Clinical trial NCT01564537
Conditions: Relapsed Multiple Myeloma Refractory Multiple Myeloma
Keywords: Drug therapy
Sponsor: Takeda
Start date: 2012-08-01; Completion date: 2022-02-08
Enrollment: 722 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine whether the addition of oral ixazomib to the background therapy of lenalidomide and dexamethasone improves progression free survival (PFS) in participants with relapsed and/or refractory multiple myeloma (RRMM).

Detailed description:
The drug being tested in this study is called Ixazomib. Ixazomib is being tested to treat people who have relapsed and/or refractory multiple myeloma (RRMM). This study will look at progression free survival (PFS), overall survival (OS) and safety in participants who take ixazomib in addition to lenalidomide and dexamethasone compared to placebo in addition to lenalidomide and dexamethasone.

The study enrolled 722 patients. Participants were randomly assigned (by chance, like flipping a coin) to one of the two treatment groups-which will remain undisclosed to the patient and study doctor during the study (unless there is an urgent medical need):

* Ixazomib 4 mg + lenalidomide + dexamethasone
* Placebo (dummy inactive pill) - this is a tablet that looks like the study drug but has no active ingredient + lenalidomide + dexamethasone

All participants will receive treatment in 28 day cycles until disease progression or unacceptable toxicity.

This multi-center trial will be conducted worldwide. The overall time to participate in this study is approximately 80 months. Participants will make multiple visits to the clinic, and will be contacted every 4 weeks for PFS and every 12 weeks for OS.

Arms: arm 1: Ixazomib 4 mg, capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until progressive disease (PD) or unacceptable toxicity, whichever occurred first up to end of treatment (EOT) up to approximately 42.9 months. arm 2: Ixazomib placebo-matching capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until PD or unacceptable toxicity, whichever occurred first up to approximately 41 months.
Interventions: intervention 1: Ixazomib intervention 2: Lenalidomide intervention 3: Dexamethasone intervention 4: Placebo
Intervention descriptions: intervention 1: Ixazomib capsules intervention 2: Lenalidomide capsules intervention 3: Dexamethasone tablets intervention 4: Ixazomib placebo-matching capsules

Protocol documents:
Prot_000.pdf: 



Title: A Phase 3, Randomized, Double-Blind, Multicenter Study Comparing Oral Ixazomib Plus 
Lenalidomide and Dexamethasone Versus Placebo Plus Lenalidomide and Dexamethasone in 
Adult Patients With Relapsed and/or Refractory Multiple Myeloma
NCT Number: NCT01564537
Protocol Approve Date: 08 January 2021
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 C16010 Amendment 8, 08 January 2021
1
CLINICAL STUDY PROTOCOL C16010 AMENDMENT 8
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 Relapsed and/or Refractory Multiple Myeloma 
Protocol Number:
C16010
Indication:
Relapsed and/or Refractory Multiple Myeloma
Phase:
3
Sponsor:
Millennium Pharmaceuticals, Inc.
EudraCT Number:
2011-005496-17 
Therapeutic Area:
Oncology
Protocol History
Original
21 February 2012
Amendment 1
14 September 2012
Amendment 2  (For use in China only)
27 November 2013
Amendment 3
08 July 2014
Amendment 4  (For use in China only)
27 August 2014
Amendment 5  (For use in China only)
23 December 2015
Amendment 6
12 December 2016
Amendment 7 (For use in China only)
20 December 2016
Amendment 8 (substantial)
08 January 2021
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.
Prop
Non-Commercial Use Only and Subject to the Applicable Terms of Use
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MLN9708
Clinical Study Protocol C16010 Amendment 8, 08 January 2021
2
Rationale for Amendment 8
This document describes the changes to the protocol incorporating Amendment 8. The 
primary rationale for this amendment is to modify the study procedures and assessments for 
patients still on study at the time of the final analysis. The final analysis data cutoff has been 
conducted and as such, the study is considered complete for statistical analysis purposes. All 
patients will be unblinded. Only patients who continue to demonstrate clinical benefit but 
who do not have other means of access to the study drugs will continue on the study.
Because no further formal statistical analyses will be performed, only assessments 
contributing to long-term safety monitoring are required. Most study assessments besides 
safety are discontinued to ease the burden of protocol-mandated assessments on patients.
Patients still on treatment at the time of the final analysis: 
Patients continuing their current study treatment may do so until such time as other 
means of accessing the study drugs are arranged. When possible, patients should 
complete an End of Treatment (EOT) visit and transition onto an alternative supply of 
(eg, commercially available) ixazomib (MLN9708) and/or LenDex, or onto another 
standard of care treatment. Discontinued patients will be treated by their physician per 
local standard of care.
Patients who are receiving ixazomib plus lenalidomide and dexamethasone (LenDex) 
will continue to receive ixazomib plus LenDex.  Patients who are receiving placebo plus 
LenDex will receive LenDex only; the placebo capsule will no longer be administered 
and patients receiving placebo will not be crossed over to ixazomib in this study.
Upon implementation of Amendment 8, data collection requirements will be limited to 
collection of adverse events (AEs), serious adverse events (SAEs), laboratory 
assessments of safety, physical examinations, and concomitant medications. Quality of 
life, health care utilization, EQ-5D, and pain assessments are discontinued. Survival data 
will no longer be collected because the analysis of overall survival (OS) will be 
complete at the time of the final analysis. Other study assessments are no longer 
required, as noted in the new Schedule of Events (the previous, full Schedule of Events 
is now moved to Section 15.12 for reference only).
Patients in the OS Follow-Up Period at the time of the final analysis:
Upon implementation of Amendment 8, patients will no longer be followed in the OS 
Follow-Up Period. The EQ-5D and skeletal-related event assessments are discontinued. 
Survival data will no longer be collected because the analysis of OS will be complete at 
the time of the final analysis. 
Descriptions of how to manage study procedures during unavoidable circumstances, such as 
the coronavirus disease 2019 (COVID-19) pandemic, have additionally been added.
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MLN9708
Clinical Study Protocol C16010 Amendment 8, 08 January 2021
3
Minor grammatical, editorial, formatting, and administrative changes not affecting the 
conduct of the study are included for clarification and administrative purposes only.
For specific descriptions of text changes and location of the changes, see Section 15.21.
Purposes for Amendment 8
The purposes of this amendment are to:
1. Clarify the study objectives as of Amendment 8.
2. Clarify the study endpoints as of Amendment 8.
3. Clarify that the final analysis data cutoff has been conducted and the study is 
considered complete for statistical analysis purposes. 
4. Add language to clarify ongoing treatment of patients—patients still receiving study 
treatment will stay on their assigned study regimen. Patients should be moved off 
study and onto an alternative supply of (eg, commercially available) ixazomib  
and/or LenDex, or onto another standard of care treatment.
5. Discontinue all remaining efficacy assessments (eg, OS, Quality of Life) and clarify
ongoing safety laboratory evaluations.
6. Discontinue the OS follow-up period.
7. Revise information regarding the interim analyses.
8. Update language about the management of clinical events in patients receiving 
ixazomib.
9. Clarify the procedures for storage, handling, and accountability.
10. Add flexibility in study conduct in unavoidable circumstances (eg, the COVID-19 
pandemic).
11. Add language requiring all patients to reconsent. 
12. Clarify the definition of Completion of Treatment.
13. Clarify the definition of Completion of Study.
14. Update the procedures for SAE reporting.
15. Add information about alternative monitoring approaches, such as remote source 
data verification, in the event a monitor cannot visit the site in a timely manner due 
to the COVID-19 pandemic.
For specific examples of changes in text and where the changes are located, see 
Section 15.21.
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MLN9708
Clinical Study Protocol C16010 Amendment 8, 08 January 2021
4
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 Relapsed and/or Refractory Multiple Myeloma
Study Phase: 3
Number of Patients: Approximately 703
Study Objectives
Note that the primary objective and corresponding endpoint have been met. Upon implementation of 
Amendment 8, the objective is to continue to collect long-term safety data from patients who are 
continuing on ixazomib (MLN9708) and LenDex or LenDex (note the placebo capsule will be 
discontinued) because of continuing clinical benefit. Data collection for all other study objectives 
and endpoints will be complete at the time of the final analysis and no further formal analyses will be 
conducted. The original lists of objectives are retained below for reference only.
Primary Objective:
! To determine whether the addition of oral MLN9708 to the background therapy of 
lenalidomide and dexamethasone improves progression-free survival (PFS) in patients with 
relapsed and/or refractory multiple myeloma (RRMM)
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 OS in high-risk patients carrying deletion del(17)
Other Secondary Objectives:
! To determine overall response rate (ORR), including partial response (PR), very good partial 
response (VGPR), and complete response (CR)
! To determine CR + VGPR
! To determine duration of response (DOR)
! To determine time to progression (TTP)
! To determine the safety of the addition of MLN9708 to lenalidomide and dexamethasone 
! To determine pain response rate, as assessed by the BPI-SF and analgesic use
! To assess change in 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 such as translocations 
t(4;14), t(14;16), +1q, del(13), or del(17)
! To evaluate the potential relationship between response or resistance to MLN9708 treatment 
and proteasome and NFKB-related genes, such as PSMB1 and TRAF-3 in blood samples 
! To collect PK data to contribute to population PK analyses
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Ter
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MLN9708
Clinical Study Protocol C16010 Amendment 8, 08 January 2021
5
Overview of Study Design: 
This is a phase 3, randomized, double-blind, multicenter study to evaluate the safety and efficacy of 
MLN9708 versus placebo in patients with relapsed and/or refractory multiple myeloma (MM) who 
are treated with lenalidomide and dexamethasone as their standard therapy. The patient population 
will consist of adult men and women who have a confirmed diagnosis of MM, who have received 
1 to 3 prior lines of therapy, and who meet other outlined eligibility criteria.
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, 
stratified by: 1 versus 2 or 3 prior therapies, proteasome-inhibitor (PI) exposed versus PI naïve, and 
International Staging System (ISS) stage at screening of 1 or 2 versus stage 3.
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 Days 1, 8, 15, 
and 22 of a 28-day cycle. Patients may continue to receive treatment until progressive disease or 
unacceptable toxicity, whichever comes first. Dose modifications may be made 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.
Treatment periods will be defined as 28-day cycles. Patients will be seen at regular treatment cycle 
intervals while they are participating in the study: twice a treatment cycle for the first 3 cycles, then 
once a treatment cycle for the remainder of their participation in the active treatment and, if 
applicable, the PFS and OS follow-up phases of the study. As of Amendment 6, however, the 
primary endpoint has been met. As such, the PFS follow-up phase has been discontinued for patients 
currently receiving study therapy.
An independent review committee (IRC) will review all cases of disease response and progression. 
Response will be assessed according to the International Myeloma Working Group (IMWG) criteria 
for all patients every 4 weeks until disease progression. As of Amendment 6, however, because PFS 
follow-up is now completed for this study, for all patients still receiving study therapy, all central 
and investigator assessments of response and progression for protocol purposes are discontinued—
IRC review will no longer be performed, and IRC response will no longer be assessed. 
All patients will continue to 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 Applic
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MLN9708
Clinical Study Protocol C16010 Amendment 8, 08 January 2021
6
The final analysis data cutoff has been conducted and as such, the study is considered complete for 
statistical analysis purposes. All patients will be unblinded. Only patients who continue to 
demonstrate clinical benefit but who do not have other means of access to the study drugs will 
continue on the study. Because no further formal statistical analyses will be performed, only 
assessments contributing to long-term safety monitoring are required. Most study assessments 
besides safety are discontinued to ease the burden of protocol-mandated assessments on patients.
Patients continuing their current study treatment may do so until such time as other means of 
accessing the study drugs are arranged. When possible, patients should complete an EOT visit and 
transition onto an alternative supply of (eg, commercially available) ixazomib and/or LenDex, or 
onto another standard of care treatment. Discontinued patients will be treated by their physician per 
local standard of care.
Patients who are receiving ixazomib plus LenDex will continue to receive ixazomib plus LenDex.  
Patients who are receiving placebo plus LenDex will receive LenDex only; the placebo capsule will 
no longer be administered and patients receiving placebo will not be crossed over to ixazomib in this 
study. Upon implementation of Amendment 8, data collection requirements will be limited to 
collection of AEs, SAEs, and concomitant medications. Quality of life, health utilization, EQ-5D, 
and pain assessments are discontinued. Survival data will no longer be collected because the analysis 
of OS will be complete at the time of the final analysis. Other study assessments are no longer 
required, as noted in the new Schedule of Events. Patients will not be followed for the OS follow-up 
period because OS data are no longer being collected.
Study Population: 
Adult patients with a confirmed diagnosis of symptomatic MM and relapsed and/or refractory 
disease will be enrolled in this study.
Duration of Study:
The duration of the study, including enrollment, treatment, and follow-up, will be approximately 
81 months.
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MLN9708
Clinical Study Protocol C16010 Amendment 8, 08 January 2021
7
STUDY OVERVIEW DIAGRAM
NOTE: Upon implementation of Protocol Amendment 8, patients receiving placebo + 
LenDex will no longer receive the placebo capsule. In addition, follow-up for OS will no 
longer occur. The full Study Overview Diagram is retained for reference.
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MLN9708
Clinical Study Protocol C16010 Amendment 8, 08 January 2021
8
SCHEDULE OF EVENTS—AMENDMENT 8 
The final analysis data cutoff has been conducted and as such, the study is considered 
complete for statistical analysis purposes. Upon implementation of Amendment 8, the 
investigator will unblind all patients remaining on study treatment and will follow the new 
Schedule of Events. 
Only patients who continue to demonstrate clinical benefit but who do not have other means 
of access to the study drugs will continue on the study. Because no further formal statistical 
analyses will be performed, only assessments contributing to long-term safety monitoring 
are required. Most study assessments besides safety are discontinued to ease the burden of 
protocol-mandated assessments on patients. Patients continuing their current study treatment 
may do so until such time as other means of accessing the study drugs are arranged. When 
possible, patients should complete an EOT visit and transition onto an alternative supply of 
(eg, commercially available) ixazomib (MLN9708) and/or LenDex, or onto another standard 
of care treatment. Discontinued patients will be treated by their physician per local standard 
of care.
Patients who are receiving ixazomib plus LenDex will continue to receive ixazomib plus 
LenDex.  Patients who are receiving placebo plus LenDex will receive LenDex only; the 
placebo capsule will no longer be administered and patients receiving placebo will not be 
crossed over to ixazomib in this study. Upon implementation of Amendment 8, data 
collection requirements will be limited to collection of AEs, SAEs, and concomitant 
medications. Quality of life, health care utilization, EQ-5D, and pain assessments are 
discontinued. Survival data will no longer be collected because the analysis of OS will be 
complete at the time of the final analysis. Other study assessments are no longer required, as 
noted in the new Schedule of Events. Patients will not be followed for the OS follow-up 
period because OS data are no longer being collected.
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MLN9708
Clinical Study Protocol C16010 Amendment 8, 08 January 2021
9
Study Procedures
Treatment Period
28-Day Cycles
End of 
Treatmentb
Cycle
Cycle Xa and Beyond
Day
1
Window
± 1 week
+ 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
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
New Primary Malignancy Assessment
Continuous from the start of study drug administration until death 
or termination of the study by the sponsor
Concomitant Medications/Procedures
Recorded from the first dose of study drug through 30 days after 
last dose of study drugi
Study Drug Administration
MLN9708j
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
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 8.
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 8, patients 
must 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 and local regulations.
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: complete physical examination, 
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MLN9708
Clinical Study Protocol C16010 Amendment 8, 08 January 2021
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symptom-directed physical examination, hematology, clinical chemistry, concomitant 
medications/procedures. 
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
Concomitant medications are to be collected and recorded in the eCRF only to the extent that they are 
needed to document an AE. 
j
Only for patients who were receiving MLN9708 in combination with LenDex. Patients who received 
placebo in combination with LenDex will receive LenDex but will no longer be administered the placebo 
capsule.
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MLN9708
Clinical Study Protocol C16010 Amendment 8, 08 January 2021
11
TABLE OF CONTENTS
LIST OF TABLES.............................................................................................................14
LIST OF FIGURES............................................................................................................15
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS ..........................................16
1. BACKGROUND AND STUDY RATIONALE..............................................................20
1.1 Scientific Background ..............................................................................................20
1.1.1 Disease Under Treatment...................................................................................20
1.1.2 MLN9708, Millennium’s Next-Generation Proteasome Inhibitor.......................21
1.2 Preclinical Experience ..............................................................................................21
1.2.1 Nonclinical Pharmacology: In Vivo Studies.......................................................21
1.3 Clinical Experience ..................................................................................................22
1.4 Study Rationale ........................................................................................................31
1.4.1 Rationale for the Combination of MLN9708, Lenalidomide, and 
Dexamethasone...........................................................................................31
1.4.2 Rationale for MLN9708, Lenalidomide, and Dexamethasone Dose and 
Schedule Selection......................................................................................33
1.4.3 Rationale for the Molecular Analyses.................................................................35
1.4.4 Rationale for the Combination of MLN9708, Lenalidomide, and 
Dexamethasone in a High-Risk Patient Population......................................37
2. STUDY OBJECTIVES ..................................................................................................38
2.1 Primary Objective.....................................................................................................38
2.2 Secondary Objectives ...............................................................................................38
2.3 Exploratory Objectives .............................................................................................39
3. STUDY ENDPOINTS....................................................................................................40
3.1 Primary Endpoint .....................................................................................................40
3.2 Secondary Endpoints................................................................................................40
3.3 Exploratory Endpoints..............................................................................................41
4. STUDY DESIGN...........................................................................................................43
4.1 Overview of Study Design........................................................................................43
4.2 Number of Patients...................................................................................................46
4.3 Duration of Study.....................................................................................................47
5. STUDY POPULATION.................................................................................................48
5.1 Inclusion Criteria......................................................................................................48
5.2 Exclusion Criteria.....................................................................................................51
6. STUDY TREATMENT..................................................................................................53
6.1 Test Article (MLN9708) and Matched Placebo.........................................................53
6.2 Standard of Care Therapies.......................................................................................54
6.2.1 Lenalidomide Administration.............................................................................54
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
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Clinical Study Protocol C16010 Amendment 8, 08 January 2021
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6.4.4 Dexamethasone-Related Treatment Modification...............................................62
6.5 Criteria for Toxicity Recovery Before Beginning the Next Cycle of Treatment.........63
6.6 Excluded Concomitant Medications and Procedures.................................................64
6.7 Permitted Concomitant Medications and Procedures.................................................65
6.8 Precautions and Restrictions .....................................................................................65
6.9 Contraception Requirements.....................................................................................66
6.10 Management of Clinical Events..............................................................................68
6.11 Blinding and Unblinding ........................................................................................71
6.12 Description of Investigational Agents .....................................................................72
6.13 Preparation, Reconstitution, and Dispensing ...........................................................73
6.14 Packaging and Labeling..........................................................................................73
6.15 Storage, Handling, and Accountability....................................................................73
6.15.1 Standard of Care Therapies ..............................................................................75
6.16 Other Protocol-Specified Materials.........................................................................75
7. STUDY CONDUCT ......................................................................................................76
7.1 Study Personnel and Organizations...........................................................................76
7.2 Arrangements for Recruitment of Patients ................................................................76
7.3 Treatment Group Assignments .................................................................................76
7.4 Study Procedures......................................................................................................77
7.4.1 Informed Consent ..............................................................................................78
7.4.2 Patient Demographics ........................................................................................78
7.4.3 Medical History.................................................................................................78
7.4.4 Physical Examination.........................................................................................78
7.4.5 Eastern Cooperative Oncology Group Performance Status.................................78
7.4.6 Vital Signs .........................................................................................................79
7.4.7 Pregnancy Test ..................................................................................................79
7.4.8 Electrocardiogram..............................................................................................80
7.4.9 Clinical Laboratory Evaluations.........................................................................80
7.4.10 Clinical Chemistry, Hematology, and Urinalysis..............................................81
7.4.11 Health Utilization Data Collection ...................................................................82
7.4.12 Quality of Life Assessment (European Organization for Research and 
Treatment of Cancer) ..................................................................................82
7.4.13 Pain Assessment ..............................................................................................83
7.4.14 Utility Measurement ........................................................................................84
7.4.15 Skeletal Survey................................................................................................84
7.4.16 Skeletal-Related Events....................................................................................85
7.4.17 Radiographic Disease Assessments ..................................................................85
7.4.18 2-Microglobulin.............................................................................................85
7.4.19 Quantification of M-Protein .............................................................................86
7.4.20 Quantification of Immunoglobulin (Ig) ............................................................86
7.4.21 Serum Free Light Chain Assay.........................................................................86
7.4.22 Immunofixation of Serum and Urine................................................................86
7.4.23 Bone Marrow Evaluation .................................................................................87
7.4.24 Response Assessment ......................................................................................88
7.4.25 Pharmacokinetic Measurements.......................................................................89
7.4.26 Blood Sample for Biomarker Analysis .............................................................90
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7.4.27 Concomitant Medications and Procedures........................................................90
7.4.28 Adverse Events................................................................................................90
7.4.29 Follow-up Assessments (PFS and OS) .............................................................90
7.5 Unscheduled Visits...................................................................................................91
7.6 Study Compliance ....................................................................................................91
7.7 Completion of Treatment..........................................................................................91
7.8 Completion of Study.................................................................................................92
7.9 Discontinuation of Treatment With Study Drug........................................................92
7.10 Withdrawal of Patients From Study ........................................................................93
8. STATISTICAL AND QUANTITATIVE ANALYSES ..................................................93
8.1 Statistical Methods ...................................................................................................94
8.1.1 Determination of Sample Size............................................................................94
8.1.2 Randomization and Stratification .......................................................................96
8.1.3 Populations for Analysis ....................................................................................96
8.1.4 Procedures for Handling Missing, Unused, and Spurious Data...........................97
8.1.5 Demographic and Baseline Characteristics.........................................................97
8.1.6 Efficacy Analysis...............................................................................................97
8.1.7 Analyses of Patient-Reported Outcomes and Health Economics.......................100
8.1.8 Pharmacokinetics 
....................................................................102
8.1.9 Safety Analysis ................................................................................................103
8.1.10 Interim Analyses............................................................................................104
9. STUDY COMMITTEES..............................................................................................105
9.1 Steering Committee................................................................................................105
9.2 Independent Review Committee.............................................................................105
9.3 Independent Data Monitoring Committee...............................................................105
10. ADVERSE EVENTS .................................................................................................106
10.1 Definitions............................................................................................................106
10.1.1 Pretreatment Event Definition........................................................................106
10.1.2 Adverse Event Definition...............................................................................106
10.1.3 Serious Adverse Event Definition ..................................................................107
10.2 Procedures for Recording and Reporting Adverse Events and Serious 
Adverse Events...............................................................................................108
10.3 Monitoring of Adverse Events and Period of Observation.....................................110
10.4 Procedures for Reporting Drug Exposure During Pregnancy and Birth Events......110
11. ADMINISTRATIVE REQUIREMENTS ...................................................................112
11.1 Good Clinical Practice..........................................................................................112
11.2 Data Quality Assurance ........................................................................................112
11.3 Electronic Case Report Form Completion.............................................................112
11.4 Study Monitoring .................................................................................................113
11.5 Ethical Considerations..........................................................................................113
11.6 Patient Information and Informed Consent............................................................113
11.7 Patient Confidentiality..........................................................................................114
11.8 Investigator Compliance.......................................................................................114
11.9 On-site Audits ......................................................................................................114
11.10 Investigator and Site Responsibility for Drug Accountability..............................114
11.11 Product Complaints and Medication Errors (Including Overdose).......................115
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11.12 Closure of the Study ...........................................................................................115
11.13 Record Retention................................................................................................117
12. USE OF INFORMATION..........................................................................................118
13. INVESTIGATOR AGREEMENT..............................................................................119
14. REFERENCES...........................................................................................................120
15. APPENDICES ...........................................................................................................125
15.1 Eastern Cooperative Oncology Group (ECOG) Scale for Performance Status.......125
15.2 Multiple Myeloma Diagnostic Criteria..................................................................125
15.3 Cockcroft-Gault Equation.....................................................................................126
15.4 ISS Staging Criteria and Durie-Salmon Criteria....................................................127
15.5 Steroid Equivalent Doses......................................................................................128
15.6 World Health Organization Steps of Analgesics and OME Conversions ...............129
15.6.1 Steps of Analgesics........................................................................................129
15.6.2 Oral Morphine Equivalent (OME) Conversions..............................................135
15.7 EQ-5D..................................................................................................................137
15.8 Brief Pain Inventory-Short Form (BPI-SF) ...........................................................140
15.9 QLQ-MY20..........................................................................................................142
15.10 European Organization for Research and Treatment of Cancer 
(EORTC QLQ-C30 (version 3).......................................................................144
15.11 Response Criteria................................................................................................146
15.12 Full Schedule of Events (as of Amendment 3) ....................................................148
15.13 Schedule of Events (as of Amendment 6)............................................................154
15.14 Amendment 1 Rationale and Purposes................................................................157
15.15 Amendment 2 Rationale and Purposes................................................................160
15.16 Amendment 3 Rationale and Purposes................................................................162
15.17 Amendment 4 Rationale and Purposes................................................................164
15.18 Amendment 5 Rationale and Purposes................................................................166
15.19 Amendment 6 Rationale and Purposes................................................................167
15.20 Amendment 7 Rationale and Purposes................................................................168
15.21 Amendment 8 Detailed Summary of Changes.....................................................170
LIST OF TABLES
Table 1-1   
Ongoing Studies of Oral MLN9708.............................................................24
Table 1-2   
MLN9708 Potential Risks (Pooled PO Formulation), as of 12 October 201125
Table 1-3   
Study C16003: Oral MLN9708, Single Agent Given Twice Weekly, in 
RRMM Most Common TEAEs as of 12 October 2011 (N = 56)..................26
Table 1-4   
Study C16004: Oral MLN9708, Single Agent Given Weekly, Most Common 
TEAE as of 12 October 2011 (N = 32) ........................................................27
Table 1-5   
Study C16005: Oral MLN9708 Given Weekly in Combination With 
Lenalidomide and Dexamethasone, Most Common TEAEs as of 12 Oct 2011 
(N = 15)......................................................................................................29
Table 6-1   
Study Drug and Lenalidomide Dose Adjustment for Thrombocytopenia .....57
Table 6-2   
Study Drug and Lenalidomide Dose Adjustment for Neutropenia................58
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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[43]...................................................................................................62
Table 6-8   
Dose Reduction Steps for Dexamethasone...................................................62
Table 6-9   
Dexamethasone–Related Treatment Modification (Delays, Reductions, and 
Discontinuations) Guidelines Due to Adverse Events[44]............................63
Table 6-10   
MLN9708 Capsules ....................................................................................73
Table 7-1   
Response Assessment..................................................................................89
Table 15-1   
Pain Medication List Categorized by World Health Organization (WHO) 
Steps I, II, and III......................................................................................129
Table 15-2   
Oral and Parenteral Opioid Equivalences and Relative Potency of Drugs as 
Compared with Morphine..........................................................................135
Table 15-3   
Recommended Dose Conversion From Other Opioids to Transdermal 
Fentanyl....................................................................................................136
LIST OF FIGURES
Figure 1-1   
No Apparent Relationship Between MLN9708 Clearance and BSA ............35
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LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS
Abbreviation
Term
5-HT3
5-hydroxytryptamine 3 serotonin receptor
AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
ATF-3
Activating Transcription Factor-3
AUC
area under the plasma concentration versus time curve
BPI-SF
Brief Pain Inventory – Short Form
BSA
body surface area
BUN
blood urea nitrogen
CBC
complete blood count
CI
confidence interval
CL
clearance, IV dosing
Cmax
single-dose maximum  (peak) concentration
CMH
Cochran-Mantel-Haenszel
CO2
carbon dioxide
CR
complete response 
CT
computed tomography
CYP
cytochrome P450
Del
deletion
DLBCL
diffuse large B cell lymphoma
DLT
dose-limiting toxicity
DNA
deoxyribonucleic acid
DOR
duration of response
DVT
deep vein thrombosis
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EORTC QLQ-C30
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire 
EOT
End of Treatment (visit)
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Abbreviation
Term
EQ-5D
EuroQol 5-Dimensional Health Questionnaire
EU
European Union
FCBP
female of childbearing potential
FDA
United States Food and Drug Administration
GADD34
Growth Arrest DNA Damage 34
GCP
Good Clinical Practice
G-CSF
granulocyte colony stimulating factor
GI
gastrointestinal
GLP
Good Laboratory Practices
GM-CSF
granulocyte macrophage-colony stimulating factor
GVHD
graft-versus-host disease
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
IMiD
immunomodulatory drugs
IMMPACT
Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials
IMWG
International Myeloma Working Group
IRB
institutional review board
IRC
independent review committee
ISS
International Staging System
ITT
intent-to-treat
IV
intravenous; intravenously
IVRS
interactive voice response system
K-M
Kaplan-Meier
LDH
lactate dehydrogenase
LMWH
low molecular weight heparin
MedDRA
Medical Dictionary for Regulatory Activities
MID
minimally important difference
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Abbreviation
Term
Millennium
Millennium Pharmaceuticals, Inc., and its affiliates
MM
multiple myeloma
MP
melphalan and prednisone
MR
minor response
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
NFKB
nuclear factor kappa-light chain enhancer of activated B cells
NSAID
nonsteroidal anti-inflammatory drugs
OME
oral morphine equivalent
ORR
overall response rate
OS
overall survival
PD
progressive disease (disease progression)
PET-CT
positron emission tomography - computed tomography
PFS
progression-free survival
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 response 
PRO
patient-reported outcome
PSMB1
Proteasome subunit beta type-1
PTCL
peripheral T-cell lymphoma
QALY
quality-adjusted life year
QD
quaque die; each day; once daily
QOL
quality of life
QTc
rate-corrected QT interval (millisec) of electrocardiograph
RP2D
recommended phase 2 dose
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Abbreviation
Term
RRAL
Relapsed or refractory Primary systemic light chain (AL) amyloidosis
RRMM
relapsed and/or refractory multiple myeloma
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
sCR
stringent complete response
SD
stable disease
SmPC
Summary of Product Characteristics
SPEP
serum protein electrophoresis
SRE
skeletal-related event
SQ
subcutaneous
T
translocation
t1/2
terminal disposition half-life
TEAE
treatment-emergent adverse event
Tmax
single-dose first time of occurrence of maximum (peak) concentration
TRAF
Tumor necrosis factor receptor-associated factor
TSH
thyroid stimulating hormone
TTP
time to progression
UK
United Kingdom
ULN
upper limit of the normal range
UPEP
urine protein electrophoresis
US
United States
VGPR
very good partial response
Vz
volume of distribution in the terminal phase
WBC
white blood cell
WHO
World Health Organization
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1.   
BACKGROUND AND STUDY RATIONALE
1.1   
Scientific Background
1.1.1   
Disease Under Treatment
Multiple myeloma (MM) is a clonal disease of plasma cells that is characterized by the 
accumulation of plasma cells in the bone marrow (and other organs) and sometimes results 
in bone marrow failure, bone destruction, hypercalcemia, 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, MM is a growing health problem with an incidence that is 
approaching western countries and a larger population base.[4,5] In the United States, 
approximately 20,000 cases of MM are diagnosed each year and 10,650 deaths per year are 
due to the disease (approximately 2% of all cancer deaths). 
Although MM is uniformly fatal, survival has dramatically improved over the last 2 decades 
because of newer and more effective treatment options. Between 1990 and 2007, the cancer 
death rate for people with MM in the United States decreased by approximately 9% for 
males and 13% for females due to introduction of stem cell transplant and novel agents 
VELCADE®, thalidomide, and lenalidomide.[6] In addition, 5-year survival improved from 
25% in 1975 to 39% in 2006 because of the development of more effective treatments.[7]
Most patients receive multiple therapies over the course of their disease; however, responses 
are transient despite the marked improvement in treatment options.
Multiple myeloma is sensitive to a number of cytotoxic drugs such as alkylating agents, 
anthracyclines, and corticosteroids for initial treatment and for relapsed disease. The last 
several years have witnessed the introduction of several agents such as VELCADE, 
thalidomide, and lenalidomide that have improved response, and contributed to the 
improved 5-year survival. VELCADE, the first proteasome inhibitor, has proven effective in 
the frontline setting including improvements in overall survival, has shown marked response 
in the relapsed setting, and is an effective agent in the pretransplant setting.
Despite the increase in the number of therapeutic options, the disease remains incurable and 
there is a need for new and better agents. Patients who relapse after their initial therapy 
demonstrate variable response to subsequent treatments with decreasing likelihood and 
duration of response (DOR). Patients ultimately become refractory to approved therapies 
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and have no alternative treatment options. In an effort to further target the proteasome with 
improved activity in MM and other cancers, Millennium has developed MLN9708, a small 
molecule 20S proteasome inhibitor.
1.1.2   
MLN9708, Millennium’s Next-Generation Proteasome Inhibitor
VELCADE (bortezomib), the first-in-class, small-molecule proteasome inhibitor developed 
by Millennium Pharmaceuticals, Inc (Millennium), validated the proteasome as a therapeutic 
target. Recognizing that proteasome inhibition is an effective anticancer therapeutic 
approach, Millennium has developed MLN9708 with the aim of improving the 
pharmacology of the agent, building on the efficacy seen with VELCADE in MM and other 
hematologic malignancies, and improving safety and convenience of drug administration.
Like VELCADE, MLN9708 is a modified peptide boronic acid analog. MLN9708 is the 
citrate ester of the biologically active dipeptide boronic acid, MLN2238. 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. 
MLN2238 is the active form that potently, reversibly, and selectively inhibits the 
proteasome. In contrast to VELCADE, MLN2238 demonstrates a faster dissociation rate 
from the proteasome that may result 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; at higher concentrations, it 
also inhibits the activity of the 1 and 2 sites. MLN2238 was selective for the proteasome 
over a panel of several proteases (IC50 values between 20 and100 M), 103 kinases 
(IC50 values > 10 M), and receptors (IC50 values > 10 M). MLN2238 and bortezomib 
have different 5 proteasome dissociation terminal disposition half-lives (t1/2), reflecting 
differences in their on-off binding kinetics (the 5 proteasome dissociation [t1/2] for 
MLN2238 and bortezomib are 18 and 110 minutes, respectively). Based on these favorable 
characteristics, MLN2238 is anticipated to be effective against MM.
1.2   
Preclinical Experience
1.2.1   
Nonclinical Pharmacology: In Vivo Studies
Antitumor activity was observed with MLN2238 in 4 xenograft models: CWR22 (a human 
prostate cancer cell line), WSU-DLCL2, OCI-Ly7-7D1-luc, and PHTX-22L (3 human 
lymphoma cell lines). In contrast, bortezomib demonstrated weaker antitumor activity in 
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these latter 3 lymphoma models, demonstrating that MLN2238 has improved activity in 
nonclinical models compared to bortezomib. MLN2238 treatment demonstrated an 
improved tumor pharmacodynamic response compared to bortezomib in WSU-DLCL2 
human diffuse large B cell lymphoma (DLBCL) xenografts. WSU-DLCL2 xenografts from 
MLN2238-treated mice displayed greater tumor 20S proteasome inhibition compared to 
xenografts from bortezomib-treated mice and demonstrated increased downstream 
biological effects, as determined by protein marker expression. 
MLN2238-treated xenografts displayed higher and more sustained 20S proteasome 
inhibition and increased downstream biological effects as determined by Growth Arrest 
DNA Damage 34 (GADD34) and Activating Transcription Factor-3 (ATF-3 levels). 
MLN2238 demonstrated both an improved efficacy profile and pharmacodynamic response 
compared to bortezomib.
Detailed information regarding the nonclinical pharmacology and toxicology of MLN9708 
may be found in the Investigator’s Brochure (IB).
1.3   
Clinical Experience
Like VELCADE, MLN9708 is a modified peptide boronic acid analog. MLN9708 is the 
first investigational oral proteasome inhibitor in clinical trials in humans with safety, 
tolerability, PK, pharmacodynamics, and disease response assessed in each study. As of 
12 October 2011, 247 patients have been treated with MLN9708 across 7 enrolling 
sponsor-led phase 1 or phase 1/2 studies with a twice-weekly and a weekly dosing schedule 
being evaluated. Regardless of the route of administration in the twice-weekly dosing 
schedule, MLN9708 is given on Days 1, 4, 8, and 11 of a 21-day cycle and, in the weekly 
dosing schedule, the drug is given on Days 1, 8, and 15 of a 28-day cycle. Details of these 
trials can be found in ClinicalTrials.gov, the current version of the IB, and the sections to 
follow. 
In addition to the trials noted above and this study, there are currently 3 planned trials, each 
of which will use the oral formulation of MLN9708:

