent understood safety profile of MLN9708.
Language was added in case of unblinding to clarify that sites must provide justification of 
unblinding and receive approval from the sponsor before unblinding.
Other changes clarify study procedures, as noted in the following list.
Purposes for Amendment 1
The purposes of this amendment are to:

Add the Intergroupe Francophone du Myelome number

Update the cover page with current signatories

Update the study overview diagram to remove subsequent antineoplastic therapy as a 
grounds for treatment discontinuation, add PFS2, and clarify flow of patients 
depending on disease response

Clarify permissible window for obtaining informed consent

Permit local laboratory evaluation of Cycles 1 and 2, Days 7 and 21 complete blood 
count assessments

Clarify timing of radiographic disease assessment

Clarify timing for serum protein electrophoresis, urine protein electrophoresis, serum 
free light chain assay, and immunofixation

Clarify timing of bone marrow aspirate for molecular analysis and cytogenetics

Clarify timing of bone marrow aspirate for MRD

Clarify required documentation of peripheral neuropathy

Add collection of subsequent therapy and disease status for assessment of PFS2

Add the duration of time permitted between randomization and initiation of treatment 
with the study drug regimen

Clarify the pharmacokinetic sampling schedule

Clarify the definition of the overall survival follow-up period
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MLN9708
Clinical Study Protocol C16014 Amendment 5, 2013-000326-54, 09 July 2020
164

Clarify the description of MLN9708

Update the details of the MLN9708 potential risks and benefits

Clarify doses of the study drug and lenalidomide beyond 18 cycles of treatment

Clarify that the assessment of disease response/progression is done by both the 
independent review committee and investigator during the treatment period and PFS 
follow-up period, and only by the investigator during the overall survival follow-up 
period for determination of PFS2

Update the list of participating sites 

Clarify permitted creatinine clearance values for reduced lenalidomide dosing

Updated the name of Revlimid RevAssist® to Revlimid REMSand specify that 
counseling must be documented

Clarify the details for concurrent aspirin use

Clarify the eligibility criteria regarding prior radiotherapy

Update exclusion criteria regarding prior diagnosis of or therapy for malignancy

Clarify the exclusion criteria regarding thromboembolism prophylaxis

Clarify eligibility for patients with cardiovascular disorders

Update exclusion criteria regarding infection

Clarify the exclusion criteria regarding prior treatment with an investigational product

Clarify confirmation and documentation of eligibility before randomization

Clarify and standardize study drug and study drug regimen terminology

Clarify lenalidomide administration guidelines

Clarify dexamethasone administration guidelines

Clarify dose modification guidelines

Clarify within cycle versus before beginning next cycle dose modifications

Clarify dose adjustment procedures for rash

Clarify study drug treatment modifications

Clarify lenalidomide treatment modification guidelines

Clarify dexamethasone dose modification guidelines

Clarify criteria for toxicity recovery before beginning the next cycle of treatment

Clarify prohibited procedures

Clarify permitted concomitant medications and procedures

Add digoxin to the list of precautions and restrictions

Update language describing the management of clinical events

Indicate that protocol changes will be communicated to the investigative sites at the 
time the study is unblinded

Clarify the description of the preparation, reconstitution, and dispensation of 
MLN9708 to be consistent across studies
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MLN9708
Clinical Study Protocol C16014 Amendment 5, 2013-000326-54, 09 July 2020
165
!
Clarify the description of the storage and handling of MLN9708 to be consistent 
across studies
!
Clarify shifts in study procedures for holidays, vacation, and other administrative 
reasons
!
Clarify assessments to be collected as part of medical history
!
Clarify the roles of the central and local laboratories for eligibility, progressive 
disease assessment, and safety
!
Clarify the timing of skeletal surveys
!
Clarify the timing of dual-energy X-ray absorptiometry scans
!
Clarify timing of M-protein assessments
!
Clarify central vs local laboratory bone marrow evaluations
!
Add in the response assessment version and clarify the timing assessment of disease 
response
!
Clarify the M-protein and free light chain to be followed for response assessment 
according to International Myeloma Working Group criteria
!
 
!
Add assessment of PFS2
!
Add a treatment discontinuation form to ensure review and approval of progressive 
disease before removing patient from treatment
!
Clarify assessment of pain
!
 
!
Remove the Steering Committee
!
Add that the independent data monitoring committee will receive reports of all cases 
of new primary malignancies during the study
!
Indicate proper reporting of overdose
!
Update the SAE reporting contact information
!
Update procedures for SAE reporting
!
Clarify instructions about how and when to report and manage pregnancies
!
Correct typographical errors, punctuation, grammar, and formatting
Cl
Cl
: For Non-Commerci
e Only and S
t to the Applicable Terms of Use
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MLN9708
Clinical Study Protocol C16014 Amendment 5, 2013-000326-54, 09 July 2020
166
15.14   Amendment 1A Rationale and Purposes
Rationale for Amendment 1A
The primary rationale for this amendment is to establish a continuation of Study C16014 in 
South Korea to enroll additional patients from South Korea only. This amendment describes 
modifications to the global study procedures specifically for patients who enroll in the South 
Korea continuation. Patients from South Korea who enroll in the global C16014 study will 
not be affected. Following completion of enrollment in the global study (701 patients), 
approximately 40 additional patients from South Korea will be enrolled in the continuation.
The South Korea continuation is an extension of the global study that will continue to assess 
the primary objective of progression-free survival (PFS) and secondary objectives of 
complete response rate, overall survival (OS), and pain response rate in patients from South 
Korea. Other secondary objectives that directly relate to disease response assessment, safety, 
and patient-reported outcomes will also be evaluated to thoroughly characterize the efficacy
and safety of MLN9708 in combination with lenalidomide and dexamethasone. Some 
secondary and exploratory objectives will be explored in the global study but are not 
included in the South Korea continuation because they are signal-seeking in nature and 
require a larger number of patients to detect a difference between arms. 
The statistical and quantitative analyses, including timing of the PFS and OS analyses, have 
been revised to reflect the change in sample size. The primary objective of PFS will be 
assessed when approximately 40 PFS events have been reported in patients from South 
Korea (pooled from patients enrolled in the global study and the continuation). OS will be 
assessed at the time of the final analysis of OS in the global study or when a total of
death events have been reported for patients in South Korea (pooled between global 
study patients and South Korea continuation patients), whichever occurs later, or termination 
of the study by the sponsor.
Purposes for Amendment 1A
The purposes of this amendment are to:
!
Update signatories to reflect clinicians involved in this protocol
!
Update the number of patients from 701 to 40 to reflect the approximate number of 
patients from South Korea that will be enrolled in the continuation
!
Reclassify key secondary objectives and other secondary objectives as 1 category of 
secondary objectives
!
Remove secondary objectives (and corresponding endpoints and study procedures) 
that do not directly contribute to the characterization of the efficacy or safety of 
MLN9708
!
Remove exploratory objectives (and corresponding endpoints and study procedures) 
that do not directly contribute to the characterization of the efficacy or safety of 
MLN9708
!
Clarify lenalidomide dose modification language for patients with low creatinine 
clearance to align with the South Korean label
!
Modify the time and number of events required for analysis of PFS
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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
Modify the time and number of events required for analysis of OS

Modify the statistical procedures for secondary efficacy

Specify that the study population is comprised of patients from South Korea

Modify the duration of study for patients in the continuation

Revise global text for pregnancy testing to only state instruction for South Korea

Revise global text for supply of lenalidomide to only state instruction for South Korea

Clarify the patient-reported outcomes analysis 

Clarify the time to pain progression and duration of pain response analyses

Correct typographical errors, punctuation, grammar, and formatting
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15.15   Amendment 2 Rationale and Purposes
Rationale for Amendment 2
The primary rationale for this amendment is to modify the statistical analysis plan to prevent 
early closure of the study in the light of the importance of collecting long-term patient
outcomes data.[86] To do so, an additional IA has been added later in the study, while 
maintaining the previous first IA for progression-free survival (PFS) at approximately 
326 events. The new second IA will analyze PFS at approximately 435 events only if the 
threshold for significance was not met at the first IA; otherwise, the first IA will serve as the 
final PFS analysis for the study, and the second IA will be conducted to assess overall 
survival (OS) when approximately 250 deaths have occurred. The addition of this second IA 
will safeguard the PFS statistical power at 95%, and serve to determine whether the final 
number of OS events might be increased from approximately 320 death events to up to 
approximately 400 death events using unblinded event re-estimation by an ISC.
In addition, this amendment modifies the study assessments to be performed after PFS 
significance is met. Endpoints relating to disease response (ie, PFS, response rate, time-to-
progression) will not be assessed for protocol purposes after the primary endpoint is met; as 
such, all efficacy response data (ie, laboratory samples) will stop being collected/sent to the 
central laboratory to minimize the burden on study patients. 
Other changes clarify study procedures, as noted in the following list.
Purposes for Amendment 2
The purposes of this amendment are to:
!
Update the title page with current signatories
!
Change the order of the key secondary objectives to move the complete response 
(CR) objective to appear after the overall survival (OS) objective
!
 
 
!
Clarify the definition of skeletal-related events
!
Add a second IA to assess PFS (only if significance is not reached at the first IA) and 
OS
!
Discontinue efficacy response assessments for protocol purposes after PFS 
significance has been met in the study (either at the first IA or second IA), except for 
investigator assessment of PFS2 (progression-free survival 2 [from randomization on 
study to PFS on the next line of treatment])
!
Remove reference to the Safety Management Attachment
!
Remove Ginkgo biloba as an excluded medicinal product
!
Clarify shifts in study procedures for holidays, vacations, and other administrative 
reasons
!
Clarify the procedure for assessment of PFS2
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
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 cytochrome P450 inhibitors do not affect MLN9708 PK

Clarify the definition of the End of Treatment visit

Clarify the administration instructions for MLN9708

Clarify the management of rash

Clarify the management of overdose

Clarify the instructions for study drug dispensing

Clarify the storage conditions for MLN9708

Clarify the procedure for performing the physical examination

Clarify the timing of bone marrow aspirates for minimal residual disease

Clarify when central laboratory results must be reviewed before initiating the next 
treatment cycle

Add an email address for reporting adverse events and serious adverse events in Japan

Clarify the monitoring of adverse events and period of observation

Update the procedures for product complaints to include instructions for reporting 
medication errors and overdose

Correct typographical errors, punctuation, grammar, and formatting
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15.16   Amendment 2A Rationale and Purposes
Rationale for Amendment 2A
This amendment describes modifications that were made to the C16014 global study
procedures (Global Amendment 2) that apply to the Korea-specific protocol continuation.
Purposes for Amendment 2A
The purposes of this amendment are to:

Update the title page with current signatories

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 cytochrome P450 inhibitors do not affect 
MLN9708 PK

Clarify when bone marrow aspirate will be collected for assessment

Remove reference to the Safety Management Attachment

Clarify the timing of bone marrow aspirates for minimal residual disease

Change the order of the secondary objectives to move the CR objective to appear after 
the OS objective

Clarify the timing of flow cytometry

Clarify the definition of skeletal-related fractures to be evaluated

Clarify the recommended frequency for response assessments

Clarify the definition of the End of Treatment visit

Clarify the administration instructions for MLN9708

Provide reference to updated excluded concomitant medication

Remove Ginkgo biloba as an excluded medicinal product

Clarify the management of rash

Clarify the management of overdose

Clarify storage conditions of MLN9708 and also clarify shifts in study procedures for 
holidays, vacations, and other administrative reasons

Provide reference for storage and shipping guidelines

Clarify the procedure for assessment of progression-free survival 2 (PFS2) and shifts 
in study procedures for holidays, vacations, and other administrative reasons

Clarify the procedure for performing the physical examination

Clarify when central laboratory results must be reviewed before initiating the next 
treatment cycle

Delete sensitivity analyses for CR rate

Clarify analgesic use

Overdose deleted from list of medically important event

Update serious adverse event (SAE) Reporting Contact Information
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
Clarify the monitoring of AEs and period of observation

Update the procedures for product complaints to include instructions for reporting 
medication errors and overdose

Section of new text added to comply with ICH E6 (GCP) regulations regarding 
investigator responsibilities

Correct typographical errors, punctuation, grammar, and formatting
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15.17   Amendment 3 Rationale and Purposes
Rationale for Amendment 3
This document describes the changes in reference to the protocol incorporating Amendment 
No. 3. The primary reason for this amendment is to follow the independent data monitoring 
committee (IDMC) recommendation to include a subgroup analysis approach focusing on 
patients who could derive particular benefit from ixazomib with manageable toxicity. To do 
so, a progression-free survival (PFS) subgroup analysis testing strategy approach is 
prospectively included to be executed at the second interim analysis in parallel with the PFS
analysis in the intent-to-treat (ITT) population should the first interim analysis fail to 
demonstrate a statistically significant PFS advantage in the ITT population. The addition of 
this analysis will serve to determine whether the ixazomib treatment arm shows superiority 
over the placebo control arm on the primary endpoint of PFS in 3 prespecified subgroups 
using the Hochberg procedure for multiplicity correction: 1) patients with baseline creatinine 
clearance > 60 mL/min, 2) patients < 75 years of age, and 3) patients harboring high-risk 
cytogenetic abnormalities defined as del(17p), t(4;14), t(14;16), amp(1q21).
Minor grammatical, editorial, formatting, and administrative changes are included for 
clarification purposes only.
Changes in Amendment 3
1. Update the statistical procedures to reflect a prespecified subgroup testing strategy.
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15.18   Amendment 4 Rationale and Purposes
Rationale for Amendment 4
This amendment describes the changes in reference to the protocol incorporating 
Amendment No. 4. The primary reason for this amendment is to modify the statistical 
analysis plan to ensure timely analysis of the primary endpoint, progression-free survival 
(PFS), in light of the slower than expected PFS event rate over the past year. The second 
interim analysis (IA) – the final analysis for PFS – will now take place when approximately 
370 PFS events have been observed. Power remains sufficient at 92%.
Additionally, this amendment clarifies other elements of the study design and procedures. 
REVLIMID or generic lenalidomide may be administered as part of the study treatment 
regimen.
 
 
The requirement to document adverse events that 
require breaking the blind in the electronic case report form (eCRF) has been removed. The 
serious adverse event (SAE) reporting contact information in Japan has been updated from 
Bell Medical Solutions to BI Medical. The duration of new primary malignancy adverse 
event (AE) assessment has additionally been clarified.
Changes in Amendment 4
1.
 
2. Update statistical procedures to modify the number of events for the final PFS analysis.
3. Clarify the statistical boundary for PFS at the second IA.
4. Clarify that REVLIMID or generic lenalidomide may be administered as part of the 
study treatment regimen.
5. Remove the requirement to document adverse events that require breaking the blind in 
the eCRF.
6. Update the SAE reporting contact information in Japan to BI Medical.
7. Clarify the duration of new primary malignancy AE assessment. 
8. Clarify the locations of study centers.
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15.19   Amendment 5 Detailed Summary of Changes
The primary section(s) of the protocol affected by the changes in Amendment No. 5
are indicated. The corresponding text has been revised throughout the protocol. 
Change 1: Updated signatories on Title Page.
The primary change occurs on the Title Page
Initial text:
Amended or 
new text:
Rationale for Change: To provide information for the current signatories.
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Change 2: Added language to clarify ongoing treatment of patients—patients should be 
moved off study and onto commercial supply of ixazomib and/or lenalidomide, if available, 
and otherwise kept on study).
The primary change occurs in the Schedule of Events—Amendment 5 and Beyond:
Added text:
As of Amendment 5, the second IA has been conducted (data cutoff date 
of 02 December 2019) and the primary endpoint of PFS did not reach 
statistical significance. Thus, the planned final analysis will not occur and 
the study is now unblinded. Although the primary endpoint was not met, 
patients in both treatment arms appeared to receive benefit. As such, 
patients deriving clinical benefit may continue their current study 
treatment if there are no other means of accessing the study drugs. When 
possible, patients should complete an End of Treatment (EOT) visit and 
transition onto a commercial supply of ixazomib and/or lenalidomide, or 
other standard of care treatment.  
Patients who continue to derive clinical benefit but are unable to access 
the study treatments outside of the clinical trial setting may continue on 
study and have treatment provided.  Patients who are receiving ixazomib 
and lenalidomide will continue to receive ixazomib and lenalidomide. 
Patients who are receiving placebo and lenalidomide will receive 
lenalidomide only; the placebo capsule will no longer be administered 
and patients receiving placebo will not be crossed over to ixazomib in this 
study.
Rationale for Change:
To clarify the ongoing treatment of patients in Study C16014. 
The following sections also contain this change:

Protocol Summary

Section 4.1 Overview of Study Design. 

Section 6.11 Blinding and Unblinding.
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Change 3: Updated Schedule of Events and placed previous Schedule of Events in the 
Appendix.
The primary change occurs the following sections:

Schedule of Events

Section 15.12 Full Schedule of Events and PK Sampling Schedule (Schedules Prior to 
Implementation of Amendment 5).
Initial text:
SCHEDULE OF EVENTS [table for schedule of events and table for 
MLN9708 Pharmacokinetic Sampling Schedule]
Amended or 
new text:
For patients continuing on study, the majority of study assessments are 
discontinued to ease the burden of protocol-mandated assessments. For 
ease of study conduct, the Schedule of Events now presented has been 
simplified to apply to the remainder of the study. Beyond the assessments 
noted here, patients still on study should be treated by the investigator 
according to the local or country-specific standard of care.
The full Schedule of Events and PK Sampling Schedule in effect prior to 
Amendment 5 have been moved to Section 15.12.
[New table: Schedule of Events – Amendment 5 and Beyond]
…
Appendix 15.12 Full Schedule of Events and PK Sampling Schedules 
(Schedules Prior to Implementation of Amendment 5) [previous table for 
schedule of events and previous table for MLN9708 Pharmacokinetic 
Sampling Schedule]
Rationale for Change: To provide an updated Schedule of Events upon implementation of 
Amendment 5.
Change 4: Revised Study Period Definitions.
The primary change occurs in Study Period Definitions.
Initial text:
Progression-free Survival Follow-up Period
Visits for patients who stop treatment with the study drug regimen for any 
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reason other than progressive disease. See the Schedule of Events for 
appropriate assessments. The progression-free survival follow-up should 
occur every 4 weeks until the occurrence of disease progression; radiographic 
disease assessments are to be performed every 8 weeks for patients with 
documented extramedullary disease.
Progression-free Survival 2 Follow-up Period
Visits for patients who stop treatment with the study drug regimen for any 
reason other than progressive disease. See the Schedule of Events for 
appropriate assessments. The progression-free survival follow-up should 
occur every 4 weeks until the occurrence of disease progression; radiographic 
disease assessments are to be performed every 8 weeks for patients with 
documented extramedullary disease.
Overall Survival Follow-up Period
Visits for patients who stop treatment with the study drug regimen for any 
reason other than progressive disease. See the Schedule of Events for 
appropriate assessments. The progression-free survival follow-up should 
occur every 4 weeks until the occurrence of disease progression; radiographic 
disease assessments are to be performed every 8 weeks for patients with 
documented extramedullary disease.
Amended or 
new text:
Progression-free Survival Follow-up Period
Visits for patients who stop treatment with the study drug regimen for any
reason other than progressive disease. See Section 15.12 for the full 
Schedule of Events before Amendment 5 was implementedSee the
Schedule of Events for appropriate assessments. The progression-free survival 
follow-up should occur every 4 weeks until the occurrence of disease 
progression; radiographic disease assessments are to be performed every 
8 weeks for patients with documented extramedullary disease. Note that with 
the implementation of Amendment 5, patients will not be followed for the 
PFS or OS follow-up periods, as PFS and OS data are no longer being 
collected.
Progression-free Survival 2 Follow-up Period
Visits for patients who stop treatment with the study drug regimen for any 
reason other than progressive disease. See Section 15.12 for the full 
Schedule of Events before Amendment 5 was implementedSee the
Schedule of Eventsfor appropriate assessments. The progression-free survival 
follow-up should occur every 4 weeks until the occurrence of disease 
progression; radiographic disease assessments are to be performed every 
8 weeks for patients with documented extramedullary disease. Note that with 
the implementation of Amendment 5, patients will not be followed for the 
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PFS or OS follow-up periods, as PFS and OS data are no longer being 
collected.
Overall Survival Follow-up Period
Visits for patients who stop treatment with the study drug regimen for any 
reason other than progressive disease. See Section 15.12 for the full 
Schedule of Events before Amendment 5 was implementedSee the
Schedule of Events for appropriate assessments. The progression-free survival 
follow-up should occur every 4 weeks until the occurrence of disease 
progression; radiographic disease assessments are to be performed every 
8 weeks for patients with documented extramedullary disease. Note that with 
the implementation of Amendment 5, patients will not be followed for the 
PFS or OS follow-up periods, as PFS and OS data are no longer being 
collected.
Rationale for Change: To explain that patients will not be followed for the PFS or OS 
follow-up periods upon implementation of Amendment 5.
The Study Overview Diagram also contains this change.
Change 5: Added explanatory text to Study Objectives.
The primary change occurs in Section 2 STUDY OBJECTIVES.
Added text:
As of this amendment, the objectives are to provide continued access to
MLN9708 and/or lenalidomide to patients who are continuing to have
clinical benefit and to continue collecting relevant safety data to monitor 
patient safety. All other study objectives will no longer be assessed. 
However, the complete list of objectives is retained below for reference.
Rationale for Change: To explain the Amendment 5 study objectives and note that the 
previous objectives are retained for reference.
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The Protocol Summary also contains this change.
Change 6: Added explanatory text to Study Endpoints.
The primary change occurs in Section 3 STUDY ENDPOINTS.
Added text:
As of this amendment, evaluation of the safety profile of MLN9708 
and/or lenalidomide is the only endpoint being assessed. All other study 
endpoints will no longer be assessed. However, the complete list of 
endpoints is retained below for reference.
Rationale for Change: To explain the Amendment 5 endpoint and that the previous 
endpoints are retained for reference.
The Protocol Summary also contains this change.
Change 7: Added explanatory text to Overview of Study Design and removed language 
regarding the previous Schedule of Events.
The primary change occurs in Section 4.1 Overview of Study Design.
Initial text:
General eligibility criteria may be assessed prior to the formal Screening 
period if it is part of standard clinical practice. However, per the Schedule of 
Events, formal screening will occur during the Screening period, which may 
last for up to 28 days prior to randomization. A Millennium Pharmaceuticals, 
Inc. (MPI)/designee clinician will confirm patient eligibility prior to 
randomization by the investigator.
Amended or 
new text:
The following describes the study design before Amendment 5 was 
implemented.
General eligibility criteria may be assessed prior to the formal Screening 
period if it is part of standard clinical practice. However, per the Schedule of 
Events, formal screening will occur during the Screening period, which may 
last for up to 28 days prior to randomization. A Millennium Pharmaceuticals, 
Inc. (MPI)/designee clinician will confirm patient eligibility prior to 
randomization by the investigator.
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Rationale for Change: To explain that the study design reflects the study design before 
implementation of Amendment 5.
Change 8: Revised information regarding the interim analyses in the Overview of Study 
Design.
The primary change occurs in Section 4.1 Overview of Study Design.
Initial text:
Two IAs are planned to occur during the study. The first analysis will be 
performed when approximately 326 PFS events (disease progression or death) 
have occurred. If the test for PFS in the ITT population is statistically significant 
at the first IA, this will be the final analysis (FA) for PFS for statistical testing 
purposes; central efficacy and investigator assessments for protocol purposes will 
be stopped and not recorded in the eCRF except for investigator assessment of 
PFS2 (see Schedule of Events). In such a case, the second IA will assess OS 
when approximately 250 death events have occurred. If the test for PFS in the
ITT is not statistically significant at the first IA, then central efficacy and 
investigator response assessments will continue until the second IA, which will 
assess PFS and OS. 
Upon implementation of this amendment (Protocol Amendment 4), the second IA
will be conducted when approximately 370 PFS events have occurred (rather 
than the previous study design of 435 PFS events). In addition, PFS will be tested 
at IA2 in both the ITT population and in 3 prespecified subgroups: 1) patients 
with baseline CrCl > 60 mL/min; 2) patients aged < 75 years; and 3) patients 
harboring high-risk cytogenetic abnormalities defined as del(17p), t(4;14), 
t(14;16), and amp(1q21).
The final OS analysis will be performed when approximately 320 to 400 deaths 
have occurred with the total event size calculation based on the adaptive sample 
size re-assessment approach.[66,67] The trial will be stopped for overwhelming 
efficacy if the O’Brien-Fleming efficacy boundary of OS is crossed. 
An independent data monitoring committee (IDMC) will review safety and 
efficacy data at the IAs. See Section 9.2 for more information. 
Amended or 
new text:
Two IAs are planned to occur during the study. The first analysis will be 
performed when approximately 326 PFS events (disease progression or death) 
have occurred. If the test for PFS in the ITT population is statistically 
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significant at the first IA, this will be the final analysis (FA) for PFS for 
statistical testing purposes; central efficacy and investigator assessments for 
protocol purposes will be stopped and not recorded in the eCRF except for 
investigator assessment of PFS2 (see Schedule of Events). In such a case, the 
second IA will assess OS when approximately 250 death events have 
occurred. If the test for PFS in the ITT is not statistically significant at the 
first IA, then central efficacy and investigator response assessments will 
continue until the second IA, which will assess PFS and OS. 
Upon implementation of this amendment (Protocol Amendment 4), the
second IA will be conducted when approximately 370 PFS events have 
occurred (rather than the previous study design of 435 PFS events). In 
addition, PFS will be tested at IA2 in both the ITT population and in 3 
prespecified subgroups: 1) patients with baseline CrCl > 60 mL/min; 
2) patients aged < 75 years; and 3) patients harboring high-risk cytogenetic 
abnormalities defined as del(17p), t(4;14), t(14;16), and amp(1q21).
The final OS analysis will be performed when approximately 320 to 400 
deaths have occurred with the total event size calculation based on the 
adaptive sample size re-assessment approach.[66,67] The trial will be stopped 
for overwhelming efficacy if the O’Brien-Fleming efficacy boundary of OS is 
crossed.
An independent data monitoring committee (IDMC) will reviewed safety and 
efficacy data at the 2 planned IAs. See Section 9.2 for more information.
As of Amendment 5, the 2 planned IAs have been conducted (data cutoff 
date of 15 February 2018 for the first IA and data cutoff date of 
02 December 2019 for the second IA). However, in the second IA, the 
primary endpoint of PFS did not reach statistical significance. Thus, the 
planned final analysis will not occur and the study is now unblinded.
Although the primary endpoint was not met, patients in both treatment 
arms appeared to receive benefit. As such, patients deriving clinical 
benefit may continue their current study treatment if there are no other 
means of accessing the study drugs, until such time as other means of 
accessing the study drugs are arranged.  When possible, patients should 
complete an EOT visit and transition onto a commercial supply of 
ixazomib and/or lenalidomide or other standard of care treatment.  
Patients who are receiving ixazomib and lenalidomide will continue to 
receive ixazomib and lenalidomide. Patients who are receiving placebo 
and lenalidomide will receive lenalidomide only; the placebo capsule will 
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no longer be administered and patients receiving placebo will not be 
crossed over to ixazomib in this study. 
For patients continuing on study, the majority of study assessments are 
discontinued to ease the burden of protocol-mandated assessments. Upon 
implementation of Amendment 5, data collection requirements will be 
limited to collection of AEs and SAEs. All other study assessments are no 
longer required. All central laboratory efficacy measures of response and 
progression are discontinued. Bone marrow aspirates for confirmation of
CR or MRD status are no longer required. No further IRC response or 
progression evaluations will be performed. Radiographic studies and 
bone density studies for study purposes are no longer required. Quality 
of life and health utilization assessments and collection of concomitant 
medications and procedures are discontinued. Patients will not be 
followed for the PFS or OS follow-up periods, as PFS and OS data are no 
longer being collected. Patients may choose to stay in the study if the 
investigator believes that the patient is continuing to benefit from the 
treatment. Alternatively, the patient may discontinue from the study and 
be treated by their physician according to standard of care. See the 
updated Schedule of Events – Amendment 5 and Beyond for more 
detailed information.
Rationale for Change: To update the text now that the 2 interim analyses have been 
conducted.
The Protocol Summary also contains this change.
Change 9: Revised thrombocytopenia text in Management of Clinical Events.
The primary change occurs in Section 6.10 Management of Clinical Events.
Initial text:
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. Lenalidomide or study drug 
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administration should be modified as noted as per dose modification 
recommendations in the protocol when thrombocytopenia occurs (see Table 6-1). 
Therapy can be reinitiated at a reduced level upon recovery of platelet counts. A 
rare risk is thrombotic thrombocytopenic purpura, a rare blood disorder where
blood clots form in small blood vessels throughout the body characterized by 
thrombocytopenia, petechiae, fever, or possibly more serious signs and 
symptoms. Thrombotic thrombocytopenic purpura should be managed 
symptomatically according to standard medical practice.
Amended or 
new text:
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. Lenalidomide or study 
drug administration should be modified as noted as per dose modification 
recommendations in the protocol when thrombocytopenia occurs (see 
Table 6-1). Therapy can be reinitiated at a reduced level upon recovery of 
platelet counts. Thrombotic microangiopathy (TMA), includingA rare risk 
is thrombotic thrombocytopeniathrombocytopenic purpura and hemolytic 
uremic syndrome, are rare, serious , a rare blood disorders that cause low 
levels of platelets and red blood cells and result indisorder where blood 
clots form in small blood vessels. Symptoms may include fatigue throughout 
the body characterized by thrombocytopenia, petechiae, fever, bruising, nose 
bleeds, and decreased urination. These disorders can occasionally be 
fatal. TMAor possibly more serious signs and symptoms. Thrombotic 
thrombocytopenic purpura should be managed symptomatically according to 
standard medical practice.
Rationale for Change: To align content with that in other protocols in the ixazomib 
program.
Change 10: Revised Blinding and Unblinding text.
The primary change occurs in Section 6.11 Blinding and Unblinding.
Initial text:
At the time when the study is unblinded, either when planned or before, any 
changes to the required procedures outlined in the Schedule of Events will be 
communicated to the investigative sites.
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Amended or
new text:
As of Amendment 5, the second IA has been conducted and the primary 
endpoint of PFS did not reach statistical significance. The study is now 
unblinded globally. Individual patient treatment assignments are now
available in the IXRS. Patients deriving clinical benefit may continue 
their current study treatment if there are no other means of accessing the 
study drugs.  When possible, patients should complete an End of
Treatment (EOT) visit and transition onto a commercial supply of 
ixazomib and/or lenalidomide or other standard of care treatment.  
Patients who continue to derive clinical benefit but are unable to access 
the study treatments outside of the clinical trial setting may continue on 
study and have treatment provided.  Patients who are receiving ixazomib 
and lenalidomide will continue to receive ixazomib and lenalidomide. 
Patients who are receiving placebo and lenalidomide will receive 
lenalidomide only; the placebo capsule will no longer be administered 
and patients receiving placebo will not be crossed over to ixazomib in this 
study.
For patients continuing on study, the majority of study assessments are 
discontinued to ease the burden of protocol-mandated assessments.
Discontinued patients will be treated by their physician per standard of 
care.
At the time when the study is unblinded, either when planned or before, any 
changes to the required procedures outlined in the Schedule of Events will be 
communicated to the investigative sites.
Rationale for Change: To explain that the study is now unblinded and to explain what will 
happen to patients now that the second interim analysis did not reach statistical significance 
and the majority of study assessments have been discontinued.
Change 11: Revised language in Preparation, Reconstitution, and Dispensing.
The primary change occurs in Section 6.13 Preparation, Reconstitution, and Dispensing.
Added text:
Study drug dispensed to the patient for take-home dosing should remain in the 
blister packaging and carton until the point of use. Refer to the Pharmacy 
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Manual or equivalent storage guidelines. In case of extenuating 
circumstances that prevent a patient from attending the study site (eg, 
the 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. Comprehensive instructions should be 
provided to the patient to ensure compliance with dosing procedures. Patients 
who are receiving take-home medication should be given only 1 cycle of 
medication at a time; more. More than 1 cycle of medication may be 
dispensed on a case-by-case basis for holidays, travel, or other circumstances 
upon discussion with the investigator and sponsor’s project clinician/designee
(Note: patients in France are only permitted to receive 1 cycle of 
medication at a time). Should more than 1 cycle of medication be dispensed, 
the investigator and/or health care provider must review the proper dosing 
instructions with the patient to avoid the potential for incorrect self 
administration or overdose of medication.
Patients should be instructed to store the medication according to the storage 
conditions that are outlined in the Pharmacy Manual or equivalent storage 
guidelines for the duration of each cycle. Patients should be instructed to 
return their empty cartons to the investigative site, rather than discarding 
them, as permitted by site policy. Reconciliation will occur accordingly when 
the patient returns for their next cycle of take-home medication. 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 extreme in 
temperature should be reported as an excursion and should be dealt with on a 
case-by-case basis.
Rationale for Change: To align content with content in other protocols in the ixazomib 
program.
Change 12: Added a sentence to Packaging and Labeling.
The primary change occurs in Section 6.14 Packaging and Labeling.
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Added text:
The capsules are individually packaged using cold form foil-foil blisters that 
are in a child-resistant carton. There are 3 capsules in each wallet/carton. See 
the Pharmacy Manual for more information.
Rationale for Change: To align content with content in other protocols in the ixazomib 
program.
Change 13: Added language in Storage, Handling, and Accountability.
The primary change occurs in Section 6.15 Storage, Handling, and Accountability.
Initial text:
On receipt at the investigative site, study drug should remain in the blister and 
carton provided until use or dispensation. All excursions that occur at the site 
storage or during transportation from depot to the site should 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.
Amended or 
new text:
On receipt at the investigative site, study drug should remain in the blister and 
carton provided until use or dispensation. All excursions that occur duringat
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.
Rationale for Change: To align content with content in other protocols in the ixazomib 
program.
Change 14: Added language regarding alternative methods for administering study 
procedures/assessments when it is not possible for the patient to come to the study site due to 
extenuating circumstances (eg, due to the COVID-19 pandemic).
The primary change occurs in Section 7.4 Study Procedures:
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Added 
text:
In acknowledgement of hospital, local, state or national government 
restrictions, or other site-related factors caused by unavoidable 
circumstances (eg, the COVID-19 pandemic) that may prevent investigators 
from conducting the study according to the Schedule of Events at the 
clinical study site, investigators may continue patients in the study despite 
departure from the Schedule of Events. Investigators are expected to 
evaluate the impact to the safety of the study participants and site personnel 
for patients to continue. In evaluating such requests, the investigator/study 
site staff will give the highest priority to the safety and welfare of the 
patients. Patients must be willing and able to continue taking study 
medication and remain compliant with the protocol.  For patients that are 
impacted: any procedures not conducted per the original study plan will be 
documented in the study records.  
If a patient misses an in-person study visit, the investigator/study team staff 
will speak directly with the patient by telephone or other medium (eg, a 
computer-based video communication) during each visit window to assess 
subject safety and overall clinical status. During this contact with the 
patient, the study site physician or other qualified site staff should at 
minimum conduct AE collection and an assessment of clinical symptoms. 
Other study assessments may be collected remotely as is feasible and may 
involve audio or video recording. Assessments/procedures that cannot be 
completed during the protocol-specified window because a site visit is done 
remotely (ie, symptom-directed physical exam, hematology, clinical 
chemistry) are waived.
Rationale for Change:
To clarify permitted alternative methods for administering study procedures/assessments 
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).
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The following sections also contain this change:

Protocol Summary

Schedule of Events—Amendment 5 and Beyond, footnote “e”
Change 15: Removed or revised several study procedures upon implementation of 
Amendment 5 and included cross-references to the Full Schedule of Events.
The primary change occurs in Section 7.4 Study Procedures.
Initial text:
Patients will be evaluated at scheduled visits over 4 study periods: Screening, 
Treatment, EOT, and Follow-Up (PFS and OS [including assessment of PFS2 
during OS follow-up]). Tests and procedures during the Treatment Period should
be performed on schedule, but occasional changes are allowable (± 2 days or a 
longer window after discussion with the Millennium project clinician or designee)
for holidays, vacations, and other administrative reasons. If the study schedule is 
shifted, assessments must be shifted to ensure that collection of assessments is 
completed before dosing.
Refer to the Schedule of Events for timing of assessments. Additional details are 
provided as necessary in the sections that follow.
7.4.1   Informed Consent
…
7.4.4   Physical Examination
A physical examination will be completed per standard of care at the times 
specified in the Schedule of Events. Symptom-directed examinations should 
include examination of organ systems related to patient symptoms to 
document potential AEs, AE severity, or AE resolutions. A baseline 
(pretreatment) evaluation of PN will be conducted as part of the visit. If PN is 
present at baseline and within the permitted criteria for study participation (see 
Section 5.2), the grade must be reported in the eCRF.
7.4.5   Vital Signs
Measurement of vital signs, including temperature, blood pressure, heart rate, 
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respiratory rate, and body weight will be done at the time points specified in 
the Schedule of Events. Height will only be measured at the Screening visit.
7.4.6   Eastern Cooperative Oncology Group Performance Status
Performance status will be assessed using the ECOG performance scale at the 
time points specified in the Schedule of Events.
…
7.4.8   Concomitant Medications and Procedures
Concomitant medications and therapy will be recorded from the first dose of 
drug in the study drug regimen through 30 days after last dose of drug in the 
study drug regimen, with the exception of narcotics and other analgesics, 
which will be recorded from first dose of study drug until progressive disease 
(see the Schedule of Events). See Section 6.6 for a list of prohibited 
concomitant medications and therapies and Section 6.7 for a list of allowed 
concomitant medications and therapies.
7.4.9   Adverse Events
Monitoring of AEs, serious and nonserious, will be conducted throughout the 
study as specified in the Schedule of Events. Refer to Section 10 for details 
regarding definitions, documentation, and reporting of pretreatment events, 
AEs, and SAEs.
…
7.4.11   Electrocardiogram
A 12-lead electrocardiogram (ECG) will be conducted at screening and at the 
times outlined in the Schedule of Events. It may be repeated as clinically 
indicated during the study at the discretion of the investigator. ECG data to be 
obtained include PR interval, QRS interval, QT interval, QTc interval, and 
waveforms.
7.4.12   Clinical Laboratory Evaluations
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…
Clinical Chemistry, Hematology, and Urinalysis
Blood and urine samples for analysis of the following clinical chemistry and
hematological parameters will be obtained as specified in the Schedule of 
Events. Blood samples should be collected prior to administration of any 
study drugs.
…
7.4.13   Health Utilization Data Collection
During the treatment and the follow-up periods indicated in the Schedule of 
Events, all medical care encounters since the previous collection will be 
collected from all patients, regardless of the reason for the medical care 
encounter. Examples of data to be collected are number and duration of 
medical care encounters, such as inpatient/outpatient admissions, homecare, 
and time of work loss.
7.4.14   Quality of Life Assessment (European Organization for Research
and Treatment of Cancer)
The QOL assessments (EORTC-QLQ-C30 and MY-20; see Sections 15.9 and 
15.10) will be completed by the patient as specified in the Schedule of Events.
The EORTC QLQ-30 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).
7.4.15   Pain Assessment
Pain assessments will be performed at study visits as described in the 
Schedule of Events. Patients who experience new or worsening pain between 
scheduled visits should be seen at an unscheduled visit, if necessary, or when 
the next scheduled visit is more than 4 weeks in the future. At the unscheduled 
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visits, pain assessments should be completed and appropriate management 
instituted. In addition, patients who report new or worsening pain at either a 
regularly scheduled visit or are seen for pain at an unscheduled visit should 
have a follow-up visit 3 to 5 weeks later for confirmation of the pain 
progression and for appropriate pain management.
…
At the time of each pain assessment including unscheduled visits, the patient 
will be queried regarding concomitant use of analgesics, if any, as specified in 
the Schedule of Events. The patient-recalled amount of analgesic use during 
the 24 hours prior to pain assessment will be recorded on both the 24-hour 
analgesic form and concomitant medication eCRFs.
A full BPI-SF instrument will be administered at each of the visits as specified 
in the Schedule of Events to collect the pain severity, location, and 
interference information with a 24-hour recall period. This must be completed 
prior to other assessments or study drug regimen being administered.
Patients will complete the BPI-SF at each visit as specified in the Schedule of 
Events. Thus, for patients who discontinue study drug before disease 
progression, the scheduled collection of pain assessment should continue until 
disease progression.
7.4.16   Utility Measurement
The EQ-5D consists of 2 pages: the EQ-5D descriptive system and the EQ 
visual analogue scale (EQ VAS). The descriptive system comprises 5 
dimensions (mobility, self care, usual activities, pain/discomfort, and 
anxiety/depression). The EQ VAS records the respondent’s self-rated health 
on a 20-cm vertical, visual analogue scale ranging from 0 (worst imaginable 
health state) to 100 (best imaginable health state). The EQ-5D will be 
administered as specified in the Schedule of Events.
7.4.17   Skeletal Survey
…
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7.4.18   Skeletal-Related Events
SREs, defined as new fractures (including vertebral compression fractures), 
irradiation of or surgery on bone, or spinal cord compression, will be captured 
from the start of the study treatment through death at the time points listed in 
the Schedule of Events until PFS significance has been claimed in this study.
7.4.19   Bone Mineral Density
DEXA scans will be done of the lumbar spine and femoral neck at screening 
(the DEXA scan does not need to be repeated if already performed within 8 
weeks of randomization), 6 months, 1 year, and then annually (4 weeks at 
the corresponding study visit to approximately 6 or every 12 months of 
treatment) until progressive disease, as indicated in the Schedule of Events.
7.4.20   Radiographic Disease Assessments
For patients with documented extramedullary disease, other assessments and 
scans such as a CT, PET-CT or MRI scan may be required to better delineate 
the sites and measurements of extramedullary disease. Follow-up scans should 
use the same imaging modality used at screening (within 8 weeks of 
randomization) at the time points specified in the Schedule of Events, until 
PFS significance has been claimed in this study.
…
7.4.22   Quantification of M-Protein
A blood sample and urine sample will be obtained at screening and at the time 
points specified in the Schedule of Events until PFS significance has been 
claimed in this study. If the screening test was performed more than 14 days 
before the first dose, the test will be repeated at baseline in the central 
laboratory.
…
7.4.23   Quantification of Immunoglobulin (Ig)
Blood samples for quantification of immunoglobulins (IgM, IgG, IgA) will be 
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obtained as specified in the Schedule of Events until PFS significance has 
been claimed in this study. Quantitative IgD and IgE will be done at screening 
(and baseline if necessary) only for all patients. For the rare patient with IgD 
or IgE multiple myeloma, the quantitative test for that antibody will be
followed at the same time points throughout the treatment period and PFS 
follow-up period as quantitative Igs (in addition to quantitative IgM, IgG, and 
IgA).
…
7.4.24   Serum Free Light Chain Assay
A blood sample for serum free light chain assay will be obtained at the time 
points specified in the Schedule of Events. Central laboratory results must be 
utilized for eligibility assessments, per guidance noted in Section 7.4.12.
7.4.25   Immunofixation of Serum and Urine
Serum and urine samples will be obtained at the time points specified in the
Schedule of Events. Central laboratory results must be utilized for eligibility 
assessments, per guidance noted in Section 7.4.12.
…
7.4.26   Bone Marrow Evaluation
Central Lab Evaluation
Molecular Analyses, Cytogenetics, and Minimal Residual Disease
…
Local Lab Evaluations
Disease Assessment
…
7.4.27   Response Assessment
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…
Response assessments are made on the basis of central laboratory data and 
should occur every cycle during the treatment period (until disease 
progression is confirmed) until PFS significance has been claimed for this
study. At that time, central efficacy and investigator assessments for protocol 
purposes will be stopped except for investigator assessment of PFS2. For 
patients who discontinue treatment before disease progression, disease 
response should occur every 4 weeks during the PFS follow-up period until 
disease progression is confirmed or the patient is started on another anticancer 
therapy (see the Schedule of Events), or until PFS significance has been 
claimed for the study.
7.4.28   Pharmacokinetic Measurements
…
Details regarding the preparation, handling, and shipping of the 
pharmacokinetic samples are provided in the Study Manual. Blood samples (3 
mL) for the determination of plasma concentrations of MLN2238 (the 
complete hydrolysis product of MLN9708) will be collected during Cycles 1 
through 12. Samples are to be collected at the time points specified in the
MLN9708 Pharmacokinetic Sampling Schedule immediately following the
Schedule of Events.
7.4.29   Blood Sample for Biomarker Analysis
…
7.4.31   Follow-up Assessments (PFS, PFS2, and OS)
Patients who stop treatment for any reason other than progressive disease will 
continue to have PFS follow-up visits. See the Schedule of Events for 
appropriate assessments. The PFS follow-up should occur every 4 weeks until 
disease progression is confirmed or the patient is started on another anticancer 
therapy, whichever comes first.
…
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Amended or 
new text:
Patients will be evaluated at scheduled visits over 4 study periods: Screening, 
Treatment, EOT, and Follow-Up (PFS and OS [including assessment of PFS2 
during OS follow-up]). Note that upon implementation of Amendment 5, 
patients will not be followed for the PFS or OS follow-up periods, as PFS 
and OS data are no longer being collected. Tests and procedures during the
Treatment Period should be performed on schedule, but occasional changes 
are allowable (± 27 days or a longer window after discussion with the 
Millennium project clinician or designee) for holidays, vacations, and other 
administrative reasons. If the study schedule is shifted, assessments must be 
shifted to ensure that collection of assessments is completed before dosing.
Refer to the Schedule of Events—Amendment 5 and Beyond for timing of 
assessments. For the timing of assessments performed before 
implementation of Amendment 5, please refer to the Full Schedule of
Events and MLN9708 Pharmacokinetic Sampling Schedule in 
Section 15.12.Schedule of Events for timing of assessments. Additional 
details are provided as necessary in the sections that follow.
7.4.1   Informed Consent
…
As of Amendment 5, patients remaining on study treatment will need to 
be reconsented. Reconsenting should be done in person.  Remote 
reconsenting is permitted as long as the process adheres to site, sponsor, 
IRB/EC, regulatory and GCP standards.
…
7.4.4   Physical Examination
Upon implementation of Amendment 5, aA physical examination will be 
completed per standard of care at the times specified in the Schedule of 
Events—Amendment 5 and Beyond. Please refer to the Full Schedule of 
Events for the timing of assessments before implementation of 
Amendment 5)Schedule of Events. Symptom-directed examinations should 
include examination of organ systems related to patient symptoms to 
document potential AEs, AE severity, or AE resolutions. A baseline 
(pretreatment) evaluation of PN will be conducted as part of the visit. If PN is
present at baseline and within the permitted criteria for study participation (see
Section 5.2), the grade must be reported in the eCRF.
7.4.5   Vital Signs
Measurement of vital signs, including temperature, blood pressure, heart rate, 
respiratory rate, and body weight will be done at the time points specified in 
the Full Schedule of Events (before implementation of 
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Amendment 5)Schedule of Events. Height will only be measured at the 
Screening visit.
Upon implementation of Amendment 5, vital signs and body weight will 
no longer be collected.
7.4.6   Eastern Cooperative Oncology Group Performance Status
Performance status will be assessed using the ECOG performance scale at the 
time points specified in the Full Schedule of Events (before implementation 
of Amendment 5)Schedule of Events.
Upon implementation of Amendment 5, ECOG performance status 
assessments will no longer be collected.
…
7.4.8  Concomitant Medications and Procedures
Concomitant medications and therapy will be recorded from the first dose of 
drug in the study drug regimen through 30 days after last dose of drug in the 
study drug regimen, with the exception of narcotics and other analgesics, 
which will be recorded from first dose of study drug until progressive disease 
(see the Full Schedule of Events [before implementation of 
Amendment 5])Schedule of Events). See Section 6.6 for a list of prohibited 
concomitant medications and therapies and Section 6.7 for a list of allowed 
concomitant medications and therapies.
Upon implementation of Amendment 5, concomitant medications and 
procedures data will no longer be collected.
7.4.9   Adverse Events
Monitoring of AEs, serious and nonserious, will be conducted throughout the 
study as specified in the Schedule of Events—Amendment 5 and Beyond 
(upon implementation of Amendment 5). Please refer to the Full Schedule 
of Events for the timing of assessments before implementation of 
Amendment 5Schedule of Events. Refer to Section 10 for details regarding 
definitions, documentation, and reporting of pretreatment events, AEs, and 
SAEs.
…
7.4.11   Electrocardiogram
A 12-lead electrocardiogram (ECG) will be conducted at screening and at the 
times outlined in the Full Schedule of Events (before implementation of 
Amendment 5)Schedule of Events. It may be repeated as clinically indicated 
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during the study at the discretion of the investigator. ECG data to be obtained 
include PR interval, QRS interval, QT interval, QTc interval, and waveforms.
Upon implementation of Amendment 5, electrocardiogram data will no 
longer be collected.
7.4.12   Clinical Laboratory Evaluations
…
Upon implementation of Amendment 5, centralized clinical laboratory 
evaluations of efficacy and safety are no longer required and local 
laboratories are to be utilized. Local laboratory evaluations should be 
entered into the eCRF only if required to understand a TEAE. For dosing
decisions and all other safety assessments for the patient, local
hematology and chemistry laboratory results should be used and do not 
need to be entered into the eCRF. Local laboratory evaluations may be 
done more frequently at the investigator’s discretion (ie, for acute 
management of TEAEs), per the investigator’s judgement of standard of 
care.
Clinical Chemistry, Hematology, and Urinalysis
Blood and urine samples for analysis of the following clinical chemistry and 
hematological parameters will be obtained as specified in the Schedule of 
Events—Amendment 5 and BeyondSchedule of Events. Blood samples 
should be collected prior to administration of any study drugs.
…
7.4.13   Health Utilization Data Collection
During the treatment and the follow-up periods indicated in the Full Schedule 
of Events (before implementation of Amendment 5)Schedule of Events, all 
medical care encounters since the previous collection will be collected from 
all patients, regardless of the reason for the medical care encounter. Examples 
of data to be collected are number and duration of medical care encounters, 
such as inpatient/outpatient admissions, homecare, and time of work loss.
Upon implementation of Amendment 5, health utilization assessments will 
no longer be collected.
7.4.14   Quality of Life Assessment (European Organization for Research 
and Treatment of Cancer)
The QOL assessments (EORTC-QLQ-C30 and MY-20; see Sections 15.9 and 
15.10) will be completed by the patient as specified in the Full Schedule of 
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Events (before implementation of Amendment 5)Schedule of Events. The 
EORTC QLQ-30 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).
…
Upon implementation of Amendment 5, quality of life assessments will no 
longer be collected.
7.4.15   Pain Assessment
Pain assessments will be performed at study visits as described in the Full 
Schedule of Events (before implementation of Amendment 5)Schedule of 
Events. Patients who experience new or worsening pain between scheduled 
visits should be seen at an unscheduled visit, if necessary, or when the next 
scheduled visit is more than 4 weeks in the future. At the unscheduled visits, 
pain assessments should be completed and appropriate management instituted. 
In addition, patients who report new or worsening pain at either a regularly 
scheduled visit or are seen for pain at an unscheduled visit should have a 
follow-up visit 3 to 5 weeks later for confirmation of the pain progression and 
for appropriate pain management.
…
At the time of each pain assessment including unscheduled visits, the patient 
will be queried regarding concomitant use of analgesics, if any, as specified in 
the Full Schedule of Events (before implementation of Amendment 5)
Schedule of Events. The patient-recalled amount of analgesic use during the 
24 hours prior to pain assessment will be recorded on both the 24-hour 
analgesic form and concomitant medication eCRFs.
A full BPI-SF instrument will be administered at each of the visits as specified 
in the Full Schedule of Events (before implementation of Amendment 5)
Schedule of Events to collect the pain severity, location, and interference 
information with a 24-hour recall period. This must be completed prior to 
other assessments or study drug regimen being administered.
Patients will complete the BPI-SF at each visit as specified in the Full 
Schedule of Events (before implementation of Amendment 5)Schedule of 
Events. Thus, for patients who discontinue study drug before disease 
progression, the scheduled collection of pain assessment should continue until 
disease progression.
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Upon implementation of Amendment 5, pain assessments will no longer 
be collected.
7.4.16   Utility Measurement
The EQ-5D consists of 2 pages: the EQ-5D descriptive system and the EQ 
visual analogue scale (EQ VAS). The descriptive system comprises 5 
dimensions (mobility, self care, usual activities, pain/discomfort, and 
anxiety/depression). The EQ VAS records the respondent’s self-rated health 
on a 20-cm vertical, visual analogue scale ranging from 0 (worst imaginable 
health state) to 100 (best imaginable health state). The EQ-5D will be 
administered as specified in the Full Schedule of Events (before 
implementation of Amendment 5)Schedule of Events.
Upon implementation of Amendment 5, utility measurement data will no 
longer be collected.
7.4.17   Skeletal Survey
…
Upon implementation of Amendment 5, skeletal survey data will no 
longer be collected.
7.4.17   Skeletal-Related Events
SREs, defined as new fractures (including vertebral compression fractures), 
irradiation of or surgery on bone, or spinal cord compression, will be captured 
from the start of the study treatment through death at the time points listed in 
the Full Schedule of Events (before implementation of
Amendment 5)Schedule of Events. until PFS significance has been claimed 
in this study.
Upon implementation of Amendment 5, skeletal survey data will no 
longer be collected.
7.4.19   Bone Mineral Density
DEXA scans will be done of the lumbar spine and femoral neck at screening 
(the DEXA scan does not need to be repeated if already performed within 8 
weeks of randomization), 6 months, 1 year, and then annually (4 weeks at 
the corresponding study visit to approximately 6 or every 12 months of 
treatment) until progressive disease, as indicated in the Full Schedule of 
Events (before implementation of Amendment 5)Schedule of Events.
Upon implementation of Amendment 5, bone mineral density data will no 
longer be collected.
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7.4.20   Radiographic Disease Assessments
For patients with documented extramedullary disease, other assessments and 
scans such as a CT, PET-CT or MRI scan may be required to better delineate 
the sites and measurements of extramedullary disease. Follow-up scans should 
use the same imaging modality used at screening (within 8 weeks of 
randomization) at the time points specified in the Full Schedule of Events 
(before implementation of Amendment 5)Schedule of Events until PFS 
significance has been claimed in this study.
…
Upon implementation of Amendment 5, radiographic disease assessments 
will no longer be collected.
7.4.22   Quantification of M-Protein
A blood sample and urine sample will be obtained at screening and at the time 
points specified in the Full Schedule of Events (before implementation of 
Amendment 5)Schedule of Events until PFS significance has been claimed in 
this study. If the screening test was performed more than 14 days before the 
first dose, the test will be repeated at baseline in the central laboratory.
…
Upon implementation of Amendment 5, all central laboratory 
assessments of response and progression are discontinued.
7.4.23   Quantification of Immunoglobulin (Ig)
Blood samples for quantification of immunoglobulins (IgM, IgG, IgA) will be
obtained as specified in the Full Schedule of Events (before implementation 
of Amendment 5)Schedule of Events until PFS significance has been claimed 
in this study. Quantitative IgD and IgE will be done at screening (and baseline 
if necessary) only for all patients. For the rare patient with IgD or IgE multiple 
myeloma, the quantitative test for that antibody will be followed at the same 
time points throughout the treatment period and PFS follow-up period as 
quantitative Igs (in addition to quantitative IgM, IgG, and IgA).
…
Upon implementation of Amendment 5, all central laboratory 
assessments of response and progression are discontinued.
7.4.24   Serum Free Light Chain Assay
A blood sample for serum free light chain assay will be obtained at the time 
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points specified in the Full Schedule of Events (before implementation of 
Amendment 5)Schedule of Events. Central laboratory results must be utilized 
for eligibility assessments, per guidance noted in Section 7.4.12.
Upon implementation of Amendment 5, all central laboratory 
assessments of response and progression are discontinued.
7.4.25   Immunofixation of Serum and Urine
Serum and urine samples will be obtained at the time points specified in the
Full Schedule of Events (before implementation of Amendment 
5)Schedule of Events. Central laboratory results must be utilized for eligibility 
assessments, per guidance noted in Section 7.4.12.
Upon implementation of Amendment 5, all central laboratory 
assessments of response and progression are discontinued.
…
7.4.26   Bone Marrow Evaluation
Central Lab Evaluation
Molecular Analyses, Cytogenetics, and Minimal Residual Disease
…
Upon implementation of Amendment 5, bone marrow aspirate is not 
required for central laboratory assessment of CR or for MRD for 
protocol purposes. Investigators may continue to take bone marrow 
aspirate per standard of care for response assessment.
Local Lab Evaluations
Disease Assessment
…
Upon implementation of Amendment 5, a bone marrow aspirate sample 
for evaluation of MRD is no longer required. Investigators should follow 
local standard of care for bone marrow aspirate samples.
7.4.27   Response Assessment
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…
Response assessments are made on the basis of central laboratory data and 
should occur every cycle during the treatment period (until disease
progression is confirmed) until PFS significance has been claimed for this 
study. At that time, central efficacy and investigator assessments for protocol 
purposes will be stopped except for investigator assessment of PFS2. For 
patients who discontinue treatment before disease progression, disease 
response should occur every 4 weeks during the PFS follow-up period until 
disease progression is confirmed or the patient is started on another anticancer 
therapy (see the Full Schedule of Events [before implementation of 
Amendment 5])Schedule of Events), or until PFS significance has been 
claimed for the study.
…
Upon implementation of Amendment 5, all central laboratory 
assessments of response and progression are no longer required.
7.4.28   Pharmacokinetic Measurements
…
Details regarding the preparation, handling, and shipping of the 
pharmacokinetic samples are provided in the Study Manual. Blood samples (3 
mL) for the determination of plasma concentrations of MLN2238 (the 
complete hydrolysis product of MLN9708) will be collected during Cycles 1 
through 12. Samples are to be collected at the time points specified in the 
MLN9708 Pharmacokinetic Sampling Schedule immediately following the 
Full Schedule of Events (before implementation of 
Amendment 5)Schedule of Events.
Upon implementation of Amendment 5, no further PK sample collection 
will be performed. The MLN9708 Pharmacokinetic Sampling Schedule
has been moved to Section 15.12 for reference.
7.4.29   Blood Sample for Biomarker Analysis
…
Upon implementation of Amendment 5, this sample is no longer be 
collected.
…
7.4.31   Follow-up Assessments (PFS, PFS2, and OS)
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Patients who stop treatment for any reason other than progressive disease will 
continue to have PFS follow-up visits. See the Full Schedule of Events 
(before implementation of Amendment 5)Schedule of Events for 
appropriate assessments. The PFS follow-up should occur every 4 weeks until 
disease progression is confirmed or the patient is started on another anticancer 
therapy, whichever comes first.
…
Upon implementation of Amendment 5, patients will no longer be 
followed during any of the follow-up periods, as PFS and OS data are not 
being collected.
Rationale for Change: To ease the burden of protocol-mandated assessments on patients.
The Schedule of Events—Amendment 5 and Beyond also contains these changes.
Change 16: Revised language regarding unscheduled visits.
The primary change occurs in Section 7.5 Unscheduled Visits.
Initial text:
Unscheduled visits may occur between treatment cycles as required. At 
unscheduled visits, the BPI-SF and HU data should be captured. Other 
assessments may be performed as clinically indicated at the discretion of the 
investigator.
Amended or 
new text:
Unscheduled visits may occur between treatment cycles as required. At 
unscheduled visits before implementation of Amendment 5, the BPI-SF and 
health utilizationHU data should be captured. Upon implementation of 
Amendment 5, pain assessments and health utilization data will no longer 
be collected. Other assessments may be performed as clinically indicated at 
the discretion of the investigator.
Rationale for Change: To describe that BPI-SF and health utilization data will not be 
collected at unscheduled visits after implementation of Amendment 5.
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Change 17: Revised language regarding completion of treatment.
The primary change occurs in Section 7.7 Completion of Treatment.
Initial text:
Patients will be considered to have completed study treatment if they receive the 
study drug regimen until disease progression or until discontinuation for 
unacceptable toxicity, withdrawal of consent, or death. Quality Review by a 
MPI/designee clinician is required prior to discontinuing a patient from treatment 
or stopping disease assessments for progressive disease. A treatment 
discontinuation form must be submitted and approved prior to removing a patient 
from study treatment for disease progression, toxicity, or any other reason. 
Patients will attend an EOT visit 30 days (+1 week) after receiving their last dose 
of the study drug regimen 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. Patients will continue to be followed for other 
follow-up assessments specified in the Schedule of Events. Refer to the Schedule 
of Events for End of Treatment visit assessments.
Amended or 
new text:
Patients will be Prior to implementation of Amendment 5, patients were 
considered to have completed study treatment if they received the study drug 
regimen until disease progression or until discontinuation for unacceptable 
toxicity, withdrawal of consent, or death. Quality Review by a MPI/designee 
clinician iswas required prior to discontinuing a patient from treatment or 
stopping disease assessments for progressive disease. A treatment
discontinuation form must behad to have been submitted and approved prior 
to removing a patient from study treatment for disease progression, toxicity, or 
any other reason. 
Upon implementation of Amendment 5, only patients who are 
demonstrating clinical benefit and are unable to access a commercial 
supply of ixazomib and/or lenalidomide will remain in the study. 
Completion of study treatment will occur when patients discontinue study 
drugs provided by the sponsor in this clinical trial setting, or when the 
patient experiences disease progression, unacceptable toxicity, 
withdrawal of consent, or death. The reason for treatment 
discontinuation must be recorded in the eCRF but no approval is 
required.   
Patients will attend an EOT visit 30 days (+1 week) after receiving their last
dose of the study drug regimen unless next-line therapy is started before 30 
days after the last dose of study drug, in which case the EOT visit should 
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occur before the start of the next-line therapy. Patients will continue to be 
followed for other follow-up assessments specified in the Schedule of Events.
Refer to the Schedule of Events—Amendment 5 and BeyondSchedule of 
Events for End of Treatment visit assessments.
Rationale for Change: To describe the change in completion of treatment upon 
implementation of Amendment 5.
Change 18: Revised language regarding completion of study.
The primary change occurs in Section 7.8 Completion of Study.
Initial text:
Patients will be considered to have completed the study if they are followed 
until death or until the sponsor terminates the study. 
Amended or
new text:
Patients will be considered to have completed the study if they are followed 
until death or until the sponsor terminates the study. Prior to implementation 
of Amendment 5, patients were considered to have completed the study if 
they were followed until death or until the sponsor terminated the study. 
Upon implementation of Amendment 5, patients will no longer be 
followed during any of the follow-up periods, as PFS and OS data are not 
being collected. Patients will be considered to have completed the study if 
they completed study treatment (see Section 7.7).
Rationale for Change: To describe the change in completion of study upon implementation 
of Amendment 5.
Change 19: Revised language regarding discontinuation of treatment with the study drug 
regimen, and patient replacement.
The primary change occurs in Section 7.9 Discontinuation of Treatment With the Study 
Drug Regimen, and Patient Replacement.
Initial text:
Once the study drug regimen has been discontinued, all study procedures outlined 
for the EOT visit will be completed as specified in the Schedule of Events. The 
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primary reason for study drug discontinuation will be recorded on the eCRF.
Amended or 
new text:
Once the study drug regimen has been discontinued, all study procedures outlined 
for the EOT visit will be completed as specified in the Schedule of Events—
Amendment 5 and BeyondSchedule of Events. The primary reason for study 
drug discontinuation will be recorded on the eCRF.
Rationale for Change: To indicate that discontinuation of treatment with the study drug 
regimen should follow the updated Schedule of Events.
Change 20: Revised language regarding withdrawal of patients from study.
The primary change occurs in Section 7.10 Withdrawal of Patients From Study.
Initial text:
The consequence of study withdrawal is that no new information will be collected 
from the withdrawn patient and added to the existing data or any database.
However, every effort will be made to follow all patients for safety.
Amended or 
new text:
Upon implementation of Amendment 5, PFS and OS follow-up will no 
longer be performed. Patients will now complete the study immediately
following the end of treatment visit. The consequence of study withdrawal is 
that no new information will be collected from the withdrawn patient and
added to the existing data or any database. However, every effort will be made 
to follow all patients for safety.
Rationale for Change: To indicate that upon implementation of Amendment 5, patients 
will complete the study immediately following the end of treatment visit and will not be
followed for PFS or OS.
Change 21: Revised language regarding statistical and quantitative analyses.
The primary change occurs in Section 8 STATISTICAL AND QUANTITATIVE 
ANALYSES.
Initial text:
8 STATISTICAL AND QUANTITATIVE ANALYSES
…
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8.1.1   Determination of Sample Size
…
The first IA will be performed when approximately 326 PFS events have 
occurred. This is expected to occur approximately 45 months after the first patient 
is enrolled, including a 27-month enrollment period and additional 18-month 
follow-up from the last patient. 
If the test for PFS in the ITT population is statistically significant at the first IA, 
this will be the FA for PFS for statistical testing purposes, and the second IA will 
assess OS when approximately 250 death events have occurred.  
If the test for PFS in the ITT is not statistically significant at the first IA, then the 
second IA will assess PFS and OS when approximately 370 PFS events have
occurred. In addition, in such a case, PFS will be tested at IA2 in 3 prespecified
subgroups: 1) patients with baseline CrCl > 60 mL/min; 2) patients aged 
< 75 years; and 3) patients harboring high-risk cytogenetic abnormalities defined 
as del(17p), t(4;14), t(14;16), and amp(1q21).
For the final OS analysis, the total event size calculation will be based on the 
adaptive sample size re-assessment approach.[66,67] The minimum event size of 
 death events is based on an optimistic assumption of a hazard ratio of 0.72 
(median survival of 50 months in the control arm vs 69.4 months in the treatment 
arm) with 80% power at a 2-sided 0.05 level of significance. The O’Brien-
Fleming alpha spending function (the Lan-DeMets method) will be used to 
calculate the significance boundary based on observed number of death events in 
each IA with a total of 320 OS events for the FA. In the second IA, if OS 
significance is not claimed, the conditional power based on OS will be calculated. 
If the conditional power falls in the favorable zone or unfavorable zone, the FA of 
OS with approximately 320 events will remain unchanged. If the conditional 
power falls in the promising zone, the event size will be determined according to 
a prespecified sample size adaptation rule, with an event cap of ~400 OS events. 
No futility analysis will be performed in the study.
The sample size adaptation rule is a prespecified stepwise function to avoid the 
back calculation problem resulting from one sample size corresponding to either 
barely promising or highly promising interim results. The sample size adaptation 
rule will be designed by the sponsor’s independent design statistician and 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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approved by the sponsor’s head of biostatistics. Neither the independent design 
statistician nor the head of biostatistics is involved in the study conduct.
The adaptation rules will be outlined in a separate document and will not be 
accessible to the sponsor’s study team until completion of the study. The rules 
will be available only to the sponsor’s independent design statistician, the
sponsor’s head of biostatistics, the IDMC, and the statistics representative on the 
sponsor’s executive committee (if different from the sponsor’s head of 
biostatistics).
…
8.1.10   Interim Analysis
There are 2 planned IAs. The first IA will be performed when approximately 
326 disease progression/death events have occurred. This IA is expected to occur 
approximately 45 months after the first patient is enrolled. If the test for PFS in 
the ITT population is statistically significant at the first IA, this will be the FA for
PFS for statistical testing purposes, central efficacy and investigator assessments 
of disease response for protocol purposes will be discontinued (except for 
investigator assessment of PFS2) given that the primary endpoint has been met, 
and the second IA will be conducted for OS when approximately 250 death
events have occurred. If the test for PFS does not reach statistical significance at 
IA1 in the ITT population, PFS will be tested in both the ITT population and in 3
prespecified subgroups, as described below.
The subgroup testing strategy approach includes 2 major components: a) 
preservation of the ability to detect the overall treatment effect using a reduced 
overall significance level of 1 = 0.04, which will be used for the ITT population, 
and b) test of treatment effect for the 3 prespecified subgroups: 1) patients with 
baseline CrCl > 60 mL/min; 2) patients aged < 75 years; and 3) patients harboring
high-risk cytogenetic abnormalities defined as del(17p), t(4;14), t(14;16), and 
amp(1q21). Subgroup testing will be conducted using the remaining 2 = 0.01 and 
the Hochberg procedure for multiplicity correction (refer to the appendix in the 
SAP for proof of strong control of the Type I error rate). Because the size of the 
treatment effect may be substantially greater in a prespecified subgroup than in 
the overall study population, analysis of patients in each subgroup at a stringent 
significance level may still provide a statistically significant outcome. The 
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detailed statistical design schema is presented in Figure 8-1.
[Figure 8-1]
For the testing of PFS in the ITT population, the Gamma(-1) alpha spending 
function will be used to calculate the significance boundary based on the 
observed number of PFS events with total alpha=0.04. The first IA will be
performed when approximately 326 PFS events have occurred. This will be the 
first analysis for PFS for statistical testing purposes. If the test is statistically 
significant, then this analysis will be the FA of PFS for statistical testing 
purposes. No subsequent PFS testing will be conducted, and central efficacy and 
investigator assessments of disease response for protocol purposes will be 
discontinued except for the investigator assessment of PFS2 (see the Schedule of 
Events). In this scenario, the second IA will be for OS testing when 
approximately 250 death events have occurred and will determine whether the 
final number of OS events might be increased.
If the test for ITT PFS is not statistically significant at the first IA, response 
assessments will continue, and PFS testing in the ITT and subgroup populations 
will be conducted in parallel at the second IA, when approximately 370 PFS 
events have occurred (rather than the previous study design of 435 PFS events);
this will be the FA of PFS for statistical testing purposes. If the test for PFS is
significant at the second IA, OS will be tested, and determination of whether the 
final number of OS events will be increased from 320 to up to 400 will occur. If 
the test for PFS in the second IA is not statistically significant in any population 
(the ITT or any of the 3 subgroups), the study will be stopped. 
Because at the time of this amendment, the boundary for ITT PFS at IA1 has 
already been calculated based on 328 PFS events observed at IA1, 435 PFS 
events targeted at PFS final analysis, and the Gamma(-1) alpha-spending 
function, this boundary will not be changed. However, the boundary for ITT PFS 
at IA2 (final analysis of ITT PFS) will be calculated based on the observed 
number of PFS events at IA2 in order to spend what is left of the overall alpha-
level 0.04 for ITT. The final boundaries at IA1 and IA2 will not approximate a
Gamma(-1) function, but type I error will remain protected under the flexible 
alpha-spending approach (see appendix in the SAP for more details).
For the testing of OS, alpha spending for IA1 and IA2 will always be based on 
the observed events (information fraction) using alpha=0.04 with a different 
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adjustment of critical value at OS FA testing (CHW test statistics [67] will be 
used for the primary analysis of OS at FA) based on the following scenarios: 
1.
If ITT PFS is significant in IA1, then ITT OS will be tested in the FA 
with a total alpha of 0.04; there is no test on subgroup PFS. 
2.
If ITT PFS is not significant in IA1, then parallel testing of the ITT 
population PFS and the subgroup populations PFS will occur in IA2: 
a.
If the ITT population’s PFS is significant and at least 1 subgroup 
is not significant, then the ITT population’s OS will be tested at 
FA using a total alpha of 0.04.
b.
If the ITT population’s PFS is significant and all 3 subgroup 
populations’ PFS are significant, then the ITT population’s OS
will be tested at FA with a total alpha of 0.05.
c.
If the ITT population’s PFS is not significant and at least 1 
subgroup population’s PFS is significant, then no formal ITT OS 
testing will be conducted. 
The family-wise error rate for the 4 null hypotheses for PFS and the 1 hypothesis 
for OS for the overall study population is controlled using a prespecified, 2-sided 
0.05 level of significance. 
The proof of strong control of the Type I error rate for testing PFS and OS in the 
ITT population and PFS in the subgroup populations is shown in the appendix in 
the SAP. For the other 2 key secondary endpoints, the CR rate will be tested at 
the same alpha level, instead of the same critical value, as that of the OS analysis 
when OS reaches statistical significance. The pain response rate will be tested at 
the same alpha level as that of the CR rate analysis when the CR rate reaches 
statistical significance. Because of the closed sequential testing property, the 
family-wise error rate is strongly controlled for both the primary endpoint and the 
3 key secondary endpoints [78].
The IAs will be conducted by the independent statistical center (ISC) and 
presented for review to the IDMC. During the closed session of the IDMC 
meeting, the IDMC will compare the conditional power for OS based on the 
interim results with the prespecified sample size and primary endpoint adaptation 
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rules and recommend to the sponsor executive committee the final adaptation
decision. This recommendation will be documented in the IDMC closed meeting
minutes.
Amended or 
new text:
8   STATISTICAL AND QUANTITATIVE ANALYSES
The second IA has been performed (data cutoff date of 02 December 2019) 
and the primary endpoint of PFS did not reach statistical significance. 
Therefore, no subsequent formal inferential statistical analyses will be 
conducted. The primary analysis of efficacy and safety was performed on 
data from the second IA and will be presented in a clinical study report 
(CSR). Minimal descriptive analyses will be performed on patient data 
collected after the second IA and will be presented in a future CSR 
addendum. The description of the statistical methods presented below 
reflects the original design and the planned analysis for the study, reflecting 
the statistical considerations up to the second IA.
…
8.1.1 Determination of Sample Size
…
The first IA will be performed when approximately 326 PFS events have 
occurred. This is expected to occur approximately 45 months after the first
patient is enrolled, including a 27-month enrollment period and additional 18-
month follow-up from the last patient. 
If the test for PFS in the ITT population is statistically significant at the first 
IA, this will be the FA for PFS for statistical testing purposes, and the second 
IA will assess OS when approximately 250 death events have occurred.  
If the test for PFS in the ITT is not statistically significant at the first IA, then 
the second IA will assess PFS and OS when approximately 370 PFS events 
have occurred. In addition, in such a case, PFS will be tested at IA2 in 3 
prespecified subgroups: 1) patients with baseline CrCl > 60 mL/min; 
2) patients aged < 75 years; and 3) patients harboring high-risk cytogenetic
abnormalities defined as del(17p), t(4;14), t(14;16), and amp(1q21).
For the final OS analysis, the total event size calculation will be based on the 
adaptive sample size re-assessment approach.[66,67] The minimum event size 
of 
 death events is based on an optimistic assumption of a hazard ratio of 
0.72 (median survival of 50 months in the control arm vs 69.4 months in the 
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treatment arm) with 80% power at a 2-sided 0.05 level of significance. The
O’Brien-Fleming alpha spending function (the Lan-DeMets method) will be 
used to calculate the significance boundary based on observed number of 
death events in each IA with a total of 320 OS events for the FA. In the 
second IA, if OS significance is not claimed, the conditional power based on 
OS will be calculated. If the conditional power falls in the favorable zone or 
unfavorable zone, the FA of OS with approximately 320 events will remain 
unchanged. If the conditional power falls in the promising zone, the event size
will be determined according to a prespecified sample size adaptation rule, 
with an event cap of ~400 OS events. No futility analysis will be performed in 
the study.
The sample size adaptation rule is a prespecified stepwise function to avoid 
the back calculation problem resulting from one sample size corresponding to 
either barely promising or highly promising interim results. The sample size 
adaptation rule waswill be designed by the sponsor’s independent design 
statistician and approved by the sponsor’s head of biostatistics. Neither the 
independent design statistician nor the head of biostatistics is involved in the 
study conduct.
The adaptation rules werewill be outlined in a separate document and will not 
be accessible to the sponsor’s study team until completion of the study. The 
rules arewill be available only to the sponsor’s independent design 
statistician, the sponsor’s head of biostatistics, the IDMC, and the statistics 
representative on the sponsor’s executive committee (if different from the 
sponsor’s head of biostatistics).
…
8.1.10   Interim Analysis
There wereare 2 planned IAs. The first IA waswill be performed when 328
PFSapproximately 326 disease progression/death events hadhave occurred. 
The data cutoff date for this This IA was 15 February 2018. The is 
expected to occur approximately 45 months after the first patient is enrolled. If 
the test for PFS in the ITT population was notis statistically significant at the 
first IA. The , this will be the FA for PFS for statistical testing purposes, 
central efficacy and investigator assessments of disease response for protocol 
purposes will be discontinued (except for investigator assessment of PFS2) 
given that the primary endpoint has been met, and the second IA waswill be
conducted for OSwhen 378 PFSapproximately 250 death events hadhave
occurred. BecauseIf the test for PFS diddoes not reach statistical significance 
at the first IAIA1 in the ITT population, in the second IA PFS waswill be
tested in both the ITT population and in 3 prespecified subgroups, as 
described below.
The subgroup testing strategy approach includedincludes 2 major 
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components: a) preservation of the ability to detect the overall treatment effect 
using a reduced overall significance level of 1 = 0.04, which waswill be used 
for the ITT population, and b) test of treatment effect for the 3 prespecified 
subgroups: 1) patients with baseline CrCl > 60 mL/min; 2) patients aged 
< 75 years; and 3) patients harboring high-risk cytogenetic abnormalities 
defined as del(17p), t(4;14), t(14;16), and amp(1q21). Subgroup testing 
waswill be conducted using the remaining 2 = 0.01 and the Hochberg 
procedure for multiplicity correction (refer to the appendix in the SAP for 
proof of strong control of the Type I error rate). Because the size of the 
treatment effect couldmay be substantially greater in a prespecified subgroup 
than in the overall study population, analysis of patients in each subgroup at a 
stringent significance level couldmay still provide a statistically significant 
outcome. The detailed statistical design schema is presented in Figure 8-1.
[Figure 8-1]
For the testing of PFS in the ITT population, the Gamma(-1) alpha spending 
function waswill be used to calculate the significance boundary based on the 
observed number of PFS events with total alpha=0.04. The first IA waswill be
performed when 328approximately 326 PFS events hadhave occurred. This 
waswill be the first analysis for PFS for statistical testing purposes.. If the test 
is statistically significant, then this analysis will be the FA of PFS for 
statistical testing purposes. No subsequent PFS testing will be conducted, and 
central efficacy and investigator assessments of disease response for protocol 
purposes will be discontinued except for the investigator assessment of PFS2
(see the Schedule of Events). In this scenario, the second IA will be for OS 
testing when approximately 250 death events have occurred and will 
determine whether the final number of OS events might be increased.
BecauseIf the test for ITT PFS wasis not statistically significant at the first 
IA, response assessments continuedwill continue, and PFS testing in the ITT 
and subgroup populations waswill be conducted in parallel at the second IA, 
when 378approximately 370 PFS events hadhave occurred (rather than the 
previous study design of 435 PFS events); this waswill be the FA of PFS for 
statistical testing purposes. If the test for PFS had beenis significant at the 
second IA, OS would have beenwill be tested, and determination of whether 
the final number of OS events wouldwill be increased from 320 to up to 400
would have occurred. Because will occur. Ifthe test for PFS in the second IA 
wasis not statistically significant in any population (the ITT or any of the 
3 subgroups), the study waswill be stopped and . Because at the time ofthis 
amendment implemented., the boundary for ITT PFS at IA1 has already been 
calculated based on 328 PFS events observed at IA1, 435 PFS events targeted 
at PFS final analysis, and the Gamma(-1) alpha-spending function, this 
boundary will not be changed. However, the boundary for ITT PFS at IA2 
(final analysis of ITT PFS) will be calculated based on the observed number 
of PFS events at IA2 in order to spend what is left of the overall alpha-level 
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Clinical Study Protocol C16014 Amendment 5, 2013-000326-54, 09 July 2020
214
0.04 for ITT. The final boundaries at IA1 and IA2 will not approximate a 
Gamma(-1) function, but type I error will remain protected under the flexible 
alpha-spending approach (see appendix in the SAP for more details).
For the testing of OS, alpha spending for IA1 and IA2 will always be based on 
the observed events (information fraction) using alpha=0.04 with a different 
adjustment of critical value at OS FA testing (CHW test statistics [67] will be 
used for the primary analysis of OS at FA) based on the following scenarios: 
3. If ITT PFS is significant in IA1, then ITT OS will be tested in the FA 
with a total alpha of 0.04; there is no test on subgroup PFS. 
4. If ITT PFS is not significant in IA1, then parallel testing of the ITT 
population PFS and the subgroup populations PFS will occur in IA2: 
d. If the ITT population’s PFS is significant and at least 1 
subgroup is not significant, then the ITT population’s OS will 
be tested at FA using a total alpha of 0.04.
e.
If the ITT population’s PFS is significant and all 3 subgroup 
populations’ PFS are significant, then the ITT population’s OS 
will be tested at FA with a total alpha of 0.05.
f.
If the ITT population’s PFS is not significant and at least 1 
subgroup population’s PFS is significant, then no formal ITT 
OS testing will be conducted. 
The family-wise error rate for the 4 null hypotheses for PFS and the 1 
hypothesis for OS for the overall study population is controlled using a 
prespecified, 2-sided 0.05 level of significance. 
The proof of strong control of the Type I error rate for testing PFS and OS in
the ITT population and PFS in the subgroup populations is shown in the 
appendix in the SAP. For the other 2 key secondary endpoints, the CR rate 
will be tested at the same alpha level, instead of the same critical value, as that 
of the OS analysis when OS reaches statistical significance. The pain response
rate will be tested at the same alpha level as that of the CR rate analysis when 
the CR rate reaches statistical significance. Because of the closed sequential 
testing property, the family-wise error rate is strongly controlled for both the 
primary endpoint and the 3 key secondary endpoints [78].
The IAs werewill be conducted by the independent statistical center (ISC) and 
presented for review to the IDMC. During the closed session of the IDMC 
meeting, the IDMC will compare the conditional power for OS based on the 
interim results with the prespecified sample size and primary endpoint 
adaptation rules and recommend to the sponsor executive committee the final 
adaptation decision. This recommendation will be documented in the IDMC 
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MLN9708
Clinical Study Protocol C16014 Amendment 5, 2013-000326-54, 09 July 2020
215
closed meeting minutes.
Rationale for Change: To update the statistical methods now that both interim analyses 
have been conducted.
Change 22: Added language to Independent Review Committee section.
The primary change occurs in Section 9.1 Independent Review Committee.
Added text:
An IRC will review all disease evaluation data from the study and determine 
disease status (response and progression, including PFS follow-up period but 
does not apply to PFS2 assessment). Data from the IRC will not be provided back 
to the investigator during the conduct of the study.
Upon implementation of Amendment 5, IRC review of response data will no 
longer be performed.
Rationale for Change: To indicate that the Independent Review Committee will no longer 
be reviewing response data upon implementation of Amendment 5.
Change 23: Added language to Procedures for Recording and Reporting Adverse Events 
and Serious Adverse Events.
The primary change occurs in Section 10.3 Monitoring of Adverse Events and Period of 
Observation.
Added text:
The paper SAE forms should be submitted via fax (see fax numbers below) 
within 24 hours of awareness. In case of fax, site personnel need to confirm 
successful transmission of all pages and include an 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 need to 
confirm successful transmission by awaiting an acknowledgment of the 
receipt via e-mail within 1 business day. If SAEs are reported via fax or by e-
mail, electronic data capture (EDC)/RAVE must be updated as soon as 
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Clinical Study Protocol C16014 Amendment 5, 2013-000326-54, 09 July 2020
216
possible with the appropriate information.
Rationale for Change: To align content in this section with content in other protocols in the
ixazomib program.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


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SAP_001.pdf: 


Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A Phase 3, Randomized, Double-Blind, Multicenter Study Comparing Oral MLN9708 
Plus Lenalidomide and Dexamethasone Versus Placebo Plus Lenalidomide and Dexamethasone 
in Adult Patients With Newly Diagnosed Multiple Myeloma
NCT Number: NCT01850524
SAP Approve Date: 14 January 2020
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable (PPD) information 
or company confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.


MLN9708 (Ixazomib)
Statistical Analysis Plan, Study C16014
Confidential
1
STATISTICAL ANALYSIS PLAN
A Phase 3, Randomized, Double-Blind, Multicenter Study Comparing Oral MLN9708
Plus Lenalidomide and Dexamethasone Versus Placebo Plus Lenalidomide and
Dexamethasone in Adult Patients With Newly Diagnosed Multiple Myeloma
Protocol #:  C16014
SAP History
Original
16 March 2018
Amendment 1
14 January 2020
Approved by: 
Note: If this document was approved electronically, then the electronic approval signatures 
may be found at the end of the document.
Date
Date
Date
Date
Property of Takeda: For Non-Commercial 
m
Fo
ject to the Applicable Terms of Use
e T
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arch 201
ch 20
January
Januar
he elelectr
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PPD


MLN9708 (Ixazomib)
Statistical Analysis Plan, Study C16014
Confidential
2
Rationale for Amendment 1
This document describes the changes in reference to the statistical analysis plan (SAP)
incorporating Amendment No. 1. The primary reason for this amendment is to modify the 
SAP to ensure timely analysis of the primary endpoint, progression-free survival (PFS), in 
light of the slower than expected PFS event rate over the past year. The second interim 
analysis (IA) – the final analysis for PFS – will now take place when approximately 370 
PFS events have been observed. Power remains sufficient at 92%.
Minor grammatical, editorial, formatting, and administrative changes are included for 
clarification purposes only.
Changes in Amendment 1
1. Update statistical procedures to modify the number of events for the final PFS analysis.
2. Clarify the statistical boundary for PFS at the second IA.
3.
 