Study C16008, oral (PO) twice-weekly administration in combination with 
lenalidomide and low-dose dexamethasone every 21 days in adult patients with 
newly diagnosed multiple myeloma (NDMM) 
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
Study C16009, PO administration on Days 1 and 15 of the first 28-day cycle to 
assess drug-drug interactions with ketoconazole, relative bioavailability, and food 
effect in patients with advanced solid tumor malignances, lymphoma, or 
Waldenstroms macroglobulinemia; PO administration in subsequent cycles on 
Days 1, 8, and 15 of a 28-day cycle
These studies are in the process of Investigational Review Board (IRB) and Ethics 
Committee reviews, but have not yet begun to enroll patients. (For additional information, 
please refer to ClinicalTrials.gov.)
Study C16011 is a phase 3 trial of weekly oral MLN9708 in combination with 
dexamethasone compared with physician’s choice of treatment from a list of defined 
chemotherapy options, which are dexamethasone alone or dexamethasone combined with 
melphalan, cyclophosphamide, thalidomide, or lenalidomide in patients with relapsed or 
refractory systemic immunoglobulin light chain (AL) amyloidosis.
Clinical Trial Experience Using the Oral Formulation of MLN9708
In the 5 studies actively enrolling patients to investigate oral MLN9708 in patients with 
differing plasma cell dyscrasias (multiple myeloma and AL amyloidosis), a total of 
115 patients have been treated thus far with different doses of MLN9708, as noted in 
Table 1-1.
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Table 1-1   
Ongoing Studies of Oral MLN9708
Trial/
Population
Description
Doses Investigated
C16003
RRMM
N = 56
PO, twice weekly (TW), single agent
0.24-2.23 mg/m2 TW
MTD: 2.0 mg/m2
DLT: rash,thrombocytopenia
C16004
RRMM
N = 32
PO, weekly (W), single agent
0.24-3.95 mg/m2 W
MTD: 2.97 mg/m2
DLT: rash, nausea, vomiting
C16005
NDMM
N = 15
PO weekly, combination with LenDex
1.68-3.95 mg/m2 W
MTD: 2.97 mg/m2
DLT: nausea, vomiting, diarrhea, syncope
RP2Da: 4.0 mg fixed (switching to fixed dosing in 
phase 2, relevant to 2.23 mg/m2)
C16006
NDMM
N = 6
PO twice weekly (Arm A) and weekly 
(Arm B), combination with melphalan 
and prednisone
Arm Aa: 3-mg fixed dose, TW: 3.7mg fixed dose
Arm Ba: 3-mg fixed dose, W: 4-mg fixed dose
C16007
RR-AL
N = 6
PO, weekly, single agent
4-5.5-mg fixed dosea W
Abbreviations: RRAL = Relapsed or refractory Primary systemic light chain (AL) amyloidosis ; BSA = 
body surface area; DLT = dose-limiting toxicity; IV = intravenously; LenDex = lenalidomide plus 
dexamethasone; NDMM = newly diagnosed multiple myeloma; PO = orally; RRMM = relapsed and/or 
refractory multiple myeloma; TW = twice weekly; W = weekly; RP2D= recommended phase 2 dose.
a Approximate BSA and flat 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.
The emerging safety profile indicates that oral MLN9708 is generally well tolerated with 
manageable and reversible treatment-emergent adverse events (TEAEs) or adverse 
reactions. As noted in Table 1-1, the maximum tolerated dose (MTD) has been established 
in 1 trial administering MLN9708 twice-weekly (Study C16003, relapsed/refractory 
multiple myeloma [RRMM]) and in 2 trials administering MLN9708 weekly as a single 
agent and in combination with lenalidomide and dexamethasone (LenDex) (Study C16004, 
RRMM and Study C16005, NDMM, respectively) with dose escalation continuing in 2 other 
enrolling studies (Study C16006, NDMM and C16007, relapsed/refractory amyloidosis 
[RRAL]). The potential risks reported with oral MLN9708 use, pooled from the enrolling 
5 phase 1 and phase 1/2 clinical studies (N = 115) are shown in Table 1-2. As of 
12 October 2011, no patient treated with the oral formulation of MLN9708 has reported 
Grade 3 peripheral neuropathy (PN); while 16% (18 patients) have reported Grade 1 or 2 PN 
with 12 of these patients reporting baseline Grade 1 neuropathy at study entry.
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Table 1-2   
MLN9708 Potential Risks (Pooled PO Formulation), as of 
12 October 2011
Adverse Drug Reactions
Thrombocytopenia
Skin rash (Includes terms: erythematous, 
generalized, pruritic, macular, macula-papular, 
papular)
Nausea, vomiting, diarrhea
Fatigue
Potential Risks Reported (> 10%) Due to MLN9708 
or Disease Under Study
Fever 
Anorexia, constipation, dehydration
Anemia, neutropenia
Headache
Upper respiratory infection, cough
Dizziness
Peripheral neuropathy
Arthralgia
Relapsed and/or Refractory Multiple Myeloma
As of 12 October 2011, 2 ongoing phase 1 clinical trials were investigating oral MLN9708 
in RRMM: Study C16003 and Study C16004. Both studies have completed the phase 1 
portion of the study and patients are enrolling into defined expansion cohorts: relapsed and 
refractory multiple myeloma, VELCADE relapsed, proteasome inhibitor naïve, or 
carfilzomib exposed. 
Study C16003 Single-agent; Twice-Weekly MLN9708
Study C16003 has enrolled 56 patients. These patients are heavily pretreated as evidenced 
by a median number of 4 (range 1–28) prior lines of therapy with 47% refractory to the last 
line of therapy.[8] Patients have received a median of 3.5 cycles of therapy (range 1-23). Six 
patients have achieved at least a partial response (PR) (1 complete response [CR] and 5 
PRs); additionally 1 patient and 28 patients achieved minor response (MR) and durable 
disease stabilization for up to 12.9 months, respectively.[8]
In Study C16003, 1 of 3 patients experienced a protocol-defined dose-limiting toxicity 
(DLT) (Grade 3 rash) at a dose of 2.23 mg/m2. An additional patient at this dose experienced 
Grade 4 thrombocytopenia (platelet count of 10,000/mm3). After a discussion with the 
participating investigators, an intermediate yet lower dose was evaluated as allowed in the 
C16003 protocol and supported by available pharmacokinetic (PK) data to further 
characterize dose-related toxicities. Six patients were treated at the intermediate dose of 
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2.0 mg/m2, a dose approximately half way between the 2 existing dose levels of 2.23 mg/m2
and 1.68 mg/m2 (a dose without any DLTs). Given that no patient (0/6) experienced a DLT, 
the MTD of PO MLN9708 administered twice weekly was determined to be 2.0 mg/m2.[8]
A summary of the safety profile of patients treated in Study C16003 is outlined in Table 1-3. 
Overall, 98% of patients experienced a TEAE of any grade and of any cause. Peripheral 
neuropathy was limited to Grade 1/2 in 10% of patients; with all of these patients reporting 
baseline Grade 1 PN at study entry.
Table 1-3   
Study C16003: Oral MLN9708, Single Agent Given Twice Weekly, in 
RRMM Most Common TEAEs as of 12 October 2011 (N = 56)
Most Common (> 20%) Any Grade and Irrespective 
of Cause
Fatigue (57%)
Skin rash (all terms) (50%)
Thrombocytopenia (41%)
Nausea (34%)
Diarrhea (36%)
Vomiting and fever (30% each)
Cough (25%)
Anorexia (23%)
Neutropenia (21%)
Drug-Related Grade 3 in 2 Patients 
Thrombocytopenia (n = 19)
Neutropenia (n = 8)
Fatigue (n = 5)
Rash (all terms) (n = 5) 
Fifteen patients have experienced drug-related serious adverse events (SAEs) involving 
thrombocytopenia, anemia, neutropenia, febrile neutropenia, nausea, vomiting, abdominal 
pain, chest pain (noncardiac), orthostatic hypotension, hypotension, hypophosphatemia, 
hyperuricemia, febrile neutropenia, fever, chills, rash, pneumonia, hypoxia, pulmonary 
hypertension, fall, headache, fatigue, or dehydration. Five patients discontinued therapy due 
to a TEAE; 3 patients due to events considered at least possibly related to MLN9708 
(thrombocytopenia, pulmonary hypertension, and pruritic rash) and 2 patients due to events 
related to disease progression (spinal cord compression and bone pain). There have been 
2 on-study deaths reported as not related to study drug.[8]
Study C16004 Single-agent; Weekly MLN9708
As of 12 October 2011, 28 patients have been enrolled in the dose escalation phase of Study 
C16004, in which MLN9708 is administered weekly. These patients are heavily pretreated 
as evidenced by a median number of 5 (range 2–15) prior lines of therapy with 59% 
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refractory to the last line of therapy.[9] Patients have received a median of 2 cycles of 
therapy (range 1-11). Two patients have achieved objective response: 1 achieved a VGPR 
and 1 achieved a PR. Additionally 6 patients achieved durable disease stabilization for up to 
9.5 months. At data cut-off, 2 patients remain on treatment; discontinuation was mainly due 
to progressive disease (PD) (69%).[9]
In Study C16004, 2 of 3 patients experienced protocol-defined DLT (Grade 3 rash and 
Grade 3 nausea, vomiting, and diarrhea) at a dose of 3.95 mg/m2. As per protocol, 
subsequent patients were treated at 1 dose level below (2.97 mg/m2) where 1 of 6 patients 
experienced a DLT (Grade 3 nausea, vomiting, and diarrhea). The MTD of weekly oral 
MLN9708 was determined to be 2.97 mg/m2. This dose cohort is currently being expanded 
to further evaluate the safety and activity of MLN9708.[9]
A summary of the safety profile of patients treated in Study C16004 (28 patients in the dose 
escalation phase and 4 in the extension phase) is outlined in Table 1-4. Overall, 97% of 
patients experienced a TEAE of any grade and of any cause. Peripheral neuropathy was 
limited to Grade 1/2 in 3 patients; with all patients reporting baseline Grade 1 PN at study 
entry.
Table 1-4   
Study C16004: Oral MLN9708, Single Agent Given Weekly, Most 
Common TEAE as of 12 October 2011 (N = 32)
Most Common (> 20%) Any Grade and Irrespective 
of Cause
Fatigue (50%)
Thrombocytopenia (34%)
Nausea (38%)
Diarrhea (31%)
Vomiting (28%)
Drug-Related Grade 3 in 2 Patients 
Thrombocytopenia (n = 4; 1 Grade 4 and 3 Grade 3)
Neutropenia and diarrhea (n = 3 each) 
There have been 2 drug-related SAEs involving diarrhea, dehydration, and dizziness. Six 
patients discontinued therapy due to a TEAE considered at least possibly related to 
MLN9708 (thrombocytopenia, rash, neutropenia, diarrhea, nausea, vomiting, and abdominal 
pain). There has been 1 on-study death reported which was considered related to disease 
progression.[9]
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Newly Diagnosed Multiple Myeloma
As of 12 Oct 2011, 2 ongoing phase 1/2 clinical trials are investigating oral MLN9708 in 
NDMM: Study C16005 and Study C16006.
In Study C16005, MLN9708 is given weekly (Days 1, 8, and 15) in combination with 
lenalidomide (Days 1-21) and dexamethasone (Days 1, 8, 15, and 22) in a 28-day cycle. 
Enrollment to the phase 1 portion of the study is complete, with enrollment open to the 
phase 2 portion. This study has enrolled 15 patients as of the clinical data cut (12 Oct 2011) 
to 4 dose cohorts. No DLTs were seen at doses up to 2.23 mg/m2. Three of 3 patients treated 
at the 3.95 mg/m2 dose cohort experienced Grade 3 nausea and vomiting despite adequate 
anti-emetic therapy; 1 of which additionally experienced Grade 2 syncope and in another 
patient the dose of lenalidomide was compromised such that they received < 80% of the 
planned doses. As per protocol, subsequent patients were treated at 1 dose level below 
(2.97 mg/m2) where 1 of 6 patients experienced a DLT (Grade 3 rash). The MTD of weekly 
MLN9708 in combination with a 28-day cycle of lenalidomide and dexamethasone was 
established at 2.97 mg/m2. The recommended phase 2 dose (RP2D) estimation was 
established following evaluation of the available data from the phase 1 portion of the trial 
which included, but was not limited to analyses of efficacy results and toxicity 
characterization (Grade 3/4 AEs, SAEs, all grades peripheral neuropathy, and treatment 
discontinuation). Based on this review the RP2D dose was determined to be 2.23 mg/m2 in 
this combination schedule. The clinical development of MLN9708 included a population PK 
analysis evaluating the feasibility of switching from body surface area (BSA)-based dosing 
to fixed dosing.[10] The results of this analysis support the transition from BSA-based 
dosing to fixed dosing. Therefore, in Study C16005, all patients treated in the phase 2 
portion of the trial will receive oral MLN9708 at a fixed dose of 4.0 mg (the RP2D dose of 
2.23 mg/m2 x the mean patient BSA of 1.86 m2.[11]
As of 12 October 2011, patients in Study C16005 have completed a median of 5 cycles 
(range 1-9). To date, all 15 response-evaluable patients have achieved a PR or better to 
therapy including 4 CRs, 4 VGPRs, and 7 PRs; 14 out of 15 patients achieved PR after 
Cycle 1, and all 15 achieved PR after Cycle 2.[11]
A summary of the safety profile of patients treated in Study C16005 is outlined in Table 1-5. 
Overall, 100% of patients experienced a TEAE of any grade and of any cause. Peripheral 
neuropathy was limited to Grade 1 or 2 in 3 patients.
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Table 1-5   
Study C16005: Oral MLN9708 Given Weekly in Combination With 
Lenalidomide and Dexamethasone, Most Common TEAEs as of 
12 Oct 2011 (N = 15)
Most Common (> 20%) Any Grade and Irrespective 
of Cause
Fatigue (60%)
Vomiting (53%)
Anemia (40%)
Diarrhea and nausea (33% each)
Insomnia, peripheral edema, and thrombocytopenia 
(27%)
Drug-Relateda Grade 3 in 2 Patients 
Rash and vomiting (n = 2 each)
a Related means to ANY drug in the study drug combination.
There have not been any on-study deaths. One patient discontinued study drug due to an 
unrelated TEAE. Four patients have experienced drug-related SAEs involving nausea, 
vomiting, dehydration, dizziness, fainting, orthostatic hypotension, hypotension, deep vein 
thrombosis (DVT), atrial fibrillation, and muscle weakness.[11]
An additional study, Study C16006, is being conducted in patients with newly diagnosed 
multiple myeloma, investigating oral MLN9708 in combination with melphalan and 
prednisone. In this study, oral MLN9708 is being administered in 2 schedules: twice-weekly 
and weekly. On the twice-weekly schedule, MLN9708 is administered twice weekly 
(Days 1, 4, 8, 11, 22, 25, 29, and 32) with melphalan and prednisone (MP, Days 1-4) in a 
42-day cycle. On the weekly schedule, MLN9708 is given weekly (Days 1, 8, and 15) with 
melphalan and prednisone (Days 1-4) in a 28-day cycle. This study recently started to enroll 
patients. Six patients, 3 in each treatment group, have been treated as of 12 October 2011; all 
patients received a fixed starting dose of 3.0 mg with standard dose MP. Early signs of 
activity were observed. No SAEs, study drug discontinuations due to TEAE, or deaths have 
been reported to date.
Relapsed or Refractory Systemic Light Chain (AL) Amyloidosis
Study C16007 is evaluating single-agent, weekly, oral dosing in patients with relapsed or 
refractory AL amyloidosis after at least 1 prior therapy. This study is currently enrolling 
patients in the phase 1 portion of the trial. 
As of 12 October 2011, 6 patients have been treated at the first dose level in the dose 
escalation portion of Study C16007. One of the first 3 patients experienced 
thrombocytopenia that lasted more than 2 weeks (meeting the definition of a DLT due to the 
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delay in starting Cycle 2 for 2 weeks). The prolonged thrombocytopenia was thought to be 
due to the patient’s underlying bone marrow reserve, as the platelet count did return to the 
patient’s baseline level but not to levels defined by the protocol. As per protocol, 
3 additional patients were treated at this first dose level without additional dose-limiting 
toxicity (DLT); thus, the dose of MLN9708 will be escalated in the next 3 patients. Early 
signs of activity were reported, including 3 of 6 patients with partial hematologic response 
after the first cycle. As of the data cut, best clinical responses include 2 hematologic VGPR, 
1 hematologic PR, and stable hematologic disease after 1 cycle of therapy in 3 patients. 
TEAEs, irrespective of grade or causality, occurring in more than 1 patient include diarrhea 
and peripheral edema (3 patients each); anemia, fatigue, nausea, and thrombocytopenia 
(2 patients each). No TEAEs have resulted in study drug discontinuation. No deaths have 
been reported. 
Clinical Trial Experience Using the IV Formulation of MLN9708
There are 2 ongoing studies investigating intravenous (IV) MLN9708 in advanced solid 
tumors and advanced lymphoma (Studies C16001 and C16002, respectively). As of 
12 October 2011, a total of 132 patients had been treated in these studies. Refer to the 
current version of the IB for more information about the potential adverse events of the IV 
formulation. Dose-limiting toxicities and preliminary observations of response as evidenced 
by at least a 50% reduction in disease burden have been reported as follows:
C16001 Solid Tumors, Twice-weekly, Single Agent (N = 111): 

DLT: rash, thrombocytopenia, and acute renal failure  

Doses investigated: 0.125 to 2.34 mg/m2

MTD: 1.76 mg/m2

Objective Response: 1 partial response in a patient with head and neck carcinoma 
[12]
C16002 Lymphoma, Weekly, Single Agent (N = 21): 

DLT: neutropenia

Doses investigated: 0.125 to 2.34 mg/m2 with enrollment currently open at 
3.11 mg/m2
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
Objective Response: 3 PR (2 in patients with follicular cell lymphoma and 1 in a
patient with peripheral T-cell lymphoma [PTCL]) [13]
Clinical Trial Safety Experience: Pooled IV and Oral Formulation
The potential risks reported with MLN9708 use, pooled from both IV and oral formulations, 
were anticipated based on preclinical data and previous experience with VELCADE and are 
noted in the MLN9708 IB and informed consent form (ICF) documents. The type of TEAE 
reported is consistent, regardless of the MLN9708 formulation, even though there are some 
differences in the frequency and severity of the reported events. While the predominant 
potential toxicities may be severe in some cases, they are largely reversible and can be 
managed by routine clinical monitoring and standard medical interventions, which may 
include dose reductions and supportive care. Please refer to the IB for further information.
1.4   
Study Rationale
Despite clinical advantages provided by the proteasome inhibitor VELCADE and 
immunomodulatory (IMiD) agents thalidomide and lenalidomide in both previously 
untreated and treated patients with MM, the disease remains incurable.[14] Although 
multiple therapies are available for RRMM patients, the frequent relapses that characterize 
this disease highlight a need for new therapies for patients in whom prior treatments have 
failed. This study is designed to determine whether adding MLN9708 to a background
therapy of lenalidomide and dexamethasone will improve the clinical outcomes of patients 
with RRMM.
1.4.1   
Rationale for the Combination of MLN9708, Lenalidomide, and 
Dexamethasone
Clinical data support the combination of a proteasome inhibitor, an IMiD, and a 
glucocorticosteroid. The combination of bortezomib, lenalidomide, and low-dose 
dexamethasone, as noted in clinical studies and the National Comprehensive Cancer 
Network (NCCN) guidelines, illustrates that this combination is very active and well 
tolerated in the MM population.[15-18] From a clinical perspective, adding proteasome 
inhibitors to lenalidomide and dexamethasone has demonstrated significant synergistic 
effects.[8,17]
Recognizing that proteasome inhibition is an effective anticancer therapeutic approach, 
Millennium developed MLN9708, which is a modified dipeptide boronic acid proteasome 
inhibitor similar to VELCADE, with the aim of improving the pharmacology of the agent 
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and improving drug administration, while building on the efficacy seen with VELCADE. 
Given that MLN9708 has improved binding kinetics and a similar pharmacologic profile 
compared with VELCADE, it is expected that these differences will translate into similar, if 
not improved, efficacy and safety profiles.[19] Nonclinical work by Chauhan and colleagues 
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-MM activity.[20]
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 TEAEs, 
regardless of causality, of single-agent MLN9708 across all dose level cohorts 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 data, the 
similar nonclinical toxicity profile between MLN2238 and bortezomib, and the toxicities 
demonstrated in studies with lenalidomide and dexamethasone and the low potential for 
drug-drug interactions, 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 laboratory tests.
Patients enrolled in both arms of C16010 will receive lenalidomide and dexamethasone, one 
of several regimens recommended by the International Myeloma Working Group (IMWG) 
as well as the NCCN. While initial data from ongoing trials are promising regarding the 
addition of bortezomib to this regimen, longer follow up and data from randomized phase III 
studies are still needed before bortezomib is broadly incorporated into treatment 
recommendations.[21]
This study is proposed based on the results of VELCADE in previously treated MM,[22] the 
emerging activity seen with MLN9708 in the treatment of previously treated and untreated 
MM (see Section 1.3), and the urgent need for better treatment options for this incurable 
disease. This study is designed to determine the efficacy and safety of MLN9708 with 
lenalidomide and dexamethasone, compared with lenalidomide and dexamethasone alone in 
patients with relapsed and/or refractory MM. The primary purpose of this study is to 
determine the progression-free survival of patients in the 2 treatment groups. 
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1.4.2   
Rationale for MLN9708, Lenalidomide, and Dexamethasone Dose and 
Schedule Selection
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 
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. Study C16004, a phase 1 study in 
adult patients with RRMM, investigated single-agent MLN9708 in this weekly schedule. 
The estimated MTD is 2.97 mg/m2 with DLTs of transient rash, nausea, and vomiting. 
Given that the weekly schedule of MLN9708 combines well with the established 28-day 
lenalidomide plus low-dose dexamethasone regimen providing a simple course of therapy 
for patients, Study C16005, a phase 1/2 study of weekly MLN9708 plus a 28-day cycle of 
lenalidomide (25 mg on Days 1-21) and dexamethasone (40 mg weekly on Days 1, 8, 15, 
and 22) was initiated. 
In the phase 1 portion of Study C16005, 3 evaluable patients were enrolled in each of the 
following dose cohorts: Cohort 1 (1.68 mg/m2), Cohort 2 (2.23 mg/m2), and Cohort 3 
(2.97 mg/m2), respectively. There were no DLTs noted for any of these patients during 
Cycle 1. Three evaluable patients were enrolled in Cohort 4 (3.95 mg/m2). DLTs were noted 
during Cycle 1 for 3 out of 3 patients in Cohort 4 at the 3.95-mg/m2 dose level. The DLTs 
were Grade 3 fainting/passing out, nausea, vomiting, and diarrhea. Per protocol, dosing at 
the 3.95-mg/m2 dose level was stopped. Since 6 patients were not enrolled at the previous 
dose level (2.97 mg/m2), 3 additional patients were enrolled at this lower dose. One of the 
additional 3 patients had a DLT of Grade 3 rash during Cycle 1. Therefore, DLTs were 
noted for 1 out of 6 patients enrolled at the 2.97-mg/m2 dose level; according to the protocol, 
2.97 mg/m2 was determined as MTD. 
The clinical data were evaluated for the available phase 1 data, which included the analyses 
of efficacy results (response rates: PR, VGPR, and CR) and toxicity characterization 
(Grade 3/4 AEs, SAEs, all grades peripheral neuropathy, dose holding, and treatment 
discontinuation). Cycle 1 data from 15 evaluable patients were reviewed, as well as the 
available clinical data supporting tolerance over multiple treatment cycles. AEs that met 
DLT criteria in Cycle 2 and beyond were considered, and toxicities leading to dose 
modification in Cycle 2 and beyond were also considered.
Six patients were enrolled at the 2.97-mg/m2 dose level. All 6 patients received all doses of 
MLN9708 and dexamethasone during Cycle 1. However, 3 out of 6 patients were not able to 
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receive all of their lenalidomide doses during Cycle 1 due to Grade 2 or 3 rash. Three 
patients were enrolled at the 2.23-mg/m2 dose level. All 3 patients received all doses of 
MLN9708, dexamethasone, and lenalidomide during Cycles 1 through 3, except 1 patient 
who did not receive 1 dose of dexamethasone during Cycle 2. After 4 cycles of treatment, 
the patients enrolled at 2.23 mg/m2 achieved responses of CR, PR, and VGPR, respectively. 
All 3 patients achieved PR after Cycle 1, 2 of them achieved VGPR after Cycle 2, and CR 
after Cycle 4 and Cycle 5. Given that the dose of MLN9708 at 2.97 mg/m2 significantly 
compromised the doses of the lenalidomide and dexamethasone background regimen, and 
that the dose of 2.23 mg/m2 is very tolerable and clinically active, the clinical team has 
proposed to use 2.23 mg/m2 as the dose for the pivotal phase 3 trial. More data will be 
gained from the phase 2 cohort of the ongoing C16005 study, in which patients will receive 
MLN9708 at 2.23 mg/m2. 
This recommended starting dose of 2.23 mg/m2 is translated into a fixed dose of 4.0 mg 
based on the results from the population PK analysis. At initiation of clinical development of 
MLN9708, early phase 1 clinical studies empirically used a BSA-based dosing approach that 
has been traditionally used in the development of cytotoxic anticancer agents. Accordingly, 
dosing of MLN9708 in individual patients was BSA-scaled (in mg/m2) in Study C16005 and 
in 4 ongoing single-agent trials (Studies C16001, C16002, C16003, and C16004). However, 
it is well known that the clearance of small molecule drugs is typically not a linear function 
of BSA and the appropriateness of traditional BSA-scaled approaches for dosing anticancer 
agents has been critically questioned in the recent scientific literature.[23-26]
Therefore, a preliminary population PK analysis was performed for MLN9708 based on the
available data from 4 ongoing phase 1 studies to quantitatively assess the contribution of 
interpatient variability in BSA to the overall interpatient variability in clearance of 
MLN9708, and thereby evaluate the feasibility of switching from BSA-based dosing to fixed 
dosing in future clinical development. A population PK model was built using data from 
both the twice-weekly and once-weekly 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 data. Covariate analyses indicate that 
interpatient variability in BSA, and/or body weight did not significantly contribute to the 
variability in clearance (CL) and volume of distribution (V2) in the central compartment. 
Clearance and volume of distribution in the central compartment (V2) are the PK parameters 
that will affect AUC and single-dose maximum (peak) concentration (Cmax). The lack of a 
discernable relationship between BSA and MLN9708 clearance based on data in 
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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). Therefore, BSA is not expected to affect Cmax or AUC after IV or oral 
dosing, and thus fixed dosing is appropriate for both oral and IV routes of administration. 
The clinical development of MLN9708 has therefore transitioned from use of BSA-based 
dosing to fixed dosing in all recently initiated phase 1/2 studies (eg, Studies C16007, 
C16008, and C16009).
Accordingly, the starting dose of MLN9708 in the proposed phase 3 study 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 patients with MM in VELCADE clinical trials for conversion to a fixed 
dose).
Figure 1-1   
No Apparent Relationship Between MLN9708 Clearance and BSA
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.
1.4.3   
Rationale for the Molecular Analyses
The heterogeneity of clinical results with myeloma therapeutics is, in large part, related to 
variation in the molecular subtypes of myeloma and the complex interaction of each tumor 
with the biology of the host. Several clinical studies have shown that tumor biology can be 
directly related to the clinical efficacy of either multidrug combinations in myeloma (a 
validated gene expression model of high-risk MM is defined by deregulated expression of 
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
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
111
1
1
11
1
1
1
1
1
1
1
1
1
1
1
1
1
1
11
1
1
1
1
1
1
1
1
1
1
11
1
1
1
1
2
2
2
22
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
33
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
33
3
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
1
16001
2
16002
3
16003
4
16004
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genes mapping to chromosome 1 [27-29] or to outcome after single-agent VELCADE 
therapy).[30,31] These studies highlight links between TRAF3, a key regulator of the NFKB 
pathway, and protein synthesis with clinical sensitivity and resistance respectively to 
VELCADE. A recent whole genome sequencing study of MM patients reported the presence 
of mutations in known cancer genes that had either not previously been reported in MM 
such as BRAF, or that were present at much higher frequency in MM than previously 
reported (KRAS, NRAS).[32] Similar studies with samples from VELCADE clinical trials 
highlighted the link between mutations in these pathways and response to proteasome 
inhibitor.[33]
In this clinical study, a screening tumor sample will be collected from each patient to test the 
link between clinical outcomes and the presence of specific gene mutations of the RAF/RAS 
pathway, as well as to test if expression of NFKB or protein synthesis gene signatures are 
related to the efficacy of the MLN9708-based combination. This hypothesis will be tested in 
all patients. Additional analyses of tumor molecular characteristics may be done to identify 
biomarkers linked to clinical outcomes in this study. These tumor analyses may include but 
are not limited to gene expression, DNA mutations, and/or epigenetic factors. Similar 
analyses will be done in tumor samples from patients who initially responded to therapy and 
subsequently relapsed.
Recent data also identify host variation, specifically germline DNA variants in proteasome 
subunits [34] and the NFKB pathway [35] as important contributors to VELCADE clinical 
activity. A blood sample will be collected at screening in order to test if specific 
polymorphisms in proteasome-related genes are associated with MLN9708 efficacy. 
Variants in NFKB-related genes will also be assessed, as they may relate to the activation of 
the NFKB pathway in the tumor or in the host microenvironment, impacting the growth, 
survival, and/or drug resistance of a given patient’s myeloma. 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.
Circulating proteasome levels have been demonstrated to be an independent prognostic 
factor in MM patients with increasing circulating proteasome levels correlating with 
advance disease.[36] Given that MLN9708 directly targets the 20S proteasome, this leads to 
the possibility that pretreatment circulating proteasome levels may be relevant for prediction 
of patient response to therapy. Retrospective analysis of baseline proteasome levels from 
clinical trial samples for patients treated with bortezomib in combination with melphalan 
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and prednisone demonstrated that circulating proteasome levels were associated with both 
overall survival (OS) and progression free survival (PFS) only for bortezomib-containing 
therapy leading to the possibility that high-circulating protesome levels could be both a poor 
prognostic and also a specific marker of poor outcome with bortezomib. These data point to 
the potential value of further exploring the relationship between predose circulating 
proteasome levels and response to MLN9708. In this study, a blood sample will be collected 
at screening in order to test the levels of circulating proteasome and its association to 
MLN9708 efficacy.
1.4.4   
Rationale for the Combination of MLN9708, Lenalidomide, and 
Dexamethasone in a High-Risk Patient Population 
The clinical outcome of relapsed myeloma 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(17p), and 
amplification of 1q impart an unfavorable prognosis.[37] Recently Klein et al and Bahlis 
et al have described the outcome of these subtypes in the context of patients with relapsed or 
refractory MM treated with lenalidomide and dexamethasone. Both del(17) and 
amplification 1q21 were associated with significantly worse PFS and OS, and the median 
OS for the del(17) patients was only 6.7 months.[38] Two recent reports showed that 
bortezomib-based treatment improves outcome in patients with MM including patients with 
high-risk chromosomal aberrations).[39,40] Patients with del(17) had a notable benefit. The 
median PFS time was 26.2 months for the bortezomib arm versus 12 months for the standard 
arm (p = 0.024), while the 3-year OS rate in this subtype improved from 17% to 69% 
(p = 0.028). After multivariate analysis, del(17) was an independent predictor for PFS 
(p < 0.0001) and OS (p < 0.0001) only in the bortezomib arm. In light of these observations, 
this study will assess the outcome of patients with del(17) RRMM to determine if addition 
of MLN9708 to lenalidomide and dexamethasone improves PFS and OS.
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2.   
STUDY OBJECTIVES
Note that the primary objective and corresponding endpoint have been met. Upon 
implementation of Amendment 8, the objective is to continue to collect long-term safety 
data from patients who are continuing on ixazomib (MLN9708) and LenDex or LenDex 
(note the placebo capsule will be discontinued) because of continuing clinical benefit. Data 
collection for all other study objectives and endpoints will be complete at the time of the 
final analysis and no further formal analyses will be conducted. The original lists of 
objectives are retained below for reference only.
2.1   
Primary Objective
The primary objective of this study is:

To determine whether the addition of oral MLN9708 to the background therapy of 
lenalidomide and dexamethasone improves PFS in patients with RRMM
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 OS in high-risk patients carrying deletion del(17)
Other secondary objectives include:

To determine overall response rate (ORR), including PR, VGPR, and CR

To determine CR + VGPR

To determine DOR

To determine time to progression (TTP)

To determine the safety of the addition of MLN9708 to lenalidomide and 
dexamethasone 

To determine pain response rate, as assessed by the BPI-SF and analgesic use
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!
To assess change in global health status as measured by the global heath 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 such as 
translocations t(4;14), t(14;16), +1q, del(13), or del(17)
!
To evaluate the potential relationship between response or resistance to MLN9708 
treatment and proteasome and NFKB-related genes, such as PSMB1 and TRAF-3, in 
blood samples
!
To collect PK data to contribute to population PK analyses
Prop
 the Applicable Terms of Use
MLN9
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3.   
STUDY ENDPOINTS
Note that the primary endpoint has been met. Upon implementation of Amendment 8, 
evaluation of the safety profile of MLN9708 and/or LenDex is the only endpoint being 
assessed. Analysis of all other study endpoints will be complete at the final analysis and no 
further formal statistical analyses will be performed. 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 IMWG 
criteria as evaluated by an independent review committee (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
!
OS in high-risk patients carrying del(17)
Other secondary endpoints are:
!
Overall response rate (CR + VGPR + PR) 
!
CR + VGPR rate
!
Duration of response, measured as the time from the date of first documentation of 
response to the date of first documented progression
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!
Time to progression, measured as the time from randomization to the date of first 
documented progression
!
Eastern Cooperative Oncology Group (ECOG) performance scores, AEs, SAEs, and 
assessments of clinical laboratory values
!
Pain response rate, measured by the proportion of pain responders, as determined by
the BPI-SF and analgesic use
!
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
!
OS and PFS in high-risk population carrying del(13), del(17), +1q21, t(4;14), or 
t(14;16)
!
Association between response or resistance to MLN9708 treatment and proteasome 
and NFKB-related genes, such as PSMB1 and TRAF-3
!
Plasma concentration-time data to contribute to future population PK analysis
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4.  
STUDY DESIGN 
MLN9708 capsules and placebo capsules will be subsequently referred to as study drug.
4.1   
Overview of Study Design
This is a phase 3, randomized, double-blind, multicenter study to evaluate the safety and 
efficacy of MLN9708 versus placebo in patients with relapsed and/or refractory MM who 
are treated with lenalidomide and dexamethasone as their standard therapy. The patient 
population will consist of adult men and women who have a confirmed diagnosis of MM, 
who have received 1 to 3 prior lines of therapy, and who meet other eligibility criteria (see 
Section 5). Approximately 703 patients will be enrolled in the study. 
The following paragraphs describe the study design before implementation of 
Amendment 8.
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. An MPI/designee clinician will confirm patient eligibility prior to 
randomization. Determination of disease progression as an entry criterion may be based 
on patient data obtained during or following the patient’s most recent prior 
antineoplastic therapy.
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, stratified by: 1 versus 2 or 3 prior therapies, 
proteasome-inhibitor exposed versus proteasome-inhibitor naïve, and ISS stage at 
screening of 1 or 2 versus stage 3.
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 Days 1, 8, 15, and 22 of a 28-day cycle. Patients may continue to receive 
treatment until PD or unacceptable toxicity, whichever comes first. Dose modifications 
may be made 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 
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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.
Treatment periods will be defined as 28-day cycles. Patients will be seen at regular 
treatment cycle intervals while they are participating in the study: twice a treatment 
cycle for the first 3 cycles, then once a treatment cycle for the remainder of their 
participation in the active treatment and, if applicable, the PFS (every 4 weeks) and OS 
(every 12 weeks) follow-up phases of the study. As of Amendment 6, the primary 
endpoint has been met; as such, the PFS follow-up phase no longer applies to patients 
currently receiving study therapy or to any patients who have discontinued treatment for 
reasons other than PD. However, all patients will continue to be followed for survival.
Patients will be assessed for disease response and progression by an IRC. Response will 
be assessed according to the IMWG criteria for all patients every 4 weeks until disease 
progression. As of Amendment 6, however, because PFS follow-up is now completed 
for this study, for all patients still receiving study therapy, all central and investigator 
assessments of response and progression for protocol purposes will be discontinued—
IRC review will no longer be performed, and IRC response will no longer be assessed.
All patients will continue to be followed for survival after progression or after 
discontinuation of treatment for reasons other than progression. Patients will be 
contacted every 12 weeks until death or termination of the study by the sponsor.
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 prior therapy or 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 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 elucidate 
the effects of disease on physical, social, psychological/emotional, and cognitive 
functioning.
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ECOG performance score, adverse events (AEs), laboratory values, and vital sign 
measurements will be collected and assessed to evaluate the safety of therapy throughout 
the study. 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 End of Treatment (EOT) visit approximately 30 days after 
receiving their last dose of study drug and will continue to be followed for other follow-
up assessments specified in the Schedule of Events. Patients discontinuing study drug 
prior to disease progression will continue to be assessed for disease progression during 
the PFS follow-up portion of the study. All patients will now only be followed for 
survival after treatment termination or progression. Patients will be contacted every 12 
weeks until death or termination of the study by the sponsor.
The final analysis data cutoff has been conducted. Upon implementation of Amendment 8,
the investigator will unblind all patients remaining on study treatment and will follow the 
new Schedule of Events presented in this amendment. Only patients who continue to 
demonstrate clinical benefit but who do not have other means of access to the study drugs 
will continue on the study. Because no further formal statistical analyses will be performed, 
only assessments contributing to long-term safety monitoring are required. Most study 
assessments besides safety are discontinued to ease the burden of protocol-mandated 
assessments on patients.
Patients continuing their current study treatment may do so until such time as other means of 
accessing the study drugs are arranged. When possible, patients should complete an EOT 
visit and transition onto an alternative supply of (eg, commercially available) ixazomib 
and/or LenDex, or onto another standard of care treatment. Discontinued patients will be 
treated by their physician per local standard of care.
Patients who are receiving ixazomib plus LenDex will continue to receive ixazomib plus 
LenDex. Patients who are receiving placebo plus LenDex will receive LenDex only; the 
placebo capsule will no longer be administered and patients receiving placebo will not be 
crossed over to ixazomib in this study. Upon implementation of Amendment 8, data 
collection requirements will be limited to collection of AEs, SAEs, local laboratory 
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assessments of safety, physical examinations, and concomitant medications. Quality of life, 
health care utilization, EQ-5D, and pain assessments are discontinued. Survival data will no 
longer be collected because the analysis of OS will be complete at the time of the final 
analysis. Other study assessments are no longer required, as noted in the new Schedule of 
Events. Patients will not be followed for the OS follow-up period because OS data are no 
longer being collected.
Three interim analyses (IAs) have been planned during the study. The first will occur when 
approximately 262 patients have experienced disease progression or death. This is the first 
analysis for PFS and the first IA for OS. The second IA will occur when approximately 
365 patients have experienced disease progression or death. This is the final analysis for PFS 
and the second IA for OS. If the test for PFS at the second IA is not statistically significant, 
the study will be claimed as unsuccessful and no further testing will be conducted. If the test 
for PFS is significant at either of the first two IAs, OS will be tested; however, the study will 
not be stopped for OS efficacy or futility due to the predicted small number of death events 
at the first IA. 
As of Amendment 8, the 3 IAs have been performed. The primary analysis (data cutoff date, 
30 October 2014) occurred when 286 patients had experienced disease progression or death; 
at this analysis, the primary endpoint of PFS was met. The next analysis (data cutoff date, 12 
July 2015) occurred when 372 patients had experienced disease progression or death. This 
was the first analysis for OS. A total of 171 deaths had been reported and the threshold for 
OS statistical significance was not met. Per the study design and statistical analysis plan, the 
study was to continue, following patients for survival. The third IA (data cutoff date, 25 
October 2017) occurred when 333 deaths had been reported. The threshold for statistical 
significance was not met and the study was to continue to the final analysis. The final 
analysis occurred in the fourth quarter of 2020. 
An independent data monitoring committee (IDMC) will review safety and efficacy data at
the IAs. See Section 9.3 for more information. 
4.2   
Number of Patients
Approximately 703 patients will be enrolled in this study from approximately 150 study 
centers globally.
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4.3   
Duration of Study
Patients will be followed up until 486 deaths have been reported. The duration of the study 
will be approximately 80 months (6 years 8 months), including 20 months for enrollment 
and 60 months follow-up from the last patient enrolled.
Patients may remain on treatment until the occurrence of PD or unacceptable toxicity. 
Delayed treatment-related AEs will be followed for 30 days after last dose of study drug. 
Patients who stop treatment for any reason other than disease progression will continue in 
PFS follow-up and be seen every 4 weeks until documented disease progression. After 
disease progression all patients will continue to the overall survival follow-up phase and be 
contacted every 12 weeks. 
Upon implementation of Amendment 8, only patients who continue to demonstrate clinical 
benefit but who do not have other means of access to the study drugs will continue on the 
study. Patients continuing their current study treatment may do so until such time as other 
means of accessing the study drugs are arranged. When possible, patients should complete 
an End of Treatment (EOT) visit and transition onto an alternative supply of (eg, 
commercially available) ixazomib and/or LenDex, or onto another standard of care 
treatment. Discontinued patients will be treated by their physician per local standard of care.
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5.   
STUDY POPULATION
Adult patients with a confirmed diagnosis of MM and relapsed and/or refractory disease will 
be enrolled in this study.
5.1   
Inclusion Criteria
To be eligible for this study, a prospective patient must meet each of the following main 
criteria:
1. Male or female patients 18 years of age or older.
2. Multiple myeloma diagnosed according to standard criteria either currently or at the 
time of initial diagnosis (see Section 15.2 for standard criteria). 
NOTE: The initial diagnosis must be symptomatic MM, although the relapsed 
disease does not need to be symptomatic.
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 with relapsed and/or refractory MM who have received 1 to 3 prior 
therapies.
NOTE: This patient population includes the following 3 categories of patients:

Patients who relapsed from their previous treatment(s) but were not refractory to 
any previous treatment.

Patients who were refractory to all lines of previous treatment(s) (ie, patients who 
have never responded to any therapies received).

Patients who were relapsed from at least 1 previous treatment AND additionally 
were refractory to at least 1 previous treatment. For the purposes of this study, 
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refractory disease is defined as disease progression on treatment or progression 
within 60 days after the last dose of a given therapy. 
A line of therapy is defined as 1 or more cycles of a planned treatment program. This 
may consist of 1 or more planned cycles of single-agent therapy or combination 
therapy, as well as a sequence of treatments administered in a planned manner. For
example, a planned treatment approach of induction therapy followed by autologous 
stem cell transplantation, followed by maintenance is considered 1 line of 
therapy.[42] Autologous and allogenic transplants are permitted.
5. 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
NOTE: 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.
6. ECOG performance status of 0, 1, or 2.
7. Patients who received prior allogenic transplant must have no active 
graft-versus-host disease (GVHD).
8. Female patients who:

Are postmenopausal for at least 24 months before the screening visit, OR
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
Are surgically sterile, OR

Females of childbearing potential (FCBP – see Section 6.9 for definition) must: 
1. Have a negative pregnancy test with a sensitivity of at least 25 mIU/mL 
within 10 to 14 days and again within 24 hours prior to starting Cycle 1 of 
lenalidomide
2. 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 TIME, at least 28 days 
before starting study drug through 90 days after the last dose of study
treatment
3. Agree to ongoing pregnancy testing
4. Adhere to the guidelines of the RevAssist program (United States [US] 
participants), RevAid program (Canadian participants), iAccess program 
(Australian participants), RevMate program (Japanese participants) or 
The Lenalidomide Pregnancy Risk Minimisation Plan as outlined  in the 
Study Manual (all other participants who are not using commercial 
supplies)
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 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 RevAssist program (US participants), RevAid 
program (Canadian participants), iAccess  program (Australian participants), 
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RevMate program (Japanese participants) or The Lenalidomide Pregnancy Risk 
Minimisation Plan as outlined in the study Manual (all other participants who are 
not using commercial supplies)
9. Must be able to take concurrent aspirin 81 to 325 mg daily (or enoxaparin 40 mg 
subcutaneously daily [or its equivalent] if allergic to aspirin), per published standard 
or institutional standard of care, as prophylactic anticoagulation.
NOTE: For patients with prior history of DVT, low molecular weight heparin 
(LMWH) is mandatory. (See Section 6.10 for thromboembolism prophylaxis.) 
10. 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.
11. 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 in the 
study:
1. Patient was refractory to lenalidomide or proteasome inhibitor-based therapy at any 
line.
NOTE: Refractory disease defined as disease progression on treatment or 
progression within 60 days after the last dose of a given therapy. Patients who 
progress after 60 days from the last dose of a given therapy will be considered 
relapsed and are eligible for inclusion in the study.
Patients who were refractory to thalidomide-based therapy are eligible.
2. Female patients who are breast feeding or pregnant.
3. Failure to have fully recovered (ie, Grade 1 toxicity) from the effects of prior 
chemotherapy (except for alopecia) regardless of the interval since last treatment.
4. Major surgery within 14 days before randomization.
5. Radiotherapy within 14 days before randomization. 
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6. Central nervous system involvement.
7. Infection requiring systemic antibiotic therapy or other serious infection within 
14 days before randomization.
8. Diagnosis of Waldenstrom’s macroglobulinemia, POEMS (polyneuropathy, 
organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) 
syndrome, plasma cell leukemia, primary amyloidosis, myelodysplastic syndrome, or 
myeloproliferative syndrome.
9. Evidence of current uncontrolled cardiovascular conditions, including uncontrolled 
hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart 
failure, unstable angina, or myocardial infarction within the past 6 months.
10. 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. 
11. Ongoing or active systemic infection, active hepatitis B or C virus infection, or 
known human immunodeficiency virus (HIV) positive. 
12. 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). 
13. Psychiatric illness/social situation that would limit compliance with study 
requirements.
14. Known allergy to any of the study medications, their analogues, or excipients in the 
various formulations of any agent.
15. Inability to swallow oral medication, inability or unwillingness to comply with the 
drug administration requirements, or gastrointestinal (GI) condition that could 
interfere with the oral absorption or tolerance of treatment.
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16. Diagnosed or treated for another malignancy within 2 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 complete resection.
6.   
STUDY TREATMENT
All protocol-specific criteria for administration of study drug must be met and documented 
prior to drug administration. Study drug will be administered only to eligible patients under 
the supervision of the investigator or identified subinvestigator(s). Patients should be 
monitored for toxicity as necessary and doses of the appropriate treatment drug or study 
drug should be modified as needed to accommodate patient tolerance to treatment; this may 
include symptomatic treatment, dose interruptions, and adjustments of MLN9708 dose. 
All doses must be taken as outlined in the Schedule of Events. Eligible patients may take 
study drug 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 placebo capsules will be subsequently referred to as study drug.
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. 
The final analysis data cutoff has been conducted and as such, the study is considered 
complete for statistical analysis purposes. Upon implementation of Amendment 8, the 
investigator will unblind all patients remaining on study treatment Patients continuing their 
current study treatment may do so until such time as other means of accessing the study 
drugs are arranged. When possible, patients should complete an EOT visit and transition 
onto an alternative supply of (eg, commercially available) ixazomib and/or LenDex, or onto 
another standard of care treatment. Discontinued patients will be treated by their physician 
per local standard of care. Patients who are receiving ixazomib plus LenDex will continue to 
receive ixazomib plus LenDex.  Patients who are receiving placebo plus LenDex will 
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receive LenDex only; the placebo capsule will no longer be administered and patients 
receiving placebo will not be crossed over to ixazomib in this study.
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. Patients should be 
instructed to swallow MLN9708/placebo capsules whole with water and not to break, chew, 
or open the capsules. Study drug should be taken on an empty stomach, at least 1 hour 
before or no sooner than 2 hours after food. The capsule should be swallowed with a sip of 
water. A total of approximately 240 mL of water should be taken with the capsules. 
Missed doses can be taken as soon as the patient remembers as long as the next scheduled 
dose is 72 hours or more away. A double dose should not be taken to make up for a missed 
dose. If the patient vomits after taking a dose, the patient should not repeat the dose but 
should resume dosing at the time of the next scheduled dose.
6.2   
Standard of Care Therapies
6.2.1   
Lenalidomide Administration
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) 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.
Administration of lenalidomide will be at approximately the same time each day. Patients 
should be instructed to swallow lenalidomide capsules whole with or without food and not 
to break, chew, or open the capsules. 
If a dose of lenalidomide is missed, it should be taken as soon as possible on the same day. 
If it is missed for the entire day, it should not be made up.
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. 
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6.2.2   
Dexamethasone Administration
Dexamethasone will be given as an oral dose of 40 mg/day weekly on Days 1, 8, 15, and 22 
of a 28-day cycle.
Dexamethasone should be taken at approximately the same time preferably with food/milk 
to avoid stomach irritation. If a dose of dexamethasone is missed, the dose should be taken 
as soon as the patient remembers it. If enough time has elapsed that it is almost time for the 
next dose (within 6 hours), the missed dose should be skipped and the next dose taken 
according to the regular dosing schedule. A double dose should not be taken to make up for 
a missed dose. If the patient vomits after taking a dose, the patient should not repeat the dose 
but should resume dosing at the time of the next scheduled dose.
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. Only 1 dose adjustment per cycle will be performed 
for a given agent when toxicity is suspected to be related primarily to that agent. Reduction 
of 1 agent and not the other is appropriate if the toxicity is suspected to be related primarily 
to 1 of the agents. Dose reduction of multiple agents may be considered after consultation 
with the Millennium clinician/study clinician designee. Guidelines for dose modification 
within cycles are provided in Sections 6.4.1 and 6.4.2. Prior to beginning the next cycle of 
treatment, refer to the guidelines in Section 6.5. 
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 most severe toxicity guidelines. 
Alternative dose modifications may be recommended after discussion with the investigator 
and MPI clinician/designee in order to maximize exposure of study treatment while 
protecting patient safety.
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6.4   
Criteria for Dose Modification (Delays, Reductions, and Discontinuations)
6.4.1   
Dose Adjustments for Hematologic and Nonhematologic Toxicity: Study 
Drug and Lenalidomide
A decision regarding which study drug requires dose reduction 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, and Table 6-3 respectively).
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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[43]
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 MLN9708 dose was 
4 mg, reduce to 3 mg
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 MLN9708 dose was 
3 mg, reduce to 2.3 mg
Do not reduce below 
2.3 mg
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
Do not reduce below 5 mg
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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[43]
Action
First fall to < 0.5 109/L
Interrupt treatment
Interrupt treatment
Follow CBC weekly; add 
G-CSF
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 MLN9708 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 MLN9708 dose was 
3 mg, reduce to 2.3 mg
Do not reduce below 2.3 mg.
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
Do not reduce below 5 mg
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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[43]
Actiona
First occurrence  
Grade 2 or 3
Maintain dose
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[43]
Eg, if lenalidomide dose was 
25 mg, reduce to 15 mg
Second occurrence 
Grade 2 or 3
Interrupt treatment
Interrupt treatment
Symptomatic recommendations 
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
Symptomatic recommendations, 
including prophylactic 
treatment, in Section 6.10
Eg, if MLN9708 dose was 
4 mg, reduce to 3mg
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 MLN9708 dose was 
3 mg, reduce to 2.3 mg
Do not reduce below 2.3 mg
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
Do not reduce below 5 mg
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. [43]
a Please refer to Table 6-7 for additional information on lenalidomide (REVLIMID®) 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
Further Considerations
Grade 1 peripheral neuropathy 
No action
Grade 1 signs & symptoms: 
asymptomatic, without pain 
or loss of function, clinical 
or diagnostic observations 
only(39)
Grade 1 peripheral neuropathy with 
pain or Grade 2
Hold study drug until resolution 
to Grade ≤ 1 or baseline
Grade 2 signs & symptoms: 
moderate symptoms, 
limiting instrumental 
activities of daily living 
(ADL) (39)
Grade 2 peripheral neuropathy with 
pain or Grade 3
Hold study drug until resolution 
to Grade ≤ 1 or baseline
Reduce study drug to next lower 
dose upon recovery
Grade 3 signs & symptoms: 
severe symptoms, limiting 
self care ADL, assistive 
device indicated(39)
Grade 4 peripheral neuropathy
Discontinue study drug
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 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
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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
Further Considerations
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
Delay of > 2 weeks in the start of a 
subsequent cycle due to lack of toxicity 
recovery as defined in Section 6.5: 
ANC < 1,000/mm3, platelet count 
< 75,000/mm3, or other nonhematologic 
toxicities > Grade 1 or not to the 
patient’s baseline condition
Hold study drug until resolution 
per criteria in Section 6.5
Restart study drug and/or 
lenalidomide at the next lower 
dose level (based on attribution or 
previous reductions)
The maximum delay before 
treatment should be 
discontinued (except in the 
case of investigator 
determined clinical benefit 
and discussion with the 
MPI/designee clinician) will 
be 3 weeks
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.
Table 6-6   
Dose Reduction Steps for Lenalidomide
Starting Dose
First Dose Reduction
Second Dose Reduction
Third Dose Reduction
25 mg QD
15 mg QD
10 mg QD
5 mg QD
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Table 6-7   
Lenalidomide (REVLIMID®) Treatment Modification (Delays, 
Reductions, and Discontinuations) Guidelines Due to Non-Hematologic 
Adverse Events[43]
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[43]
Do not dose below 5 mg daily
Renal dysfunction
Dose reduce per lenalidomide package 
insert/SmPC for impaired renal 
function
Care should be taken in dose 
selection/modification in the 
elderly as they are more likely 
to have decreased renal 
function. Monitor renal 
function regularly
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[43]
Grade 2/3 skin rash
Hold or discontinue lenalidomide per 
package insert/ SmPC[43]
Grade 4 exfoliative or bullous 
rash 
Permanently discontinue lenalidomide 
per package insert/SmPC[43]
Tumor Lysis syndrome
Dose modify as per lenalidomide 
package insert/SmPC[43]
Monitor closely and take 
appropriate medical 
precautions
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.
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
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Table 6-9   
Dexamethasone–Related Treatment Modification (Delays, Reductions, 
and Discontinuations) Guidelines Due to Adverse Events[44]
Adverse Event (Severity)
Action on Dexamethasone
Gastrointestinal
Dyspepsia, gastric, or duodenal ulcer, 
gastritis Grade 1-2 (requiring medical 
management)
Treat with histamine-2 blockers, sucralfate, 
or omeprazole. If symptoms persist despite 
these measures, decrease dexamethasone 
by 1 dose level.
Grade 3 (requiring hospitalization or 
surgery)
Hold dexamethasone until symptoms 
adequately controlled. Restart and decrease 
1 dose level of current dose along with 
concurrent therapy with histamine-2 
blockers, sucralfate, or omeprazole. If 
symptoms persist despite these measures, 
discontinue dexamethasone and do not 
resume.
Acute pancreatitis
Discontinue dexamethasone and do not 
resume.
Cardiovascular
Edema > Grade 2 (limiting function and 
unresponsive to therapy or anasarca)
Diuretics as needed and decrease 
dexamethasone by 1 dose level. If edema 
persists despite these measures, decrease 
dose another level. Discontinue 
dexamethasone and do not resume if 
symptoms persist despite second reduction.
Neurological
Confusion or mood alteration > Grade 2 
Hold dexamethasone until symptoms 
resolve. Restart with 1 dose level 
reduction. If symptoms persist despite 
these measures, discontinue 
dexamethasone and do not resume.
Musculoskeletal
Muscle weakness > Grade 2 (interfering 
with function interfering with activities 
of daily living)
Decrease dexamethasone dose by 1 dose 
level. If weakness persists despite these 
measures, decrease dose by 1 dose level. 
Discontinue dexamethasone and do not 
resume if symptoms persist. 
Metabolic
Hyperglycemia Grade 3 
Treatment with insulin or oral 
hypoglycemics as needed. If uncontrolled 
despite these measures, decrease dose by 
1 dose level until levels are satisfactory.
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, or 
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
Other clinically significant nonhematologic toxicities ≤Grade 1 or to the patient’s 
baseline condition.
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. 
See Section 6.4 for recommended dose reduction because of incomplete recovery from 
treatment-related toxicity. The maximum delay before treatment should be 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 during the study. 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 6. Please 
refer to 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.
The following procedures are prohibited during the study: 

Any antineoplastic treatment with activity against MM, other than study drugs

Radiation therapy (note that, in general, the requirement for local radiation therapy 
indicates disease progression). Palliative radiotherapy for pain control in a 
preexisting lesion may be considered after discussion with the sponsor’s clinical 
representative. 
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
Platelet transfusions to help patients meet eligibility criteria are not allowed within 
3 days prior to study drug dosing
6.7   
Permitted Concomitant Medications and Procedures 
All necessary supportive care consistent with optimal patient care per local standard will be 
available to patients, as necessary. All blood products and concomitant medications received 
from first dose of study drug until 30 days after the final dose will be recorded in the CRFs. 
The following medications and procedures are permitted during the study:

Myeloid growth factors (eg, granulocyte colony stimulating factor [G-CSF], 
granulocyte macrophage-colony stimulating factor [GM-CSF]) are permitted. Their 
use should follow published guidelines and/or institutional practice; however, 
alternative usage may be reviewed with the Millennium clinician or study clinician 
designee.

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.

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.

Concomitant treatment with bisphosphonates will be permitted.

Supportive measures consistent with optimal patient care may be given throughout 
the study.
6.8   
Precautions and Restrictions 

Fluid deficit should be corrected before initiation of treatment and during treatment.
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
Nonsteroidal anti-inflammatory drugs (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. FCBP is a sexually 
mature female 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 not had menses 
at any time during the preceding 24 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 study drug 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 practice 2 reliable methods of contraception, at the same time, for at least 
28 days before starting study drug through 90 days after the last dose of study
treatment

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:
o
Intrauterine device (IUD)
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o
Hormonal (birth control pills, injections, implants)
o
Tubal ligation
o
Partner’s vasectomy
Additional effective methods:
o
Condom
o
Diaphragm
o
Cervical Cap

Must also adhere to the guidelines of the RevAssist program (US participants), 
RevAid program (Canadian participants), iAccess program (Australian participants), 
RevMate program (Japanese participants), or The Lenalidomide Pregnancy Risk 
Minimisation Plan as outlined in the Study Manual (all other participants who are not 
using commercial supplies)
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 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

Adhere to the guidelines of the RevAssist program (US participants), RevAid 
program (Canadian participants), iAccess program (Australian participants), 
RevMate program (Japanese 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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6.10   
Management of Clinical Events 
Prophylaxis Against Risk of Reactivation of Herpes Infection
Patients may be at an increased risk of infection including reactivation of herpes zoster and 
herpes simplex viruses. Unless there is a clinical contraindication, prophylactic antiviral 
therapy is required for all patients while receiving study treatment. Examples of acceptable 
antiviral therapy include acyclovir (eg, 400 mg given orally, 3 times a day), famciclovir (eg, 
125 mg given orally, twice a day), or valacyclovir (eg, 500 mg given orally, twice a day) or 
standard of care/local practice.
Thromboembolism Prophylaxis
While on lenalidomide, patients should be on routine thromboprophylaxis.[45] Prophylactic 
therapy with aspirin (81 - 325 mg PO once daily) 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. Thromboprophylaxis 
according to the American Society of Clinical Oncology (ASCO) guidelines or institutional 
standard of care is recommended.[46]
Nausea and/or Vomiting
Prophylaxis with standard antiemetics, including serotonin 5-hydroxytryptamine 3 receptor 
antagonists, is recommended for emesis. Any fluid deficit occurring during treatment should 
be promptly corrected.
Diarrhea
Diarrhea should be managed according to clinical practice, including the administration of 
antidiarrheals once infectious causes are excluded. Fluid intake should be maintained to 
avoid dehydration. Any fluid deficit occurring during treatment should be promptly 
corrected.
Erythematous Rash With or Without Pruritus
Rash 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 package 
insert.[43,47,48] Serious skin reactions such as Stevens-Johnson Syndrome, toxic epidermal
necrolysis, and erythema multiforme have been reported. Lenalidomide interruption or 
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discontinuation should be considered as described in the package insert (PI)/ summary of 
product characteristics (SmPC).[43]
Rash may range from limited erythematous areas, macular or small papular bumps that may 
or may not be pruritic over a few areas of the body, to a more generalized eruption that is 
predominantly on the trunk or extremities. Rash has been most commonly characterized as 
maculopapular or macular. To date, when it does occur, rash is most commonly reported 
within the first 3 cycles of therapy. The rash is often transient and self-limiting and is 
typically Grade 1 or 2 in severity. As in many other oncology trials, 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; these other causative agents should be discontinued and alterative agents considered if 
medically necessary.
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). 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. Study medications should be 
discontinued in the event of severe, potentially life-threatening rash. 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 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, including fatal cases, 
have been reported in patients receiving MLN9708. If TMA is suspected, consider 
withdrawal of the suspected causative agent and manage 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 previously noted 
gastrointestinal toxicities and dehydration. Fluid deficit should be promptly corrected before 
initiation of study drug and as needed during treatment to avoid dehydration (see 
Section 6.8).
Hypotension
Symptomatic hypotension and orthostatic hypotension with or without syncope have been 
reported with MLN9708. Blood pressure should be closely monitored as per standard of care 
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while the patient is on study treatment and fluid deficit should be corrected as needed, 
especially in the setting of concomitant symptoms such as nausea, vomiting, diarrhea, or 
decreased appetite. Patients taking medications and/or diuretics to manage their blood 
pressure (for either hypo- or hypertension) should be managed according to standard clinical 
practice, including considerations for dose adjustments of their concomitant medications 
during the course of the trial. Fluid deficit should be corrected before initiation of study drug 
and as needed during treatment to avoid dehydration.
Posterior Reversible Encephalopathy Syndrome
Posterior reversible encephalopathy syndrome (PRES) has been reported with MLN9708. 
This condition is usually transient and reversible. It is characterized by headache, seizures, 
and visual loss, as well as abrupt increase in blood pressure. Diagnosis may be confirmed by 
magnetic resonance imaging (MRI) or computed tomography (CT). If the syndrome is 
diagnosed or suspected, symptom-directed treatment should be maintained until the 
condition is reversed by control of hypertension or other instigating factors. 
Transverse Myelitis
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.
Kit assignments will be obtained through the interactive voice response system (IVRS) 
according to the procedures outlines in the Study Manual. Information regarding the kit 
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assignments will be kept securely at Millennium or designee, per its standard operating 
procedures. Emergency unblinding, if necessary, will be conducted via the IVRS.
Records of the patient number, the date study drug was dispensed, and the kit assignment 
will be maintained by the study site. If the treatment assignment must be revealed for the 
safety of the patient or to treat an AE, the investigator will contact the Millennium clinician/ 
study clinician designee (contact information is in the Study Manual). 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 IVRS 
independent of the Millennium clinician/ study clinician designee only 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. 
The event requiring breaking the blind must be documented in the electronic case report 
form (eCRF), including the date the blind was broken. In addition, the patient will be 
discontinued from further study drug administration in this study.
The final analysis data cutoff has been conducted and as such, the study is considered 
complete for statistical analysis purposes. Upon implementation of Amendment 8, the 
investigator will unblind all patients remaining on study treatment and will follow the new 
Schedule of Events presented in this amendment. Only patients who continue to demonstrate 
clinical benefit but who do not have other means of access to the study drugs will continue 
on the study. Patients continuing their current study treatment may do so until such time as 
other means of accessing the study drugs are arranged. When possible, patients should 
complete an EOT visit and transition onto an alternative supply of (eg, commercially 
available) ixazomib and/or LenDex, or onto another standard of care treatment. 
Discontinued patients will be treated by their physician per local standard of care. Patients 
who are receiving ixazomib plus LenDex will continue to receive ixazomib plus LenDex.  
Patients who are receiving placebo plus LenDex will receive LenDex only; the placebo 
capsule will no longer be administered and patients receiving placebo will not be crossed 
over to ixazomib in this study.
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 
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acid. Three forms of 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 Capsules
Dose Strength
Capsule Size
Capsule Color
4.0 mg
Size 3
Ivory
3.0 mg
Size 4
Light Gray
2.3 mg
Size 4
Flesh
For additional details, please see the MLN9708 IB and Pharmacy Manual.
6.13   
Preparation, Reconstitution, and Dispensing
For blistered material, the capsules are packaged in cold form foil-foil blisters in a 
child-resistant carton.
6.14   
Packaging and Labeling
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 4.0-, 3.0-, and 2.3-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. 
6.15   
Storage, Handling, and Accountability
On receipt at the investigative site, study drug should remain in the blister pack and carton 
provided until use or dispensation. All excursions that occur at the site storage or during 
transportation from depot to the site should immediately be brought to the sponsor’s 
attention for assessment and authorization for continued use. Ensure that the drug is used 
before the retest expiry date provided by Millennium. Expiry extensions will be 
communicated accordingly with updated documentation to support the extended shelf life.
Study drug dispensed to the patient 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 
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COVID-19 pandemic), sites may use alternative strategies to deliver study drug to patients 
(eg, via courier or site staff), per local standard practice and regulations and with prior 
approval from the investigator and the sponsor’s project clinician/designee. Comprehensive 
instructions should be provided to the patient in order to ensure compliance with, and 
understanding of, dosing procedures. Patients who are receiving take-home medication 
ordinarily should be given only 1 cycle of study drug 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 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. Patients should be 
instructed to return their empty cartons to the investigative site, rather than discarding them. 
Reconciliation will occur accordingly when the patient returns for their next cycle of study 
drug. 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. 
Because MLN9708 is an anticancer agent, 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 federal, state, 
and local regulations. 
In case of contact with the powder (eg, from a broken capsule), skin should be washed 
immediately with soap and copious amounts of water for at least 15 minutes. In case of 
contact with the eyes, copious amounts of water should be used to flush the eyes for at least 
15 minutes. Medical personnel should be notified.
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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.
6.15.1   
Standard of Care 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 RevAssist program 

Canada: Subjects will receive lenalidomide through the RevAid program

Australia: Subjects will receive lenalidomide through the iAccess program

Japan: Subjects will receive lenalidomide through the RevMate program

All other countries: Subjects will receive lenalidomide from the site through supply 
provided by sponsor
6.15.1.2   Dexamethasone
Dexamethasone may be supplied by the site from commercial sources, depending on 
regional availability. Additional details are provided in the package insert and Pharmacy 
Manual.[44]
Dexamethasone tablets should be stored according to the instructions provided in the 
manufacturer’s package insert 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 central recruitment from a 
vendor, 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 IVRS.
Patient eligibility will be confirmed by an MPI/designee clinician before randomization by 
the investigator into the study, as patients will not be permitted to re-enroll. A centralized 
randomization using IVRS 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.
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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 
requests, the investigator/study site staff will give the highest priority to the safety and 
welfare of the patients. Patients must be willing and able to continue taking study 
medication and remain compliant with the protocol.  For patients that are impacted by these 
unavoidable circumstances, any procedures not conducted per the study protocol will be 
documented in the eCRF.  
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 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 (eg, 
complete physical examination, symptom-directed physical examination, hematology, 
clinical chemistry, concomitant medications/procedures) are waived. 
Upon implementation of Amendment 8, patients continuing to derive clinical benefit will be 
evaluated for safety only during the treatment period and at EOT. The primary endpoint has 
been met and all other formal statistical analyses will be complete at the time of the final 
analysis. As such, the PFS and OS follow-up phases are discontinued for patients currently 
receiving study therapy. Patients in the OS follow-up phase will be discontinued. 
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Refer to the updated Schedule of Events for the timing of assessments. Tests and procedures 
should be performed on schedule, but occasional changes are allowable (± 7 days) 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.
Additional details are provided as necessary in the sections that follow.
7.4.1   
Informed Consent
Each patient must provide written informed consent before any study-required procedures 
are conducted, unless those procedures are performed as part of the patient’s standard care.
Patients remaining on study treatment will need to be reconsented. Reconsenting should be 
done in person. Remote reconsenting is permitted as long as the process adheres to site, 
IRB/IEC, and GCP standards and local regulations.
7.4.2   
Patient Demographics
The date of birth, race, ethnicity, and sex of the patient are to be recorded during screening. 
7.4.3   
Medical History
During the Screening period, a complete medical history will be compiled for each patient, 
including diagnosis (Section 15.2) and current staging (Section 15.4) of MM. The history 
should include a review of all current medications, prior radiation or antineoplastic therapy, 
and the patient’s current smoking status. 
7.4.4   
Physical Examination
A complete physical examination and symptom-directed physical exam will be conducted at 
the time points 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, and AE resolution. 
7.4.5   
Eastern Cooperative Oncology Group Performance Status
Performance status will be assessed using the ECOG performance scale (see Section 15.1) at 
the time points specified in the Schedules of Events in Section 15.12 and Section 15.13. 
Upon implementation of Amendment 8, ECOG performance status will no longer be 
collected. 
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7.4.6   
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 Schedule of Events. 
Height will only be assessed at the Screening visit.
7.4.7   
Pregnancy Test
Two pregnancy tests with sensitivity of at least 25 mIU/mL will be performed for all women 
of childbearing potential prior to initiation of study drug treatment. The first pregnancy test 
must be performed within 10 to 14 days prior to the start of study drug and the second 
pregnancy test must be performed within 24 hours prior to the start of study drug, and as 
required by the lenalidomide package insert. A female of childbearing potential (FCBP) is a
sexually mature female 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).
FCBP with regular or no menstruation must have a pregnancy test weekly 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 study drug. 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. All patients must be counseled about 
pregnancy precautions, risks of fetal exposure, and other risks in accordance with the 
RevAssist program (US participants), RevAid program (Canadian participants), iAccess 
program (Australian participants), RevMate program (Japanese participants), or The 
Lenalidomide Pregnancy Risk Minimisation Plan as outlined in the Study Manual (all other 
participants who are not using commercial supplies).
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 study drug is administered.
Pregnancy tests may also be repeated during the study as per request of IEC/IRBs or if 
required by local regulations.
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7.4.8   
Electrocardiogram
A 12-lead ECG will be conducted at screening and at the times outlined in the Schedules of 
Events in Section 15.12 and Section 15.13. 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.
Upon implementation of Amendment 8, ECG data will no longer be collected.
7.4.9   
Clinical Laboratory Evaluations
Clinical laboratory evaluations will be performed by a central laboratory. For dosing 
decisions, local hematology and chemistry laboratory results may be used; however, samples 
must still be sent to central labs as well. 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. Per Amendment 6, centralized clinical laboratory evaluations of safety will be 
performed only on Day 1 of every cycle. For dosing decisions and for all other safety 
assessments for the patient, local hematology and chemistry laboratory results may be used; 
however, samples must still be sent to central labs also. Local laboratory evaluations may be 
done more frequently at the investigator’s discretion, ie for acute management of TEAEs. In 
general, local laboratory results of safety will not need to be entered into the eCRF. Local 
laboratory evaluations should be entered into the eCRF only if required to document an AE, 
dose modification, or other event, and the information entered should be limited to that 
required to understand the event (eg, for a dose hold for thrombocytopenia, enter the platelet 
count only). Handling and shipment of central clinical laboratory samples are outlined in the 
Study Manual.
As the centralized laboratory results may not be available at the initiation of the next cycle, 
it is not required that these centralized measurements be reviewed before initiating the next 
treatment cycle unless either of the following applies:
1. The patient has an ongoing toxicity. If the patient has had a toxicity resulting in a 
dose hold, it is mandatory that safety labs (local or central) are collected AND 
reviewed before starting the next cycle of treatment.
2. It is required per your local practice or guidelines to have safety labs reviewed before 
starting the next cycle of treatment. 
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Upon implementation of Amendment 8, 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 document or 
support 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.
7.4.10
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.
Note that as the primary endpoint of PFS has now been met, for all patients still receiving 
study therapy, all central and investigator assessments of response and progression for 
protocol purposes are discontinued, including urinalysis assessments and collection of 
thyroid-stimulating hormone. Upon implementation of Amendment 8, blood samples for 
analysis of the remaining hematology parameters below will continue to be obtained on Day 
1 of each cycle for purposes of dosing decisions and safety assessments only.
Hematology

Hemoglobin

Hematocrit

Platelet Count 

WBC Count with Differential
Serum Chemistry

BUN

Creatinine

Total bilirubin

Uric Acid

LDH

Alkaline phosphatase

AST

ALT 

Albumin

Glucose 

Sodium

Potassium

Chloride

CO2

Magnesium

Calcium

Phosphate

Thyroid stimulating 
hormone (TSH; no 
longer done as of 
Amendment 6)
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Urinalysis (no longer done as of Amendment 6)

Appearance and color 

pH 

Specific gravity 

Protein 

Ketones 

Bilirubin 

Blood 

Nitrite 

Urobilinogen 

Glucose

Leukocytes 

Microscopic 
assessment
7.4.11   
Health Utilization Data Collection
During the treatment and the follow-up periods indicated in the Schedules of Events in 
Section 15.12 and Section 15.13, 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 8, health utilization data will no longer be collected.
7.4.12   
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 Schedules of Events in Section 15.12 and 
Section 15.13. 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. 
These QOL assessments must be completed before other assessments are performed or study 
drug is administered. 
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Upon implementation of Amendment 8, quality of life data will no longer be collected.
7.4.13   
Pain Assessment
Pain assessments will be performed at study visits as described in the Schedules of Events in 
Section 15.12 and Section 15.13 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 being administered. 
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 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 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 Schedule of Events. The 
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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.
Upon implementation of Amendment 8, pain assessments will no longer be collected.
7.4.14   
Utility Measurement
Because oncology therapies may positively or negatively affect a subject’s QOL, a common 
methodologic approach is used to quantify this effect by “quality-adjusting” survival in 
comparative treatment groups. The result, quality-adjusted life years (QALYs), is a measure 
of both the length and quality of life and is used as a measure of benefit in costutility 
analysis. General PRO instruments such as the EORTC QLQ-C30 are not specifically 
designed to measure subject preferences (or utilities) in a way that is suitable for calculating 
QALYs. Therefore, a separate validated instrument, in this case the EuroQoL EQ-5D, will 
be used to quantify utilities to calculate QALYs for a costutility analysis
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 Schedules of Events in Section 15.12 and Section 15.13.
Upon implementation of Amendment 8, EQ-5D data will no longer be collected.
7.4.15   
Skeletal Survey
A complete skeletal survey, using roentgenography, will be performed at screening (within 
8 weeks of the first dose of study drug) and annually in all patients, as specified in the 
Schedule of Events in Section 15.12. 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.
At the discretion of the investigator and where regionally permitted,  CT scan, a positron 
emission tomography-computed tomography (PET-CT) scan, or whole body magnetic 
resonance imaging (MRI) may be done at screening in place of a skeletal survey, provided 
that the same modality for assessment is used throughout the study.
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Radiographs will be analyzed locally and reports maintained with the patient record for 
review during monitoring visits.
As of Amendment 6, however, the primary endpoint of PFS has been met; as such, all 
assessments of response for protocol purposes are now discontinued. Therefore, skeletal 
survey will no longer be done for protocol purposes for patients on study therapy.
7.4.16   
Skeletal-Related Events
Selected skeletal-related events (SREs), defined as new fractures (excluding vertebral 
compression or rib 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 Schedules of Events in Section 15.12 and Section 15.13. 
Upon implementation of Amendment 8, skeletal-related events data will no longer be 
collected.
7.4.17   
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) and at the time points specified in the Schedule 
of Events in Section 15.12, until disease progression. 
All follow-up scans should use the same imaging modality used at screening.
Radiographs will be analyzed locally and reports maintained with the patient record for 
review during monitoring visits.
As of Amendment 6, however, the primary endpoint of PFS has been met; as such, all 
assessments of response for protocol purposes are now discontinued. Therefore, 
radiographic disease assessments will no longer be done for protocol purposes for patients 
on study therapy.
7.4.18   
2-Microglobulin
A blood sample will be collected at screening for serum 2-microglobulin testing. A sample 
for both central and local laboratory evaluation is required. Stratification by ISS stage 1 or 2 
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vs 3 will be conducted using local results and will be confirmed by the central laboratory. 
Local and central results will be utilized for analysis.
As of Amendment 6, however, the primary endpoint of PFS has been met; as such, all 
assessments of response for protocol purposes are now discontinued. Therefore, 
2-microglobulin testing will no longer be done for protocol purposes for patients on study 
therapy.
7.4.19   
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.
As of Amendment 6, however, the primary endpoint of PFS has been met; as such, all 
assessments of response for protocol purposes are now discontinued. Therefore, M-protein 
quantification will no longer be done for protocol purposes for patients on study therapy.
7.4.20   
Quantification of Immunoglobulin (Ig)
Blood samples for quantification of immunoglobulins will be obtained as specified in the 
Schedule of Events.
As of Amendment 6, however, the primary endpoint of PFS has been met; as such, all 
assessments of response for protocol purposes are now discontinued. Therefore, Ig 
quantification will no longer be done for protocol purposes for patients on study therapy.
7.4.21   
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.
As of Amendment 6, however, the primary endpoint of PFS has been met; as such, all 
assessments of response for protocol purposes are now discontinued. Therefore, the serum 
free light chain assay will no longer be done for protocol purposes for patients on study 
therapy.
7.4.22   
Immunofixation of Serum and Urine
Serum and urine samples for the analysis of immunofixation of immunoglobulins will be 
obtained at the time points specified in the Schedule of Events (refer to Section 15.2). 
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As of Amendment 6, however, the primary endpoint of PFS has been met; as such, all 
assessments of response for protocol purposes are now discontinued. Therefore, 
immunofixation will no longer be done for protocol purposes for patients on study therapy.
7.4.23   
Bone Marrow Evaluation
As of Amendment 6, the primary endpoint of PFS has been met; as such, all assessments of 
response for protocol purposes are now discontinued. Therefore, central and local laboratory 
evaluations will no longer be done for protocol purposes for patients on study therapy, with 
the exception of the optional aspirate for molecular analysis that may be collected at the time 
of disease relapse only if the patient had previously responded to study drug and consents to 
this procedure.
Central Lab Evaluation
Molecular Analyses and Cytogenetics
The sample of the bone marrow aspirate obtained at screening will be used for molecular 
analyses and for evaluation of cytogenetics that will cover a panel of high-risk abnormalities 
including the following: del(13), +1q21, t(4;14), t(4;16), and del(17). This aspirate sample 
will also be used to assess mutation status of key genes of the RAS/RAF pathway and 
expression levels of key genes involved in MM. 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. 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 and consents to this procedure. This sample may be collected at the time of PD 
confirmation, at the End of Study visit, or prior to starting a new therapy and will be sent to 
the central laboratory for analysis. 
Upon implementation of Amendment 8, bone marrow aspirate for molecular analysis will no 
longer be performed. 
Local Lab Evaluations
Disease Assessment
A bone marrow aspirate will be obtained at screening for disease assessment and at any time 
bone marrow aspirate sample is obtained to assess CR or to investigate suspected PD. This 
evaluation will be performed locally. Determination of the kappa/lambda ratio by 
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immunohistochemistry or immunofluorescence should be performed to assess for stringent 
CR (sCR) when a CR has been documented. A bone marrow biopsy can additionally be 
performed per local standards for disease assessments. 
Upon implementation of Amendment 8, bone marrow aspirate is not needed for assessment 
of CR or PD for protocol purposes. Investigators may continue to take bone marrow aspirate 
per standard of care for response assessment.
Cytogenetics
An additional bone marrow aspirate or bone marrow sample may also be submitted for 
cytogenetics to be analyzed locally, 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, whereas local laboratory cytogenetic results 
(where available) will only be utilized in instances when central laboratory results are not 
available.
Upon implementation of Amendment 8, a bone marrow sample for evaluation of 
cytogenetics is no longer needed. Investigators should follow local standard of care for bone 
marrow aspirate samples.
7.4.24   
Response Assessment
Patients will be assessed for disease response according to the IMWG criteria, versions 2006 
and 2011 (see Section 15.11).[49,50]
Response assessments should occur every cycle until progression. The MPI/designee 
clinician will confirm the investigator assessment of PD prior to the investigator taking the 
patient off treatment.
Response and relapse categories are as follows:
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Table 7-1   
Response Assessment
Complete response
CR
Subcategory: stringent complete response
sCR
Very good partial response
VGPR
Partial response
PR
Stable disease
SD
Progressive disease
PD
CR must be confirmed with follow-up assessments of SPEP, UPEP, immunofixation of 
blood and urine, and serum free light chains 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 immunofluorescence for kappa/lambda ratio, as well as serum 
free light chain assay, 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.
As of Amendment 6, however, the primary endpoint of PFS has been met; as such, all 
assessments of response for protocol purposes are now discontinued. Therefore, response 
assessment will no longer be done for protocol purposes for patients on study therapy.
7.4.25   
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 for the determination of plasma 
concentrations of MLN2238 (the complete hydrolysis product of MLN9708) will be 
collected during Cycles 1 through 10. Samples are to be collected at the time points 
specified in the MLN9708 Pharmacokinetic Sampling Schedule immediately following the 
Schedule of Events. 
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As of Amendment 6, PK sample collection has been completed for all patients. The PK 
sampling schedule has been moved to Section 15.12.
7.4.26   
Blood Sample for Biomarker Analysis
Two blood samples will be collected at screening for testing candidate biomarker 
relationship to response or resistance to MLN9708 therapy. Polymorphisms in mechanism 
and pathway-related genes including proteasome subunits, such as PSMB1, and NFKB 
regulators, such as NFKB1, TRAF3, and IKB, will be assessed. Polymorphisms of NFKB 
family genes are associated with development of multiple myeloma and treatment outcome 
in patients receiving bortezomib-based regimens and may be relevant for the efficacy of 
proteasome inhibitors generally. Relationship between response to MLN9708 and 
proteasome levels in plasma will also be analyzed. These have been linked to the efficacy of 
bortezomib. Polymorphisms of NFKB family genes are associated with development of MM 
and treatment outcome in patients undergoing bortezomib-based regimens. 
As of Amendment 6, however, the primary endpoint of PFS has been met; as such, all 
assessments of response for protocol purposes are now discontinued. 
7.4.27   
Concomitant Medications and Procedures
Concomitant medications and therapy will be recorded from the first dose of study drug 
through 30 days after last dose of study drug, with the exception of narcotics and other 
analgesics, which will be recorded from first dose of study drug until PD (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.
7.4.28   
Adverse Events
Monitoring of AEs, both nonserious and serious, will be conducted throughout the study as 
specified in the Schedule of Events. See Section 10 for details regarding definitions, 
documentation, and reporting of pretreatment events, AEs, and SAEs. 
7.4.29
Follow-up Assessments (PFS and OS)
Prior to implementation of Amendment 6, patients who stopped treatment for any reason 
had PFS follow-up visits. See the Schedule of Events in Section 15.12 for the appropriate 
assessments. All subsequent antineoplastic therapies were to be recorded, regardless if they 
were initiated before or after PD. Patients who started an alternative antineoplastic therapy 
prior to disease progression continued to be followed for progression. As of Amendment 6, 
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however, the primary endpoint has been met. As such, the PFS follow-up phase was
discontinued for all patients receiving study therapy and for any patients who discontinued 
treatment for other reasons, including patients who started an alternative therapy before PD. 
Prior to implementation of Amendment 8, patients who stopped treatment due to PD 
continued to have overall survival visits/assessments. During the OS follow-up, assessments 
could be made over the phone and did not require a clinic visit. Data may have been
collected by methods that included but were not limited to telephone, e-mail, mail, and 
social security indexes. The OS follow-up was conducted every 12 weeks after documented 
PD until death or termination of the study by the sponsor. All subsequent antineoplastic 
therapies were to be recorded during the OS follow-up period.
Upon implementation of Amendment 8, patients will no longer be followed during any of 
the follow-up periods. NOTE: Prior to implementation of Amendment 8, related SAEs must 
have been reported to the Millennium Department of Pharmacovigilance or designee. This 
included deaths that the investigator considered related to study drug that occurred during 
the posttreatment follow-up. In addition, new primary malignancies that occurred during the 
follow-up periods, irrespective of causality to study regimen, must have been 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 
prior to implementation of Amendment 8, the BPI-SF and HU data should be captured. 
Upon implementation of Amendment 8, pain assessments and HU data will no longer be 
collected. Other assessments may be performed as clinically indicated at the discretion of 
the investigator. 
7.6   
Study Compliance
Study drug will be administered or dispensed only to eligible patients under the supervision 
of the investigator or identified subinvestigator(s). The appropriate study personnel will 
maintain records of study drug receipt and dispensing.
7.7   
Completion of Treatment
Prior to implementation of Amendment 8, patients were considered to have completed study 
treatment if they received study drug until disease progression or until discontinuation for 
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unacceptable toxicity, withdrawal of consent, or death. An MPI/designee clinician reviewed 
the source data documenting disease progression prior to the investigator taking the patient 
off treatment or stopping disease assessments for PD. As of Amendment 6, however, the 
primary endpoint has been met; as such, the PFS follow-up phase has been discontinued for 
patients currently receiving study therapy. All central and investigator assessments of 
response and progression for protocol purposes will be discontinued, such that there will no 
longer be an MPI/designee clinician review of the source data documenting disease 
progression.
Upon implementation of Amendment 8, only patients who are demonstrating clinical benefit 
and are unable to access a commercial supply of ixazomib and/or lenalidomide and 
dexamethasone 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, 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 for End of Treatment visit assessments.
7.8   
Completion of Study
Prior to implementation of Amendment 8, 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 8, 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 Study Drug
Treatment with study drug may be discontinued for any of the following reasons:

AE

Protocol violation
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
Study terminated by sponsor

Withdrawal by patient

Lost to follow-up

PD

Other
Prior to the investigator taking the patient off treatment, the investigator is required to 
submit the rationale to the MPI/designee clinician for review. Note that this is no longer 
required as of Amendment 6.
Once study drug has been discontinued, all study procedures outlined for the EOT visit will 
be completed as specified in the Schedule of Events. The primary reason for study drug 
discontinuation will be recorded on the eCRF. 
7.10   
Withdrawal of Patients From Study
A patient may also be withdrawn from the study for any of the following reasons: 

Study terminated by sponsor

Withdrawal by patient

Lost to follow-up

Death

Other
Upon implementation of Amendment 8, 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 final analysis data cutoff has been conducted and as such, the study is considered 
complete for statistical analysis purposes. The final analysis occurred in the fourth quarter of 
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2020. Upon implementation of Amendment 8, the investigator will unblind all patients 
remaining on study treatment and will follow the new Schedule of Events presented in this 
amendment. No subsequent formal inferential statistical analyses will be conducted; 
minimal descriptive analyses of safety will be performed on patient data collected after the 
final analysis. The description of the statistical methods presented below reflects the full 
design for the study for reference.
8.1   
Statistical Methods
In general, summary tabulations will be presented by treatment arm and will display the 
number of observations, mean, standard deviation, median, minimum, and maximum for 
continuous variables, and the number and percent per category for categorical data. The 
Kaplan-Meier survival curves and 25th, 50th (median), and 75th percentiles will be provided 
along with their 2-sided 95% confidence intervals (CIs) for time-to-event data. 
Details for the final analysis will be provided in the statistical analysis plan (SAP). The SAP 
will be written by Millennium and will be finalized prior to the first planned IA. 
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 when added to lenalidomide and 
dexamethasone in patients with relapsed and/or refractory 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 event rate and statistical power for OS analysis. To maintain the overall 
strong control of Type I error rate at a 2-sided alpha level of 0.05, the closed sequential 
testing procedure will be used to test PFS and OS sequentially both at a 2-sided alpha level 
of 0.05. That is, only if PFS is significant based on the O’Brien-Fleming alpha spending 
function (the Lan-DeMets method) at the first IA and the second IA, the test of OS will be 
conducted on its own alpha spending functions.
The total sample size was calculated based on maintaining 80% power to test the OS. The 
study is also adequately powered to test PFS. Assuming a hazard ratio of 0.77 (median 
survival of 30 months in control arm versus 39 months in treatment arm), the number of 
death events needed is 486 (80% power and 2-sided alpha of 0.05). A total of approximately 
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703 patients will need to be randomized in a 1:1 ratio into those 2 arms, assuming an 
average enrollment rate of approximately 13 patients/month for the first 6 months, 
approximately 45 patients/month thereafter, and approximately 10% dropout rate at month 
35. The final analysis of OS is estimated to occur approximately 80 months from the 
enrollment of first patient, including a 20-month randomization period and an additional 
60-month follow up from the last patient enrolled. With an observed hazard ratio of 0.833 
(eg, median OS of 30 months for control versus 36 months for treatment, 20% 
improvement), statistical significance can be claimed at the final analysis with 486 death 
events. 
Assuming a hazard ratio of 0.728 (median PFS of 15 months in control arm versus 
20.6 months in treatment arm), 365 PFS events will be needed (85% power and 2-sided 
alpha of 0.05) with 2 planned IAs and the second IA as the final PFS analysis. The first IA 
will be performed when approximately 262 PFS events have occurred. This will be the first 
analysis for PFS for statistical testing purpose. Based on the O’Brien-Fleming stopping 
boundary, the alpha level at the first IA and second IA on PFS would be 0.0163 and 0.0337, 
respectively, if the number of PFS events at the first IA is exactly 262.[41] Correspondingly, 
if the observed p value is less than 0.0163 and 0.0451 at the first IA and the second IA, 
respectively, the test for PFS will be claimed to be statistically significant. With an 
assumption of approximately 13 patients/month for the first 6 months, 45 patients/month 
thereafter, and approximately 10% dropout rate over 30-month follow-up period, 262 PFS 
events is expected to occur at approximately 24.5 months after the first patient is enrolled 
and approximately 703 patients have been enrolled. This is the first IA of the study with the 
opportunity to claim PFS benefit. With an observed hazard ratio of 0.743 (eg, median PFS 
of 15 months in control arm versus 20.2 months in treatment arm), statistical significance 
can be claimed at the analysis for PFS with 262 progression/death events. If the test for PFS 
is statistically significant at the first IA, a non-inferential analysis of PFS will be performed 
at the second IA where the PFS data is considered mature.
If the test for PFS is not statistically significant at the first IA, the study will continue and 
PFS testing will be conducted at the second IA when approximately 365 PFS events have 
occurred, which will also be the final analysis of PFS for statistical testing purpose. An 
observed hazard ratio 0.810 (median PFS of 15 months in control arm versus 18.5 months in 
treatment arm) or better will lead to statistical significance for the PFS endpoint. If the test 
for PFS is not statistically significant at second IA, the study will be claimed as unsuccessful 
and no further testing will be conducted. If the test for PFS is significant at an IA, the OS 
will be tested; however, the trial will not be stopped for overwhelming evidence of efficacy 
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or futility at the first IA. The third IA will be for OS and will be performed when 
approximately 322 deaths (two-thirds of the total expected deaths) have occurred, with the 
opportunity to stop the study for overwhelming evidence of efficacy or futility. This IA is 
expected to occur approximately 44 months after the first patient is enrolled. 
Based on the O’Brien-Fleming stopping boundary, the alpha levels at the 3 planned OS IAs 
and final analysis would be 0.00014, 0.0017, 0.0100, and 0.0382, respectively if the 
numbers of events at these analysis time points are exactly 154, 222, 322, and 486.[41]
Correspondingly, if the nominal p value is less than 0.0001, 0.0018, 0.0112, and 0.0462, 
respectively, at the first, second, and third IAs, and the final analysis, the test for OS will be 
claimed to be statistically significant. However, the study will not be stopped after the first 
IA based on the test for OS. However, the actual boundary could be adjusted if the actual 
number of events does not correspond to the projected number of events in the IAs or in the 
FA.
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 IVRS. 
Eligible patients will be randomized in a 1:1 ratio into those 2 treatment arms, stratified by: 
1) 1 versus 2 or 3 prior therapies, 2) proteasome inhibitor exposed versus proteasome 
inhibitor naïve, and 3) ISS stage at screening of 1 or 2 versus stage 3.
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 received the 
regimen in the control arm will be included in the control arm; those patients who are 
randomized to the control arm but received 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 were randomized to 
receive, regardless of any errors of dosing. 
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Per-Protocol (PP) population: The PP population is a subset of the ITT population. The PP 
population consists of all patients who do not violate the terms of the protocol in a way that 
would affect the study outcome significantly, as determined by the study clinician, who is 
blinded to study drug assignment. All decisions to exclude patients from the PP population 
will be made before the unblinding of the study.
8.1.4   
Procedures for Handling Missing, Unused, and Spurious Data
All available efficacy and safety data will be included in data listings and tabulations. No 
imputation of values for missing data will be performed, unless specified otherwise. The 
relevance of missing sample data will be assessed. Data that are potentially spurious or 
erroneous will be examined according to standard data management operating procedures.
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
8.1.6.1   
Analyses for Primary Efficacy Endpoints
Note that, as of Amendment 6, the primary endpoint of PFS has been met, and analyses for 
the PFS have been completed. 
The analysis of primary endpoint, PFS, will be based on the ITT population using 
IRC-assessed progression data. PFS is defined as the time from the date of randomization to 
the date of first documentation of PD or death due to any cause, whichever occurs first. 
Patients without documentation of PD will be censored at the date of last response 
assessment that is stable disease (SD) or better. 
PFS will be analyzed when approximately 262 and 365 PFS events have occurred for the 
first IA and for the second IA, respectively. 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 0.0163 and 
0.0337, which corresponds to a nominal p value of 0.0451 based on O’Brien-Fleming 
stopping boundary (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 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 neoplastic 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. 
If it is determined that the study will continue after PFS is significant at a 2-sided alpha level 
of 0.0163 at the first IA, a non-inferential analysis of PFS will be performed at the second 
IA. The PFS data will be considered as matured at the second IA.
8.1.6.2   
Analyses of Key Secondary Efficacy
In addition to the primary comparison of PFS and the first key secondary endpoint OS, there 
is 1 additional key secondary endpoint: OS in high-risk patients carrying del(17). This key 
secondary endpoint will be tested only if the test of OS is statistically significant at the IAs 
or final analysis at the same significance level as OS to ensure strong type I error control for 
both key secondary endpoints.
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. 
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 IAs and final analysis 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.
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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. 
Overall Survival in High-Risk Patients With del(17)
OS within the high-risk subgroup will be analyzed using the similar method as OS in the 
overall population. 
8.1.6.3   
Analyses of Other Secondary Efficacy Endpoints
Other secondary efficacy parameters include overall response rate (ORR), the combined 
CR + VGPR rate, time to progression, duration of response, time to subsequent 
antineoplastic therapy, OS and PFS in high-risk population carrying del(13), del(17), +1q21, 
translocation t(4;14) or t(14;16), and pain response rate. 
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. Stratified Cochran-Mantel-Haenszel (CMH) test will be used to compare ORR 
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.
The IRC-assessed response data will be used for the analysis. Investigator-assessed response 
data will be used as sensitivity analysis.
Combined CR + VGPR rate
The combined CR + VGPR rate will be analyzed using the same similar method as ORR. 
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.
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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.
OS and PFS in High-Risk Population
OS and PFS in a high-risk population, defined as patients carrying del(13), del(17), +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   
Quality of Life Analysis
Patient-reported outcome (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
EQ-5D scores will be summarized in descriptive statistics for treatment arms. 
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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.
8.1.7.3   
Pain 
Pain response rate will be analyzed in patients with baseline 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. The CMH test will be used to compare the 
2 treatment groups by stratification factors. In addition, the absolute treatment difference in 
pain response rate will be provided, along with 95% CI.
Pain response is defined as the occurrence of a 30% reduction from baseline in BPI-SF 
worst pain score over the last 24 hours without an increase in analgesic use at 2 consecutive 
evaluations. 
Additional analyses on pain include:

Time to pain response/progression, as assessed by the time from randomization to 
initial response/progression classification

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 among patients with pain response. 
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 progression.

A ≥ 2 point and 30% increase from baseline in BPI-SF worst pain score without an 
increase in analgesic use, or
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!
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
Confirmation is not required if surgical treatment for pain, palliative radiation for pain, or 
subsequent antineoplastic therapy has been received prior to a confirmatory assessment 
(refer to Section 15.2 for a list of Step II and III analgesics). 
In addition to the primary analysis for pain response rate, the change in BPI-SF worst pain 
scores between baseline and each postbaseline assessment will be described overall and 
according to the response to treatment. 
8.1.8   
Pharmacokinetics and Biomarkers
Pharmacokinetic Analysis
PK data collected in this study will contribute to population PK analyses.
As of Amendment 6, PK sample collection has been completed for all patients. The PK 
sampling schedule has been moved to Section 15.12.
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8.1.9   
Safety Analysis
Summary tabulations will be presented that 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. 
Safety will be evaluated by the incidence of AEs, severity and type of AEs, and by changes 
from baseline in the patient’s vital signs, weight, and clinical laboratory results using the 
safety population. Exposure to study drug and reasons for discontinuation will be tabulated.
Treatment-emergent AEs that occur after administration of the first dose of study drug and 
through 30 days after the last dose of study medication 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 discontinuation will be 
provided.
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Development of new or worsening of existing selected SREs (eg, new fractures [excluding 
vertebral compression or rib 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.
Descriptive statistics for the actual values and 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 post baseline value. Graphical displays of key safety 
parameters, such as scatter plots of baseline versus worst post baseline values, may be used 
to understand the MLN9708 safety profile.
All concomitant medications collected from the first dose of study drug through the study 
period will be classified to preferred terms according to the World Health Organization 
(WHO) drug dictionary.
Additional safety analyses may be performed to most clearly enumerate rates of toxicities 
and to further define the safety profile of MLN9708.
8.1.10   
Interim Analyses
There are 3 planned IAs. The first IA will be performed when approximately 262 of the 
disease progression/death events have occurred. This IA is expected to occur approximately 
24.5 months after the first patient is enrolled. This is the first analysis for PFS for statistical 
testing purpose and first IA for OS. During this IA, enrollment to the study will continue. If 
the test for PFS is not statistically significant at 2 sided alpha level of 0.0163, the study will 
continue and PFS testing will be conducted again at the second IA when approximately 
365 PFS events have occurred, which will also be the final analysis of PFS for statistical 
testing purpose. Based on the projected number of PFS events, the statistical significance of 
PFS could be claimed if the observed p value is less than 0.0451 (corresponding to nominal 
alpha of 0.0337). The trial will not be stopped due to the test for OS at the first IA. The third 
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IA will be performed when approximately 322 deaths (two-thirds of the total expected 
deaths) have been observed. The third IA is expected to occur approximately 44 months 
after the first patient is enrolled. At that time, all patients have been enrolled. 
The test significance for the interim and final analyses of OS will be determined using 
O’Brien-Fleming boundaries (the Lan-DeMets method). Based on the projected number of 
death events, the trial will be stopped for overwhelming efficacy if the observed p value is 
less than 0.0018 and 0.0112 at the second and third IA, respectively. The final analysis will 
be tested at 2-sided alpha level of 0.0462 (corresponding to nominal alpha of 0.0382).
9.   
STUDY COMMITTEES 
9.1   
Steering Committee
A steering committee that includes a subset of investigators in this study and representatives 
from Millennium will be formed to provide advice on the conduct of the study and 
publications (see also Section 12).
9.2   
Independent Review Committee
An independent review committee (IRC) has completed review of all disease evaluation data 
from the study and determined disease status (response and progression). Data from the IRC 
will not be provided back to the investigator during the conduct of the study. As of 
Amendment 6, however, because PFS follow-up is now completed for this study, for all 
patients still receiving study therapy, no further IRC reviews of disease response will take 
place. 
9.3   
Independent Data Monitoring Committee
An IDMC supported by an independent statistician will review safety and efficacy data at 
3 planned IAs. The IDMC will provide a recommendation regarding study continuation 
based on the safety and efficacy parameters. In the event that the study is terminated early 
based on the IDMC recommendation, 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.
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The first formal safety review will occur after approximately 60 subjects (30 in each arm) 
have been randomized and received at least 1 cycle of study treatment. Subsequently, 
periodic safety reviews will also occur as prespecified in the IDMC charter.
Study accrual will not be interrupted 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, treatment-related, and 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 
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previous condition that has increased in severity or frequency since the administration of 
study drug.
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is 
considered by the investigator to be a clinically significant change from baseline. 
10.1.3   
Serious Adverse Event Definition
Serious AE (SAE) means any untoward medical occurrence that at any dose:

Results in death.