4. Update list of covariates in the adjustment of overall survival analysis for potential 
confounding effects by subsequent therapies after patients discontinue study treatment.
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 Applicable Terms of Use
d for 
for 
he final
e final
urvival 
urvi
atitients 
ents
CCI


MLN9708 (Ixazomib)
Statistical Analysis Plan, Study C16014
Confidential
3
TABLE OF CONTENTS
1. INTRODUCTION............................................................................................................8
1.1 Study Design..............................................................................................................8
1.2 Study Objectives ........................................................................................................9
2. POPULATIONS FOR ANALYSIS................................................................................11
2.1 Intent-to-Treat Population.........................................................................................11
2.2 Safety Population .....................................................................................................11
2.3 Response-Evaluable Population:...............................................................................12
2.4 Per-Protocol (PP) population ....................................................................................12
3. HYPOTHESES AND DECISION RULES.....................................................................12
3.1 Statistical Hypotheses...............................................................................................12
3.2 Statistical Decision Rules .........................................................................................13
4. INTERIM ANALYSIS...................................................................................................14
4.1 Interim Analysis .......................................................................................................14
4.2 Independent Data Monitoring Committee (IDMC)....................................................17
4.3 Independent Review Committee (IRC).....................................................................18
5. STATISTICAL METHODOLOGY ...............................................................................18
5.1 Sample Size Justification..........................................................................................18
5.2 Randomization and Stratification..............................................................................19
5.3 Blinding and Unblinding ..........................................................................................20
5.4 Data Handling ..........................................................................................................20
5.4.1 Methods for Handling Missing Data...................................................................20
5.4.2 Definition of Baseline Values ............................................................................23
5.4.3 Windowing of Visits..........................................................................................23
5.4.4 Pooling ..............................................................................................................23
5.4.5 Withdrawals, Dropouts, Loss to Follow-up ........................................................23
5.5 Patient Disposition ...................................................................................................23
5.6 Demographics and Baseline Disease Characteristics.................................................24
5.6.1 Demographics....................................................................................................24
5.6.2 Medical History.................................................................................................24
5.6.3 Baseline Disease Status......................................................................................24
5.6.4 Bone Marrow Cytogenetic Results at Baseline...................................................25
5.7 Treatments and Medications .....................................................................................26
5.7.1 Concomitant Medications ..................................................................................26
5.7.2 Study Treatments...............................................................................................26
5.8 Efficacy Analyses.....................................................................................................29
5.8.1 Primary Efficacy Endpoint.................................................................................29
5.8.2 Key Secondary Efficacy Endpoints....................................................................31
5.8.3 Other Secondary Efficacy Endpoints and Analyses ............................................34
5.9 Pharmacokinetic and Biomarker Analysis.................................................................36
5.9.1 Pharmacokinetic Analyses .................................................................................36
5.9.2 Biomarker Analysis ...........................................................................................37
5.9.3 Minimal Residual Disease Analysis ...................................................................38
5.10 Analyses of Patient-Reported Outcomes and Health Economics .............................38
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MLN9708 (Ixazomib)
Statistical Analysis Plan, Study C16014
Confidential
4
5.10.1 Patient Reported Outcomes (PROs)..................................................................38
5.10.2 Health Economics Analysis Using Medical Resource Utilization and Utility....40
5.10.3 Pain..................................................................................................................40
5.11 Safety Analyses ......................................................................................................42
5.11.1 Adverse Events ................................................................................................42
5.11.2 Laboratory Data...............................................................................................45
5.11.3 Electrocardiograms ..........................................................................................46
5.11.4 Vital Signs .......................................................................................................47
5.11.5 Eastern Cooperative Oncology Group (ECOG) Performance Status .................47
5.11.6 Other Safety Assessments ................................................................................47
6. CHANGES TO PLANNED ANALYSES FROM PROTOCOL .....................................47
7. PROGRAMMING CONSIDERATIONS .......................................................................47
7.1 Statistical Software...................................................................................................47
7.2 Rules and Definitions ...............................................................................................47
8. APPENDIX....................................................................................................................48
8.1 Proof of Strong Control of Type I Error Rate............................................................48
8.2 Calculating the Significance Boundary for ITT PFS at IA2.......................................52
9. REFERENCES...............................................................................................................53
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MLN9708 (Ixazomib)
Statistical Analysis Plan, Study C16014
Confidential
5
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS
Abbreviation
Term
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
ASCT
autologous stem cell transplant
BM
bone marrow
BSA
body surface area
CBC
complete blood count
CFR
Code of Federal Regulations
CL
clearance, IV dosing
CLP
plasma clearance
CLTotal
total clearance
Cmax
single-dose maximum (peak) concentration  
CO2
carbon dioxide
CR
complete response
CT
computed tomography
CTCAE
Common Toxicity Criteria for Adverse Events
Ctrough
single-dose end of dosing interval (trough) concentration
CV
coefficient of variation 
CYP
cytochrome P450
DDI
drug-drug interaction(s)
DLT
dose-limiting toxicity
DNA
deoxyribonucleic acid
DOR
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EOS
End of Study (visit)
EOT
End of Treatment (visit)
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MLN9708 (Ixazomib)
Statistical Analysis Plan, Study C16014
Confidential
6
Abbreviation
Term
EU
European Union
FA
final analysis
FDA
United States Food and Drug Administration
GCP
Good Clinical Practice
GI
gastrointestinal
GLP
Good Laboratory Practices
GM-CSF
granulocyte macrophage-colony stimulating factor
GMP
Good Manufacturing Practice
Hb
hemoglobin
HU
health utilization
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
IDMC
Independent Data Monitoring Committee
IEC
independent ethics committee
IMWG
International Myeloma Working Group
IRB
institutional review board
IRC
independent review committee
ITT
intent-to-treat
IV
intravenous; intravenously
IVRS
interactive voice response system
KPS
Karnofsky Performance Status
LFT
liver function test(s)
MedDRA
Medical Dictionary for Regulatory Activities
MID
minimally important difference
Millennium
Millennium Pharmaceuticals, Inc., and its affiliates
MM
multiple myeloma
MRI
magnetic resonance imaging
MRU
medical resource utilization
MTD
maximum tolerated dose
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
Property of Takeda: For Non-Commercial Use On
d Subject to the Applicable Terms of Use
on
on
mittee
mittee
a Workin
Work
w board
board
eview co
eview c
treat
eat
venous; i
enous
interactiv
nteract
Karn
Ka
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nium
MM
MRI
M
M
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MLN9708 (Ixazomib)
Statistical Analysis Plan, Study C16014
Confidential
7
Abbreviation
Term
NDMM
Newly diagnosed multiple myeloma
ORR
overall response rate
OS
Overall survival
PBMC
peripheral blood mononuclear cell
PD
progressive disease (disease progression)
PFS
Progression-free survival
PK
pharmacokinetic(s)
PO
per os; by mouth (orally)
PR
partial remission or partial response 
PRO
patient-reported outcome(s)
PSA
prostate-specific antigen
QOL
quality of life
QTc
rate-corrected QT interval (millisec) of electrocardiograph
RBC
red blood cell
RECIST
Response Evaluation Criteria in Solid Tumors
SAE
serious adverse event
SC
subcutaneous
SCT
stem cell transplant
SD
stable disease
SMA
Safety Management Attachment to the Investigator’s Brochure
t1/2
terminal disposition half-life
TEAE
Treatment-emergent adverse event
TGI
tumor growth inhibition
Tmax
single-dose time to reach maximum (peak) concentration
TTP
Time to (disease) progression
ULN
upper limit of the normal range
US
United States
VGPR
Very good partial response
WBC
white blood cell
WHO
World Health Organization
Property of Ta
For Non-Commercial Use Only and Su
to the Applicable Terms of Use
isec) of e
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Criteria in
Criteria i
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transplan
ranspl
e disease
disea
Safety M
afety M
term
term
TP
TP
ULN
U
U
CCI
CCI
CCI


MLN9708 (Ixazomib)
Statistical Analysis Plan, Study C16014
Confidential
8
1.   
INTRODUCTION
In general, the purpose of the Statistical Analysis Plan (SAP) is to provide a framework that 
addresses the protocol objectives in a statistically rigorous fashion, with minimized bias or 
analytical deficiencies.  Specifically, this plan has the following purpose:
To prospectively (a priori) outline the types of analyses and data presentations that will 
address the study objectives outlined in the protocol, and to explain in detail how the data 
will be handled and analyzed, adhering to commonly accepted standards and practices of 
biostatistical analysis in the pharmaceutical industry.
1.1   Study Design
This is a phase 3, randomized, double-blind, multicenter study to evaluate the safety and 
efficacy of MLN9708 versus placebo when added to lenalidomide and dexamethasone in 
patients with newly diagnosed multiple myeloma (NDMM).  Patients must be previously 
untreated for symptomatic MM, be ineligible for high-dose therapy plus stem cell 
transplantation (HDT-SCT) because of age (ie, 65 years) or coexisting conditions per 
investigator judgment, be candidates for treatment with lenalidomide and dexamethasone as 
their standard therapy, and meet other eligibility criteria.   
Following the Screening period, patients to be enrolled will be randomized to receive either 
MLN9708 or placebo in a double-blind fashion in addition to the background therapy of 
lenalidomide plus dexamethasone (LenDex).  Eligible patients will be randomized in a 1:1 
ratio into those 2 treatment arms, stratified by age (<75 years vs ≥75), ISS (stage I or II vs 
stage III), and BPI-SF worst pain score (4 vs 4) at Screening.
Patients may continue to receive treatment for a maximum duration of 18 cycles 
(approximately 18 months with 28 days per cycle), or until progressive disease (PD) or 
unacceptable toxicity, whichever comes first. Patients remaining on study after 18 cycles 
will continue treatment in the same randomization arm on the same schedule with modified 
dose levels of the study drug and LenDex: reduce MLN9708 (or placebo) dose to 3.0 mg, 
reduce lenalidomide dose to 10 mg, and no dexamethasone. 
Patients will be assessed for disease response and progression by an independent review 
committee (IRC).  Response will be assessed according to the International Myeloma 
Working Group (IMWG) criteria for all patients every cycle during the treatment period and 
subsequently every 4 weeks during the PFS follow-up period until disease progression.  All 
patients will be followed for survival after progression.  Patients will be contacted every 12 
weeks until death or termination of the study by the sponsor.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


MLN9708 (Ixazomib)
Statistical Analysis Plan, Study C16014
Confidential
9
1.2   Study Objectives
The primary objective is:

To determine whether the addition of oral MLN9708 to lenalidomide and 
dexamethasone improves progression-free survival (PFS) in patients with NDMM
The key secondary objectives are:

To determine whether the addition of oral MLN9708 to lenalidomide and 
dexamethasone improves overall survival (OS)

To determine whether the addition of oral MLN9708 to lenalidomide and 
dexamethasone improves the rate of complete response (CR)

To determine whether the addition of oral MLN9708 to lenalidomide and 
dexamethasone improves pain response rate, as assessed by the Brief Pain Inventory 
– Short Form (BPI-SF) and analgesic use
Other secondary objectives are:

To determine overall response rate (ORR), including partial response (PR), very 
good partial response (VGPR), and CR

To determine time to response (TTR), duration of response (DOR), and time to 
progression (TTP)

To determine the effect of the addition of MLN9708 to lenalidomide and
dexamethasone on progression-free survival 2 (PFS2), defined as the date from
randomization to the date of second disease progression or death from any cause,
whichever comes first

To determine the safety of the addition of MLN9708 to lenalidomide and 
dexamethasone

To assess change in global health status, as measured by the global health status, 
functioning, and symptoms as measured by the patient-reported outcome (PRO) 
instrument European Organization for Research and Treatment of Cancer Quality of 
Life Questionnaire (EORTC QLQ-C30) and MY20 module
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MLN9708 (Ixazomib)
Statistical Analysis Plan, Study C16014
Confidential
10
#
To determine the PFS and OS in high-risk cytogenetic patient groups defined by the 
following cytogenetic abnormalities: t(4;14), t(14;16), amp(1q21), and del(17p)
#
To evaluate minimal residual disease status (MRD), via flow cytometry, in patients 
suspected to have reached CR at any time during the entire conduct of the study, and 
at Cycle 18 for patients who have maintained a CR until that point. The impact of 
MRD status on TTP, PFS, and OS will be assessed.
#
To assess time to pain progression
#
To collect pharmacokinetic (PK) data to contribute to population PK analyses
#
To evaluate the frequency of skeletal-related events (eg, new fractures [including 
vertebral compression or rib fractures], irradiation of or surgery on bone, or spinal 
cord compression) from baseline through the last survival assessment
Exploratory Objectives are:
Propert
ubject to the Applicable Terms of Use
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MLN9708 (Ixazomib)
Statistical Analysis Plan, Study C16014
Confidential
11
2.   
POPULATIONS FOR ANALYSIS
2.1
Intent-to-Treat Population
The Intent-to-Treat (ITT) population is defined as all patients who are randomized.  Patients 
will be analyzed according to the treatment they were randomized to receive, regardless of 
any errors of dosing.  If patients are regarded as screen failure, either were not randomized 
yet, or were randomized without being dosed, they will be excluded from ITT population.
The ITT population will be used for the primary, secondary efficacy analyses, and resource 
utilization and patient reported outcome analysis.
2.2   Safety Population
The safety population is defined as all patients who receive at least 1 dose of any study drug. 
Patients will be analyzed according to the treatment actually received. That is, those patients 
who are randomized to the active arm but receive the regimen in the control arm will be 
included in the control arm; those patients who are randomized to the control arm but 
receive the regimen in the active arm will be included in the active arm for safety analyses.
More specifically, patients who received any dose of ixazomib will be included in the 
MLN9708 + LenDex arm and patients who did not receive any dose of ixazomib will be 
included in the placebo plus LenDex arm, regardless of their randomized treatment.
Safety population will be used for all safety related analyses such as AE, concomitant 
medication, laboratory tests, and vital signs.
Property of Takeda: For Non-Commercial Use Only and Subject to 
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MLN9708 (Ixazomib)
Statistical Analysis Plan, Study C16014
Confidential
12
2.3    Response-Evaluable Population:
The response-evaluable population was defined as all patients in the ITT population who 
receive at least 1 dose of any study drug, have measurable disease at baseline, and at least 
1 post baseline response assessment assessed by an IRC. The response-evaluable population 
will be used for the analyses of time to response, and duration of response (defined in 
patients with confirmed response and will be summarized descriptively). Patients have 
measurable disease defined by at least 1 of the following 3 measurements:
Serum M-protein 1 g/dL (10 g/L).
Urine M-protein 200 mg/24 hours.
Serum free light chain assay: involved free light chain level 10 mg/dL
(100 mg/L) provided the serum free light chain ratio is abnormal.
2.4   Per-Protocol (PP) population
The PP population is a subset of the ITT population. The PP population consists of all 
patients who do not have major protocol violations, as determined by the study clinician, 
who is blinded to study drug assignment. All decisions to exclude patients from the PP 
population will be made before the unblinding of the study.
The PP population will be used as a sensitivity analysis of the ITT population for the 
primary efficacy endpoint PFS if there are more than 5% patients are excluded from the ITT 
population.  
3.   
HYPOTHESES AND DECISION RULES
3.1   Statistical Hypotheses
There is one primary endpoint in this study. (See section 5.7.2 for study treatment arms) 
The null and alternative hypothesis for PFS is:
H0: PFS in Arm MLN9708+LenDex= PFS in Arm LenDex
Ha: PFS in Arm MLN9708+LenDex > PFS in Arm LenDex
There are three key secondary efficacy endpoints in this study.
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The null and alternative hypothesis for OS is:
H0: OS in Arm MLN9708+LenDex = OS in Arm LenDex
Ha: OS in Arm MLN9708+LenDex > OS in Arm LenDex
The null and alternative hypothesis for CR rate during the treatment period is:
H0: CR rate in Arm MLN9708+LenDex = CR rate in Arm LenDex
Ha: CR rate in Arm MLN9708+LenDex > CR rate in Arm LenDex
The null and alternative hypothesis for pain response rate (analyzed in patients with baseline 
worst pain score ≥ 4) is:
H0: Pain response rate in Arm MLN9708+LenDex = Pain response rate in Arm 
LenDex
Ha: Pain response rate in Arm MLN9708+LenDex > Pain response rate in Arm 
LenDex
3.2   Statistical Decision Rules
A closed sequential testing procedure will be used to test the primary endpoints and all 3 key 
secondary endpoints with the following testing order: 
1. PFS (primary endpoint) in the ITT population at the first or both IAs  and PFS at IA2
in 3 prespecified subgroups: 1) patients with baseline CrCl > 60 mL/min; 2) patients 
aged < 75 years; and 3) patients harboring expanded high-risk cytogenetic 
abnormalities defined as del(17p), t(4;14), t(14;16), and amp(1q21); 
2. OS (first key secondary endpoint) at the IAs or FA; 
3. CR rate (second key secondary endpoint) at the IAs or FA; and 
4. Pain response rate (third key secondary endpoint) at the IAs or FA. 
OS will be tested at the IAs or FA at the significance level determined by the O’Brien-
Fleming alpha spending function (the Lan-DeMets method). The proof of strong control of 
the Type I error rate for testing PFS and OS in the ITT population and PFS in the subgroup 
populations is shown in the appendix in the SAP. CR rate will be tested at the same alpha 
level as that for OS whenever OS reaches statistical significance. Pain response rate will be 
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tested at the same alpha level as that for CR rate whenever CR rate reaches statistical 
significance. Due to the closed sequential testing property, the family-wise type I error is 
strongly controlled for both the primary endpoint and key secondary endpoints. 
All other efficacy endpoints will be tested at a 2-sided alpha level of 0.05. 
4.   
INTERIM ANALYSIS
4.1   Interim Analysis
There are 2 planned IAs. The first IA will be performed when approximately 326 disease 
progression/death events have occurred. This IA is expected to occur approximately 
45 months after the first patient is enrolled. If the test for PFS in the ITT population is 
statistically significant at the first IA, this will be the FA for PFS for statistical testing 
purposes, central efficacy and investigator assessments of disease response for protocol 
purposes will be discontinued (except for investigator assessment of PFS2) given that the 
primary endpoint has been met, and the second IA will be conducted for OS when 
approximately 250 death events have occurred. If the test for PFS does not reach statistical 
significance at IA1 in the ITT population, then at IA2 PFS will be tested in both the ITT 
population and in 3 prespecified subgroups, as described below.
The subgroup testing strategy approach includes 2 major components: a) preservation of the 
ability to detect the overall treatment effect using a reduced overall significance level of 
1 = 0.04, which will be used for the ITT population, and b) test of treatment effect for the
3 prespecified subgroups: 1) patients with baseline CrCl > 60 mL/min; 2) patients aged
< 75 years; and 3) patients harboring expanded high-risk cytogenetic abnormalities defined 
as del(17p), t(4;14), t(14;16), and amp(1q21). Subgroup testing will be conducted using the
remaining 2 = 0.01 and the Hochberg procedure for multiplicity correction among the 3 
prespecified subgroups (refer to the appendix in the SAP for proof of strong control of the 
Type I error rate). Because the size of the treatment effect may be substantially greater in a 
prespecified subgroup than in the overall study population, analysis of patients in each 
subgroup at a stringent significance level may still provide a statistically significant 
outcome. The detailed statistical design schema is presented in Figure 4-1.
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Figure 4-1
Schematic of Statistical Plan
For the testing of PFS in the ITT population, the Gamma(-1) alpha spending function will be 
used to calculate the significance boundary based on the observed number of PFS events 
with total alpha=0.04. The first IA will be performed when approximately 326 PFS events 
have occurred. This will be the first analysis for PFS for statistical testing purposes. If the 
test is statistically significant, then this analysis will be the FA of PFS for statistical testing 
purposes. No subsequent PFS testing will be conducted, and central efficacy and 
investigator assessments of disease response for protocol purposes will be discontinued 
except for the investigator assessment of PFS2 (see the Schedule of Events of protocol). In 
this scenario, the second IA will be for OS testing when approximately 250 death events 
have occurred and will determine whether the final number of OS events might be increased.
If the test for ITT PFS is not statistically significant at the first IA, response assessments will 
continue until IA2, and PFS testing in the ITT and subgroup populations will be conducted 
in parallel at the second IA, when approximately 370 PFS events have occurred (rather than 
the previous study design of 435 PFS events); this will be the FA of PFS for statistical 
testing purposes. If the test for PFS is significant at the second IA, OS will be tested, and 
determination of whether the final number of OS events will be increased from 320 to up to 
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400 will occur. If the test for PFS in the second IA is not statistically significant in any 
population (the ITT or any of the 3 subgroups), the study may be stopped. 
Because at the time of this amendment, the boundary for ITT PFS at IA1 has already been 
calculated based on 328 PFS events observed at IA1, 435 PFS events targeted at PFS final 
analysis, and the Gamma(-1) alpha-spending function, this boundary will not be changed. 
However, the boundary for ITT PFS at IA2 (final analysis of ITT PFS) will be calculated 
based on the observed number of PFS events at IA2 in order to spend what is left of the 
overall alpha-level 0.04 for ITT. The final boundaries at IA1 and IA2 will not approximate a 
Gamma(-1) function, but type I error will remain protected under the flexible alpha-
spending approach (see appendix in the SAP for more details).
For the testing of OS, alpha spending for IA1 and IA2 will always be based on the observed 
events (information fraction) using alpha=0.04 with a different adjustment of critical value 
at OS FA testing (CHW test statistics [3] will be used for the primary analysis of OS at FA) 
based on the following scenarios: 
1. If ITT PFS is significant in IA1, then ITT OS will be tested in the FA with a total 
alpha of 0.04; there is no test on subgroup PFS. 
2. If ITT PFS is not significant in IA1, then parallel testing of the ITT population PFS 
and the subgroup populations PFS will occur in IA2: 
a.
If the ITT population’s PFS is significant and at least 1 subgroup is not 
significant, then the ITT population’s OS will be tested at IA2 and FA with 
potential sample size re-estimation using a total alpha of 0.04.
b. If the ITT population’s PFS is significant and all 3 subgroup populations’ 
PFS are significant, then the ITT population’s OS will be tested at IA2 and 
FA where the critical value at FA can be updated based on a total alpha of 
0.05.
c.
If the ITT population’s PFS is not significant and at least 1 subgroup 
population’s PFS is significant, then no formal ITT OS testing will be 
conducted. 
The family-wise error rate for the 4 null hypotheses for PFS and the 1 hypothesis for OS for 
the overall study population is controlled using a prespecified, 2-sided 0.05 level of 
significance. The proof of strong control of the Type I error rate for testing PFS and OS in 
the ITT population and PFS in the subgroup populations is shown in the appendix in the 
SAP. For the other 2 key secondary endpoints, the CR rate will be tested at the same alpha 
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level, instead of the same critical value, as that of the OS analysis when OS reaches 
statistical significance. The pain response rate will be tested at the same alpha level as that 
of the CR rate analysis when the CR rate reaches statistical significance. Because of the 
closed sequential testing property, the family-wise error rate is strongly controlled for both 
the primary endpoint and the 3 key secondary endpoints [4]. 
The IAs will be conducted by the independent statistical center (ISC) and presented for 
review to the IDMC. During the closed session of the IDMC meeting at IA2, the IDMC will 
compare the conditional power for OS based on the interim result with the prespecified 
adaptation rules and recommend to the sponsor executive committee the final adaptation 
decision on OS. The adaptation rule will be included in the appendix of IDMC charter and 
can only be accessed by ISC, IDMC, Head of Biostatistics and the sponsor design 
statistician who are not involved in the study conduct. This recommendation will be 
documented in the IDMC closed meeting minutes.
4.2   Independent Data Monitoring Committee (IDMC)
An IDMC supported by an independent statistician will review safety at regular intervals 
additionally safety and efficacy data at 2 planned interim analyses. The IDMC will provide a 
recommendation regarding study continuation based on the safety and efficacy parameters. 
In the event that the study is terminated early based on the IDMC recommendation, 
Millennium will notify the appropriate regulatory authorities. In addition, the IDMC will 
periodically review safety data at regularly scheduled meetings prespecified in the IDMC 
charter.
The first formal safety review will occur after approximately 60 subjects have been 
randomized and receive at least 1 cycle of study treatment. Subsequently, periodic safety 
reviews will also occur as prespecified in the IDMC charter.
Study accrual will not be interrupted due to the scheduled safety reviews. The IDMC or
MLN9708 study team may request an ad hoc meeting for any reason, including a significant
unexpected safety event, unplanned unblinding of study results, follow-up of an observation
during a planned IDMC meeting, or a report external to the study, such as publication of
study results from a competing product. At each review, subject incidence rates of AEs
(including all serious AEs, treatment-related AEs, serious treatment-related events, and
events requiring the discontinuation of study drug) will be tabulated by System Organ Class,
preferred term, and severity grade. Listings and/or narratives of “on-study” deaths and other
serious and significant AEs, including any early withdrawals due to AEs, will be provided.
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Records of all meetings will be archived. The IDMC will communicate major safety
concerns and recommendations regarding study modification or termination to Millennium.
Further details will be provided in the IDMC charter.
4.3   Independent Review Committee (IRC)
An independent review committee (IRC) will review all blinded disease evaluation data 
from the study and determine disease status (response and progression). Data from the IRC 
will not be provided back to the investigator during the conduct of the study. Likewise, 
investigator response assessments will not be provided to the IRC.
5.   
STATISTICAL METHODOLOGY
In general, summary tabulations will be presented by treatment arm and will display the
number of observations, mean, standard deviation, median, minimum, and maximum for
continuous variables, and the number and percent per category for categorical data. The
Kaplan-Meier survival curves and 25th, 50th (median), and 75th percentiles will be provided
along with their 2-sided 95% CIs for time-to-event data.
5.1   Sample Size Justification
The primary objective of this study is to determine if MLN9708 plus lenalidomide and 
dexamethasone improves PFS compared with placebo plus lenalidomide and dexamethasone 
in patients with newly diagnosed MM. The study will not be stopped after the PFS analysis, 
however, even if a significant PFS is observed, in order to obtain an adequate statistical 
power for OS. 
The total sample size was calculated based on maintaining 80% power to test the OS. The 
study is also adequately powered to test PFS. There is 2 planned IA and 1 FA.
Assuming a hazard ratio of 0.70 (median PFS of 25 months in control arm versus 
35.8 months in treatment arm), 370 PFS events will be needed (92% power and 2-sided 
alpha of 0.04) with up to 2 planned PFS analyses conducted as described in the section 4.1.
The first IA will be performed when approximately 326 PFS events have occurred. This is 
expected to occur approximately 45 months after the first patient is enrolled, including a 
27-month enrollment period and additional 18-month follow-up from the last patient. 
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If the test for PFS in the ITT population is statistically significant at the first IA, this will be 
the FA for PFS for statistical testing purposes, and the second IA will assess OS when 
approximately 250 death events have occurred.  
If the test for PFS in the ITT is not statistically significant at the first IA, then the second IA 
will assess PFS and OS when approximately 370 PFS events have occurred. In addition, in 
such a case, PFS will be tested at IA2 in 3 prespecified subgroups: 1) patients with baseline 
CrCl > 60 mL/min; 2) patients aged < 75 years; and 3) patients harboring expanded high-
risk cytogenetic abnormalities defined as del(17p), t(4;14), t(14;16), and amp(1q21).
For the final OS analysis, the total event size calculation will be based on the adaptive 
sample size re-assessment approach.[3, 5] The minimum event size of 320 death events is 
based on an optimistic assumption of a hazard ratio of 0.72 (median survival of 50 months in 
the control arm vs 69.4 months in the treatment arm) with 80% power at a 2-sided 0.05 level 
of significance. The O’Brien-Fleming alpha spending function (the Lan-DeMets method) 
will be used to calculate the significance boundary based on observed number of death 
events in each IA with a total of 320 OS events for the FA. In the second IA, if OS 
significance is not claimed, the conditional power based on OS will be calculated. If the 
conditional power falls in the favorable zone or unfavorable zone, the FA of OS with 
approximately 320 events will remain unchanged. If the conditional power falls in the 
promising zone, the event size will be determined according to a prespecified sample size 
adaptation rule, with an event cap of 400 OS events. No futility analysis will be performed 
in the study.   
5.2
Randomization and Stratification 
Randomization scheme will be generated by an independent statistician at Millennium who
is not on the study team. Prior to dosing, a randomization number will be assigned to each
patient. The randomization assignment will be implemented by an interactive voice/ web 
response system (IXRS).
Eligible patients will be randomized in a 1:1 ratio into those 2 treatment arms, stratified by:
age (<75 years vs 75), ISS (stage 1 or 2 vs stage 3), and BPI-SF worst pain score (< 4 vs
4) at screening.
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5.3   Blinding and Unblinding
This is a double-blind study: all study personnel including the investigators, site personnel, 
study clinicians, and the sponsor will be blinded to the treatment assignments for the 
duration of the study. Only the independent statistical center (ISC) and IDMC will have 
access to un-blinded individual patient level data.  The periodic safety analyses will be 
generated for the IDMC by an ISC. The formal interim efficacy analyses will also be 
conducted by ISC for the IDMC.  
Refer to section 4.2 for the roles and responsibilities of IDMC.
5.4   Data Handling
5.4.1   
Methods for Handling Missing Data
All available efficacy and safety data will be included in data listings and tabulations. Data
that are potentially spurious or erroneous will be examined according to standard data
management operating procedures.
In general, missing data will be treated as missing and no data imputation will be applied,
unless otherwise specified. For patient reported outcomes data, primarily missing data
imputation will be based on published instrument specific methods. Other missing data
imputation method such as Last Observation Carry Forward (LOCF) and multiple
imputation method may be explored as sensitivity analyses for patient reported outcomes
data.
For the key secondary endpoints CR rate, missing value is defined as no post-baseline
response assessment either due to lost to follow-up or withdrawal by patient. In the primary
analysis, if the response assessment in either arm is missing on comparing response rates, it
will be counted as a failure (non-responder) instead of a missing value. The procedure to 
deal with missing data in the primary analysis for the pain response rate will be using the
same method as CR rate.
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5.4.1.1   Missing/Partial Dates in Screening Visit
The following rules apply to dates recorded in the screening visits. 