Is life-threatening (refers to an AE in which the patient was at risk of death at the 
time of the event. It does not refer to an event which hypothetically might have 
caused death if it were more severe).

Requires inpatient hospitalization or prolongation of an existing hospitalization
(see clarification in the paragraph below on planned hospitalizations).

Results in persistent or significant disability or incapacity. (Disability is defined 
as a substantial disruption of a person’s ability to conduct normal life functions).

Is a congenital anomaly/birth defect.

Is a medically important event. This refers to an AE that may not result in death, be 
immediately life threatening, or require hospitalization, but may be considered 
serious when, based on appropriate medical judgment, may jeopardize the patient, 
require medical or surgical intervention to prevent 1 of the outcomes listed above, or 
involves suspected transmission via a medicinal product of an infectious agent. 
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or 
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.[51] Clarification should be 
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made between a serious AE (SAE) and an AE that is considered severe in intensity (Grade 3 
or 4), because the terms serious and severe are NOT synonymous. The general term severe
is often used to describe the intensity (severity) of a specific event; the event itself, however, 
may be of relatively minor medical significance (such as a Grade 3 headache). This is NOT 
the same as serious, which is based on patient/event outcome or action criteria described 
above, and is usually associated with events that pose a threat to a patient’s life or ability to 
function. A severe AE (Grade 3 or 4) does not necessarily need to be considered serious. For 
example, a white blood cell count of 1000/mm3 to less than 2000 is considered Grade 3 
(severe) but may not be considered serious. Seriousness (not intensity) serves as a guide for 
defining regulatory reporting obligations.
10.2   
Procedures for Recording and Reporting 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) by faxing the SAE Form within 24 hours after becoming aware of the event. The 
SAE Form, created specifically by Millennium, will be provided to each clinical study site. 
A sample of the SAE Form may be found in the Study Manual. Follow-up information on 
the SAE or serious pretreatment event may be requested by Millennium. SAE report 
information must be consistent with the data provided on the eCRF.
The paper SAE forms must be submitted via fax (see fax numbers below) within 24 hours of 
awareness. In case of fax, site personnel must confirm successful transmission of all pages 
and include an e-mail address on the fax cover sheet so that an acknowledgment of receipt 
can be returned via e-mail within 1 business day. E-mail submission of paper SAE forms 
with a PDF attachment should only be used in the case where fax is not possible within 24 
hours of receiving the event. In case of e-mail, site personnel must confirm successful 
transmission by awaiting an acknowledgment of the receipt via e-mail within 1 business 
day. If SAEs are reported via fax or by e-mail, the EDC application must be updated as soon 
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as possible with the appropriate information.
Planned hospital admissions or surgical procedures for an illness or disease that existed 
before the patient was enrolled in the study are not to be considered AEs unless the 
condition deteriorated in an unexpected manner during the study (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.[51] 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?
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10.3   
Monitoring of Adverse Events and Period of Observation
AEs, both nonserious and serious, will be monitored throughout the study as follows:
!
AEs will be reported from the first dose of study drug through 30 days after 
administration of the last dose of study drug and recorded in the eCRFs. In addition, 
skeletal-related events that occur during the follow-up periods must be reported from 
the first dose of study drug through death or termination of the study by the sponsor. 
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 Millennium 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 Millennium 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 
comes first, and recorded in the eCRF. After this period only related SAEs must be 
reported to the Millennium Department of Pharmacovigilance or designee. Serious 
adverse events should be monitored until they are resolved or are clearly determined 
to be due to a patient’s stable or chronic condition or intercurrent illness(es). In 
addition, new primary malignancies that occur during the follow-up periods must be 
reported, irrespective of causality to study regimen, to the Millennium Department of 
Pharmacovigilance for a minimum of 3 years after last dose of the investigational 
product, from the first dose of study drug through death or termination of the study
by the sponsor. 
10.4   
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of 
age or disease state) of a female subject occurring while the subject is on study drug, or 
within 90 days of the subject’s last dose of study drug, are considered immediately 
reportable events. Study drug is to be discontinued immediately. The sponsor must also be 
contacted immediately by faxing a completed Pregnancy Form to the 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 
 Drug Safety 
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immediately by facsimile, or other appropriate method, using the Pregnancy Initial Report 
Form, or approved equivalent form. The female subject should be referred to an obstetrician-
gynecologist, preferably one experienced in reproductive toxicity for further evaluation and 
counseling.
The Investigator will follow the female subject until completion of the pregnancy, and must 
notify 
 Drug Safety 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 
Drug Safety 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 IP should also be reported to 
 Drug Safety 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 their 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.
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11.   
ADMINISTRATIVE REQUIREMENTS
11.1   
Good Clinical Practice
The study will be conducted in accordance with the ICH-GCP and the appropriate regulatory 
requirement(s). The investigator will be thoroughly familiar with the appropriate use of the 
study drug as described in the protocol and the IB.
11.2   
Data Quality Assurance
The investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each study 
patient. Study data will be entered into an eCRF by site personnel using a secure, validated, 
web-based electronic data capture (EDC) application. Millennium will have access to all 
data upon entry in the EDC application. 
Study monitors will discuss instances of missing or uninterpretable data with the 
investigator for resolution. Any changes to study data will be made to the eCRF and 
documented via an electronic audit trail associated with the affected eCRF.
11.3   
Electronic Case Report Form Completion 
Millennium or designee will provide the study sites with secure access to and training on the 
EDC application, sufficient to permit site personnel to enter or correct information in the 
eCRFs for the patients for whom they are responsible.
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.
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Millennium, or a designee, will retain the eCRF data and corresponding audit trails. A copy 
of the final archival eCRF in the form of a compact disk (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.
All information recorded on the eCRFs for this study must be consistent with the patient’s 
source documentation. During the course of the study, the study monitor will make study 
site visits to review protocol compliance, verify eCRFs against source documentation, assess 
drug accountability, and ensure that the study is being conducted according to pertinent 
regulatory requirements. The review of medical records will be performed in a manner that 
ensures that patient confidentiality is maintained. 
In the event a monitor cannot visit the site in a timely manner due to the COVID-19 
pandemic, alternative monitoring approaches such as remote source data verification (SDV) 
or telephone contact may be used to ensure data quality and integrity and maintain patient 
safety. Alternative monitoring approaches should be used only where allowed by the local 
Health Authority and permitted by the IRB/IEC.
11.5   
Ethical Considerations
The study will be conducted 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.
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Upon implementation of Amendment 8, patients on study treatment must be reconsented 
before dosing on Day 1 of the next full treatment cycle. Written consent documents will 
embody the elements of informed consent as described in the Declaration of Helsinki and 
the ICH Guidelines for GCP and will be in accordance with all applicable laws and 
regulations.
11.7   
Patient Confidentiality
To maintain patient privacy, all eCRFs, study drug accountability records, study reports, and 
communications will identify the patient by initials where permitted and/or by the assigned 
patient number. The patient’s confidentiality will be maintained and will not be made 
publicly available to the extent permitted by the applicable laws and regulations.
11.8   
Investigator Compliance
The investigator will conduct the trial in compliance with the protocol provided by 
Millennium and given approval/favorable opinion by the IRB/IEC and the appropriate 
regulatory authority(ies). Modifications to the protocol are not to be made without 
agreement of both the investigator and Millennium. Changes to the protocol will require 
written IRB/IEC approval/favorable opinion before implementation, except when the 
modification is needed to eliminate an immediate hazard or hazards to patients. Millennium, 
or a designee, will submit all protocol modifications to the appropriate regulatory 
authority(ies) in accordance with the governing regulations.
When immediate deviation from the protocol is required to eliminate an immediate hazard 
or hazards to patients, the investigator will contact Millennium, or a designee, if 
circumstances permit, to discuss the planned course of action. Any departures from the 
protocol must be documented.
11.9   
On-site Audits
Regulatory authorities, the IEC/IRB, and/or Millennium/designee 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 
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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. Refer to the 
Pharmacy Manual for additional details.
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. Individuals who 
identify a potential medication error situation should immediately report this via the phone 
number or e-mail address provided below.
For Product Complaints or Medication Errors (Including 
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
The study will be considered complete after the third interim analysis (if OS endpoints are 
met) or after the final analysis for OS has been completed or the study has been terminated 
by the sponsor. Patients remaining on study after the final analysis will be assessed for either 
Property of Takeda: For N
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access to commercial drug supply (if available and reimbursable in their region) or 
continued treatment in another extension or rollover study, if and when such a study is made 
available.
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 study results will be 
submitted to the competent authorities and IECs in all member states involved in the study.
Study participation by individual sites or the entire study may be prematurely terminated if, 
in the opinion of the investigator or Millennium, there is sufficient reasonable cause. Written
notification documenting the reason for study termination will be provided to the 
investigator or Millennium by the terminating party.
Circumstances that may warrant termination include, but are not limited to:

Determination of unexpected, significant, or unacceptable risk to patients

Failure to enter patients at an acceptable rate

Insufficient adherence to protocol requirements

Insufficient, incomplete, and/or unevaluable data

Determination of efficacy based on interim analyses

Plans to modify, suspend or discontinue the development of the study drug
Should the study be closed prematurely, the site will no longer be able to access the EDC 
application, will not have a right to use the EDC application, and will cease using the 
password or access materials once their participation in the study has concluded. In the event 
that any access devices for the EDC application have been provided, these will be returned 
to Millennium once the site’s participation in the study has concluded.
Within 15 days 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.
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11.13   Record Retention
The investigator will maintain all study records according to the ICH-GCP and applicable 
regulatory requirement(s). Records will be retained for at least 2 years after the last 
marketing application approval or 2 years after formal discontinuation of the clinical 
development of the investigational product or according to applicable regulatory 
requirement(s). If the investigator withdraws from the responsibility of keeping the study 
records, custody must be transferred to a person willing to accept the responsibility and 
Millennium notified. 
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12.   
USE OF INFORMATION
All information regarding 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 study results pursuant
to the terms contained in the applicable Clinical Trial Agreement.
A Steering Committee that includes a subset of investigators in this study and 
representatives from Millennium will be formed to advise on the conduct of the study and 
development of publications and presentations. This policy may be changed with the 
agreement of both the investigators and Millennium.
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13.   
INVESTIGATOR AGREEMENT
I have read Protocol C16010 Amendment 8: 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 Relapsed 
and/or Refractory Multiple Myeloma.
I agree to conduct the study as detailed herein and in compliance with Good Clinical 
Practice and applicable regulatory requirements and to inform all who assist me in the 
conduct of this study of their responsibilities and obligations.
Principal investigator printed name
Principal investigator signature
Date
Investigational site or name of institution and 
location (printed)
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14.   
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Qiu L, Wang Y, Qi P, Zou D, Zhao Y, Qi J. Clinical Epidemiological Study on 
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Richardson P, Baz R, Wang L, Jakubowiak A, Berg D, Liu G, et al. Investigational 
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Kumar S, Bensinger W, Reeder C, Zimmerman T, Berenson J, Berg D, et al. Weekly 
Dosing of the Investigational Oral Proteasome Inhibitor MLN9708 in Patients with 
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Gupta N, Saleh M, Venkatakrishnan K. Flat-Dosing Versus BSA-Based Dosing for 
MLN9708, An Investigational Proteasome Inhibitor: Population Pharmacokinetic 
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1433.
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Berdeja J, Richardson P, Lonial S, Niesvizky R, Hui A-M, Berg D, et al. Phase 1/2 
Study of Oral MLN9708, A Novel, Investigational Proteasome Inhibitor, in 
Combination with Lenalidomide and Dexamethasone in Patients with Previously 
Untreated Multiple Myeloma (MM). Abstract 469. 53rd ASH Annual Meeting and 
Exposition; 10-13 December 2011; San Diego, CA.
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Smith D, Infante J, Siu L, Sullivan D, Vlahovic G, Kauh J, et al. Phase 1 study of 
ixazomib citrate (MLN9708), an investigational proteasome inhibitor, in advanced 
nonhematologic malignancies: Updated results. 36th European Society for Medical 
Oncology (ESMO) Congress; 23-27 September 2011; Stockholm, Sweden.
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Assouline S, Chang J, Rifkin R, Hui A-M, Berg D, Gupta N, et al. MLN9708, a 
Novel, Investigational Proteasome Inhibitor, in Patients with Relapsed/Refractory 
Lymphoma: Results of a Phase 1 Dose-Escalation Study Blood (ASH Annual 
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Richardson P, Mitsiades C, Schlossman R, Ghobrial I, Hideshima T, Chauhan D, et 
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al. The treatment of relapsed and refractory multiple myeloma. Hematology 
2007:317-23.
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Oncology (NCCN Guidelines):  Multiple Myeloma, Version 1.2011.
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Anderson K, Weller E, Lonial S, Jakubowiak A, Jagannath S, Raje N, et al. 
Lenalidomide, bortezomib, and dexamethasone in patients with newly diagnosed 
multiple myeloma (MM): Updated Results of a Multicenter Phase I/II Study after 
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abstr 8016.
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Kumar S, Flinn I, Richardson P, Hari P, Callander N, Noga S, et al. Novel Three-
and Four-Drug Combination Regimens of Bortezomib, Dexamethasone, 
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Richardson PG, Weller E, Lonial S, Jakubowiak AJ, Jagannath S, Raje NS, et al. 
Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with 
newly diagnosed multiple myeloma. Blood 2010;116(5):679-86.
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Dick LR, Fleming PE. Building on bortezomib: second-generation proteasome 
inhibitors as anti-cancer therapy. Drug Discov Today 2010.
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Chauhan D, Tian Z, Hideshima T, Munshi N, Richardson P, Anderson K. An 
Investigational Novel Orally Bioavailable Proteasome Inhibitor 
MLN9708/MLN2238 Triggers Cytotoxicity In Multiple Myeloma Cells Via p21-
and Caspase-8-Dependent Signaling Pathway. Blood (ASH Annual Meeting 
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Richardson PG, Laubach J, Mitsiades C, Schlossman RL, Doss D, Colson K, et al. 
Tailoring treatment for multiple myeloma patients with relapsed and refractory 
disease. Oncology (Williston Park) 2010;24(3 Suppl 2):22-9.
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Kumar SK, Flinn I, Noga SJ, Hari P, Rifkin R, Callander N, et al. Bortezomib, 
dexamethasone, cyclophosphamide and lenalidomide combination for newly 
diagnosed multiple myeloma: phase 1 results from the multicenter EVOLUTION 
study. Leukemia 2010;24(7):1350-6.
23.
Mathijssen RH, de Jong FA, Loos WJ, van der Bol JM, Verweij J, Sparreboom A. 
Flat-fixed dosing versus body surface area based dosing of anticancer drugs in 
adults: does it make a difference? Oncologist 2007;12(8):913-23.
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In vivo dose-response evaluation of Aurora kinase inhibitor SYR134901 in H460 
human non-small cell lung carcinoma implanted in nude rats. Takeda San Diego, Inc.
25.
Baker SD, Verweij J, Rowinsky EK, Donehower RC, Schellens JH, Grochow LB, et 
al. Role of body surface area in dosing of investigational anticancer agents in adults, 
1991-2001. J Natl Cancer Inst 2002;94(24):1883-8.
26.
Felici A, Verweij J, Sparreboom A. Dosing strategies for anticancer drugs: the good, 
the bad and body-surface area. Eur J Cancer 2002;38(13):1677-84.
27.
Shaughnessy JD, Jr., Zhan F, Burington BE, Huang Y, Colla S, Hanamura I, et al. A 
validated gene expression model of high-risk multiple myeloma is defined by 
deregulated expression of genes mapping to chromosome 1. Blood 
2007;109(6):2276-84.
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Nair B, van Rhee F, Shaughnessy JD, Jr., Anaissie E, Szymonifka J, Hoering A, et 
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al. Superior results of Total Therapy 3 (2003-33) in gene expression profiling-
defined low-risk multiple myeloma confirmed in subsequent trial 2006-66 with VRD 
maintenance. Blood 2010;115(21):4168-73.
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Broyl A, Hose D, Lokhorst H, de Knegt Y, Peeters J, Jauch A, et al. Gene expression 
profiling for molecular classification of multiple myeloma in newly diagnosed 
patients. Blood 2010;116(14):2543-53.
30.
Mulligan G, Mitsiades C, Bryant B, Zhan F, Chng WJ, Roels S, et al. Gene 
expression profiling and correlation with outcome in clinical trials of the proteasome 
inhibitor bortezomib. Blood 2007;109(8):3177-88.
31.
Keats JJ, Fonseca R, Chesi M, Schop R, Baker A, Chng WJ, et al. Promiscuous 
mutations activate the noncanonical NF-kappaB pathway in multiple myeloma. 
Cancer Cell 2007;12(2):131-44.
32.
Chapman MA, Lawrence MS, Keats JJ, Cibulskis K, Sougnez C, Schinzel AC, et al. 
Initial genome sequencing and analysis of multiple myeloma. Nature 
2011;471(7339):467-72.
33.
Mulligan G, Lichter D, Di Bacco A, Blakemore S, Berger A, Koenig E, et al. 
Mutational Analysis of Tumor Samples From Patients with Relapsed or Refractory 
Multiple Myeloma (MM) Highlights the Prevalence of RAS/RAF Pathway 
Activation and Demonstrates Previously Unreported Mutations in Known Cancer 
Genes. Blood (ASH Annual Meeting Abstracts) 2011;118(21):abstr 1377.
34.
Coiffier B, Osmanov E, Hong X, Scheliga A, Mayer J, Offner F, et al. A Phase 3 
Trial Comparing Bortezomib Plus Rituximab With Rituximab Alone in Patients 
With Relapsed, Rituximab-Naive or -Sensitive, Follicular Lymphoma. Abstract 857. 
52nd ASH Annual Meeting and Exposition; 4-7 December; Orlando, FL.
35.
Du J, Huo J, Shi J, Yuan Z, Zhang C, Fu W, et al. Polymorphisms of nuclear factor-
{kappa}B family genes are associated with development of multiple myeloma and 
treatment outcome in patients receiving bortezomib-based regimens. Haematologica 
2011;96(5):729-37.
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Jakob C, Egerer K, Liebisch P, Turkmen S, Zavrski I, Kuckelkorn U, et al. 
Circulating proteasome levels are an independent prognostic factor for survival in 
multiple myeloma. Blood 2007;109(5):2100-5.
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Fonseca R, Bergsagel PL, Drach J, Shaughnessy J, Gutierrez N, Stewart K, et al. 
International Myeloma Working Group molecular classification of multiple 
myeloma: spotlight review. Leukemia 2009;23:2210-21.
38.
Klein U, Jauch A, Hielscher T, Hillengass J, Raab MS, Seckinger A, et al. 
Chromosomal aberrations +1q21 and del(17p13) predict survival in patients with 
recurrent multiple myeloma treated with lenalidomide and dexamethasone. Cancer 
2011;117(10):2136-44.
39.
Sonneveld P, Schmidt-Wolf I, van der Holt B, el Jarari L, Bertsch U, Salwender H, 
et al. HOVON-65/GMMG-HD4 Randomized Phase III Trial Comparing 
Bortezomib, Doxorubicin, Dexamethasone (PAD) Vs VAD Followed by High-Dose 
Melphalan (HDM) and Maintenance with Bortezomib or Thalidomide In Patients 
with Newly Diagnosed Multiple Myeloma (MM). Blood (ASH Annual Meeting 
Abstracts) 2010;116(21):abstr 40.
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Neben K, Jauch A, Bertsch U, Heiss C, Hielscher T, Seckinger A, et al. Combining 
information regarding chromosomal aberrations t(4;14) and del(17p13) with the 
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International Staging System classification allows stratification of myeloma patients 
undergoing autologous stem cell transplantation. Haematologica 2010;95(7):1150-7.
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1983;70:659-63.
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Rajkumar SV, Harousseau JL, Durie B, Anderson KC, Dimopoulos M, Kyle R, et al. 
Consensus recommendations for the uniform reporting of clinical trials: report of the 
International Myeloma Workshop Consensus Panel 1. Blood 2011;117(18):4691-5.
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2010.
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DEXAMETHASONE Tablets USP, DEXAMETHASONE Oral Solution [package 
insert]. Columbus (OH): Roxane Laboratories, Inc, a division of Boehringer 
Ingelheim, September 2007.
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Palumbo A, Rajkumar SV, Dimopoulos MA, Richardson PG, San Miguel J, Barlogie 
B, et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in 
myeloma. Leukemia 2008;22(2):414-23.
46.
Lyman GH, Khorana AA, Kuderer NM, Lee AY, Arcelus JI, Balaban EP, et al. 
Venous thromboembolism prophylaxis and treatment in patients with cancer: 
American Society of Clinical Oncology clinical practice guideline update. J Clin 
Oncol 2013;31(17):2189-204.
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Sviggum HP, Davis MD, Rajkumar SV, Dispenzieri A. Dermatologic adverse effects
of lenalidomide therapy for amyloidosis and multiple myeloma. Arch Dermatol 
2006;142(10):1298-302.
48.
Castaneda CP, Brandenburg NA, Bwire R, Burton GH, Zeldis JB. Erythema 
multiforme/Stevens-Johnson syndrome/toxic epidermal necrolysis in lenalidomide-
treated patients. J Clin Oncol 2009;27(1):156-7.
49.
Bladé J, Samson D, Reece D, Apperley J, Bjorkstrand B, Gahrton G, et al. Criteria 
for evaluating disease response and progression in patients with multiple myeloma 
treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma 
Subcommittee of the EBMT. European Group for Blood and Marrow Transplant. Br 
J Haematol 1998;102(5):1115-23.
50.
Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, et al. A 
Phase 2 Study of Bortezomib in Relapsed, Refractory Myeloma. N Engl J Med 
2003;348(26):2609-17.
51.
Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03. U.S. 
Department of Health and Human Services National Cancer Institute. 14 June 2010.
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Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. 
Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J 
Clin Oncol 1982;5(6):649-55.
53.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. 
Nephron 1976;16(1):31-41.
54.
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.
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Knoben J, Anderson P. Handbook of Clinical Drug Data, 6th ed.: Drug Intelligence 
Pub, Inc.; 1988.
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Foley KM. The treatment of cancer pain. N Engl J Med 1985;313(2):84-95.
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Durie BG, Harousseau JL, Miguel JS, Blade J, Barlogie B, Anderson K, et al. 
International uniform response criteria for multiple myeloma. Leukemia 
2006;20(9):1467-73.
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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 et al. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5 (6):649-55.[52]
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
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.[53]
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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.[54]
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.[55]
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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 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.[56]
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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.[7]
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 oral morphine equivalent (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.[7]
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 [57]).
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)
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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 
Patients will be assessed for disease response according to the IMWG criteria below, 
versions 2006 and 2011.
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International Myeloma Working Group Uniform Response Criteria: Disease 
Progression and Relapse [58]
Relapse Subcategory
Relapse Criteria
Progressive disease (PD)a
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)
Progressive Disease: 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 plasmacytomasc
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 anytime 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.
c A definite increase of plasmacytoma is defined as a 50% (and at least 1 cm) increase as measured serially 
by the sum of the products of the cross-diameters of the measurable lesion.
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15.12   Full Schedule of Events (as of Amendment 3)
This full Schedule of Events is no longer in effect, as of Amendment 8.
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 daysb
± 1 wk
± 1 wk
± 1 wk
Informed Consent
X
Inclusion/Exclusion Criteriac
X
Demographics
X
Complete Medical History
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) & Weight (kg)
Xd
Xd
Pregnancy Teste
X
X
X
X
X
X
X
X
X
X
12-lead ECG 
X
X
X
Hematology Laboratoryf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry Laboratoryf
X
X
X
X
X
X
X
Thyroid testing
X
Xg
Xg
X
Urinalysis
X
X
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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 daysb
± 1 wk
± 1 wk
± 1 wk
EORTC-QLQ-C30 and 
MY-20h
X
X
X
Xi
Xi
X
X
EQ-5Dh
X
X
X
X
X
X
X
X
X
BPI-SF & 24 hour analgesic 
form (also for unscheduled 
visit)h
X
X
X
X
X
X
X
X
HU Asssessmenth
X
X
X
X
X
X
X
X
Skeletal Surveyj
X
X
X
X
Radiographic Disease 
Assessmentk
X
X
X
X
X
X
2-microglobulin
X
M-protein Measurements 
(SPEP)
X
Xl
X
X
X
X
X
X
M-protein Measurements 
(UPEP [24hr Urine 
collection])
X
Xl
X
X
X
X
X
X
Serum Free Light Chain 
Assay
X
Xl
X
X
X
X
X
X
Immunofixation - serum and 
urine
X
Xl
X
X
X
X
X
X
Quantification of Ig
X
Xl
X
X
X
X
X
X
Bone Marrow Aspiration
Disease Assessment
Xm
Xm
Xm
Xm
Xm
Xm
Xm
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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 daysb
± 1 wk
± 1 wk
± 1 wk
Molecular analysis and 
high-risk cytogenetic 
assessment 
Xn
Xn
Cytogenetics
Xo
Blood samples for 
biomarker analysis
Plasma biomarker 
(proteasome level)
X
Blood samples for 
germline DNA 
X
Adverse Event Reporting
Recorded from the first dose of study drug through 30 days after last dose of study drug
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 any study drug
Concomitant 
Medications/Procedures
Recorded from the first dose of study drug through 30 days after last dose of study drug
Skeletal-related Events
Continuous from the start of study drug administration until death or termination of the study by the sponsor
New Primary Malignancy 
Assessment
Continuous from the start of study drug administration until death or termination of the study by the sponsor
Survival
X
Study Drug Administration
MLN9708/Placebo
Days 1, 8, and 15 of each cycle
Lenalidomide
Continuous D1-21 of each cycle
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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 daysb
± 1 wk
± 1 wk
± 1 wk
Dexamethasone
Days 1, 8, 15 and 22 of each cycle
Abbreviations: D = study day; del = deletion; ECOG = Eastern Cooperative Oncology Group; OS = overall survival; PET-CT = positron emission tomography-
computed tomography; PFS = progression-free survival; SPEP = serum protein electrophoresis; t = translocation; UPEP = urine protein electrophoresis; wk = week.
a Review by MPI/designee clinician required prior to discontinuing patient from treatment.
b Tests and procedures should be performed on schedule, but occasional changes may be allowed (± 2 days) 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. If extenuating circumstances 
prevent a patient from beginning treatment or completing a scheduled procedure or assessment within this time, the patient may continue the study only with the 
permission of the MPI/designee clinician.
c Confirmation of patient eligibility by MPI/designee clinician required prior to randomization.
d Height assessed at screening only.
e Pregnancy tests (Refer to Section 7.4.7):

Screening: Females of childbearing potential (FCBP) must have 2 negative pregnancy tests prior to starting study drug. The first pregnancy test must be 
performed within 10 to 14 days prior to the start of study drug and the second pregnancy test must be performed within 24 hours prior to the start of study drug.

On-Treatment: Pregnancy tests for FCBP to be collected weekly during Cycle 1 and then within 24 hours before the first dose of 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.

End of Treatment: Pregnancy tests for FCBP to be collected at treatment discontinuation and at Day 28 following therapy. If menstrual cycles are irregular, the 
pregnancy testing must occur at drug discontinuation and at Days 14 and 28 following drug discontinuation.
f
Clinical laboratory evaluations will be performed by a central laboratory. For dosing decisions, local hematology and chemistry laboratory results may be used; 
however, samples must still be sent to central labs as well. 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 
TEAEs (refer to Section 7.4.9). 
g Thyroid testing required every 4 cycles on treatment.
h Patient-reported outcomes and HU assessment should be completed before any other study procedures are performed or study drug is administered. During the OS 
follow-up, assessments can be made over the phone and do not require a clinic visit. (Refer to Sections 7.4.11 to 7.4.14.)
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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 daysb
± 1 wk
± 1 wk
± 1 wk
i
Required every other cycle, after Cycle 2 (ie, Cycles 1, 2, 4, 6, etc.) during the treatment period.
j
Skeletal survey will be performed at screening (within 8 weeks prior to the first dose of study drug) and, at a minimum, annually for all patients. More frequent 
assessments can be done at the discretion of the investigator (ie, for suspected increased or new bone lesions). 
k Patients with documented extramedullary disease must have radiographic disease assessments (CT/PET-CT/MRI) performed at screening, every other cycle during 
treatment, and every 8 weeks during the PFS follow-up period, until disease progression. 
l
If the screening test was performed more than 14 days prior to the first dose, the test will be repeated at baseline.
m To be performed at local lab to assess disease status at baseline. 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.
n Bone marrow aspirate (first or second pull preferred) for molecular analysis and cytogenetics are required to be sent to the central lab at baseline. For patients who 
had responded to therapy and subsequently relapsed, a bone marrow aspirate sample is requested at end of study treatment. This sample is not mandatory but highly 
recommended.
o Cytogenetics may also be done locally if the site has the capability to perform analysis and sufficient specimen available. Assessment of the following: +1q21, 
translocations t(4;14) and t(14;16), del(17), del(13). 
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MLN9708 Pharmacokinetic Sampling Schedule
Cycle 1
Cycle 2
Cycles 3-10
Day 1 
Day 14 
Day 1 
Day 14 
Day 1 
1 hour postdosea
(15 minutes)
4 hour postdosea
(45 minutes)
Predosec
Predosec
X
X
Xb
X
Xb
X
a Sample to be obtained after  MLN9708 and can be obtained either before or after lenalidomide and dexamethasone dose.
b If PK sample is taken on a dosing day (due to allowable 2-day window of visits), PK sample must be taken within 4 hours prior to dose of any 
study drug. If PK sample is taken on non-dosing day, ie sample on Day 14 and dose on Day 15, PK sample can be taken at any time during the 
visit. 
c Day 1 predose PK assessments should occur within 4 hours of dosing. Note: If a pre-dose sample is drawn from a patient and the patient does not 
receive a dose on that protocol visit day, a second pre-dose sample does not need to be drawn on the subsequent visit where the dose is 
administered. All future visits should be done per the protocol.
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15.13
Schedule of Events (as of Amendment 6)
This full Schedule of Events is no longer in effect, as of Amendment 8.
Study Procedures
Treatment Period
End of Treatment
OS Follow-up
28-Day Cycles
Every 12 weeks
Cycle
Cycle 13 and Beyond
Days
1
Window
± 2 daysa
± 1 wk 
± 1 wk
Complete Physical Exam
X
Symptom-Directed 
Physical Exam
X
ECOG Performance Status
X
X
Vital Signs
X
X
Weight (kg)
X
Pregnancy Testb
X
X
12-lead ECG 
X
Hematology Laboratoryc
X
X
Chemistry Laboratoryc
X
X
EORTC-QLQ-C30 and 
MY-20d
Xe
X
EQ-5Dd
X
X
X
HU Asssessmentd
X
X
BPI-SF & 24 hour 
analgesic form (also for 
unscheduled visit)d
X
X
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Study Procedures
Treatment Period
End of Treatment
OS Follow-up
28-Day Cycles
Every 12 weeks
Cycle
Cycle 13 and Beyond
Days
1
Window
± 2 daysa
± 1 wk 
± 1 wk
Bone Marrow Aspiration
for molecular analysis and 
high-risk cytogenetic 
assessment 
Xf
Adverse Event Reporting
Recorded from the first dose of study drug through 30 days after last dose of study drug
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 any study drug
Concomitant 
Medications/Procedures
Recorded from the first dose of study drug through 30 days after last dose of study drug
Skeletal-related Events
Continuous from the start of study drug administration until death or termination of the study by the sponsor
New Primary Malignancy 
Assessment
Continuous from the start of study drug administration until death or termination of the study by the sponsor
Survival
X
Study Drug Administration
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; PET-CT = positron emission tomography-
computed tomography; PFS = progression-free survival; SPEP = serum protein electrophoresis; t = translocation; UPEP = urine protein electrophoresis; wk = 
week.
a Tests and procedures should be performed on schedule, but, unless otherwise specified, occasional changes are allowable within a 2-day window for 
holidays, vacations, and other administrative reasons or a longer window after discussion with the Millennium Pharmaceuticals Inc. (Millennium) project 
clinician or designee. If the study schedule is shifted, assessments must be shifted to ensure that collection of assessments is completed before dosing. .
b Pregnancy tests (Refer to Section 7.4.7):
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Study Procedures
Treatment Period
End of Treatment
OS Follow-up
28-Day Cycles
Every 12 weeks
Cycle
Cycle 13 and Beyond
Days
1
Window
± 2 daysa
± 1 wk 
± 1 wk

On-Treatment: Pregnancy tests for FCBP to be collected weekly during Cycle 1 and then within 24 hours before the first dose of 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.

End of Treatment: Pregnancy tests for FCBP to be collected at treatment discontinuation and at Day 28 following therapy. If menstrual cycles are 
irregular, the pregnancy testing must occur at drug discontinuation and at Days 14 and 28 following drug discontinuation.
c Centralized clinical laboratory evaluations of safety will be performed by a central laboratory on Day 1 of every cycle. For dosing decisions and for all other 
safety assessments for the patient, local hematology and chemistry laboratory results may be used; however, samples must still be sent to central labs as well. 
Hematology and chemistry panels may be collected up to 3 days before Day 1 dosing. Local laboratory evaluations may be done more frequently at the 
investigators discretion, ie, for acute management of TEAEs (refer to Section 7.4.9). 
d Patient-reported outcomes and HU assessment should be completed before any other study procedures are performed or study drug is administered. During 
the OS follow-up, EQ-5D assessments can be made over the phone and do not require a clinic visit. (Refer to Section 7.4.14.)
e Required every other cycle, after Cycle 2 (ie, Cycles 1, 2, 4, 6, etc.) during the treatment period.
f
For patients who had responded to therapy and subsequently relapsed, a bone marrow aspirate sample is requested at end of study treatment. This sample is 
not mandatory but highly recommended. 
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15.14   Amendment 1 Rationale and Purposes
Rationale for Amendment 1
This protocol amendment addresses regulatory feedback received from several competent 
authorities and clarifies inconsistencies identified in the original protocol. 
Purposes for Amendment 1
The purposes of this amendment are to:

Clarify the time of collection for EORTC-QLQ-C30, EQ-5D, and MY-20 outcome 
measures

Change the term from ‘progressive disease confirmation’ to ‘progressive disease 
review’

Clarify the pharmacokinetics schedule with regard to study dosing and requirements 
for fasting

Clarify the duration of collection and evaluation of new or worsening of existing 
selected skeletal events from baseline through the last survival assessment to be in line 
with the Schedule of Events

Clarify the reference to baseline creatinine clearance values and permitted re-escalation 
of lenalidomide

Clarify that urine pregnancy tests are acceptable if they meet minimum sensitivity 
levels

Clarify the definition of abstinence to be in line with the preferred and usual lifestyle of 
the patient

Clarify the use of aspirin for prophylactic anticoagulation in the inclusion criteria

Clarify that subjects with deep vein thrombosis can take low molecular weight heparin 
in the inclusion criteria

Clarify the acceptable grade for recovery from effects of prior chemotherapy in the 
exclusion criteria

Clarify reference to hepatitis B and C virus infections in the exclusion criteria

Clarify comorbid systemic illness or other severe concurrent disease in the exclusion 
criteria 

Change the volume of water that should be taken with the study drug from 150 mL to 
240 mL

Clarify dose modification procedures

Clarify the toxicity recovery before beginning the next cycle of treatment

Clarify the procedures for dose modifications due to nonhematologic toxicity judged to 
be related to study drug

Clarify the reference to St. John’s wort and Ginkgo biloba as medicinal products

Clarify that palliative radiotherapy for pain control in a preexisting lesion may be 
considered
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
Clarify the timing for collection of concomitant medications

Clarify the contraception requirements, pregnancy prevention plans, and reference the 
Study Manual (in place of Sections 15.11 through 15.14)

Update the clinical management of erythematous rash with or without pruritus to 
include Stevens-Johnson Syndrome

Update the clinical management of thrombocytopenia to include thrombotic 
thrombocytopenic purpura (TTP)

Clarify the clinical management of fluid deficit

Add the clinical management of hypotension

Add the clinical management of Posterior Reversible Encephalopathy Syndrome

Remove the typographical error that refers to the 5.5-mg dose of MLN9708 capsules, 
as this is not a dose used in this study

Clarify how lenalidomide will be supplied worldwide 

Clarify the reference to contact information for study personnel in the Study Manual

Clarify that treatment groups will be assigned using interactive voice response system 

Add thyroid testing and additional hematology testing to align with the lenalidomide 
SmPC 

Clarify the collection of pain assessments on the BPI-SF and 24-hour analgesic forms

Change the frequency of the skeletal survey and clarify acceptable alternatives to 
skeletal surveys

Clarify the radiographic disease assessments that are needed for patients with 
extramedullary disease

Remove cost assessment section 

Clarify that bone marrow aspirate is used to confirm complete response and/or 
progressive disease

Clarify that local labs may be used for dosing decisions, management of 
treatment-emergent adverse events, and collection and analyses of cytogenetics 
samples

Remove the requirement for a bone marrow biopsy in the study procedures 

Clarify the biomarker analyses that are to be performed at local versus central 
laboratories

Clarify that the plasma concentrations will be measured using a validated LC/MS/MS 
assay and remove the optional PK collection at the time of SAEs

Clarify that radiographic disease assessments are to be performed every 8 weeks during 
the progression-free survival (PFS) follow-up period 

Clarify collection and reporting requirements for SAEs related to study drug during 
posttreatment follow-up

Clarify that assessments to be performed for the End of Treatment visit are listed in the 
Schedule of Events

Add an analysis for pain response 
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
Update the definition of pain progression

Clarify that Eastern Cooperative Oncology Group (ECOG) performance scores will be 
summarized using a shift table

Correct the role of the independent data monitoring committee

Indicate that serious adverse events will be reported within 24 hours rather than 
1 business day

Update language to current company standards and remove text regarding the start of 
antineoplastic or anticancer therapy as it relates to follow-up AEs

Update the version of the International Myeloma Working Group (IMWG) uniform 
response criteria in Section 15.11 from the 2006 version to the 2011 version

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 establish a China continuation of 
Study C16010. This amendment describes modifications to the global study procedures 
specifically for patients who enroll in the China continuation. Patients from China who 
enroll in the global study will not be affected. Following completion of enrollment in the 
global study (703 patients), up to approximately 120 additional patients from China will be 
enrolled in the China continuation. 
The China continuation is an extension of the global study that will continue to assess the 
primary objective of progression-free survival (PFS) in patients from China. Select other 
secondary objectives that directly relate to disease response assessment and safety will also 
be evaluated to thoroughly characterize the efficacy and safety signals of MLN9708 in this 
population. These objectives are overall survival (OS), overall response rate (ORR), 
complete response + very good partial response rate (CR + VGPR), duration of response 
(DOR), time to progression (TTP), and safety. Additional secondary and exploratory 
objectives will be explored in the global study but are not included in the China continuation 
because they are signal-seeking in nature. Objectives that are subsequently determined to be 
of clinical relevance may be evaluated in future clinical studies.
The primary objective of PFS will be assessed when 50% of PFS events have occurred or a 
minimum of 18 months after the first patient is enrolled in the China continuation, 
whichever occurs first. OS will be assessed when 50% of events have occurred or a 
minimum of 2 years after the last patient is enrolled in the China continuation, whichever 
occurs first. These assessment times will allow detection of any trends in the data and 
demonstrate consistency with the global dataset.
This amendment will allow for in-depth characterization of the pharmacokinetic (PK) 
properties of MLN9708 for patients in China. While the global study implements sparse PK 
sampling, the China continuation includes extensive PK sampling on up to 30 patients to 
obtain data on approximately 12 PK-evaluable patients in the MLN9708 plus lenalidomide 
and dexamethasone (LenDex) arm. 
Purposes for Amendment 2
The purposes of this amendment are to:

Add background epidemiology information on multiple myeloma in the Chinese 
population

Clarify that the primary objective will be assessed in patients from China

Update the number of patients from 703 to 120 to reflect the approximate number of 
patients from China that will be enrolled in the China continuation

Modify the PK objective and corresponding endpoint to remove sparse PK sampling 
and add full characterization of PK in up to 30 patients

Remove secondary objectives (and corresponding endpoints and study procedures) that 
do not directly contribute to the characterization of the efficacy or safety of MLN9708
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
Remove exploratory objectives (and corresponding endpoints and study procedures) 
that do not directly contribute to the characterization of the efficacy or safety of 
MLN9708

Modify the duration of study for patients in the China continuation

Modify the time and number of events required for the primary analysis of PFS

Modify the time and number of events required for the secondary analysis of OS

Remove the 2 interim analyses

Modify the inclusion criteria to specify patients from China

Modify the populations for analysis to be specific for the China continuation

Clarify independent data monitoring committee (IDMC) procedures as they 
specifically relate to the China continuation
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15.16   Amendment 3 Rationale and Purposes
Rationale for Amendment 3
The primary reason for this amendment is to add an additional progression-free survival 
(PFS) analysis, which will be considered the final PFS analysis. The second PFS analysis 
will allow more PFS data at a later date in addition to the first PFS analysis in the current 
protocol, and update the assumption on median PFS for both arms for sample size 
calculation based on the reported delayed events in 2 ongoing phase 3 studies (also being 
conducted in the same disease setting with the same primary endpoint). The original planned 
first interim analysis (IA [which was the final analysis (FA) for PFS]) will be conducted at a 
later date when approximately 262 PFS events have occurred. The added PFS analysis (the 
new FA) is to be conducted when approximately 365 PFS events have occurred. The alpha 
allocation for PFS will be based on the O’Brien-Fleming alpha spending function (the 
Lan-DeMets method). If the PFS IA is statistically significant, the PFS FA will be a 
non-inferential test only. Those 2 PFS analyses also serve as the first IA and second IA for 
overall survival (OS).
Purposes for Amendment 3
The purposes of this amendment are to:

Update the statistical and quantitative analyses sections to include the assumptions on 
PFS for sample size calculation and additional IA

Remove the non-inferential test on PFS at the original planned second IA

Reclassify of the secondary biomarker objectives to exploratory objectives

Update the cover page with current signatories

Update the study overview diagram to remove subsequent anti-neoplastic therapy as a 
grounds for treatment discontinuation

Clarify the timing of the EuroQol 5-Dimensional Health Questionnaire (EQ-5D) and 
skeletal survey

Clarify the pharmacokinetic sampling schedule

Remove assessments of specific gene mutations of the P13K pathway and indicate that 
similar analyses will be done in tumor samples from patients who initially responded to 
therapy and subsequently relapsed

Indicate that circulating proteasome levels will be assessed

Clarify the PFS and OS assessment intervals in the Overview of the Study Design 
section to be consistent with the Schedule of Events

Update the inclusion criteria to align with current standard informed consent form 
(ICF) contraception durations

Clarify lenalidomide administration guidelines

Clarify that use of alternative dose modifications must be approved by 
sponsor/designee clinician

Clarify lenalidomide treatment modification guidelines
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
Clarify the gastrointestinal and metabolic adverse event severities for 
dexamethasone-related treatment modification guidelines 

Clarify dexamethasone dose modification guidelines

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 

Update the description of the investigational agents

Clarify the description of the preparation, reconstitution, and dispensation of 
MLN9708 to be consistent across studies

Clarify the description of the storage and handling of MLN9708 to be consistent across 
studies

Clarify wording about permitted changes to the timing of tests and procedures

Clarify the roles of the central and local laboratories for eligibility and progressive 
disease assessment

Clarify the M-protein and free light chain to be followed for response assessment 
according to IMWG criteria 

Clarify the proteasome subunits that will be assessed

Update the criteria for completion of treatment 

Indicate that the investigator is required to submit the rationale for discontinuing a 
patient from study treatment

Clarify that the intent-to-treat (ITT) population is used for patient-reported outcome 
assessments

Replace “time to pain response” with “duration of pain response” and indicate how 
data for this response will be summarized

Add that the independent data monitoring committee (IDMC) will receive reports of all 
cases of new primary malignancies during the study

Indicate proper reporting of cases of overdose

Update the serious adverse event (SAE) reporting contact information

Update the SAE reporting information

Update the procedures for reporting drug exposure during pregnancy to be consistent 
throughout the protocol

Correct the bracket placement in the Cockcroft–Gault equations

Clarify the International Myeloma Working Group (IMWG) response criteria version 
used for the study and clarify very good partial response (VGPR) in terms of 
plasmacytoma 

Correct typographical errors, punctuation, grammar, and formatting
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15.17   Amendment 4 Rationale and Purposes
Rationale for Amendment 4
This amendment describes modifications that were made to the global study procedures 
(Global Amendment 3) that apply to the China-specific protocol continuation.  
Purposes for Amendment 4
The purposes of this amendment are to:

Update the cover page with current signatories

Update the study overview diagram to remove subsequent antineoplastic therapy as a 
grounds for treatment discontinuation

Clarify the timing of the skeletal survey 

Clarify the pharmacokinetic sampling schedule 

Update terms in the List of Abbreviations

Remove assessments of specific gene mutations of the P13K pathway and indicate that 
similar analyses will be done in tumor samples from patients who initially responded to 
therapy and subsequently relapsed

Clarify the progression-free survival and overall survival assessment intervals in the 
Overview of the Study Design section to be consistent with the Schedule of Events

Clarify the timing of the End of Treatment visit

Update the inclusion criteria to align with current standard informed consent form 
(ICF) contraception durations

Remove references to country-specific pregnancy risk guidelines other than for China

Clarify lenalidomide administration guidelines

Clarify dexamethasone administration guidelines

Clarify lenalidomide treatment modification guidelines

Clarify the gastrointestinal and metabolic adverse event severities for 
dexamethasone-related treatment modification guidelines

Clarify that use of alternative dose modifications must be approved by 
sponsor/designee clinician

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 

Update the description of the investigational agents

Clarify the description of the preparation, reconstitution, and dispensation of 
MLN9708 to be consistent across studies

Clarify the description of the storage and handling of MLN9708 to be consistent across 
studies

Remove references to country-specific suppliers of lenalidomide other than for China
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
Remove references to country-specific suppliers of dexamethasone other than for 
China

Clarify wording about permitted changes to the timing of tests and procedures

Clarify the roles of the central and local laboratories for eligibility and progressive 
disease assessment

Clarify the M-protein and free light chain to be followed for response assessment 
according to IMWG criteria 

Update the criteria for completion of treatment 

Indicate that the investigator is required to submit the rationale for discontinuing a 
patient from study treatment

Add that the independent data monitoring committee (IDMC) will receive reports of all 
cases of new primary malignancies during the study

Indicate proper reporting of cases of overdose

Update the serious adverse event (SAE) reporting contact information

Update the SAE reporting information

Update the procedures for reporting drug exposure during pregnancy to be consistent 
throughout the protocol

Update the product complaint reporting contact information 

Correct the bracket placement in the Cockcroft–Gault equations

Clarify the International Myeloma Working Group (IMWG) response criteria version 
used for the study and clarify very good partial response (VGPR) in terms of 
plasmacytoma

Define “definite increase of plasmacytoma” in the Response Criteria appendix 

Correct typographical errors, punctuation, grammar, and formatting
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15.18    Amendment 5 Rationale and Purposes
Rationale for Amendment 5
The rationale for this amendment is to require prophylactic antiviral therapy for every 
patient receiving study treatment (unless there is a clinical contraindication) to prevent 
herpes zoster reactivation.  This amendment is in response to the Independent Data 
Monitoring Committee (IDMC), which has recommended this modification to the study.
Purposes for Amendment 5

Update the cover page with current signatories.

Require prophylactic antiviral therapy for all patients receiving study treatment.

Correct typographical errors, punctuation, grammar, and formatting.
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15.19    Amendment 6 Rationale and Purposes
Rationale for Amendment 6
The primary reason for this amendment is to discontinue study assessments and the PFS 
follow-up period for patients still receiving study therapy, now that the primary endpoint of 
progression-free survival (PFS) is complete. 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, blood, serum, and urine 
samples for assessment of response) will stop being collected/sent to the central laboratory 
to minimize the burden on study patients and avoid unnecessary procedures. The other main 
reason for this amendment is to remove the futility boundary for overall survival (OS) at the 
third interim analysis to ensure the collection of sufficient long-term safety data and avert 
potential premature termination of OS evaluation, a key secondary endpoint.
Other changes clarify study procedures, as noted in the following list.
Purposes for Amendment 6
The purposes of this amendment are to:

Remove mention of the Safety Management Attachment, which no longer exists

Discontinue the PFS follow-up period and all efficacy response assessments, including 
laboratory assessments, for protocol purposes because PFS significance has been met 
in the study

Remove the futility boundary for OS at the third interim analysis and note that the 
actual efficacy boundaries may be adjusted if the actual number of events does not 
correspond to the projected number of events in the remaining analyses

Update the excluded concomitant medication information to reflect recent population 
pharmacokinetics (PK) analyses and drug-drug interaction study results from Study 
C16009 demonstrating that cytochrome P450 inhibitors do not affect MLN9708 PK

Clarify the management of rash, including adding a table of steroid equivalent doses

Clarify the management of overdose

Clarify the instructions for study drug dispensing

Clarify the procedure for performing the physical examination

Clarify when central laboratory results must be reviewed before initiating the next 
treatment cycle

Note that PK sample collection for the study has now been completed for all patients

Add an email address for reporting adverse events (AEs) and serious AEs in Japan

Clarify the monitoring of AEs and period of observation

Update the procedures for product complaints to include instructions for reporting 
medication errors and overdose

Clarify the definition of closure of the study

Correct typographical errors, punctuation, grammar, and formatting
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15.20   Amendment 7 Rationale and Purposes
Rationale for Amendment 7
This document describes the changes in reference to the protocol incorporating Amendment
No. 7. This amendment describes modifications to the study procedures specifically for 
patients who are enrolled in the China-specific protocol continuation of Study C16010. 
Patients from China who are enrolled in the global C16010 study will not be affected by this 
amendment. 
As of Amendment 7, analysis of the primary endpoint of progression-free survival (PFS) (at 
the primary analysis) and of the secondary endpoint of overall survival (OS) (at the final 
analysis) have been completed. The rationale for this amendment is to discontinue disease 
response assessments (ie, PFS, response rate, time to progression), discontinue efficacy 
response assessments (ie, blood, serum, and urine samples), discontinue PFS and OS 
follow-up assessments for all patients, and discontinue all follow-up of patients who have 
completed study treatment. In addition, the objective of this amendment is to provide 
patients who are still on study treatment with continued access to study drugs and to 
continue to collect relevant safety information. Also, after unblinding of patients after the 
positive final survival analysis, this amendment will allow patients who are currently 
receiving placebo in combination with lenalidomide and dexamethasone the option to 
continue receiving lenalidomide and dexamethasone alone or, based on the investigator’s 
opinion, MLN9708 in combination with lenalidomide and dexamethasone.
Other changes clarify study procedures as noted in the following list. 
Minor grammatical, editorial, and formatting changes are included for clarification purposes 
only. 
For specific descriptions of text changes and where the changes are located, see 
Section 15.15.
Changes in Amendment 7
1. Discontinue all disease and efficacy response assessments, including laboratory 
assessments, for protocol purposes because PFS and OS analyses have been 
completed in the study.
2. Include final C16010 China Continuation study results.
3. Discontinue the PFS and OS follow-up periods.
4. Include the option for patients, based on the investigator’s opinion, currently 
receiving placebo in combination with lenalidomide and dexamethasone to continue 
with lenalidomide and dexamethasone alone, or cross over to receive MLN9708 in 
combination with lenalidomide and dexamethasone.
5. Revise the definition of the duration of study treatment.
6. Define the long-term safety assessments as of Amendment 7.
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7. Update the excluded concomitant medication information.
8. Clarify the management of rash, including adding a reference table of steroid 
equivalent doses.
9. Clarify the management of overdose.
10. Clarify study unblinding.
11. Clarify the storage conditions for MLN9708.
12. Clarify withdrawal of patients from study.
13. Clarify details regarding review and entry of laboratory results.
14. Clarify the population for analysis of safety as of Amendment 7.
15. Remove the efficacy analysis.
16. Revise the safety analysis.
17. Specify that no further independent review committee reviews are needed as of 
Amendment 7.
18. Specify that no further independent data monitoring committee reviews of safety and 
efficacy are needed as of Amendment 7.
19. Clarify the monitoring of adverse events. 
20. Update the procedures for product complaints to include instructions for medication 
errors and overdose.
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15.21  Amendment 8 Detailed Summary of Changes 
THE PRIMARY SECTIONS OF THE PROTOCOL AFFECTED BY THE CHANGES IN 
AMENDMENT 8 ARE INDICATED. THE CORRESPONDING TEXT HAS BEEN 
REVISED THROUGHOUT THE PROTOCOL.
Change 1: Clarify the study objectives as of Amendment 8.
The primary change occurs in Section 2 STUDY OBJECTIVES:
Added 
text:
Note that the primary objective and corresponding endpoint have been met. 
Upon implementation of Amendment 8, the objective is to continue to collect 
long-term safety data from patients who are continuing on ixazomib 
(MLN9708) and LenDex or LenDex (note the placebo capsule will be 
discontinued) because of continuing clinical benefit. Data collection for all 
other study objectives and endpoints will be complete at the time of the final 
analysis and no further formal analyses will be conducted. The original lists 
of objectives are retained below for reference only.
Rationale for Change:
To clarify the study objective at this point in the study.
The Protocol Summary also contains this change.
Change 2: Clarify the study endpoints as of Amendment 8.
The primary change occurs in Section 3 STUDY ENDPOINTS:
Added 
text:
Note that the primary endpoint has been met. Upon implementation of 
Amendment 8, evaluation of the safety profile of MLN9708 and/or LenDex 
is the only endpoint being assessed. Analysis of all other study endpoints will 
be complete at the final analysis and no further formal statistical analyses 
will be performed. However, the complete list of endpoints is retained below 
for reference. 
Rationale for Change:
To clarify the study endpoint at this point in the study.
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Change 3: Clarify that the final analysis data cutoff has been conducted and the study is 
considered complete for statistical analysis purposes.
The primary change occurs in Section 8 STATISTICAL AND QUANTITATIVE 
ANALYSES:
Added 
text:
The final analysis data cutoff has been conducted and as such, the study is 
considered complete for statistical analysis purposes. The final analysis is 
expected to occur in the fourth quarter of 2020. Upon implementation of 
Amendment 8, the investigator will unblind all patients remaining on study 
treatment and will follow the new Schedule of Events presented in this 
amendment. No subsequent formal inferential statistical analyses will be 
conducted; minimal descriptive analyses of safety will be performed on 
patient data collected after the final analysis. The description of the 
statistical methods presented below reflects the full design for the study for 
reference.
Rationale for Change:
To note that the data cutoff date for the final analysis has now occurred; no subsequent 
formal inferential statistical analyses will be conducted after the final analysis. 
Change 4: Add language to clarify ongoing treatment of patients—patients still receiving 
study treatment will stay on their assigned study regimen. Patients should be moved off 
study and onto an alternative supply of (eg, commercially available) ixazomib  and/or 
LenDex, or onto another standard of care treatment.
The primary change occurs in the Schedule of Events:
Initial 
wording:
As of Amendment 6, the primary endpoint of PFS has been met, and as such, the 
PFS follow-up period is now completed and for all patients still receiving study 
therapy, all central and investigator assessments of response and progression for 
protocol purposes will be discontinued. Thus, for ease of study conduct, the 
Schedule of Events now presented has been simplified to apply to the remainder 
of the study. The full Schedule of Events as of Amendment 3 has been moved to 
Section  15.12. The PK sampling schedule has also been moved to Section  
15.12, as it was applicable through Cycle 10, which has been completed for all 
patients.
Amended 
or new 
wording:
The final analysis data cutoff has been conducted and as such, the study is 
considered complete for statistical analysis purposes. Upon implementation 
of Amendment 8, the investigator will unblind all patients remaining on 
study treatment and will follow the new Schedule of Events. 
Only patients who continue to demonstrate clinical benefit but who do not 
have other means of access to the study drugs will continue on the study. 
Because no further formal statistical analyses will be performed, only 
assessments contributing to long-term safety monitoring are required. Most 
study assessments besides safety are discontinued to ease the burden of 
protocol-mandated assessments on patients. Patients continuing their 
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current study treatment may do so until such time as other means of 
accessing the study drugs are arranged. When possible, patients should 
complete an EOT visit and transition onto an alternative supply of (eg, 
commercially available) ixazomib (MLN9708) and/or LenDex, or onto 
another standard of care treatment. Discontinued patients will be treated by 
their physician per local standard of care.
Patients who are receiving ixazomib plus LenDex will continue to receive 
ixazomib plus LenDex.  Patients who are receiving placebo plus LenDex will 
receive LenDex only; the placebo capsule will no longer be administered 
and patients receiving placebo will not be crossed over to ixazomib in this 
study. Upon implementation of Amendment 8, data collection requirements 
will be limited to collection of AEs, SAEs, and concomitant medications. 
Quality of life, health care utilization, EQ-5D, and pain assessments are 
discontinued. Survival data will no longer be collected because the analysis 
of OS will be complete at the time of the final analysis. Other study 
assessments are no longer required, as noted in the new Schedule of Events. 
Patients will not be followed for the OS follow-up period because OS data 
are no longer being collected.
As of Amendment 6, the primary endpoint of PFS has been met, and as such, the 
PFS follow-up period is now completed and for all patients still receiving study 
therapy, all central and investigator assessments of response and progression for 
protocol purposes will be discontinued. Thus, for ease of study conduct, the 
Schedule of Events now presented has been simplified to apply to the remainder 
of the study. The full Schedule of Events as of Amendment 3 has been moved to 
Section  15.12. The PK sampling schedule has also been moved to Section  
15.12, as it was applicable through Cycle 10, which has been completed for all 
patients.
Rationale for Change:
To clarify which patients may remain on study at this point and what treatment they will 
receive. 
The following sections also contain this change:

Protocol Summary.

Study Overview Diagram.

Section 4.1 Overview of Study Design. 

Section 4.3 Duration of Study.

Section 6.1 Test Article (MLN9708) and Matched Placebo.

Section 6.11 Blinding and Unblinding.
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Change 5: Discontinue all remaining efficacy assessments (eg, OS, Quality of Life) and 
clarify ongoing safety laboratory evaluations.
The primary change occurs in the Schedule of Events:
Description of 
Change:
Added a new Schedule of Events table that details assessments that will be 
conducted upon implementation of Amendment 8.  The only assessments 
that will continue to be collected are:

Informed Consent (reconsent)

Complete Physical Examination

Symptom-Directed Physical Exam

Pregnancy Test

Hematology

Clinical Chemistry

Adverse Event/Serious Adverse Event Reporting

New Primary Malignancy Assessment

Concomitant Medications/Procedures
The previous Schedule of Events table was moved to Section 15.13
Schedule of Events (as of Amendment 6). 
Rationale for Change:
To clarify what procedures patients on study will follow.
The following sections also contain this change:

Section 7.4 Study Procedures.

Section 7.4.5 Eastern Cooperative Oncology Group Performance Status.

Section 7.4.8 Electrocardiogram.

Section 7.4.9 Clinical Laboratory Evaluations.

Section 7.4.10 Clinical Chemistry, Hematology, and Urinalysis.

Section 7.4.11 Health Utilization Data Collection.

Section 7.4.12 Quality of Life Assessment (European Organization for Research and 
Treatment of Cancer).

Section 7.4.13 Pain Assessment.

Section 7.4.14 Utility Measurement.

Section 7.4.15 Skeletal Survey.

Section 7.4.16 Skeletal-Related Events.

Section 7.4.17 Radiographic Disease Assessments.

Section 7.4.23 Bone Marrow Evaluation.

Section 7.5 Unscheduled Visits.
Change 6: Discontinue the OS follow-up period.
The primary change occurs in Section 7.4.29 Follow-up Assessments (PFS and OS):
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Initial 
wording:
Patients who stop treatment for any reason will continue to have OS follow-up 
visits. See the Schedule of Events for appropriate assessments. All subsequent 
antineoplastic therapies will be recorded, regardless if they are initiated before or 
after PD. Patients who start an alternative antineoplastic therapy prior to disease 
progression will continue to be followed for progression. As of Amendment 6, 
however, the primary endpoint has been met. As such, the PFS follow-up phase 
has been discontinued for all patients currently receiving study therapy and for 
any patients who discontinued treatment for other reasons, including patients 
who start an alternative therapy before PD. All patients discontinuing study 
treatment will be assessed for OS but no longer for PFS.
Patients who stop treatment due to PD will continue to have overall survival 
visits/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. 
The OS follow-up should be conducted every 12 weeks after documented PD 
until death or termination of the study by the sponsor. All subsequent 
antineoplastic therapies will be recorded during the OS follow up period.
Information for new primary malignancy should be collected during the study, 
including the PFS and OS follow-up periods. As of Amendment 6, however, the 
primary endpoint has been met; as such, the PFS follow-up phase has been 
discontinued for patients currently receiving study therapy. All patients 
discontinuing study treatment will be assessed for OS but no longer for PFS.
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 during the follow-up periods, 
irrespective of causality to study regimen, must be reported to the Millennium 
Department of Pharmacovigilance or designee.
Amended 
or new 
wording:
Prior to implementation of Amendment 6, Ppatients who stopstopped
treatment for any reason will continue to havehad OPFS follow-up visits. See 
the Schedule of Events forSchedule of Events in Section 15.12 for the
appropriate assessments. All subsequent antineoplastic therapies willwere to be 
recorded, regardless if they arewere initiated before or after PD. Patients who 
started an alternative antineoplastic therapy prior to disease progression will 
continued to be followed for progression. As of Amendment 6, however, the 
primary endpoint has been met. As such, the PFS follow-up phase has beenwas
discontinued for all patients currently receiving study therapy and for any 
patients who discontinued treatment for other reasons, including patients who 
started an alternative therapy before PD. All patients discontinuing study 
treatment will be assessed for OS but no longer for PFS.
Prior to implementation of Amendment 8, Ppatients who stopstopped
treatment due to PD will continued to have overall survival visits/assessments. 
During the OS follow-up, assessments cancould be made over the phone and 
dodid not require a clinic visit. Data may behave been collected by methods that 
included but arewere not limited to telephone, e-mail, mail, and social security 
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indexes. The OS follow-up should bewas conducted every 12 weeks after 
documented PD until death or termination of the study by the sponsor. All 
subsequent antineoplastic therapies willwere to be recorded during the OS 
follow-up period.
Information for new primary malignancy should be collected during the study, 
including the PFS and OS follow-up periods. As of Amendment 6, however, the 
primary endpoint has been met; as such, the PFS follow-up phase has been 
discontinued for patients currently receiving study therapy. All patients 
discontinuing study treatment will be assessed for OS but no longer for PFS.
NOTE:Upon implementation of Amendment 8, patients will no longer be 
followed during any of the follow-up periods. NOTE: Prior to 
implementation of Amendment 8, Rrelated SAEs must behave been reported 
to the Millennium Department of Pharmacovigilance or designee. This includesd
deaths that the investigator considersed related to study drug that occurred
during the posttreatment follow-up. In addition, new primary malignancies that 
occurred during the follow-up periods, irrespective of causality to study 
regimen, must behave been reported to the Millennium Department of 
Pharmacovigilance or designee. 
Rationale for Change:
To explain that patients will not be followed for the PFS or OS follow-up periods upon 
implementation of Amendment 8.
The following sections also contain this change:

Study Overview Diagram.

Section 7.4 Study Procedures.