If only the day-component is missing, the first day of the month will be used if the 
year and the month are the same as those for the first dose of study drug. Otherwise, 
the 15th will be used. 

If only a year is present, and it is the same as the year of the first dose of study drug, 
the 15th of January will be used unless it is later than the first dose, in which case the 
date of the first of January will be used, unless other data indicates that the date is 
earlier. 

If only a year is present, and it is not the same as the year of the first dose of study 
drug, the 15th of June will be used, unless other data indicates that the date is earlier. 
5.4.1.2   Missing/Partial Dates in Adverse Events/Concomitant Therapies/Subsequent 
Therapies
Every effort will be made to avoid missing/partial dates in on-study data. 
Adverse events with stop dates that are completely or partially missing will be imputed as 
follows:

If the stop date has month and year but day is missing, the last day of the month will 
be imputed

If the stop date has year, but day and month are missing, the 31th of December will 
be imputed
After the imputation, the imputed dates will be compared against the date of death, if 
available.  If the date is later than the date of death, the date of death will be used as the 
imputed date instead.
Adverse events with start dates that are completely or partially missing will be imputed as 
follows:

If the start date has month and year but day is missing, the first day of the month will 
be imputed
o
If this date is earlier than the first dose date, then the first dose date will be 
used instead
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o
If this date is later than the stop date (possibly imputed), then the stop date 
will be used instead

If the start date has year, but day and month are missing, the 15th of June will be 
imputed
o
If this date is earlier than the first dose date, then the first dose date will be 
used instead
o
If this date is later than the stop date (possibly imputed), then the stop date 
will be used instead
If the start date of an event is completely missing, then it is imputed with the first dose date.
Concomitant therapies with start dates that are completely or partially missing will be 
analyzed as follows:

If the start date has month and year but day is missing, the therapy will be included 
in the summary table if the month and year of the start date of the event are: 
o
On or after the month and year of the date of the first dose of study drug
and 
o
On or before the month and year of the date of the last dose of study drug
plus 30 days.

If the start date has year, but day and month are missing, the therapy will be included 
in the summary table if the year of the start date of the event is:
o
On or after the year of the date of the first dose of study drug
and 
o
On or before the year of the date of the last dose of study drug plus 30 days.
If the start date of an event is completely missing, then the therapy will be included in the 
summary table.  
Subsequent therapies with start dates that are completely or partially missing will be 
analyzed as follows:

When month and year are present and the day of the month is missing, 
o
If the onset month and year are the same as the month and year of last dose 
with study drug, the day of last dose + 1 will be imputed.  
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o
If the onset month and year are not the same as the month and year of last 
dose with study drug, the first day of the month is imputed. 

When only a year is present, 
o
If the onset year is the same as the year of last dose with study drug, the date 
of last dose + 1 will be imputed.  
o
If the onset year is not the same as the year of last dose with study drug, the 
first day of the year is imputed. 

If no components of the onset date are present the date of last dose + 1 will be 
imputed.
5.4.2   
Definition of Baseline Values
Unless otherwise specified, the baseline value is defined as the value collected at the time 
closest to, but prior to, the start of study drug administration.
5.4.3   
Windowing of Visits
All data will be categorized based on the scheduled visit at which it was collected.  These 
visit designators are predefined values that appear as part of the visit tab in the eCRF.  
5.4.4   
Pooling
All data from all sites will be pooled.  Study center or treatment-by-center interaction will 
not be included in any statistical analysis.
5.4.5   
Withdrawals, Dropouts, Loss to Follow-up
Time to event parameters will be censored if patients withdraw, drop out, or are lost to 
follow-up before documentation of the events (progressive disease / death).  Rules for 
censoring are detailed in section 5.8.
5.5   Patient Disposition
Patient disposition includes the number and percentage of patients for the following 
categories:  patients in each of the study populations, patients discontinued from the 
treatment, primary reason 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 ITT population.  
A listing will present data concerning patient disposition.
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5.6   Demographics and Baseline Disease Characteristics
5.6.1   
Demographics
Demographics will be summarized by treatment groups in a descriptive fashion in the ITT 
population.  Baseline demographic data to be evaluated will include age, sex, race, ethnicity, 
height, weight, and other parameters as appropriate.  Patient enrollment by region and 
country will also be summarized by treatment groups.
5.6.2   
Medical History
General medical history and prior medications will be listed for all patients. 
Medical history will be summarized (frequency and percentage) for both treatment groups 
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 safety population within 
each treatment group.
5.6.3   
Baseline Disease Status
Baseline disease characteristics (Eastern Cooperative Oncology Group [ECOG]) 
performance status, co-morbidity status by age (<65, 65≤ age <75, ≥75), type of myeloma, 
ISS stage, serum M-protein, urine M-protein, 
2
-microglobin by category (ie, < 2.5, 2.5-5.5, 
> 5.5 mg/L), serum creatinine and its category (≤ 2, >2 mg/dL), creatinine clearance by 
category (ie, >30-60, >60 mL/min), serum albumin by category (ie, < 3.5, ≥3.5 g/dL), 
corrected calcium, Durie-Salmon stage, Lytic bone lesions, extramedullary disease will be 
summarized for all patients. Months from initial diagnosis to first dose of MLN9708 will be 
summarized for all patients if there is sufficient data for analysis. 
A patient’s type of myeloma is determined by the combination of heavy chain type (IgG, 
IgA, IgM, IgD, IgE, and other) and light chain type (Kappa, Lambda, and biclonal). In 
descriptive summaries, Myeloma type will be summarized separately for the heavy chain 
patients (according to IgG, IgA, IgM, IgD, IgE, biclonal, other) and for the light chain 
patients (according to kappa or lambda or biclonal). 
Creatinine clearance is to be calculated using the Cockcroft-Gault formulas as follows:
For male patients: 
[mg/dL])
creatinine
(serum
72
weight[kg]
Age[yrs])
(140
clearance
creatinine




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For female patients:
[mg/dL])
creatinine
(serum
72
weight[kg]
Age[yrs])
(140
85
.0
clearance
creatinine





Integer values will be used. 
Months from diagnosis to the randomization date for each treatment is calculated by 
                                       
randomization date - date of diagnosis  
./
Distribution of stratification factors will also be summarized.
5.6.3.1   
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 (% plasma cells, % 
megakaryocytes present), number of patients with bone marrow biopsy, bone marrow biopsy 
results (% plasma cells, % cellularity, type of cellularity, % Kappa/Lambda ratio 
performed), skeletal survey results and imaging including Magnetic Resonance Imaging/
Computed 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, type of extramedullary plasmacytoma. 
Percentage for all categorical summarizations for bone marrow biopsy/aspirate and aspirate 
is based on patients with an adequate sample for the specified test.
5.6.4  
Bone Marrow Cytogenetic Results at Baseline
Bone marrow cytogenetic results at baseline from the conventional/karyotype and 
molecular/FISH cytogenetic analyses methods will be displayed. The results will be 
categorized as “Normal”, “Abnormal” and “Indeterminate”. The percentage of each 
category will be summarized. 
The following are the categories of interest:
1. Del 17 positive group (made up of del 17 alone or in combination with 
t(4;14) or t(14;16) or amp(1q21))
2. t(4;14) alone [no del 17, t(4;14), t(14;16) or amp(1q21)]
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3. t(14;16) alone [no del17, t(4;14), t(14;16) or amp(1q21)]
4. amp(1q21) alone [no del17,  t(4;14) or t(14;16)]
5. High risk group: made up of del17, t(4;14) or t(14;16)
6. Expanded High risk group: made up of del17, t(4:14), t(14;16) or  amp(1q21)
Standard risk group definition will differ for the high risk and the expanded high risk group 
and will be defined as patients for whom the tests for del17, t(4;14), t(14;16) and amp(1q21)
are normal. Detailed definitions are listed in the section 5.8.1.1 on definition of subgroup.
Abnormal types of interest, including but not limited to del 13, del 17, t(4;14),  t(14;16),  
will also be tabulated. 
5.7   Treatments and Medications
5.7.1   
Concomitant Medications
Concomitant medications will be coded by preferred term using the World Health 
Organization (WHO) Drug Dictionary.  The number and percentage of patients taking 
concomitant medications from the first dose through the end of the on-treatment period will 
be tabulated by Anatomical Therapeutic Chemical (ATC) classification pharmacological 
subgroup and WHO drug preferred term for each treatment group in the safety population.  
By-patient listing will also be presented for concomitant medications.
Concomitant procedures will not be coded, but will be presented in a data listing in the 
safety population.
Types of subsequent therapy will also be summarized accordingly in the table and listing.
5.7.2   
Study Treatments
Following the Screening period, patients who will be enrolled and treated with lenalidomide 
plus dexamethasone will be randomized to receive a study drug in a double-blind fashion, 
either MLN9708 or placebo.  Eligible patients will be randomized in a 1:1 ratio into those 2 
treatment arms.
Arm MLN9708+LenDex: Patients will receive MLN9708 4.0 mg capsule on Days 1, 8, and 
15 plus lenalidomide (25 mg) on Days 1 through 21 and dexamethasone (40 mg) on Days 1, 
8, 15, and 22 of a 28-day cycle.  
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Arm LenDex: Patients will receive placebo capsule on Days 1, 8, and 15 plus lenalidomide 
(25 mg) on Days 1 through 21 and dexamethasone (40 mg) on Days 1, 8, 15, and 22 of a 28-
day cycle.  
In both arms, patients over 75 years of age will receive reduced dexamethasone dose 
(20mg).  Dose modifications may be made throughout the study based on toxicities.   
Patients with a low creatinine clearance 60 mL/min (or 50 mL/min, according to local 
label/practice) will receive a reduced lenalidomide dose of 10 mg once daily on Days 1 
through 21 of a 28-day cycle.  The lenalidomide dose may be escalated to 15 mg once daily 
after 2 cycles if the patient is not responding to treatment and is tolerating the treatment.  If 
renal function normalizes (ie, creatinine clearance > 60 mL/min or > 50 mL/min, according 
to local label/practice) and the patient continues to tolerate this treatment, lenalidomide may 
then be escalated to 25 mg once daily.
Patients may continue to receive treatment as outlined previously for 18 cycles 
(approximately 18 months), or until progressive disease (PD) or unacceptable toxicity, 
whichever comes first. After 18 cycles, patients will continue treatment in the same 
randomization arm on the same schedule with modified dose levels of the study drug and 
LenDex: reduce MLN9708 (or placebo) dose to 3.0 mg, reduce lenalidomide dose to 10 mg, 
and no dexamethasone.
5.7.2.1   Duration of Follow-up
The duration of follow-up is defined as time from randomization to the death or last known 
visit. If a subject dies, the duration equal to date of death minus study start + 1 with censor 
variable =1 (censored for follow up). If a subject is alive, the duration equal to the date 
subject last known to be alive minus study start + 1 with censor variable=0 (event for follow 
up). 
Duration of follow-up for maintenance portion is defined as time from the date of first dose 
of maintenance to the death or last known visit. 
5.7.2.2    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 ≥36 treated cycles, for each 
treatment group in the safety population.  Aggregate summary of numbers and percentages 
of patients who had 1-6, 7-12, 13-18, 19-24, 25-30, 31-36, ≥37 treated cycles will also be 
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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 dexamethasone 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 ≥36 treated cycles, and relative dose intensity (%) for each 
treatment group in the safety population. Aggregate summary of numbers and percentages 
of patients who had 1-6, 7-12, 13-18, 19-24, 25-30, 31-36, ≥37 treated cycles will also be 
presented in the same table.  
MLN9708 and lenalidomide exposure will be summarized similarly as dexamethasone for 
the applicable treatment group/option.
A treated cycle is defined as a cycle in which the patient received any amount of any study 
drug. 
A treated cycle for a specific drug is defined as a cycle in which the patient received any 
amount of the specific drug.
Relative dose intensity (RDI) (%) is defined as 100 x (total dose received in mg) / (sum of 
prescribed dose over all treated cycles). For prescribed dose, if patients with a low creatinine 
clearance 60 mL/min received reduced lenalidomide dose of 10 mg at C1D1, then 10 mg 
will be used in the denominator per protocol dosing administration. Similarly, 20 mg will be 
used for Dexamethasone RDI calculation for patients over 75 years old. After 18 cycles, 
MLN9708 will be reduced to3 mg, Len will be reduced to 10 mg daily and Dex will be 
discontinued, so prescribed dose per protocol will be updated and reflected in the calculation 
accordingly.  
Dosing data will also be presented in a by-patient listing.
5.7.2.3   Treatment Modifications
Action on each study drug will be summarized by each of the Cycle 1 through 36, sum of 
the remainder Cycles, Cycles 1-6, Cycles 7-12, Cycle 13-18, Cycles 19-24, Cycle 25-30, 
Cycle 31-36, >=37 and total for each treatment group in the safety population. 
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5.8   Efficacy Analyses
All efficacy evaluations will be conducted using the ITT population unless otherwise 
specified.
5.8.1   
Primary Efficacy Endpoint
There is 1 primary endpoint: PFS, which is defined as the time from the date of 
randomization to the date of first documentation of PD or death due to any cause, whichever 
occurs first. Patients without documentation of PD will be censored at the date of last 
response assessment. The details regarding the handling of missing assessment and 
censoring for PFS analysis are presented in Table 5-1.
Table 5-1   
Handling of Missing Assessment and Censoring for PFS Primary 
Analysis based on FDA guidance 
Situation
Date of Progression or Censoring
Outcome
No baseline and/or no post baseline 
assessment,  no subsequent anticancer therapy 
after study treatment, no death
Date of Randomization 
Censored
Disease progression documented between 
scheduled visits 
Date of documented disease progression 
Event
No documented death or disease progression 
Date of last adequate assessment*
Censored
Lost to follow-up, withdraw consent before any 
documented death or disease progression  
Date of last adequate assessment*
Censored 
Death or progression after more than one 
missed visit 
Date of last adequate assessment*
Censored
Alternate antineoplastic therapy started prior to 
disease progression 
Date of last adequate assessment prior to 
starting alternate antineoplastic therapy
Censored
Death before first assessment
Date of death
Event
Death between adequate assessment visits
Date of death
Event
* Adequate disease assessment is defined as there is sufficient data to evaluate a patient’s disease status.
5.8.1.1   Primary Efficacy Analysis
PFS will be analyzed when approximately 326 PFS events have occurred. A 2-sided,
stratified log-rank test will be used to compare the treatment groups with respect to PFS at a
2-sided alpha level of 0.05. In addition, an unadjusted stratified Cox model will be used to
estimate the hazard ratio and its 95% CIs for the treatment effect using the stratification
factors. The Kaplan Meier (K-M) survival curves and K-M medians (if estimable), along
with their 2-sided 95% CIs, will also be provided for each treatment group.
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Sensitivity analyses for PFS include:
1. PFS assessed by investigator will be analyzed in the ITT population.
2. PFS assessed by IRC will be analyzed in the per protocol population.
PFS assessed by IRC using different censoring mechanisms will be analyzed in the ITT 
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 5-2. 
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. 
Table 5-2   
Handling of missing assessment and censoring for PFS Sensitivity 
Analysis based on EMA guidance 
Situation
Date of Progression or Censoring
Outcome
Alternate antineoplastic therapy started 
prior to disease progression
Date of documented disease progression 
Event
Death or disease progression after more 
than one missed visit
Date of death or disease progression 
Event
Subgroup analyses will be performed for PFS relative to baseline stratification factors, 
demographic data such as sex, race, region (e.g. North America, Europe and Other), and 
disease characteristics, 
 The details on subgroups are 
presented in the following:
Subgroup
Definition of Group
Age
< 75 years,  ≥75 years
Sex
male vs female
Race
white, black-African American, Asian, other
Region
North America, Europe, APAC, other
Cytogenetic risk
Standard-risk1, high-risk [(del17); t(4;14); t(14;16)], not available
Standard-risk2, expanded high-risk [(del17); t(4;14); t(14;16); 
amp(1q21)], not available
ISS stage
In additional to stratification factors , also define as I or II or III
Renal function based on baseline 
creatinine clearance
< 60 mL/min, and ≥60 mL/min
ECOG performance status
0 or 1 vs 2
1.
Standard Risk in this analysis is defined as del (17), t(4:14) and t(14:16) normal
2.
Standard Risk in this analysis is defined as  del (17), t(4:14) ,  t(14:16)  and 1q 21 normal
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5.8.2   
Key Secondary Efficacy Endpoints
There are 3 key secondary endpoints: CR rate, OS and Pain response rate.
Overall Survival
OS is defined as the time from the date of randomization to the date of death. Patients 
without documentation of death at the time of analysis will be censored at the date last 
known to be alive. OS will be analyzed based on the ITT population.
CR Rate
The CR rate is defined as the proportion of patients who achieve CR assessed by an IRC
relative to the ITT population during the treatment period. If the response assessment in
either arm is missing on comparing CR rates, it will be counted as a failure (non-responder)
instead of a missing value.
Pain Response Rate
Pain response is defined, among patients whose baseline pain score are >=4, as the 
occurrence of at least a 30% reduction from baseline in BPI-SF worst pain score over the 
last 24 hours without an increase in analgesic use for 2 consecutive measurements >=28 
days apart.
5.8.2.1   Key Secondary Efficacy Analysis
Three key secondary efficacy endpoints will be tested sequentially in the order of 1) OS; 2)
CR rate; 3) Pain response rate. OS will be tested at the IAs or FA at the significance level 
determined by the O’Brien-Fleming alpha spending function (the Lan-DeMets method). CR 
rate will be tested at the same alpha level as that for OS whenever OS reaches statistical 
significance. Pain response rate will be tested at the same alpha level as that for CR rate 
whenever CR rate reaches statistical significance. Due to the closed sequential testing 
property, the family-wise type I error is strongly controlled for both the primary endpoint 
and key secondary endpoints.
Overall Survival
A 2-sided, stratified log-rank test will be used to compare the treatment groups with respect
to OS. The test significance level at the IA and FA is decided by the O’Brien-Fleming alpha
spending function (the Lan-DeMets method). In addition, an unadjusted stratified Cox
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model will be used to estimate the hazard ratio and its 95% CIs for the treatment effect using
the stratification factors. The K-M survival curves and K-M medians (if estimable), along
with their 2-sided 95% CIs, will also be provided for each treatment group.
To adjust for the potential confounding effects of subsequent therapies after patients 
discontinue study treatment, the following 2 methods will be used:

Marginal Structural Models (MSMs) by Robins and Finkelstein [2000]

Inverse Probability of Censoring Weighted (IPCW) method by Robins and 
Finkelstein [2000]
In the MSM and IPCW analyses, in order to derive weights adjusting for the time-fixed and 
time-varying confounding effects due to taking alternative therapies, the covariates that 
affect disease progression and post-progression treatment, and the OS endpoint will be used.
Baseline covariates include region (North America, others), age (< 75, ≥75), race (white,
non-white), ECOG score (0 or 1, 2), type of myeloma (IgA, other), presence of 
extramedullary plasmacytomas (yes, no), presence of lytic bone lesions (yes, no), 
cytogenetic abnormalities (high risk, others), baseline hemoglobin, baseline platelets, 
baseline creatinine clearance, baseline albumin, baseline LDH, baseline 2 microglobulin, 
and baseline corrected calcium. Time-varying covariates include duration of exposure, 
disease progression status at each study visit, hemoglobin value at each study visit and 
progression/relapse, platelets value at each study visit and progression/relapse, M-protein 
value at each study visit and progression/relapse, and MRD status over time.  The final 
criteria for selected covariates would need to be statistically have a p-value of less than or 
equal to 0.1 in the multivariate logistic regression models for weight calculations. If there 
are more than 5% missing in the baseline covariate, then this covariate will be dropped from 
the weighting calculation and final OS model. For both MSM and IPCW analyses, logistic 
regression models on repeated measurements will be used to approximate the Cox models in 
the weight derivations from which stabilized weights will be derived per subject per 
observation. SAS proc PHREG procedure with counting process type of data input, which 
takes multiple observations per subject, will be used as the final Cox model for OS for both 
MSM and IPCW approaches, where robust variance will be used to accommodate 
covariance introduced by correlated longitudinal observations within each subjects and other 
extra variabilities due to departure from model assumptions. Adjusted HRs, their 
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corresponding 95% confidence intervals, and adjusted p-values will be presented. Specific to 
MSM, interaction between active treatment and alternative therapy will be included in the 
final model if the p-value for this term is <0.1. For IPCW, adjusted K-M curves will be 
presented.
Subgroup analyses will be performed for OS, similarly as detailed in section 5.8.1.1 of PFS 
analysis.
CR Rate
CR rate will only be tested after statistical significance is achieved for PFS and OS. 
Stratified Cochran-Mantel-Haenszel (CMH) test will be used to compare CR rates between
the 2 treatment arms. A logistic regression model will be used to estimate the treatment
effect in terms of odds ratio. The odds ratio and its associated 95% CIs will be presented.
Sensitivity analyses for CR rate include but are not limited to:
1. Response assessed by investigator in the ITT population
2. Response assessed by IRC in the per protocol population
3. Response assessed by IRC in the response evaluable population
Pain Response Rate
If CR is significant, then Pain response rate will be analyzed in patients with baseline worst 
pain score ≥ 4 in the ITT population. Pain response rate is the proportion of patients who 
have a pain response and will be summarized by treatment groups. If the pain assessment in 
either arm is missing on comparing pain response rates, it will be counted as a failure (non-
responder) instead of a missing value. The stratified CMH test will be used to compare the 2 
treatment arms. In addition, the absolute treatment difference in pain response rate will be 
provided, along with 95% CI.
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5.8.3   
Other Secondary Efficacy Endpoints and Analyses
Other secondary efficacy parameters include overall response rate (ORR) , time to response 
(TTR), time to progression, duration of response, OS and PFS in high-risk population 
defined by del(17), and translocation t(4;14) and t(14;16) (at least one of these 
abnormalities), and expanded high-risk population defined as del(17), amp(1q21), and 
translocation t(4;14) and t(14;16) (at least one of these abnormalities)
Disease response-related endpoints will be analyzed using IRC-assessed response rate.
ORR
ORR is defined as the proportion of patients who achieved PR or better relative to the ITT 
population. ORR will be analyzed based on the ITT population using the method similar to 
that used in the CR rate analysis. Additional analysis will also be presented for CR+VGPR.
Time to Response
Time to response is defined as the time from randomization to the first documentation of PR 
or better. Time to response will be compared in the ITT population and summarized 
descriptively for the responders.
Time to Progression
TTP is defined as the time from the date of randomization to the date of first documentation 
of PD. Patients without documentation of PD at the time of analysis will be censored at the 
date of last response assessment that is SD or better. TTP will be analyzed based on the ITT 
population using the similar method as PFS.
Duration of Response
DOR is defined as the time from the date of first documentation of a PR or better to the date 
of first documentation of PD for responders. Responders without documentation of PD will 
be censored at the date of last response assessment that is SD or better. DOR will be 
summarized descriptively using the Kaplan-Meier method.
Progression-free survival 2 
Progression-free survival 2 (PFS2) is defined as the time from the date of randomization to 
the date of first documentation of PD on the next antineoplastic therapy following study 
treatment or death due to any cause, whichever occurs first. 
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PFS2 will be analyzed based on the ITT population. A 2-sided, stratified log-rank test will 
be used to compare the treatment groups with respect to PFS2 at a 2-sided alpha level of 
0.05. In addition, an unadjusted stratified Cox model will be used to estimate the hazard 
ratio and its 95% CIs for the treatment effect using the stratification factors. The Kaplan 
Meier (K-M) survival curves and K-M medians (if estimable), along with their 2-sided 95% 
CIs, will also be provided for each treatment group.
The details of the handling of missing assessment and censoring are presented in Table 5-3
and Table 5-4.
Table 5-3  
Censoring for PFS2 For Those Who have Received Second line 
Therapy following Study Treatment 
Situation
Date of Progression or Censoring
Outcome
Documented death or disease progression 
during second line therapy 
Date of death/disease progression
Event
No documented death or disease progression 
during second line therapy
Date of last disease assessment
Censored
Lost to follow-up, withdraw consent before 
any documented death or disease progression 
during second line therapy   
Date of last disease assessment
Censored 
Start of third line therapy prior to the disease 
progression during second line therapy
Date of last disease assessment prior to 
starting the third line therapy
Censored
Table 5-4   
Censoring for PFS2 for Those Who have not received Second Line of 
Therapy
Situation
Date of Progression or Censoring
Outcome
No documented death 
Date of last visit
Censored
Death 
Date of death
Event
Clinical Outcomes in High-Risk Population 
Overall survival, PFS, ORR and DOR in the high-risk subgroups will be analyzed using a 
similar method as those in the ITT population.  The following high-risk populations will be 
analyzed: 

By individual abnormality group within high risk:  patients carrying 1 of the 
following cytogenetic abnormalities:  del(17), translocation t(4;14),  t(14;16)
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o
the del17 will include pts with del17 alone along with pts where the del17 is 
associated to t(4;14),or t(14;16)
o
the t(4;14) group will include ONLY pts with t(4;14) ALONE (no del17, 
t(14;16))
o
the t(14;16) group will include ONLY pts with t(14;16) ALONE (no del17, 
t(4;14))

By individual abnormality group within expanded high risk:  patients carrying 1 of 
the following cytogenetic abnormalities:  del(17), translocation t(4;14),  t(14;16) or 
amp(1q21)
o
the del17 will include pts with del17 alone along with pts where the del17 is 
associated to t(4;14),or t(14;16) or amp(1q21)
o
the t(4;14) group will include ONLY pts with t(4;14) ALONE (no del17, t(14;16) 
or amp(1q21))
o
the t(14;16) group will include ONLY pts with t(14;16) ALONE (no del17, 
t(4;14); or amp(1q21)))
o
the amp(1q21) group will include ONLY patients with amp(1q21) ALONE (no 
del17, t(4;14) or t(14;16))

Cytogenetic high-risk group defined as  patients carrying any of the following 
cytogenetic abnormalities:  del(17), translocation t(4;14), or t(14;16)

Cytogenetic expanded high-risk group defined as: patients carrying any of the 
following cytogenetic abnormalities: del17, t(4;14), t(14; 16) or amp(1q21)
5.9   Pharmacokinetic and Biomarker Analysis
5.9.1   
Pharmacokinetic Analyses
Plasma concentration-time data will be presented in listings.  PK 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 PK after including data from other studies, if 
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possible.  The analysis plan for the population PK analysis will be separately defined and the 
results of these analyses will be reported separately.
5.9.2   
Biomarker Analysis
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5.9.3   
Minimal Residual Disease Analysis
The absence of minimal residual disease (MRD negativity) will be tested in all patients who
achieve a CR, using bone marrow aspirates. 
1)
The rate of MRD negativity achieved in the ITT and CR populations will be 
compared between the IRd and Rd arms.  PFS and OS and DOR will be assessed in 
MRD positive and MRD negative patients in each treatment arm.
2)
The rate of MRD negativity achieved in high-risk and expanded high-risk 
populations will be compared between the IRd and Rd arms.  PFS, OS and DOR will 
be assessed in MRD positive and MRD negative patients in each treatment arm.
3)
PFS, OS and DOR in patients achieving MRD negativity within the first 12 months 
of therapy will be compared with the PFS, OS and DOR in patients achieving MRD 
negativity after 12 months of therapy.  This will be evaluated in both arms.
5.10   Analyses of Patient-Reported Outcomes and Health Economics
5.10.1   Patient Reported Outcomes (PROs)
Patient-reported outcome (PRO) assessments using the EORTC QLQ-C30 and the MY20
will be analyzed using ITT population. The descriptive statistics of actual value and change 
from baseline of the subscale scores for EORTC QLQ-C30 and MY20 will be summarized 
by treatment group over time. Additionally, the descriptive statistics of actual values and 
changes from baseline of global health status/quality of life (QOL) will be summarized by 
treatment group over time for responders and then nonresponders. The subscales of EORTC 
QLQ-C30 and MY20 are defined as shown in Table 5-5 and Table 5-6.
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Table 5-5   
Definition of Subscale Scores of EORTC QLQ-C30
Subscale
Individual Items
Physical functioning
1-5
Role functioning
6-7
Emotional functioning
21-24
Cognitive functioning
20, 25
Social functioning
26-27
Quality of life
29-30
Fatigue
10, 12, 18
Nausea and vomiting
14-15
Pain
9, 19
Dyspnea
8
Insomnia
11
Appetite loss 
13
Constipation 
16
Diarrhea
17
Financial difficulties 
28
Table 5-6   
Definition of Subscale Scores of EORTC QLQ-MY20
Subscale
Individual Items
Future perspective
18-20
Body image
17
Disease symptoms
1-6
Side effects of treatment
7-16
Differences between treatment groups in the EORTC QLQ-C30 and MY20 subscale scores 
will be evaluated using published minimally important difference (MID) values. Patients 
with a change from baseline score ≥MID in a direction reflecting deteriorating functioning 
or increased symptoms at a given time point will be classified as “worsened”, whereas those 
with a change for better of ≥MID will be classified as “improved”. Those with a change 
from baseline score within MID will be classified as “stable”. The number and percentage of 
patients with a change from baseline in subscale scores >=MID and <= -MID will be 
summarized by treatment group over time. Specific interest centers on physical functioning, 
global quality of life, fatigue, nausea/vomiting, pain, dyspnea, appetite loss, and 
constipation/diarrhea.  The main endpoint for the PRO analysis will be the global health 
status/quality of life subscale of the EORTC QLQ-C30 and functional scales and symptom 
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scales of MY20.  The other PRO endpoints include the remaining EORTC QLQ-C30 and 
MY20 subscale scores. The change from baseline in subscale scores at Cycle 18 will be 
presented using cumulative distribution function (CDF) figures. Additionally, CDF curves
will be generated for global health status/quality of life score change from baseline at Cycle 
18 by treatment group among responders and non-responders, respectively.
The change from baseline in subscale scores will be also analyzed using the repeated 
measures linear mixed effects models, including treatment group, baseline score, ISS stage 
at screening, age, sex and race as covariates. The repeated-measures analysis will use 
measurements collected from all available time points specified in the schedule of events in 
the protocol.  Estimation of the variance- covariance matrix and statistics such as Akaike 
information criteria (AIC), Bayesian information criteria (BIC) will be included in 
evaluating the linear mixed-effects model. The 95% confidence intervals of the difference of 
the changes from baseline between the two treatments will also be provided.  
Details of scoring and initial handling of missing data are included in the EORTC QLQ-C30 
and MY20 scoring guidelines.
Missing data pattern will be examined.  As sensitivity analyses, different imputation 
methods for missing data including Last Observation Carry Forward (LOCF), random slope 
model, and pattern mixture model may be performed if appropriate after examining missing 
data patterns.  
5.10.2   Health Economics Analysis Using Medical Resource Utilization and Utility
5.10.3   Pain
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ISS stag
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Pain progression is defined as the occurrence of 1 of the following and confirmed by 2 
consecutive evaluations (To qualify as progression, the patient must have a BPI-SF worst 
pain score ≥ 4 during pain progression):
#
A ≥ 2 point and 30% increase from baseline in BPI-SF worst pain score without an
decrease in analgesic use, or
#
A 25% or more increase in analgesic use from baseline without a decrease in BPI-SF
worst pain score from baseline
Analgesic use can be stable or increased according to the following definitions:
#
Stable analgesic use is defined as less than a 25% change of the oral morphine
equivalent (OME) dose from baseline
#
Increased analgesic use is defined as an increase of 25% or more in OME from
baseline
A sensitivity analysis will be conducted on pain progression without confirmation by 2 
consecutive assessments. 
In addition, the actual value and change from baseline of BPI-SF pain scores will be 
summarized by treatment group over time. The change from baseline in worst pain score 
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will be also analyzed using the repeated measures linear mixed effects models, including 
treatment group, baseline score, ISS stage at screening, sex, race, and age as covariates.
5.11   Safety Analyses
Safety will be evaluated by the incidence of AEs, severity and type of AEs, and by changes 
from baseline in the patient’s vital signs, weight, and clinical laboratory results using the 
safety population. Exposure to the study drug regimen and reasons for discontinuation will 
be tabulated.
5.11.1   Adverse Events
5.11.1.1   Adverse Events
Adverse events will be coded using MedDRA.  All AEs will be presented in a by-patient 
listing.  Treatment-emergent AEs are AEs that occur after administration of the first dose of 
any study drug and through 30 days after the last dose of any study drug. 
AEs will be tabulated according to the MedDRA by system organ class, high level terms and 
preferred terms and will include the following categories: 

Treatment-emergent AEs

Drug-related treatment-emergent AEs

Grade 3 or higher treatment-emergent AEs (also report Grade 3 and 4 separately)

Grade 3 or higher drug-related treatment-emergent AEs (also report Grade 3 and 4 
separately)

The most commonly reported treatment-emergent AEs (ie, those events reported by 
10% of patients in either treatment group) 

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 Toxicity Criteria (NCI CTCAE) version 4.03.  Patients with the same AE 
more than once will have the maximum intensity of that event counted within each body 
system, once within each high level term, and once within each preferred term. 
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The most commonly reported treatment-emergent AEs (ie, those events reported by 10% of 
any treatment arm) will be tabulated by preferred term.  Patients with the same AE more 
than once will have that event counted only once within each preferred term.
An overall summary AE table will include numbers and percentages of patients who had any 
AE, drug-related AE, grade 3 or higher AE, grade 3 or higher drug-related AE, serious AE 
(SAE), drug-related SAE, AE resulting in discontinuation, and on-study deaths.  On-study 
death is defined as the death that occurs between the first dose of any study drug and within 
30 days of the last dose of any study drug.  
Development of new or worsening of existing SREs (eg, new fractures, irradiation of or 
surgery on bone, or spinal cord compression) from baseline through the development of PD 
will be summarized and presented. 
All concomitant medications collected from screening through the study period will be
classified to preferred terms according to the World Health Organization (WHO) drug
dictionary.
Two types of incidence rates will be calculated for the safety population based on the new
primary malignancy assessment:

Incidence proportions, defined as the percentage of the subjects reporting any new 
primary malignancy in the safety population with available information