Section 7.10 Withdrawal of Patients From Study.
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Change 7: Revise information regarding the interim analyses.
The primary change occurs in Section 4.1 Overview of Study Design:
Initial 
wording:
As of Amendment 6, the first 2 IAs have been performed. The primary analysis 
(data cutoff date, 30 October 2014) occurred when 286 patients had experienced 
disease progression or death; at this analysis, the primary endpoint of PFS was 
met. The next analysis (data cutoff date, 12 July 2015) occurred when 372 
patients had experienced disease progression or death. This was the first analysis 
for OS. It was found that OS data were not yet mature and the study was to 
continue, following the patients for survival. 
The third IA for OS will occur when approximately 322 deaths have been 
reported. The trial will be stopped for overwhelming efficacy if the O’Brien-
Fleming efficacy boundary is crossed at the third IA.[41] However, the actual 
boundary could be adjusted if the actual number of events does not correspond to 
the projected number of events in the remaining IA or in the final analysis (FA).
An independent data monitoring committee (IDMC) will review safety and 
efficacy data at the IAs. See Section 9.3 for more information.
Amended 
or new 
wording:
As of Amendment 68, the first 23 IAs have been performed. The primary 
analysis (data cutoff date, 30 October 2014) occurred when 286 patients had 
experienced disease progression or death; at this analysis, the primary endpoint 
of PFS was met. The next analysis (data cutoff date, 12 July 2015) occurred 
when 372 patients had experienced disease progression or death. This was the 
first analysis for OS. It was found that OS data were not yet mature andA total 
of 171 deaths had been reported and the threshold for OS statistical 
significance was not met. Per the study design and statistical analysis plan,
the study was to continue, following the patients for survival. The third IA 
(data cutoff date, 25 October 2017) occurred when 333 deaths had been 
reported. The threshold for statistical significance was not met and the 
study was to continue to the final analysis. The final analysis occurred in the 
fourth quarter of 2020. 
The third IA for OS will occur when approximately 322 deaths have been 
reported. The trial will be stopped for overwhelming efficacy if the O’Brien-
Fleming efficacy boundary is crossed at the third IA.[41] However, the actual 
boundary could be adjusted if the actual number of events does not correspond to 
the projected number of events in the remaining IA or in the final analysis (FA).
Rationale for Change:
To update the results from the 3 interim analyses. 
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Change 8: Update language about the management of clinical events in patients receiving 
ixazomib.
The primary change occurs in Section 6.10 Management of Clinical Events:
Initial 
wording:
Prophylaxis Against Risk of Reactivation of Herpes Infection
Patients may be at an increased risk of infection including reactivation of herpes 
zoster and herpes simplex viruses. Antiviral therapy such as acyclovir or 
valacyclovir may be initiated as clinically indicated. 
…
Nausea and/or Vomiting
Standard anti-emetics including 5-hydroxytryptamine 3 serotonin receptor (5-
HT3) antagonists are recommended for emesis if it occurs once treatment is 
initiated; prophylactic anti-emetics may also be considered at the physician’s 
discretion. Dexamethasone should not be administered as an anti-emetic. Fluid 
deficit should be corrected before initiation of study drug and during treatment.
Diarrhea
Prophylactic antidiarrheals will not be used in this protocol. However, diarrhea 
should be managed according to clinical practice, including the administration of 
antidiarrheals once infectious causes are excluded. Fluid intake should be 
maintained to avoid dehydration. Fluid deficit should be corrected before 
initiation of treatment and during treatment. 
Erythematous Rash With or Without Pruritus
…
Rash may range from 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 predominantly on the trunk or extremities. Rash has 
been most commonly characterized as maculopapular or macular. To date, when 
it does occur, rash is most commonly reported within the first 3 cycles of 
therapy. The rash is often transient and self-limiting and is typically Grade 1 to 2 
in severity. As in many other oncology trials, 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.
…
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 
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(eg, Bactrim, lenalidomide, aspirin), and/or in the setting of confounding 
TEAEs. These severe, potentially life-threatening or deadly conditions may 
involve rash with skin peeling and mouth sores and should be clinically managed 
according to standard medical practice. Punch biopsies for histopathological 
analysis are encouraged at the discretion of the investigator. Additional 
information regarding these reactions can be found in the IB. 
Thrombocytopenia
Blood counts should be monitored regularly as outlined in the protocol with 
additional testing obtained according to standard clinical practice. 
Thrombocytopenia may be severe but has been manageable with platelet 
transfusions according to standard clinical practice. Lenalidomide or study drug 
administration should be modified 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.
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 previously noted gastrointestinal toxicities and dehydration. 
Fluid deficit should be corrected before initiation of study drug as needed during 
treatment to avoid dehydration (see Section 6.8).
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 concomitant symptoms such as nausea, 
vomiting, diarrhea, or decreased appetite. Patients taking medications and/or 
diuretics to manage their blood pressure (for either hypo- or hypertension) 
should be managed according to standard clinical practice, including 
considerations for dose adjustments of their concomitant medications during the 
course of the trial. Fluid deficit should be corrected before initiation of study 
drug and as needed during treatment to avoid dehydration.
Posterior Reversible Encephalopathy Syndrome
One case of posterior reversible encephalopathy syndrome (PRES), which 
ultimately resolved, has been reported with MLN9708. This condition is 
characterized by headache, seizures, and visual loss, as well as abrupt increase in 
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blood pressure. Diagnosis may be confirmed by magnetic resonance imaging 
(MRI). If the syndrome is diagnosed or suspected, symptom-directed treatment 
should be maintained until the condition is reversed by control of hypertension 
or other instigating factors. 
Transverse Myelitis
One case of transverse myelitis has been reported with 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.
Amended 
or new 
wording:
Prophylaxis Against Risk of Reactivation of Herpes Infection
Patients may be at an increased risk of infection including reactivation of herpes 
zoster and herpes simplex viruses. Unless there is a clinical contraindication, 
prophylactic Aantiviral therapy such as acyclovir or valacyclovir may be 
initiated as clinically indicated. is required for all patients while receiving 
study treatment. Examples of acceptable antiviral therapy include acyclovir 
(eg, 400 mg given orally, 3 times a day), famciclovir (eg, 125 mg given orally, 
twice a day), or valacyclovir (eg, 500 mg given orally, twice a day) or 
standard of care/local practice.
…
Nausea and/or Vomiting
Standard anti-emetics including 5-hydroxytryptamine 3 serotonin receptor (5-
HT3) antagonists are recommended for emesis if it occurs once treatment is 
initiated; prophylactic anti-emetics may also be considered at the physician’s 
discretion. Dexamethasone should not be administered as an anti-emetic. Fluid 
deficit should be corrected before initiation of study drug and during treatment.
Prophylaxis with standard antiemetics, including serotonin 5-
hydroxytryptamine 3 receptor antagonists, is recommended for emesis. Any 
fluid deficit occurring during treatment should be promptly corrected. 
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Diarrhea
Prophylactic antidiarrheals will not be used in this protocol. However, dDiarrhea 
should be managed according to clinical practice, including the administration of 
antidiarrheals once infectious causes are excluded. Fluid intake should be 
maintained to avoid dehydration. Any Ffluid deficit should be corrected before 
initiation of treatment andoccurring during treatment should be promptly 
corrected.
Erythematous Rash With or Without Pruritus
…
Rash may range from somelimited 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 predominantly on the trunk or extremities. 
Rash has been most commonly characterized as maculopapular or macular. To 
date, when it does occur, rash is most commonly reported within the first 3 
cycles of therapy. The rash is often transient and self-limiting and is typically 
Grade 1 toor 2 in severity. As in many other oncology trials, 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; these other causative agents should be 
discontinued and alterative agents considered if medically necessary.
…
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. Study medications 
should be discontinued in the event of severe, potentially life-threatening 
rash. Additional information regarding these reactions can be found in the IB. 
Thrombocytopenia
Blood counts should be monitored regularly as outlined in the protocol, with 
additional testing obtained according to standard clinical practice. 
Thrombocytopenia may be severe but has been manageable with platelet 
transfusions according to standard clinical practice. Lenalidomide or study drug 
administration should be modified 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 
isThrombotic microangiopathy (TMA), including thrombotic 
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Clinical Study Protocol C16010 Amendment 8, 08 January 2021
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thrombocytopenica purpura, a and hemolytic uremic syndrome, are rare, 
serious blood disorders wherethat cause low levels of platelets and red blood 
cells and result in blood clots form in small blood vessels throughout the body 
characterized by thrombocytopenia, petechiae, fever, or possibly more serious 
signs and symptoms. Thrombotic thrombocytopenic purpura should be managed 
symptomatically. Symptoms may include fatigue, fever, bruising, nose 
bleeds, and decreased urination. These disorders, including fatal cases, have 
been reported in patients receiving MLN9708. If TMA is suspected, 
consider withdrawal of the suspected causative agent and manage according 
to standard medical practice. 
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 previously noted gastrointestinal toxicities and dehydration. 
Fluid deficit should be promptly corrected before initiation of study drug and as 
needed during treatment to avoid dehydration (see Section 6.8).
Hypotension
Symptomatic hypotension and orthostatic hypotension with or without syncope 
have been reported with MLN9708. Blood pressure should be closely monitored 
as per standard of care while the patient is on study treatment and fluid deficit 
should be corrected as needed, especially in the setting of concomitant symptoms 
such as nausea, vomiting, diarrhea, or decreased appetite. Patients taking 
medications and/or diuretics to manage their blood pressure (for either hypo- or 
hypertension) should be managed according to standard clinical practice, 
including considerations for dose adjustments of their concomitant medications 
during the course of the trial. Fluid deficit should be corrected before initiation 
of study drug and as needed during treatment to avoid dehydration.
Posterior Reversible Encephalopathy Syndrome
One case of pPosterior reversible encephalopathy syndrome (PRES), which 
ultimately resolved, has been reported with MLN9708. This condition is usually 
transient and reversible. It is characterized by headache, seizures, and visual 
loss, as well as abrupt increase in blood pressure. Diagnosis may be confirmed 
by magnetic resonance imaging (MRI) or computed tomography (CT). If the 
syndrome is diagnosed or suspected, symptom-directed treatment should be 
maintained until the condition is reversed by control of hypertension or other 
instigating factors. 
Transverse Myelitis
One case of tTransverse 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 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


MLN9708
Clinical Study Protocol C16010 Amendment 8, 08 January 2021
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have contributed to transverse myelitis cannot be excluded. Transverse myelitis 
should be managed according to standard medical practice.
Rationale for Change:
To add information currently available around clinical events.
Change 9: Clarify the procedures for storage, handling, and accountability.
The primary change occurs in Section 6.15 Storage, Handling, and Accountability:
Added 
text:
On receipt at the investigative site, study drug should remain in the blister pack 
and carton provided until use or dispensation. All excursions that occur at the 
site storage or during transportation from depot to the site should immediately 
be brought to the sponsor’s attention for assessment and authorization for 
continued use. Ensure that the drug is used before the retest expiry date provided 
by Millennium. Expiry extensions will be communicated accordingly with 
updated documentation to support the extended shelf life.
Study drug dispensed to the patient 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 use 
alternative strategies to deliver study drug to patients (eg, via courier or site 
staff), per local standard practice and regulations and with prior approval 
from the investigator and the sponsor’s project clinician/designee. 
Comprehensive instructions should be provided to the patient in order to ensure 
compliance with, and understanding of, dosing procedures. Patients who are 
receiving take-home medication ordinarily should be given only 1 cycle of 
study drug 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 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. Patients should be instructed to return their empty cartons to the 
investigative site, rather than discarding them. Reconciliation will occur 
accordingly when the patient returns for their next cycle of study drug. 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. 
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Rationale for Change:
To add clarification to this protocol.
Change 10: Add flexibility in study conduct in unavoidable circumstances (eg, the COVID-
19 pandemic).
The primary change occurs in Section 7.4 Study Procedures:
Initial 
wording:
Patients will be evaluated at scheduled visits over 4 study periods: Screening, 
Treatment, End of Treatment (EOT), and Follow-Up (PFS and OS). As of 
Amendment 6, however, the primary endpoint has been met; as such, the PFS 
follow-up phase has been discontinued for patients currently receiving study 
therapy and for patients who discontinued therapy for reasons other than PD. As 
of Amendment 6, the follow-up period will solely be for OS follow-up.
Amended 
or new 
wording:
Patients will be evaluated at scheduled visits over 4 study periods: Screening, 
Treatment, End of Treatment (EOT), and Follow-Up (PFS and OS). As of 
Amendment 6, however, the primary endpoint has been met; as such, the PFS 
follow-up phase has been discontinued for patients currently receiving study 
therapy and for patients who discontinued therapy for reasons other than PD. As 
of Amendment 6, the follow-up period will solely be for OS follow-up.
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 by these unavoidable circumstances, any procedures not 
conducted per the study protocol will be documented in the eCRF.  
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 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 (eg, complete physical 
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MLN9708
Clinical Study Protocol C16010 Amendment 8, 08 January 2021
184
examination, symptom-directed physical examination, hematology, clinical 
chemistry, concomitant medications/procedures) are waived. 
Rationale for Change:
To account for unavoidable circumstances affecting study conduct.
The following sections also contain this change:

Schedule of Events, window for Study Procedures.

Schedule of Events, footnote “e”.
Change 11: Add language requiring all patients to reconsent.
The primary change occurs in Section 7.4.1 Informed Consent:
Added 
text:
Patients remaining on study treatment will need to be reconsented. 
Reconsenting should be done in person. Remote reconsenting is permitted 
as long as the process adheres to site, IRB/IEC, and GCP standards and 
local regulations.
Rationale for Change:
To clarify the need for reconsenting.
The following sections also contain this change:

Schedule of Events, footnote “c”.

Section 11.6 Patient Information and Informed Consent.
Change 12: Clarify the definition of Completion of Treatment.
The primary change occurs in Section 7.7 Completion of Treatment:
Initial 
wording:
Patients will be considered to have completed study treatment if they receive 
study drug until disease progression or until discontinuation for unacceptable 
toxicity, withdrawal of consent, or death. An MPI/designee clinician will review 
the source data documenting disease progression prior to the investigator taking 
the patient off treatment or stopping disease assessments for PD. Refer to the 
Schedule of Events for End of Treatment visit assessments. As of Amendment 6, 
however, the primary endpoint has been met; as such, the PFS follow-up phase 
has been discontinued for patients currently receiving study therapy. All central 
and investigator assessments of response and progression for protocol purposes 
will be discontinued, such that there will no longer be an MPI/designee clinician 
review of the source data documenting disease progression.
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Clinical Study Protocol C16010 Amendment 8, 08 January 2021
185
Amended 
or new 
wording:
Prior to implementation of Amendment 8, Ppatients will bewere considered 
to have completed study treatment if they received study drug until disease 
progression or until discontinuation for unacceptable toxicity, withdrawal of 
consent, or death. An MPI/designee clinician will reviewed the source data 
documenting disease progression prior to the investigator taking the patient off 
treatment or stopping disease assessments for PD. Refer to the 
Schedule of Events for End of Treatment visit assessments. As of Amendment 6, 
however, the primary endpoint has been met; as such, the PFS follow-up phase 
has been discontinued for patients currently receiving study therapy. All central 
and investigator assessments of response and progression for protocol purposes 
will be discontinued, such that there will no longer be an MPI/designee clinician 
review of the source data documenting disease progression.
Upon implementation of Amendment 8, only patients who are 
demonstrating clinical benefit and are unable to access a commercial supply 
of ixazomib and/or lenalidomide and dexamethasone 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, 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 for End of Treatment visit assessments.
Rationale for Change:
To clarify the definition of completion of treatment upon implementation of Amendment 8.
Change 13: Clarify the definition of Completion of Study.
The primary change occurs in Section 7.8 Completion of Study:
Initial 
wording:
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 
wording:
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 8, 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 8, 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). 
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Rationale for Change:
To clarify the definition of completion of study upon implementation of Amendment 8.
Change 14: Update the procedures for SAE reporting.
The primary change occurs in Section 10.2 Procedures for Recording and Reporting 
Adverse Events and Serious Adverse Events:
Added 
text:
The paper SAE forms must be submitted via fax (see fax numbers below) 
within 24 hours of awareness. In case of fax, site personnel must confirm 
successful transmission of all pages and include an e-mail address on the fax 
cover sheet so that an acknowledgment of receipt can be returned via e-mail 
within 1 business day. E-mail submission of paper SAE forms with a PDF 
attachment should only be used in the case where fax is not possible within 
24 hours of receiving the event. In case of e-mail, site personnel must 
confirm successful transmission by awaiting an acknowledgment of the 
receipt via e-mail within 1 business day. If SAEs are reported via fax or by 
e-mail, the EDC application must be updated as soon as possible with the 
appropriate information.
Rationale for Change:
To assist in timely submission of SAE reports.
Change 15: Add information about alternative monitoring approaches, such as remote 
source data verification, in the event a monitor cannot visit the site in a timely manner due to 
the COVID-19 pandemic.
The primary change occurs in Section 11.4 Study Monitoring:
Added 
text:
In the event a monitor cannot visit the site in a timely manner due to the 
COVID-19 pandemic, alternative monitoring approaches such as remote 
source data verification (SDV) or telephone contact may be used to ensure 
data quality and integrity and maintain patient safety. Alternative 
monitoring approaches should be used only where allowed by the local 
Health Authority and permitted by the IRB/IEC.
Rationale for Change:
To clarify remote source data verification procedures to account for unavoidable 
circumstances due to the COVID-19 pandemic.
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 Ixazomib Plus 
Lenalidomide and Dexamethasone Versus Placebo Plus Lenalidomide and Dexamethasone in 
Adult Patients With Relapsed and/or Refractory Multiple Myeloma
NCT Number: NCT01564537
SAP Approve Date: 16 December 2014
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.


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MLN9708 (Ixazomib)
Statistical Analysis Plan, Study C16010
2
Purpose for this amendment:
The main purpose of this amendment is to incorporate changes from Clinical Study Protocol
C16010 Amendment 3, dated 08 July 2014.

to add an additional progression-free survival (PFS) analysis, which will be 
considered the final PFS analysis.  The original planned first interim analysis (IA 
[which was the final analysis (FA) for PFS]) will be conducted at a later date when 
approximately 262 PFS events have occurred. The added PFS analysis (the new FA)
is to be conducted when approximately 365 PFS events have occurred. The alpha 
allocation for PFS will be based on the O’Brien-Fleming alpha spending function 
(the Lan-DeMets method).  
Details of major changes are specified in Section 1.1, Section 5.1, and Section 4.1.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


MLN9708 (Ixazomib)
Statistical Analysis Plan, Study C16010
3
TABLE OF CONTENTS
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS ............................................5
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................................................................................11
2.4 Per-Protocol Population............................................................................................12
3. HYPOTHESES AND DECISION RULES.....................................................................12
3.1 Statistical Hypotheses...............................................................................................12
3.2 Statistical Decision Rules .........................................................................................13
4. INTERIM ANALYSIS...................................................................................................15
4.1 Interim Analysis .......................................................................................................15
4.2 Independent Data Monitoring Committee (IDMC)....................................................15
4.3 Independent Review Committee (IRC).....................................................................16
5. STATISTICAL METHODOLOGY ...............................................................................16
5.1 Sample Size Justification..........................................................................................16
5.2 Randomization and Stratification..............................................................................17
5.3 Blinding and Unblinding ..........................................................................................17
5.4 Data Handling ..........................................................................................................18
5.4.1 Methods for Handling Missing Data...................................................................18
5.4.2 Definition of Baseline Values ............................................................................20
5.4.3 Windowing of Visits..........................................................................................21
5.4.4 Justification of Pooling ......................................................................................21
5.4.5 Withdrawals, Dropouts, Loss to Follow-up ........................................................21
5.5 Patient Disposition ...................................................................................................21
5.6 Demographics and Baseline Disease Characteristics.................................................21
5.6.1 Demographics....................................................................................................21
5.6.2 Medical History.................................................................................................21
5.6.3 Baseline Disease Status......................................................................................22
5.7 Treatments and Medications .....................................................................................23
5.7.1 Concomitant Medications ..................................................................................23
5.7.2 Study Treatments...............................................................................................23
5.8 Efficacy Analyses.....................................................................................................25
5.8.1 Primary Efficacy Endpoint.................................................................................25
5.8.2 Key Secondary Efficacy Endpoints....................................................................28
5.8.3 Other Secondary Efficacy Endpoints and Analyses ............................................31
5.9 Pharmacokinetic, Pharmacodynamic, and Biomarker Analyses.................................32
5.9.1 Pharmacokinetic Analyses .................................................................................32
5.9.2 Pharmacodynamic Analyses...............................................................................33
5.9.3 Biomarker Analysis ...........................................................................................33
5.10 Resource Utilization and Patient-Reported Outcome Analysis ................................34
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5.10.1 Patient-Reported Outcomes (PROs) .................................................................34
5.10.2 Health Economics (Health Care Resource Use)................................................36
5.10.3 Pain..................................................................................................................36
5.11 Safety Analyses ......................................................................................................37
5.11.1 Adverse Events................................................................................................38
5.11.2 Laboratory Data...............................................................................................39
5.11.3 Electrocardiograms ..........................................................................................40
5.11.4 Vital Signs .......................................................................................................41
5.11.5 Eastern Cooperative Oncology Group (ECOG) Performance Status .................41
5.11.6 Other Safety Assessments ................................................................................41
6. MAJOR PROTOCOL DEVIATIONS ............................................................................42
7. CHANGES TO PLANNED ANALYSES FROM PROTOCOL .....................................42
8. PROGRAMMING CONSIDERATIONS .......................................................................42
8.1 Statistical Software...................................................................................................42
8.2 Rules and Definitions ...............................................................................................42
9. REFERENCES...............................................................................................................44
10. APPENDIX..................................................................................................................45
10.1 Proof of Strong Control of Type I Error Rate for Key Secondary Endpoints ...........45
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LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS
Abbreviation
Term
AE
adverse event
CI
confidence interval
CL
clearance
CMH
Cochran-Mantel-Haenszel
CR
complete response 
del
deletion
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
EORTC
European Organization for Research and Treatment of Cancer 
EOT
End of Treatment (visit)
EQ-5D
EuroQol 5-Dimensional Health Questionnaire
EU
European Union
FA
final analysis
FDA
United States Food and Drug Administration
GCP
Good Clinical Practice
GLP
Good Laboratory Practices
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
IMiD
immunomodulatory drug
IMMPACT
Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials
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
K-M
Kaplan-Meier
MedDRA
Medical Dictionary for Regulatory Activities
MID
minimally important difference
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Abbreviation
Term
Millennium
Millennium Pharmaceuticals, Inc., and its affiliates
MM
multiple myeloma
MR
minor response
MRI
magnetic resonance imaging
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
NFKB
nuclear factor kappa-light chain enhancer of activated B cells
NSAID
nonsteroidal anti-inflammatory drugs
OME
oral morphine equivalent
ORR
overall response rate
OS
overall survival
PD
progressive disease (disease progression)
PET-CT
positron emission tomography - computed tomography
PFS
progression-free survival
PI
package insert 
PK
pharmacokinetic(s)
PN
peripheral neuropathy
PO
per os; by mouth (orally)
PR
partial response 
PRO
patient-reported outcome
PSMB1
Proteasome subunit beta type-1
QALY
quality-adjusted life year
QLQ
Quality of Life Questionnaire (EORTC)
QOL
quality of life
QTc
rate-corrected QT interval (millisec) of electrocardiograph
RP2D
recommended phase 2 dose
RRMM
relapsed and/or refractory multiple myeloma
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
sCR
stringent complete response
SD
stable disease
SMA
safety management attachment
SQ
subcutaneous
t
translocation
t1/2
half-life
TEAE
treatment-emergent adverse event
TRAF
Tumor necrosis factor receptor-associated factor
TTP
time to progression
UK
United Kingdom
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Abbreviation
Term
US
United States
VGPR
very good partial response
WBC
white blood cell
WHO
World Health Organization
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1.   
INTRODUCTION
In general, the purpose of the Statistical Analysis Plan (SAP) is to provide a framework that 
addresses the protocol objectives in a statistically rigorous fashion, with minimized bias 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 ixazomib versus placebo in patients with relapsed and/or refractory multiple 
myeloma (MM) who are treated with lenalidomide and dexamethasone (LenDex) as their 
standard therapy.  The patient population will consist of adult men and women who have a 
confirmed diagnosis of MM, who have received 1 to 3 prior lines of therapy, and who meet 
other outlined eligibility criteria.
Following the Screening period, patients who will be enrolled and treated with lenalidomide 
plus dexamethasone will be randomized to receive either ixazomib or placebo in a double-
blind fashion.  Eligible patients will be randomized in a 1:1 ratio into those 2 treatment 
arms, stratified by:  1 versus 2 or 3 prior therapies, proteasome-inhibitor (PI) exposed versus 
PI naïve, and International Staging System (ISS) stage at screening of 1 or 2 versus stage 3.
Patients will receive ixazomib 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 Days 1, 8, 15, 
and 22 of a 28-day cycle.  Patients may continue to receive treatment until disease 
progression (PD) or unacceptable toxicity, whichever comes first.  
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.  All patients will be followed for survival after PD.  In 
survival follow-up, patients will be contacted every 12 weeks until death or termination of 
the study by the sponsor.
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1.2   
Study Objectives
The primary objective is:

To determine whether the addition of oral ixazomib to the background therapy of 
lenalidomide and dexamethasone improves progression-free survival (PFS) in 
patients with relapsed and/or refractory multiple myeloma (RRMM)
The key secondary objectives are:

To determine whether the addition of oral ixazomib to lenalidomide and 
dexamethasone improves overall survival (OS)

To determine whether the addition of oral ixazomib to lenalidomide and 
dexamethasone improves the OS in high-risk patients carrying deletion del(17)
Other secondary objectives are:

To determine overall response rate (ORR), including partial response (PR), very 
good partial response (VGPR), and complete response (CR)

To determine CR + VGPR

To determine duration of response (DOR)

To determine time to progression (TTP)

To determine the safety of the addition of ixazomib to lenalidomide and 
dexamethasone 

To determine pain response rate, as assessed by the BFI-SF and analgesic use

To assess change in 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

To determine the PFS and OS in high-risk cytogenetic patient groups such as 
translocations t(4;14), t(14;16), +1q, del(13), or del(17)
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! To evaluate the potential relationship between response or resistance to ixazomib
treatment and proteasome and NFKB-related genes, such as PSMB1 and TRAF-3 in 
blood samples
!
To collect pharmacokinetic (PK) data to contribute to population PK analyses
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2.   
POPULATIONS FOR ANALYSIS
2.1   
Intent-to-Treat Population
The Intent-to-Treat (ITT) population is defined as all patients who are randomized.  Patients 
will be analyzed according to the treatment they were randomized to receive, regardless of 
any errors of dosing.  
The ITT population will be used for the primary and 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 Arm B but received the regimen in Arm A will be included 
in Arm A; those patients who are randomized to Arm A but received the regimen in Arm B 
will be included in Arm B for safety analyses. More specifically, patients who received any 
dose of ixazomib will be included in the ixazomib + 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.
The Safety population will be used for all safety-related analyses such as AEs, concomitant 
medications, laboratory tests, and vital signs.
2.3   
Response-Evaluable Population
The Response-Evaluable population consists of patients who receive at least 1 dose of study 
drug, have measurable disease at baseline, and at least 1 postbaseline response 
assessment. The Response-Evaluable population will be used for the analyses of response 
rates, time to response, and DOR (More specifically, TTR and DOR is defined in patients
with confirmed response and will be summarized descriptively). 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 the serum free light chain ratio is abnormal
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2.4   
Per-Protocol Population
The Per-Protocol (PP) population consists of all ITT patients who do not violate the terms of 
the protocol in a way that would affect the study outcome significantly as determined by the 
medical monitor, who is blinded to study drug assignment. The PP population includes 
patients who 

Do not have major inclusion/exclusion violation (inclusion criteria #3, #4; exclusion 
criteria #1, #8), and

Do not have low drug compliance ( compliance rate ≤ 70%) or overdose (compliance 
rate ≥120%) or dispensing error, and 

Have not taken excluded concomitant medication (ie, 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).   
The PP population will be used as a sensitivity analysis of the ITT population for the 
primary efficacy endpoint PFS.  
All patients in the PP population will be analyzed according to the actual treatment received.
3.   
HYPOTHESES AND DECISION RULES
3.1   
Statistical Hypotheses
There is 1 primary endpoint, PFS, in this study (see Section 5.7.2 for study treatment arms).
The null and alternative hypotheses for PFS are:
H0: PFS in Arm Ixazomib + LenDex = PFS in Arm LenDex
Ha: PFS in Arm Ixazomib + LenDex > PFS in Arm LenDex
There are 2 key secondary efficacy endpoints in this study, OS and OS in high-risk patients 
carrying deletion del (17).
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The null and alternative hypotheses for OS are:
H0: OS in Arm Ixazomib + LenDex = OS in Arm LenDex
Ha: OS in Arm Ixazomib + LenDex > OS in Arm LenDex
The null and alternative hypotheses for OS in high-risk patients carrying deletion del(17)
are:
H0: OS in high-risk patients carrying deletion del(17) in Arm Ixazomib + LenDex = 
OS in high-risk patients carrying deletion del(17) in Arm LenDex
Ha: OS in high-risk patients carrying deletion del(17) in Arm Ixazomib + LenDex > 
OS in high-risk patients carrying deletion del(17) in Arm LenDex
3.2   
Statistical Decision Rules
A closed sequential testing procedure will be used to control type I error rate at a 2-sided 
alpha level of 0.05 for the primary endpoint (PFS) and key secondary endpoints (OS, OS in 
high-risk patients carrying del(17)). That is, only if PFS is significant based on the O’Brien-
Fleming alpha spending function (the Lan-DeMets method) at the first interim analysis (IA)
or the second IA (whichever occur first), the test of OS will be conducted on its own alpha 
spending functions.
The first IA will be performed when approximately 262 PFS events have occurred based on 
IRC assessment.  This will be the first analysis for PFS for statistical testing purposes.  
Based on the O’Brien-Fleming stopping boundary, the alpha level at the first IA and second 
IA on PFS would be 0.0163 and 0.0337, respectively, if the number of PFS events at the first 
IA is exactly 262.(1) Correspondingly, if the observed p value is less than 0.0163 and 0.0451 
at the first IA and the second IA, respectively, the test for PFS will be claimed to be 
statistically significant. If the test for PFS is statistically significant at the first IA, a 
non-inferential analysis of PFS will be performed at the second IA where the PFS data is 
considered mature.
If the test for PFS is not statistically significant at the first IA, the study will continue and
PFS testing will be conducted at the second IA when approximately 365 PFS events have 
occurred, which will also be the final analysis of PFS for statistical testing purpose. If the 
test for PFS is not statistically significant at second IA, the study will be claimed as 
unsuccessful and no further testing will be conducted.
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The key secondary endpoint, OS, will be tested at the 3 planned IAs with approximately 
154, 222, and 322 death events and again at the final analysis (FA) with approximately 486
events if necessary.  The O’Brien-Fleming boundary will be calculated using the Lan-
DeMets method. The information fraction for the IA is equal to the number of death events 
observed divided by 486.  If there are exactly 154 death events at the first IA, the null 
hypothesis for OS will be rejected if the observed p value of the stratified log-rank test is 
less than 0.0001. If there are exactly 222 death events at the second IA, the null hypothesis 
for OS will be rejected if the observed p value of the stratified log-rank test is less than 
0.0018. If there are exactly 322 death events at the second IA, the null hypothesis for OS 
will be rejected if the observed p value of the stratified log-rank test is less than 0.0112. The 
trial will be stopped for futility if the observed p value is greater than 0.366 at the third IA;
otherwise, the OS hypothesis will be tested again at the FA. If the observed p value of the 
stratified log-rank test is less than 0.0462 at the FA (corresponding to a nominal alpha of 
0.0382), the null hypothesis for OS will be rejected. However, the study will not be stopped 
after the first IA based on the test for OS.  
The hypothesis for the additional key secondary endpoint, OS in high-risk patients carrying 
del(17), will be tested sequentially when the OS null hypothesis is rejected either at the IAs
or at the FA.  The testing levels of significance will be the same as those used for OS.  For 
instance, if OS is significant at the 0.0382 level at FA, OS in high-risk patients carrying 
del(17) will also be tested at 2-sided alpha level of 0.0382 at the FA.  
The rejection boundary for OS in high-risk patients carrying del(17) at the FA will be 
calculated on the basis of the actual correlation between the test statistics at the second IA 
and the FA. Examples of critical values at the FA based on different correlations between 
the test statistics at the IA and the FA using a 2-sided alpha of 0.0379 are presented below.
The formula to calculate the critical values is also shown in the proof of strong control of 
error rate in Section 10.1. 
Information fraction ( 
⁄
)
Correlation (	 
⁄
)
Critical value
1/2
0.71
2.02
2/3
0.82
1.99
5/6
0.91
1.97
1
1
1.96
Where n1 and n2 are the number of death events at the second IA and FA, respectively.
Because the testing of the key secondary endpoints is gated by the significance of the 
primary endpoint, and the type I error rate for all key secondary endpoints is controlled at a
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2-sided alpha level, the overall type I error rate for all endpoints, ie, 1 primary and 2 key 
secondary endpoints, is also controlled strongly at the 2-sided 0.05 alpha level.
4.   
INTERIM ANALYSIS
4.1   
Interim Analysis
There are 3 planned IAs.  The first IA will be performed when approximately 262 of the 
disease progression/death events have occurred.  This IA is expected to occur approximately 
24.5 months after the first patient is enrolled.  This is the first analysis for PFS for statistical 
testing purpose and first IA for OS.    If the test for PFS is not statistically significant at a 2 
sided alpha level of 0.0163, the study will continue and PFS testing will be conducted again 
at the second IA when approximately 365 PFS events have occurred, which will also be the 
final analysis of PFS for statistical testing purposes and the second IA for OS. Based on the 
projected number of PFS events, the statistical significance of PFS could be claimed if the 
observed p value is less than 0.0451 (corresponding to nominal alpha of 0.0337).   The third
IA will be performed when approximately 322 deaths (two thirds of the total expected 
deaths) have been observed.  The third IA is expected to occur approximately 44 months 
after the first patient is enrolled.  
The test significance for the interim and final analyses of OS will be determined using 
O’Brien-Fleming boundaries (the Lan-DeMets method).  The alpha level of OS at the first 
IA will be 0.00014 if there are 154 death events. However, the study will not be stopped 
after the first IA based on the test for OS. Based on the projected number of death events, 
the trial will be stopped for overwhelming efficacy if the observed p value is less than 
0.0018 and 0.0112 at the second and third IA, respectively.  Also the trial will be stopped for 
futility if the observed p value is greater than 0.366 at the third IA.  The final analysis will 
be tested at the 2-sided alpha level of 0.0462 (corresponding to nominal alpha of 0.0382).
4.2   
Independent Data Monitoring Committee (IDMC)
An independent data monitoring committee (IDMC) will periodically review safety and 
efficacy data at regularly scheduled meetings prespecified in the IDMC charter.  All 
activities of the IDMC (eg, type of data reviewed, frequency of meetings, location of 
meetings) have been summarized in the charter. At the time of the IAs, the IDMC will be 
responsible for providing a recommendation regarding study continuation based on the 
safety and efficacy parameters.  
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4.3   
Independent Review Committee (IRC)
An independent review committee (IRC) will review all disease evaluation data from the 
study and determine disease status (response and progression).  
5.   
STATISTICAL METHODOLOGY
In general, summary tabulations will be presented that display the number of observations, 
mean, standard deviation, median, minimum, and maximum for continuous variables, and 
the number and percentage (of nonmissing) per category for categorical data, unless 
specified otherwise.  
5.1   
Sample Size Justification
The primary endpoint, PFS, along with the key secondary endpoints of OS and OS in high-
risk patients carrying del(17), will be sequentially tested in this study.
The total sample size was calculated to provide 80% power for the OS endpoint.  The study 
is also adequately powered to test PFS. There are 3 planned IAs and 1 FA.
The parameters used for sample size calculation on OS are a 2-sided test at the significance 
level of α = 0.05, power of 80%, a control arm median OS of 30 months, and testing arm
median OS of 39 months (assuming exponential distribution, hazard ratio 0.77). A total of 
approximately 703 patients will need to be randomized in a 1:1 ratio into those 2 arms, 
assuming an average enrollment rate of approximately 13 patients/month for the first 
6 months, approximately 45 patients/month thereafter, and an approximately 10% dropout 
rate at month 35.  The FA of OS is estimated to occur approximately 80 months from the 
enrollment of the first patient, including a 20-month randomization period and an additional
60-month follow-up from the last patient enrolled.  With an observed hazard ratio of 0.833 
(eg, median OS of 30 months for control vs 36 months for treatment, 20% improvement), 
statistical significance can be claimed at the FA with 486 death events. 
Assuming a hazard ratio of 0.728 (median PFS of 15 months in the control arm versus 
20.6 months in the treatment arm), 365 PFS events will be needed (85% power and 2-sided 
alpha of 0.05) with 2 planned IAs and the second IA as the final PFS analysis. The first IA 
will be performed when approximately 262 PFS events have occurred. With an assumption 
of approximately 13 patients/month for the first 6 months, 45 patients/month thereafter, and 
approximately 10% dropout rate at month 30, 262 PFS events is expected to occur at 
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approximately 24.5 months after the first patient is enrolled and approximately 703 patients 
have been enrolled.  This is the first IA of the study with the opportunity to claim PFS 
benefit.  With an observed hazard ratio of 0.743 (eg, median PFS of 15 months in the control 
arm versus 20.2 months in the treatment arm), statistical significance can be claimed at the 
analysis for PFS with 262 progression/death events.  If the test for the PFS at the first IA is 
statistically significant, the PFS test at the second IA will be non-inferential .
If the test for PFS is not statistically significant at the first IA, the study will continue and
PFS testing will be conducted at the second IA when approximately 365 PFS events have 
occurred, which will also be the final analysis of PFS for statistical testing purposes.  An 
observed hazard ratio of 0.810 (median PFS of 15 months in thr control arm versus 
18.5 months in the treatment arm) or better will lead to statistical significance for the PFS 
endpoint. 
5.2   
Randomization and Stratification 
The randomization scheme will be generated by an independent statistician at Millennium 
who is not on the study team.  Before dosing, a randomization number will be assigned to
each patient.  The randomization assignment will be implemented by an interactive voice 
response system (IVRS).  
Eligible patients will be randomized in a 1:1 ratio into those 2 treatment arms, stratified by 
1) 1 versus 2 or 3 prior therapies; 2) proteasome inhibitor exposed versus proteasome 
inhibitor naïve; and 3) ISS stage at screening of 1 or 2 versus stage 3. Randomization error 
may occur during study conduct; if this happens in the study, original stratification factors 
will be used in the primary analyses.
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 unblinded individual patient data in the electronic data capture system.  The 
periodic safety analyses will be generated for the IDMC by an ISC.  Three formal efficacy 
IAs will also be conducted by ISC for the IDMC.  
Refer to Section 4.2 for the roles and responsibilities of IDMC.
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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 under the auspices of standard 
data management operating procedures.
In general, missing data will be treated as missing and no data imputation will be applied, 
unless otherwise specified.  
For PRO data, primarily missing data imputation will be based on published instrument 
specific methods.  
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 indicate that the date is 
earlier. 

If only a year is present, and it is not the same as the year of the first dose of study 
drug, the 15th of June will be used, unless other data indicate that the date is earlier.  
5.4.1.2   
Missing/Partial Dates in Adverse Events/Concomitant 
Therapies/Subsequent Therapies
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 a month and year but the day is missing, the last day of the month 
will be imputed.
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
If the stop date has a year but the day and month are missing, the 31st 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 a month and year but the 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.
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 a year, but the 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 a month and year but the 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
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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 the year but the 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 the month and year are present but the day is missing:
o
If the onset month and year are the same as the month and year of the last dose of
study drug, the day of the last dose + 1 will be imputed.  
o
If the onset month and year are not the same as the month and year of the last 
dose of 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 the last dose of study drug, the date of 
last dose + 1 will be imputed.  
o
If the onset year is not the same as the year of the last dose of study drug, the first 
day of the year is imputed. 

If no components of the onset date are present, the date of the last dose of study drug
+ 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 before, the start of study drug administration.   
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5.4.3   
Windowing of Visits
All data will be categorized on the basis of the scheduled visit at which they are collected.  
These visit designators are predefined values that appear as part of the visit tab in the 
electronic case report form (eCRF).  
5.4.4   
Justification of Pooling
All data from all sites will be pooled.  Study center or treatment-by-center interaction will 
not be included in any statistical analysis.
5.4.5   
Withdrawals, Dropouts, Loss to Follow-up
Time-to-event parameters will be censored if patients withdraw, drop out, or are lost to 
follow-up before documentation of the events (PD/death).  Rules for censoring are detailed 
in Section 5.8.
5.5   
Patient Disposition
Patient disposition includes the number and percentage of patients for the following 
categories:  patients in each of the study populations, patients discontinued from treatment, 
primary reason for discontinuation from treatment, patients discontinued from the study, and 
primary reason for discontinuation from the study.  All percentages will be based on the 
number of patients in the ITT population.  
A listing will present data concerning patient disposition.
5.6   
Demographics and Baseline Disease Characteristics
5.6.1   
Demographics
Demographics will be summarized by treatment group in a descriptive fashion for 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. 
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5.6.3   
Baseline Disease Status
Baseline disease characteristics including Eastern Cooperative Oncology Group (ECOG)
performance status; type of myeloma; ISS stage; serum M-protein; urine M-protein; serum 
FLC; 2-microglobulin by category (ie, < 3.5, 3.5-5.5, ≥5.5 mg/L); serum creatinine and its 
category (≤2, > 2 mg/dL); creatinine clearance by category (ie, 30-60, ≥60 mL/min); serum 
albumin by category (ie, < 3.5, ≥3.5 g/dL); corrected calcium; hemoglobin; Durle-Salmon 
stage; Lytic bone lesions; and extramedullary disease will be summarized for all patients.  
A patient’s type of myeloma is determined by the combination of heavy chain type (IgG, 
IgA, IgM, IgD, and other) and light chain type (kappa, lambda, and biclonal). In descriptive 
summaries, the disease will be categorized by the heavy chain type first, then within each of 
these categories, patients will be further classified according to their light chain type. 
Patients are to be classified into 3 stages on the basis of the ISS. The derivation is based on 
the baseline 2-microglobulin and baseline albumin level measurements.
Stage
Criteria
Stage I
Serum 2-microglobulin < 3.5 mg/L
Serum albumin 3.5 g/dL
Stage II
Neither Stage I nor Stage III
Stage III
Serum 2-microglobulin 5.5 mg/L 
If corrected calcium is not reported directly, it can be calculated using either of the 
following 2 formulas according to the units of calcium and albumin:
L])
albumin[g/
serum
(40
0.0246
(mmol/L)
calcium
serum
(mmol/L)
calcium
corrected
dL])
albumin[g/
serum
(4
0.98
(mg/dL)
calcium
serum
(mg/dL)
calcium
corrected








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




For female patients:
[mg/dL])
creatinine
(serum
72
weight[kg]
Age[yrs])
(140
85
.0
clearance
creatinine





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Integer values will be used. 
A separate table will summarize the numbers and percentages of patients who had prior 
systemic therapy, prior transplant, prior surgery, and prior radiation therapy. This table will 
also include regimens and the number of lines of prior systemic therapies, best hematologic
responses to prior systemic therapy, relapsed and/or refractory status to prior systemic 
therapy, and months since progression from last prior systemic therapy and months since 
diagnosis for each treatment group in the ITT population. A by-patient listing will also be 
presented for prior systemic therapy.
Months from diagnosis to the randomization date for each treatment is calculated by:
randomization date - date of diagnosis  
365.25/12
Distribution of stratification factors will also be summarized.   
5.7   
Treatments and Medications
5.7.1   
Concomitant Medications
Concomitant medications will be coded by Preferred Term using the World Health 
Organization (WHO) Drug Dictionary.  The number and percentage of patients taking 
concomitant medications from the first dose through the end of the on-treatment period will 
be tabulated by Anatomical Therapeutic Chemical (ATC) classification pharmacological 
subgroup and WHO drug generic term for each treatment group in the Safety population.  A 
by-patient listing will also be presented for concomitant medications.
Concomitant procedures will not be coded but will be presented in a data listing for the
Safety population.
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 ixazomib or placebo.  Eligible patients will be randomized in a 1:1 ratio into those 
2 treatment arms.
Arm Ixazomib + LenDex: Patients will receive ixazomib (4.0 mg) orally (PO) on Days 1, 
8, and 15 plus lenalidomide (25 mg) on Days 1 through 21 and dexamethasone (40 mg) on 
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Days 1, 8, 15, and 22 of a 28-day cycle.  Patients may continue to receive treatment until PD 
or unacceptable toxicity, whichever comes first. Dose modifications may be made on the 
basis of toxicities.  Patients with creatinine clearance ≤ 60 mL/min (or ≤ 50 mL/min based 
on regional label) 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.
Arm Placebo + LenDex: Patients will receive a 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 may continue to receive treatment until PD or 
unacceptable toxicity, whichever comes first. Dose modifications may be made on the basis 
of toxicities.  Patients with creatinine clearance ≤ 60 mL/min (or ≤ 50 mL/min based on 
regional label) 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.
5.7.2.1   
Duration of Follow-up
The duration of follow-up is defined as time from randomization to the date of death or last 
known visit. If a subject dies, the duration will equal the date of death minus the date of 
study start + 1, with a censor variable = 1 (censored for follow-up). If a subject is alive, the 
duration will equal the date when the subject was last known to be alive minus the date of 
study start + 1, with a censor variable = 0 (event for follow-up). 
5.7.2.2   
Extent of Exposure
An overall summary of drug exposure will be presented, including number of treated cycles, 
and numbers and percentages of patients who had ≥1, ≥2, …, and ≥18 treated cycles, for 
each treatment group in the Safety population.  An aggregate summary of numbers and 
percentages of patients who had 1 to 6, 7 to 12, 13 to 18, and ≥19 treated cycles will also be 
presented in the same table.  
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 ≥18 treated cycles, and relative dose intensity (%) for 
each treatment group in the Safety population. An aggregate summary of numbers and 
percentages of patients who had 1 to 6, 7 to 12, 13 to 18, and ≥19 treated cycles will also be 
presented in the same table.  
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Ixazomib/placebo and lenalidomide exposure will be summarized similarly 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 (%) =  100 ×
total dose received 
sum of prescrbed dose over treated cycles 
The number of patients with 100% relative dose intensity, 80% to < 100%, 50% to < 80%, 
and < 50% will be summarized by treatment group and for all patients. 
Percent compliance is calculated as 100% * (study drug taken in mg) / (study drug expected 
to be taken in mg). Only reduced prescribed or increased prescribed or dose hold or 
discontinued permanently will change the expected prescribed dose.
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 Cycles 1 through 18, sum of the 
remainder cycles, Cycles 1 through 6, Cycles 7 through 12, 13 through 18, and 19 cycles 
and total for each treatment group in the Safety population. 
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, defined as the time from the date of randomization to the 
date of first documentation of PD based on central laboratory results and IMWG criteria as 
evaluated by an IRC, or death due to any cause, whichever occurs first. PD confirmation is 
required by 2 consecutive evaluations (at least 1 week apart) as per IMWG criteria. 
Confirmation is not required if PD occurs at the date of the last response assessment (special 
cases, e.g. PR->PD->NE, will be considered as confirmed PD if NE occurs at the last visit). 
Patients without documentation of PD will be censored at the date of the last response 
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assessment that is stable disease (SD) or better. The details regarding the handling of 
missing assessments and censoring for the PFS analysis are presented Table 5-1.
Table 5-1   
Handling of Missing Assessments and Censoring for PFS Primary 
Analysis Based on FDA guidance 
Situation
Date of Progression or Censoring
Outcome
No baseline and/or no post baseline assessment, no 
subsequent anticancer therapy after study 
treatment, no death
Date of Randomization 
Censored
Disease progression documented between 
scheduled visits 
Date of next scheduled visit
Progressed
No documented death or disease progression 
Date of last adequate assessmenta
Censored
Lost to follow-up, withdraw consent before any 
documented death or disease progression  
Date of last adequate assessmenta
Censored 
Death or progression after more than 1 missed 
visitb
Date of last adequate assessmenta
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
Progressed
Death between adequate assessment visits
Date of death
Progressed
a Adequate disease assessment is defined as there is sufficient data to evaluate a patient’s disease status.
b Death or progression occur more than 90 days from previous adequate assessment. 
5.8.1.1   
Primary Efficacy Analysis
PFS will be analyzed when approximately 262 and 365 PFS events have occurred for the 
first IA and for the second IA, respectively.  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 0.0163 and 
0.0337, which corresponds to a nominal p value of 0.0451 based on the O’Brien-Fleming 
stopping boundary (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 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 PP population.
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Progression-free survival 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 neoplastic therapy. The details of the handling 
of missing assessments and censoring for additional sensitivity analyses are presented in
Table 5-2. 
Table 5-2   
Handling of Missing Assessments and Censoring for PFS Sensitivity 
Analysis Based on EMA Guidance 
Situation
Date of Progression or Censoring
Outcome
Disease progression documented 
between scheduled visits 
Date of documented disease progression
Progressed
Alternate antineoplastic therapy started 
prior to disease progression
Date of documented disease progression 
Progressed
Death or disease progression after more 
than one missed visit
Date of death or disease progression 
Progressed 
In addition, a stepwise Cox model will be implemented to identify potential predictive 
factors using relevant demographic or diagnostic covariates, with the entry level fixed at 
0.25 and a stay level fixed at 0.10. Besides treatment and the stratification factors, the 
model may include the following prognostic factors including, but not limited to, age; race 
(white, non-white); prior therapy (immunomodulatory drug [IMiD]-exposed vs IMiD-
naïve); baseline ECOG score; cytogenetic test (high-risk group [del(17); t(4;14) and 
t(14;16)] vs standard ); and corrected serum calcium.  
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. The details on subgroups are presented in the following:
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Subgroup
Definition of Group
Age
65 years, >65 and 75 years,  > 75 years
Sex
male vs female
Race
white, black-African American, Asian, other
Region
North America, Europe, Asian, other
Western Countries
North America + Western Europe
Cytogenetic risk
Standard-risk, high-risk [(del17); t(4;14); t(14;16)], not available
ISS stage
In additional to stratification factors , also define as 1 or 2 or 3
Lines of prior therapies
In additional to stratification factors , also define as 1 or 2 or 3
Prior proteasome inhibitor therapy
exposed vs naïve
Prior IMiD therapy
exposed vs naïve
Thalidomide Refractory
yes vs no
Refractory to any line of prior therapy
yes vs no
Refractory to last line of prior therapy
yes vs no
Relapsed and/or refractory
Relapsed, efractory, Relapse and refractory
Prior Velcade therapy
Exposed vs naïve
Renal function based on baseline 
creatinine clearance
< 60 mL/min, and ≥60 mL/min
Liver Function based on baseline ALT 
or AST
≥1.5ULN vs. <1.5 ULN
ECOG performance status
0 or 1 vs 2
If it is determined that the study will continue after PFS is significant at a 2-sided alpha level 
of 0.0163 at the first IA, a non-inferential analysis of PFS will be performed at the second 
IA.  
5.8.2   
Key Secondary Efficacy Endpoints
There are 2 key secondary endpoints: OS and OS in high-risk patients carrying del(17).
Overall Survival
Overall survival is defined as the time from the date of randomization to the date of death.  
Patients without documentation of death at the time of the analysis will be censored at the 
date when they were last known to be alive.  Overall survival will be analyzed using the ITT 
population. 
Overall Survival in High-Risk Patients With del(17)
The high-risk patients with del(17) subgroup is defined as the cases reported as positive for 
del(17) by the central laboratory combined with those cases that lack a central laboratory 
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result for del(17) and were reported positive for del(17) by local laboratory.  Overall 
survival within the high-risk patients with del(17) subgroup is defined the same as OS in the 
overall population.
5.8.2.1   
Key Secondary Efficacy Analysis
Two key secondary efficacy endpoints will be tested sequentially in the order of 1) OS, and
2) OS in high-risk patients carrying del(17). The second key secondary endpoint will be 
tested only if the test for OS is statistically significant at the IAs or FA at the same 
significance level as OS to ensure strong type I error control for both key secondary 
endpoints.
Overall Survival
Overall survival will be tested only after statistical significance is achieved for PFS.  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 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.
In addition, a stratified Cox regression model will be used to further evaluate the treatment 
effects on OS after adjusting for some prognostic factors. Besides treatment and the 
stratification factors, the model may include, but will not be limited to, the following 
prognostic factors simultaneously: age; race (white, non-white); prior therapy (IMiD-
exposed vs IMiD-naïve); baseline ECOG score; cytogenetic results (high risk vs normal); 
and corrected serum calcium.
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(2)

Inverse Probability of Censoring Weighted (IPCW) method by Robins and 
Finkelstein(3)
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 
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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), relapse and/or refractory relapsed, refractory, relapse 
and refractory), type of myeloma (IgA, other), percentage of plasma cells (≤30, > 30; 
missing), presence of extramedullary plasmacytomas (yes, no), presence of lytic bone 
lesions (yes, no), cytogenetic abnormalities (high risk, others), prior lenalidomide (yes, no), 
prior thalidomide (yes, no), prior proteasome inhibitor (yes, no), number of line therapies (1 
vs 2 or 3), baseline hemoglobin, baseline platelets, creatinine clearance (median), albumin
(median), LDH (median), 2 microglobulin (median), and corrected calcium (median). 
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 progression/relapse, type of 
subsequent therapy with proteasome inhibitor, types of subsequent therapy with IMIDs.  The 
final criteria for selected covariates would need to be statistically have a p-value of less than 
or equal to 0.1 in the multivariate Cox regression models for weight calculations, and in the 
final Cox model for OS. If there are more than 5% missing in the covariate, then this 
covariate will be dropped from the weighting calculation and final OS model. For both 
MSM and IPCW analyses, logistic regression models on repeated measurements will be 
used to approximate the Cox models in the weight derivations(4) from which stabilized 
weights will be derived per subject per observation. Adjusted K-M curves(5) will also be 
presented along with hazard ratios (HRs), 95% confidence intervals for HRs, and adjusted p-
values based on MSM and IPCW approaches.SAS proc PHREG procedure with counting 
process type of data input, which takes multiple observations per subject, will be used as the 
final Cox model for OS for both MSM and IPCW approaches.
Furthermore, a versatile test for the equality of the 2 survival functions based on weighted 
differences of K-M curves proposed by Uno, Tian, Claggett, and Wei(6) will be used to test 
the treatment differences as a sensitivity analysis.
Subgroup analyses will be performed for OS relative to baseline stratification factors and
demographic data such as sex, race, age, and disease characteristics, such as type of prior 
regimen. 
Additional exploratory analyses may be performed if deemed necessary.
Overall Survival in High-Risk Patients With del(17)
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Overall survival within the high-risk patients with del(17) subgroup will be analyzed using a
similar method as the OS in the overall population. 
5.8.3   
Other Secondary Efficacy Endpoints and Analyses
Other secondary efficacy parameters include overall response rate (ORR); the combined 
CR + VGPR rate; time to progression; DOR; time to subsequent antineoplastic therapy; OS 
and PFS in high-risk subgroups harboring del(17), translocation t(4;14), or t(14;16); and 
pain response rate. 
The high-risk patients are defined as the cases reported as positive by the central laboratory 
combined with those cases that lack a central laboratory result and were reported positive by 
a local laboratory.
Disease response-related endpoints will be analyzed using the IRC-assessed response rate.
Overall Response Rate
The ORR is defined as the proportion of patients who achieved PR or better relative to the 
ITT population.  The ORR is determined from the start of the study treatment until the end 
of treatment, taking into account any requirement for confirmation. To calculate the 
confirmed response, 1 visit after end of treatment (EOT) is used to confirm the assessment at 
EOT. A stratified Cochran-Mantel-Haenszel (CMH) test will be used to compare ORR 
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.
The IRC-assessed response data will be used for the analysis.  Investigator-assessed 
response data will be used for the sensitivity analysis.
Combined Complete Response + Very Good Partial Response Rate
The combined CR + VGPR rate will be analyzed using the same method as ORR.  
Time to Progression
Time to progression is defined as the time from the date of randomization to the date of first 
documentation of PD.  Patients without documentation of PD at the time of the analysis will 
be censored at the date of their last response assessment that is SD or better. Patients with 
no response assessment will be censored at the day of randomization. Patients who do not 
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experience progression and start new systemic therapy for multiple myeloma will be 
censored at the date of their last response assessment that is SD or better. Time to 
progression will be analyzed using the ITT population using a similar method as PFS.
Duration of Response
Duration of response is defined as the time from the date of first documentation of a PR or 
better to the date of first documentation of PD for responders.  Responders without 
documentation of PD will be censored at the date of their last response assessment that is SD 
or better.  Duration of response will be summarized descriptively using the K-M method.
Kaplan Meier (K-M) survival curves and K-M medians (if estimable) will be provided for 
each treatment group.  
OS and PFS in High Risk Cytogenetic Patient Groups 
Overall survival, PFS, and ORR 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: 

Individual abnormality group: patients carrying 1 of the following cytogenetic 
abnormalities: del(17), translocation t(4;14), or t(14;16)
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
o
the t(14;16) group will include ONLY pts with t(14;16) ALONE

Cytogenetic high-risk group:  patients carrying any of the following cytogenetic 
abnormalities: del(17), translocation t(4;14), or t(14;16)
5.9   
Pharmacokinetic, Pharmacodynamic, and Biomarker Analyses
5.9.1   
Pharmacokinetic Analyses
Plasma concentration-time data will be presented in listings.  Pharmacokinetic data will be 
used to perform population PK analysis using a nonlinear mixed effects modeling approach 
and to assess the effect of various covariates on PK after including data from other studies, if 
possible.  The analysis plan for the population PK analysis will be separately defined, and 
the results of these analyses will be reported separately.
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5.9.2   
Pharmacodynamic Analyses 
Not applicable.
Prop
se
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5.10   
Resource Utilization and Patient-Reported Outcome Analysis
5.10.1   
Patient-Reported Outcomes (PROs)
Patient-reported outcome assessments using the EORTC QLQ-C30 and MY20 will be 
analyzed using the ITT population.  The descriptive statistics of actual values and changes
from baseline of the subscale scores for the 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 the EORTC QLQ-C30 and QLQ-MY20 are defined in Table 5-3 and Table 5-4, 
respectively.
Table 5-3   
Definition of Subscale Scores of EORTC QLQ-C30
Subscale
Individual Items
Physical functioning
1-5
Role functioning
6-7
Emotional functioning
21-24
Cognitive functioning
20, 25
Social functioning
26-27
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 5-4   
Definition of Subscale Scores of EORTC QLQ-MY20
Subscale
Individual Items
Future perspective
18-20
Body image
17
Disease symptoms
1-6
Side effects of treatment
7-16
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Differences between treatment groups in the EORTC QLQ-C30 and MY20 subscale scores 
will be evaluated using published minimally important difference (MID) values of 10 points. 
Patients with a change from baseline score ≥MID in a direction reflecting improved
QOL/functioning or decreased symptoms at a given time point will be defined as 
improvement. The number and percentage of patients with an improvement from baseline 
in subscale scores will be summarized by treatment group over time. Specific areas of
interest include physical functioning, global QOL, fatigue, nausea/vomiting, pain, dyspnea, 
appetite loss, and constipation/diarrhea.  The main endpoint for the PRO analysis will be the 
global health status/QOL subscale of the EORTC QLQ-C30 and functional scales and 
symptom scales of the MY20.  The other PRO endpoints include the remaining EORTC 
QLQ-C30 and MY20 subscale scores. The change from baseline in subscale scores at any 
postbaseline visit will be presented using cumulative distribution function (CDF) figures. 
The patient’s largest improvement from baseline will be determined first, and CDF curves
will then be used to display the cumulative percentage of patients experiencing that 
improvement by treatment group. Additionally, CDF curves will be generated for global 
health status/QOL score by treatment group among responders and nonresponders, 
respectively.
The change from baseline in subscale scores will be also analyzed using the repeated-
measures linear mixed-effects (random-intercept only) models, including treatment group, 
time (a discrete variable), the interaction between treatment group and time, baseline score, 
and stratification factors as covariates. The repeated-measures analysis will use 
measurements collected from all available time points specified in the Schedule of Events in 
the protocol.  The estimation of variance-covariance matrix and statistics such as Akaike 
information criteria (AIC) and Bayesian information criteria (BIC) will be included in 
evaluating the linear mixed-effects model. The estimated mean difference in the changes 
from baseline between the 2 treatments and the 95% CIs will be provided.  
Details of scoring and initial handling of missing data are included in the EORTC QLQ-C30 
and MY20 scoring guidelines.
Missing data patterns will be examined.  For sensitivity analyses, different imputation 
methods for missing data including LOCF, the random slope model, and the pattern mixture 
model may be performed if appropriate after examining missing data patterns.  
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5.10.2   
Health Economics (Health Care Resource Use)
EuroQol 5 Dimensional Health Questionnaire scores will be summarized in descriptive 
statistics for treatment arms over time. 
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.
Further modeling will be performed separately at post hoc analyses.
5.10.3   
Pain
Pain response rate will be analyzed in patients with a baseline 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.  The CMH test will be used to compare the 
2 treatment groups by stratification factors.  In addition, the absolute treatment difference in 
pain response rate will be provided, along with the 95% CI. A CDF plot will be generated 
for pain response. 
Pain response is defined as the occurrence of a 30% reduction from baseline in BPI-SF 
worst pain score over the last 24 hours without an increase in analgesic use at 2 consecutive 
evaluations.
Additional analyses on pain include:

Time to pain response/progression, as assessed by the time from randomization to 
initial response/progression classification

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 among patients with pain response.
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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 worst BPI-SF 
score ≥ 4 during 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 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
Confirmation is not required if surgical treatment for pain, palliative radiation for pain, or 
subsequent antineoplastic therapy has been received before a confirmatory assessment.
In addition, the actual value and change from baseline in BPI-SF pain scores will be 
summarized by treatment group over time. The change from baseline in worst pain score 
will be also analyzed using the repeated-measures linear mixed-effects (random-intercept 
only) models, including treatment group, time (a discrete variable), the interaction between 
treatment group and time, baseline score, prior therapies, ISS stage at screening, sex, race,
and age as covariates.
Compliance rates for EORTC QLQ-C30, MY20, BPI-SF, and EQ-5D will be summarized 
over time by treatment group. 
5.11   
Safety Analyses
Safety evaluations will be based on the incidence, intensity, type of AEs, clinically 
significant changes in the patient’s physical examination findings, electrocardiograms 
(ECGs), vital sign measurements, and clinical laboratory results.
These analyses will be performed using the Safety population. All analyses will be 
performed for each treatment arm.
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5.11.1   
Adverse Events
5.11.1.1   Adverse Events
Adverse events will be coded using MedDRA version 14.0 or higher.  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.
Adverse events will be tabulated according to the MedDRA by System Organ Class, High 
Level Term, and Preferred Term, and will include the following categories:

Treatment-emergent AEs

Drug-related treatment-emergent AEs

Grade 3 or higher treatment-emergent AEs (also report Grade 3 and 4 separately)

Grade 3 or higher drug-related treatment-emergent AEs (also report Grade 3 and 4 
separately)

The most commonly reported treatment-emergent AEs (ie, those events reported by 
10% of patients in either treatment group) 

Serious AEs (SAEs)
Patients with the same AE more than once will have that event counted only once within 
each body system, once within each High Level Term, and once within each Preferred Term.
Drug-related treatment-emergent AEs will also be summarized by the National Cancer 
Institute Common Toxicity Criteria (NCI CTCAE) version 4.03.  Patients with the same AE 
more than once will have the maximum intensity of that event counted within each body 
system, once within each High Level Term, and once within each Preferred Term. 
The most commonly reported treatment-emergent AEs (ie, those events reported by 10% 
of any treatment arm) will be tabulated by Preferred Term.  Patients with the same AE more 
than once will have that event counted only once within each Preferred Term.
An overall summary AE table will include numbers and percentages of patients who had any 
AE, drug-related AE, Grade 3 or higher AE (also Grade 3 and 4 AE), Grade 3 or higher 
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drug-related AE (also Grade 3 and 4 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.  
Incidence rates will be calculated for the safety population based on AEs and SAEs.
Incidence rate is defined as the number of events divided by the total number of person-
years at risk (per 100) in the Safety population.
5.11.1.2   Serious Adverse Events
The number and percentage of patients experiencing at least 1 treatment-emergent SAE will 
be summarized by MedDRA primary System Organ Class, High Level Term, and Preferred 
Term. Drug-related SAEs will be summarized similarly.
In addition, a by-patient listing of the SAEs will be presented (the patient listing will contain 
all SAEs regardless of treatment-emergent AE status).
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 
will be presented.
5.11.2   
Laboratory Data
For the purposes of summarization in both the tables and listings, all laboratory values will 
be converted to standardized units.  If a lab value is reported using a non-numeric qualifier 
(eg, less than (<) a certain value, or greater than (>) a certain value), the given numeric value 
will be used in the summary statistics, ignoring the non-numeric qualifier. However, for the 
bone marrow plasma cell percentage, the convention of (x-1)% (mainly for < 5% for CR) 
will be used.
Laboratory test results from the central laboratory will be used when they are available.  
Laboratory test results from local laboratory will be used only when no central laboratory 
test result exists at the same scheduled sample collection time point.
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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, absolute neutrophil count (ANC), absolute 
lymphocyte count (ALC), monocytes, platelets, and white blood cell (WBC) count

Serum chemistry:  blood urea nitrogen, creatinine, total bilirubin, uric acid, lactate 
dehydrogenase, albumin, alkaline phosphatase, aspartate aminotransferase (AST), 
alanine aminotransferase (ALT), glucose, calcium, sodium, potassium, chloride, 
carbon dioxide, magnesium, and phosphate.
Shift tables will be constructed for laboratory parameters to tabulate changes in NCI 
CTCAE for toxicity (version 4.03) from baseline to worst postbaseline CTC grade.  
Parameters to be tabulated will include:

Hematology: ALC, ANC, hemoglobin, platelets, and WBC

Serum chemistry: ALT, AST, alkaline phosphatase, creatinine, total bilirubin, 
calcium, magnesium, potassium, sodium, and phosphate
Summary statistics will also be presented for shift from baseline urinalysis values.
Mean laboratory values and box plots over time for key lab parameters will be produced 
including, but not limited to, ANC, platelets, and liver function tests (ALT, AST, alkaline 
phosphatase, and total bilirubin).
By-patient listings to be presented include hematology, serum chemistry, urinalysis, urine 
total protein, and urine creatinine.
5.11.3   
Electrocardiograms
Descriptive statistics for the actual values and changes from baseline in ECGs will be 
tabulated by time point.
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Corrected QT interval (QTc) 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 will be performed for each time point.  The 
number and percentage of patients in each QTc category (< 450 msec, 450-480 msec, 481-
500 msec, and ≥500 msec) will be summarized at baseline and at each subsequent time 
point.  Categories of changes from baseline (≥ 30 msec and ≥ 60 msec) will also be 
summarized.
Maximum QTc and maximum changes from baseline will be summarized similarly in a 
separate display.
Electrocardiogram abnormalities will be presented in a data listing.
5.11.4   
Vital Signs
The actual values of vital sign parameters including oral temperature, pulse rate, systolic and 
diastolic blood pressure, and 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 postbaseline 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 ixazomib.
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6.  
MAJOR PROTOCOL DEVIATIONS
A listing will be presented for major protocol deviation, for example, if 1 of the following 
criteria is met:
1. Major inclusion/exclusion violation (any violations)
2. Have major dosing compliance errors (ie, 70%) or overdose (≥120%) or 
dispensing error
3. Take excluded concomitant medication (ie, 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);
4. Missed pregnancy testing;
7.   
CHANGES TO PLANNED ANALYSES FROM PROTOCOL
Reference materials for this statistical plan include Clinical Study Protocol C16010
Amendment 3 (Protocol dated 08 July 2014). Additional major changes inlcude:

Futhur clarify per protocol populaiton using programatic approach
8.   
PROGRAMMING CONSIDERATIONS
8.1   
Statistical Software 
SAS version 9.1 (or higher) will be used for all analyses, except for RPSFT and Uno’s 
method, which may be done using R (version 3.0.1 or higher)
8.2   
Rules and Definitions
Patient populations are defined in Section Error! Reference source not found.Error! 
Reference source not found..
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Baseline values are defined in Section 5.4.2.
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9.   
REFERENCES
1.
Lan K, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika 
1983;70:659-63.
2.
Robins JM, Hernan M, Brumback B. Marginal strucural models and causal inference 
in epidemiology. Epidemiology 2000; 11(5): 550-560.  
3.
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.
4.
D’Agostino R.B., Lee M.L., Belanger A.J., Cupples L.A., Anderson K., and Kannel 
W.B. Relation of pooled logistic regression to time dependent Cox regression 
analysis: the Framingham Heart Study. Statistics in Medicine, 9(12): 1501–1515, 
1990.
5.
Xie J. and Liu C. (2005). Adjusted Kaplan-Meier Estimator and Log-Rank Test with 
Inverse Probability of Treatment Weighting for Survival Data. Statistics in Medicine,
10;26(10):2276, 2007.
6.
Uno H, Tian L, Claggett B, Wei LJ. A versatile test for equality of two survival 
functions based on weighted differences of Kaplan-Meier curves. Harvard University 
Biostatistics Working Paper Series 2013:Paper 159.
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10.   
APPENDIX
10.1   
Proof of Strong Control of Type I Error Rate for Key Secondary Endpoints
Proof of strong control of Type I error rate for both key secondary endpoints (OS and OS in 
high-risk patients carrying del(17)):
With the proposed testing procedure of the 2 key secondary endpoints (OS and OS in high-
risk patients carrying del(17)), this is to prove the strong control of overall Type I error rate 
for both  endpoints at one-sided 0.025 level. 
To facilitate the probability presentation, we introduce the following notations. Let P, S 
indicate the first and second key secondary, OS and OS in high-risk patients carrying 
del(17). Denote the family of null hypotheses of interest as: 
0
  
:
H
P
P
0


(OS is not 
efficacious); 
0
:
H S
0

S

(OS in high-risk patients is not efficacious). Let 
P
1
T , 
P
2
T
be the 
log-rank test statistic for OS at the second interim and FA, and 
S
2
S
1 T
,
T
be the log-rank test 
statistic for OS in high risk patients at the second interim and FA. Denote zα as the upper α 
quantile from the standard normal distribution.
We use the fundamental multiple testing technique, partitioning principle to prove the 
overall Type I error rate control for both endpoints. 
Table 10-1   Partition Hypotheses for Testing Both Key Secondary Endpoints
Index
Partition Hypothesis
1
0
,0


S
P


2
0
,0


S
P


3
0
,0


S
P


By partition principle, as long as each of the partition hypothesis is tested at level 0.025, the 
overall Type I error rate is also controlled at the same level.
1. Under partition hypothesis 
0
,0


S
P


, a false rejection is {reject P or reject S}. 
Due to the closed sequential testing between P and S at both second IA and FA, 
rejecting S implies rejecting P, therefore probability of false rejection is simply the 
probability of rejecting P, i.e.
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)
or 
(
2
1
P
2
P
1


z
T
z
T
P


where α1 and α2 are calculated based on the actual information fraction at second IA 
from O’Brien-Fleming boundary (Lan-DeMets method). Base on this boundary, the 
probability is no greater than 0.025.                                            
2. Under partition hypothesis 
0
,0


S
P


, the probability of false rejection: 
Pr{reject P} is again controlled at 0.025 by O’Brien-Flemming boundary.
3. Under partition hypothesis 
0
,0


S
P


, a false rejection is {reject S}={(reject P 
at IA and reject S at IA) or (failed to reject P at IA and reject P at FA and reject S at 
FA)} which is a subset of {reject S at IA or reject S at FA}. Therefore, the 
probability of false rejection is bounded by:
)
and
P(
)
(
)
or 
(
S
2
S
1
S
1
S
2
S
1
1
1
1
c
T
z
T
z
T
P
c
T
z
T
P










          (1)
The critical value c will be calculated as follows 
1
S
2
S
1
025
.0
)
and
P(
1






c
T
z
T
to maintain the probability equation (1) at 0.025 level using following asymptotic 
multivariate normal distribution:                                       






































1
1
,
0
0
~
2
1
2
1
2
1
n
n
n
n
MVN
T
T
S
S
where n1 and n2 are the size of the patient population at the second IA and FA, 
respectively. 
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