Incidence rates, defined by the number of the subjects reporting any new primary 
malignancy divided by the total duration of follow-up (patient-years = pt-yrs) in the 
safety population with available information up to the onset of new primary 
malignancies
For incidence proportions, the relative risks, defined as the ratio of incidence proportions
between the 2 randomized treatment groups, were provided along with their 95% CIs. For
incidence rates, the relative risks, along with their 95% CIs, will be calculated using an
exponential regression model for lifetime data (assuming constant hazards).
Due to the distinct nature of hematologic and nonhematologic neoplasms, as well as the
emerging signals of new primary malignancies for immunomodulating agents, analyses of
new primary malignancies may be performed separately for hematologic and 
nonhematologic malignancies.
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Additional safety analyses may be performed to most clearly enumerate rates of toxicities
and to further define the safety profile of MLN9708.
Time to Resolution and Improvement of Peripheral Neuropathy Events
Peripheral neuropathy is defined as the treatment emergent adverse event in the high-level 
term of peripheral neuropathies NEC according to MedDRA.
A PN event is considered as resolved if its final outcome is resolved with no subsequent PN 
event of the same preferred term occurring on the resolution date or the day before and after. 
A PN event is considered as improved if the event improves from the maximum grade. That 
is, all the grades recorded after the maximum grade is less than the maximum grade.
Time to resolution and time to improvement are to be defined for each PN event. Time to 
resolution is defined as the time from the initial onset date (inclusive) to the resolution date 
for resolved events. Time to improvement is defined as the time from the initial onset date 
(inclusive) of the maximum grade to the first onset date that the toxicity grade is below the 
maximum grade with no higher grade thereafter, or the resolution date, whichever occurs 
first.
Time to improvement and time to resolution of PN events will be summarized by outcome 
(improvement or resolution) using the Kaplan-Meier method. The K-M survival curve and 
K-M medians (if estimable), along with their 2-sided 95% CIs, will be presented. This 
analysis is event based, thus 1 subject could contribute multiple observations if the subject 
has more than 1 PN event.
The analysis may be conducted for patients with any PN events or those with grade ≥ 2 PN 
event or those with grade ≥ 3 PN event, respectively, if data permits.
5.11.1.2   Serious Adverse Events
The number and percentage of patients experiencing at least one treatment-emergent SAE 
will be summarized by MedDRA primary system organ class, high level term, and preferred 
term. Drug-related SAE will be summarized similarly.
In addition, a by-patient listing of the SAEs will be presented (the patient listing will contain 
all SAEs regardless of treatment-emergent AE status).
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5.11.1.3   Deaths
A by-patient listing of the deaths will be presented.  All deaths occurring on-study and 
during follow-up will be displayed (regardless of treatment-emergent AE status). 
5.11.1.4   Adverse Events Resulting in Discontinuation of Study Drug
A by-patient listing of treatment-emergent AEs resulting in discontinuation of study drug 
regimen will be presented.
5.11.2   Laboratory Data
For the purposes of summarization in both the tables and listings, all laboratory values will 
be converted to standardized units.  If a lab value is reported using a non-numeric qualifier 
(e.g., less than (<) a certain value, or greater than (>) a certain value), the given numeric 
value will be used in the summary statistics, ignoring the non-numeric qualifier. However, 
for the bone marrow plasma cell percentage, the convention as (x-1)% (mainly for < 5% for 
CR) will be used.
Laboratory test results from the central laboratory will be used when they are available.  
Laboratory test results from local laboratory will only be used when no central laboratory 
test results exist at the same scheduled sample collection time point.
If a patient has repeated laboratory values for a given time point, the value from the last 
evaluation will be used.
Laboratory test results will be summarized according to the scheduled sample collection 
time point.  Change from baseline will also be presented.  Unscheduled laboratory test 
results will be listed and included in laboratory shift tables.  The parameters to be analyzed 
are as follows:

Hematology:  hemoglobin, hematocrit, ANC, ALC, platelets, and white blood cell 
(WBC) count

Serum chemistry:  blood urea nitrogen, creatinine, total bilirubin, uric acid, LDH, 
albumin, alkaline phosphatase, AST, ALT, glucose, calcium, sodium, potassium, 
magnesium, phosphate, and PT.
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Shift tables will be constructed for laboratory parameters to tabulate changes in NCI 
CTCAE for toxicity (version 4.03) from baseline to post baseline worst CTC 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 over time through Cycle 36 for key lab parameters will be produced, 
including but not limited to ANC, platelets, and liver function tests (ALT/SGPT, 
AST/SGOT, alkaline phosphatase, and total bilirubin).
By-patient listings to be presented include hematology, serum chemistry, urinalysis, urine 
total protein, and urine creatinine.
5.11.3   Electrocardiograms
Descriptive statistics for the actual values and changes from baseline in ECGs will be 
tabulated by time point.
QTc interval will be calculated using Bazett’s correction and Fridericia’s correction, if 
necessary.  The formulas are:
QTc (Bazett) = QT / (RR0.5)
QTc (Fridericia) = QT / (RR0.33)
where RR = 60 / heart rate (bpm)
In addition, a categorical analysis of QTc intervals will be performed for each time point.  
The number and percentage of patients in each QTc interval (< 450 msec, 450-480 msec, 
481-500 msec, and ≥500msec) will be summarized at baseline and each of the subsequent 
time points.  Categories of changes from baseline (≥ 30 msec and ≥ 60 msec) will be 
summarized as well. 
Maximum QTc intervals and maximum changes from baseline will also be summarized 
similarly in a separate display.
ECG abnormalities will be presented in a data listing.
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5.11.4   Vital Signs
The actual values of vital sign parameters including temperature, blood pressure, heart rate, 
respiratory rate, and body weight, will be summarized over time for each treatment arm.  
Change from baseline will also be presented.  
A by-patient listing will also be presented.
5.11.5
Eastern Cooperative Oncology Group (ECOG) Performance Status
Eastern Cooperative Oncology Group performance status and change from baseline will be 
summarized.  Shifts from baseline to the worst post-baseline score will be tabulated by 
treatment arm.
5.11.6   Other Safety Assessments
Pregnancy testing results will be presented in a by-patient listing.
Additional safety analyses may be performed to most clearly enumerate rates of toxicities 
and to further define the safety profile of MLN9708, e.g. analyses of TEAEs of clinical 
importance. Tables will be provided with a summary of the patient incidence of all TEAEs 
of clinical importance by PT, severity, and seriousness for each analysis set within each 
category of TEAEs of clinical importance.
6.   
CHANGES TO PLANNED ANALYSES FROM PROTOCOL
Reference materials for this statistical plan include Clinical Study Protocol C16014
(Protocol Amendment 3 dated 10 May 2017).
7.   
PROGRAMMING CONSIDERATIONS
7.1   Statistical Software 
SAS version 9.1 (or higher) will be used for all analyses.  
7.2   Rules and Definitions
Patient populations are defined in Section 2.
Baseline values are defined in Section 5.4.2.
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8.       APPENDIX
8.1 Proof of Strong Control of Type I Error Rate 
Proof of strong control of Type I error rate for testing PFS and OS in ITT and PFS in 
subgroups:
With the proposed testing procedure for the PFS testing in ITT population and three 
subgroups and OS testing in ITT population, this is to prove the strong control of overall 
Type I error rate at one-sided 0.025 level. All alpha specified in the proof is one-sided. 
We will first prove the strong control of Type I error rate under the original plan without 
sample size re-estimation for OS. The proof can be easily generalized to incorporate the OS 
sample size adaptation by switching the regular logrank test statistics at final analysis with 
the CHW test statistic. All the equations related to OS ITT testing still hold because the join 
multivariate distribution of log-rank test statistics at IA1, IA2 and  FA based on planned 
design is the same as the log-rank test statistics at IA1, IA2, and CHW test statistic at FA.  
To facilitate the probability presentation, we introduce the following notations. Let the 
family of null hypotheses of interest be:

)
(
  
)
(
:
H
PFS
PFS
PFS
0
0
1
t
S
t
S

(no difference in PFS ITT between treatment and control 
arm)

)
(
  
)
(
:
H
PFS
PFS
PFS
0
,0
1
S
,1
1
S
1
t
S
t
S

(no difference in PFS subgroup 1 between treatment and 
control)

)
(
  
)
(
:
H
PFS
PFS
PFS
0
,0
2
S
,1
2
S
2
t
S
t
S

(no difference in PFS subgroup 2 between treatment and 
control)

)
(
  
)
(
:
H
PFS
PFS
PFS
0
,0
3
S
,1
3
S
3
t
S
t
S

(no difference in PFS subgroup 3 between treatment and 
control)

)
(
  
)
(
:
H
OS
OS
OS
0
0
1
t
S
t
S

(no difference in OS ITT between treatment and control arm)
Let 
, 
 (and 
, 
) denote the ITT PFS logrank test statistic (and corresponding p-
values) at IA1 and IA2; 
, 
 , 
  (and 
, 
, 
) denote the ITT OS logrank test 
statistic (and corresponding p-values) at IA1, IA2, and FA; ,  ,  (and , , ) 
denote the PFS logrank test statistic (and corresponding p-values) at IA2 for subgroup 1, 2 
and 3. Also let (), (), () denote the ordered p-values among the three subgroups; 
()
{,}, ()
{,} denote the ordered p-values among subgroup 1, and 2; ()
{,}, ()
{,} denote the 
ordered p-values among subgroup 1, and 3; ()
{,}, ()
{,} denote the ordered p-values among 
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subgroup 2, and 3. Let c1, c2 be the critical value for PFS ITT testing based on O’Brien 
Fleming alpha spending function where #{
 < % or  
 < %}=0.02 under &'
(; d1, d2, d3
be the critical value for OS ITT testing based on O’Brien Fleming alpha spending function 
where #{
 < ) or 
 < ) or 
 < )} = 0.02 under &'
; )
∗be the new critical value 
for OS ITT testing at FA where )
∗is calculated such that P{
 ≥), 
 ≥), 
 <
)
∗}=0.025 - P{
 < ) or 
 < )} under &'
.
Since the key secondary endpoint - OS in ITT population is not of interest unless efficacy in 
the primary endpoint - PFS in ITT population is shown, there are defined paths to decision 
making. Liu and Hsu (2006) [6] outlined a decision path principle stating that null 
hypotheses should be formulated so that decision making naturally follows logical paths. We 
will follow this principle in formulating the null hypotheses in this proof. As a result, instead 
of testing all 2^5-1=31 intersection hypotheses by closed testing, we only need to test 
(2+1)*(2^3)-1=23 hypotheses as listed in Table 1. 
Table 1: Partition hypotheses following decision paths for the proposed testing procedure
Index
Partition Hypothesis
Rejection Rule
1
3
2
1
PFS
0
PFS
0
PFS
0
PFS
0
H
H
H
H



{
 < %or  
 < %} or { () <
'.''

or 
() <
'.''

or  () < 0.005}
2


c
3
2
1
PFS
0
PFS
0
PFS
0
PFS
0
H
H
H
H



{
 < %or 
 < %} or { ()
{,} <
'.''

or 
()
{,} < 0.005} 
3


3
2
1
PFS
0
PFS
0
PFS
0
PFS
0
H
H
H
H



c
{
 < %or 
 < %} or { ()
{,} <
'.''

or 
()
{,} < 0.005}
4




c
c
3
2
1
PFS
0
PFS
0
PFS
0
PFS
0
H
H
H
H



{
 < %or 
 < %} or {  < 0.005}
5


3
2
1
PFS
0
PFS
0
PFS
0
PFS
0
H
H
H
H



c
{
 < %or 
 < %} or { ()
{,} <
'.''

or 
()
{,} < 0.005}
6




c
c
3
2
1
PFS
0
PFS
0
PFS
0
PFS
0
H
H
H
H



{
 < % or 
 < %} or {  < 0.005}
7




3
2
1
PFS
0
PFS
0
PFS
0
PFS
0
H
H
H
H



c
c
{
 < % or 
 < %} or {  < 0.005}
8






c
c
c
3
2
1
PFS
0
PFS
0
PFS
0
PFS
0
H
H
H
H



{
 < % or 
 < %}
9


3
2
1
PFS
0
PFS
0
PFS
0
OS
0
PFS
0
H
H
H
H
H




c
{
 < ) or 
 < ) or 
 < )} or { () <
'.''
   or () <
'.''

or  () < 0.005}
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10




c
c
3
2
1
PFS
0
PFS
0
PFS
0
OS
0
PFS
0
H
H
H
H
H




{
 < ) or 
 < ) or 
 < )} or { ()
{,} <
'.''
   or ()
{,} < 0.005}
11




3
2
1
PFS
0
PFS
0
PFS
0
OS
0
PFS
0
H
H
H
H
H




c
c
{
 < ) or 
 < ) or 
 < )} or { ()
{,} <
'.''
   or ()
{,} < 0.005}
12






c
c
c
3
2
1
PFS
0
PFS
0
PFS
0
OS
0
PFS
0
H
H
H
H
H




{
 < ) or 
 < ) or 
 < )} or {  <
0.005}
13




3
2
1
PFS
0
PFS
0
PFS
0
OS
0
PFS
0
H
H
H
H
H




c
c
{
 < ) or 
 < ) or 
 < )} or { ()
{,} <
'.''
   or ()
{,} < 0.005}
14






c
c
c
3
2
1
PFS
0
PFS
0
PFS
0
OS
0
PFS
0
H
H
H
H
H




{
 < ) or 
 < ) or 
 < )} or {  <
0.005}
15






3
2
1
PFS
0
PFS
0
PFS
0
OS
0
PFS
0
H
H
H
H
H




c
c
c
{
 < ) or 
 < ) or 
 < )} or {  <
0.005}
16








c
c
c
c
3
2
1
PFS
0
PFS
0
PFS
0
OS
0
PFS
0
H
H
H
H
H





 < ) or 
 < ) or 
 < )
∗
17




3
2
1
PFS
0
PFS
0
PFS
0
OS
0
PFS
0
H
H
H
H
H




c
c
() <
'.''

or () <
'.''

or  () < 0.005
18






c
c
c
3
2
1
PFS
0
PFS
0
PFS
0
OS
0
PFS
0
H
H
H
H
H




()
{,} <
'.''

or ()
{,} < 0.005
19






3
2
1
PFS
0
PFS
0
PFS
0
OS
0
PFS
0
H
H
H
H
H




c
c
c
()
{,} <
'.''

or ()
{,} < 0.005
20








c
c
c
c
3
2
1
PFS
0
PFS
0
PFS
0
OS
0
PFS
0
H
H
H
H
H




 < 0.005
21






3
2
1
PFS
0
PFS
0
PFS
0
OS
0
PFS
0
H
H
H
H
H




c
c
c
()
{,} <
'.''

or ()
{,} < 0.005
22








c
c
c
c
3
2
1
PFS
0
PFS
0
PFS
0
OS
0
PFS
0
H
H
H
H
H




 < 0.005
23








3
2
1
PFS
0
PFS
0
PFS
0
OS
0
PFS
0
H
H
H
H
H




c
c
c
c
 < 0.005
By partition principle, as long as each of the disjoint partition hypothesis is tested at level 
0.025, the overall Type I error rate is also strongly controlled at the same level.
For hypotheses 17-23, Huang and Hsu (2007) [7] showed that the rejection rule in Table 1 is 
equivalent to the Hochberg procedure with overall 0.005 for testing the three subgroups.
For hypothesis 1, using Bonferroni inequality, the probability of false rejection is no greater 
than P{
 < %or  
 < %} + P{ () <
'.''

or () <
'.''

or  () <
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51
0.005}=0.02+0.005=0.025. Similarly, for hypotheses 2-7, using Bonferroni inequality easily 
shows that the probability of false rejection is no greater than 0.02+0.005=0.025. 
For hypothesis 8, P{
 < % or 
 < %}=0.02<0.025. 
For hypothesis 9, using Bonferroni inequality, the probability of false rejection is no greater 
than P{
 < ) or 
 < ) or 
 < )} + P{ () <
'.''
   or () <
'.''

or  () <
0.005}=0.02+0.005=0.025. Similarly, for hypotheses 10-15, using Bonferroni inequality 
easily shows that the probability of false rejection is no greater than 0.02+0.005=0.025.
For hypothesis 16, P{
 < ) or  
 < ) or  
 < )
∗}= P{
 < ) or 
 < )} + 
P{
 ≥), 
 ≥), 
 < )
∗}+ =0.025.
Since each partition hypothesis in Table 1, is tested at 0.025 level, the overall Type I error 
rate is also controlled at the 0.025 level. 
Next is to see that after collating results from the rejection rules in Table 1, it is equivalent to 
the proposed testing procedure. In order to reject &'
(, all of partition hypotheses 1-8 have 
to be rejected (since they involve the null space of  &'
() which means {
 < % or 
 <
%} which corresponds to the group sequential testing of PFS in ITT population. In order to 
reject  &'
(0, hypotheses 1-4, 9-12, 17-20 have to be rejected which is the same as requiring 
hypothesis 17-20 be rejected. Similarly, hypothesis 17, 18, 21, 22 are required to be rejected 
for &'
(1 and hypotheses 17, 19, 21, 23 are required to be rejected for &'
(2. All the 
involved hypotheses are 17-23 and based on Huang and Hsu (2007), the testing procedure is 
exactly the Hochberg procedure with overall alpha of 0.005 level. In order to reject  &'
, all 
of partition hypotheses 1-16 have to be rejected. This means PFS in ITT population has to be
rejected first (hypotheses 1-8). Then either {
 < ) or 
 < ) or 
 < )} when 
() ≥0.005; or {
 < ) or 
 < ) or 
 < )
∗} when () < 0.005 has to hold. This 
means OS in ITT population can either be rejected at first IA based on d1 (given PFS in ITT 
is rejected first) or second IA based on d2 (given PFS in ITT is rejected); if not, depending 
on whether all three subgroups at second IA can be rejected or not, OS in ITT population 
can be tested again at final analysis based on either d3 or d3*.  
For the other two key secondary endpoints, CR rate will be tested at the same alpha level, 
instead of same critical value, as that for OS whenever OS reaches statistical significance. 
Pain response rate will be tested at the same alpha level as that for CR rate whenever CR 
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52
rate reaches statistical significance. Due to the closed sequential testing property, the family-
wise error rate is strongly controlled for both the primary endpoint and three key secondary 
endpoints.
8.2 Calculating the Significance Boundary for ITT PFS at IA2
All alpha specified in this section is one-sided. 
In the previous SAP (SAP version 1), the significance boundaries c1 and c2 for ITT PFS at 
IA1 and IA2 were to be calculated based on the Gamma(-1) alpha-spending approach. 
Specifically, c1 was to be calculated using the observed number of PFS events at IA1 and in 
anticipation of 435 PFS events at IA2. c2 was to be calculated with the purpose of 
exhausting the remaining available alpha while considering the correlation between c1 and 
the observed number of PFS events at IA2.
This SAP (SAP version 2) modifies the target number of PFS events at IA2 from 
approximately 435 to approximately 370. It is also proposed after the Sponsor observed an 
aggregate 328 PFS events at IA1, while remaining blinded to any data by treatment arm. 
Therefore, to preserve the type I error rate, the significance boundary for ITT PFS at IA2 
(the FA for ITT PFS) will be re-calculated while the boundary at the past IA will remain 
unchanged. What follows is an example calculation for the situation that exactly 370 PFS 
events are observed at IA2. Note that the actual value of c2 will vary slightly depending on 
the eventual observed number of events.
Given 328 PFS events observed at IA1, 435 PFS events planned at IA2, and the Gamma(-1) 
alpha-spending function, the one-sided significance cutoffs for the log-rank test statistic T1
and p-value p1 at IA1 are given by u1=2.223 and c1=0.0131, respectively. Now suppose IA2 
is performed after 370 PFS events are observed instead of the planned 435. Because the 
correlation between the log-rank test statistic T2 at IA2 and T1 changes as a result, the 
information fraction I at IA1 should be adjusted to exhaust the remaining alpha while 
preserving the type I error rate.
Set I=328/370 and keep u1=2.223. That is, update the information rate at IA1, but fix the 
alpha already spent at IA1. Under the null hypothesis of no treatment benefit, the vector (T1,
T2) follows the bivariate normal distribution
3
4 ~678 9:0
0;, 3 1
√>
√>
1
4?
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Statistical Analysis Plan, Study C16014
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53
By performing a grid search, it can be found that setting u2=2.131 preserves type I error rate 
at alpha-level 0.02:
Pr( > B) + Pr( < B and  > B) = 0.02
The p-value cutoff corresponding to u2 is c2=0.0165.
9.   
REFERENCES
1)
Durie BG, Harousseau JL, Miguel JS, Blade J, Barlogie B, Anderson K, et al. 
International uniform response criteria for multiple myeloma. Leukemia 2006; 20(9): 
1467-73.
2)
Lan K, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika 
1983;70:659-63.
3)
Robins JM, Hernan M, Brumback B. Marginal strucural models and causal inference in 
epidemiology. Epidemiology 2000; 11(5): 550-560.  
4)
Robins JM, Finkelstein DM. Correcting for noncompliance and dependent censoring in 
an AIDS Clinical Trial with inverse probability of censoring weighted (IPCW) log-rank 
tests. Biometrics 2000;56(3):779-88.
5)
D’Agostino R.B., Lee M.L., Belanger A.J., Cupples L.A., Anderson K., and Kannel 
W.B. Relation of pooled logistic regression to time dependent Cox regression analysis: 
the Framingham Heart Study. Statistics in Medicine, 9(12): 1501–1515, 1990.
6)
Cui L, Hung HM, Wang SJ. Modification of sample size in group sequential clinical 
trials. Biometrics 1999; 55:853–857.
7)
Glimm E, Maurer W, Bretz F. Hierarchical testing of multiple endpoints in group 
sequential trials. Stat Med 2010;29(2):219-28.
8)
Mehta CR, Pocock SJ. Adaptive increase in sample size when interim results are 
promising: a practical guide with examples. Stat Med 2011;30(28):3267-84
9)
Liu Y, Hsu J (2009). Testing for efficacy in primary and secondary endpoints by 
partitioning decision paths. Journal of the American Statistical Association, 104: 1661-
1670.
10)
Huang Y, Hsu J; Hochberg's Step-Up Method: Cutting Corners Off Holm's Step-Down 
Method. Biometrika 2007; 94 (4): 965-975. doi: 10.1093/biomet/asm067
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