Conditions: Relapsed or Refractory Systemic Light Chain Amyloidosis
Keywords: MLN9708 Amyloidosis Light Chain IXAZOMIB Tourmaline AL1 Drug Therapy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 177
Healthy volunteers: no

Brief summary:
The purpose of this study is to provide continued access of ixazomib and/or other study medications and to continue collecting relevant safety data to monitor participant's safety, determine whether dexamethasone plus IXAZOMIB improves hematologic response, 2-year vital organ (that is, heart or kidney) deterioration and mortality rate versus a physician's choice of a chemotherapy regimen in participants diagnosed with relapsed or refractory systemic light chain (AL) amyloidosis.

Detailed description:
The drug being tested in this study is called IXAZOMIB. IXAZOMIB was being tested to treat people who have relapsed or Refractory Systemic Light Chain (AL) Amyloidosis.

The study will enroll approximately 177 patients. Participants will be randomly assigned (by chance, like flipping a coin) to one of the two treatment groups:

* IXAZOMIB 4 mg plus Dexamethasone 20 mg
* Physician's choice: Participants will receive one of the following treatment options as selected by the physician:

  1. Dexamethasone 20 mg
  2. Dexamethasone 20 mg + Melphalan 0.22 mg/kg
  3. Dexamethasone 20 mg + Cyclophosphamide 500 mg
  4. Dexamethasone 20 mg + Thalidomide 200 mg
  5. Dexamethasone 20 mg + Lenalidomide 15 mg
  6. All participants will be asked to take oral formulation of the drugs. In both treatment arms, each participant will continue to receive sequential cycles of therapy until disease progression, unacceptable toxicity, or until the study is terminated, whichever occurs first. Participants in Arm B receiving melphalan and dexamethasone will be treated to best response plus 2 additional cycles.

This multi-center trial will be conducted worldwide. The overall time to participate in this study is 120 months (10 years), including 84 months of enrollment and 36 months of follow-up after the last participant is enrolled.

Arms:
arm 1: Ixazomib 4 mg, capsules, orally, once on Days 1, 8, and 15 and dexamethasone 20 mg, orally, once weekly on Days 1, 8, 15, and 22 of each 28-day cycle for up to a maximum of 95.2 months. Dexamethasone was increased up to 40 mg/day after 4 weeks, if tolerated. arm 2: Participants received dexamethasone 20 mg, orally, and melphalan 0.22 mg/kg, orally once on Days 1 through 4 of each 28-day cycle, for up to a maximum of 72.4 months. arm 3: Participants received dexamethasone 20 mg, orally, once weekly on Days 1, 8, 15, and 22, and cyclophosphamide 500 mg, orally, on Days 1, 8 and 15 of each 28-day cycle for up to a maximum of 72.4 months. arm 4: Participants received dexamethasone 20 mg, orally, once weekly on Days 1, 8, 15 and 22 of each 28-day cycle, and thalidomide daily at a starting dose of 50 mg and increased, as tolerated, to a maximum of 200 mg, orally for up to a maximum of 72.4 months. arm 5: Participants received dexamethasone 20 mg, orally, once weekly on Days 1, 8, 15 and 22 of each 28-day cycle and lenalidomide 15 mg, orally, once on Days 1 through 21 every 28 days for up to a maximum of 72.4 months.

Interventions: intervention 1: IXAZOMIB intervention 2: Dexamethasone intervention 3: Melphalan intervention 4: Cyclophosphamide intervention 5: Thalidomide intervention 6: Lenalidomide
Intervention descriptions: intervention 1: IXAZOMIB capsules intervention 2: Dexamethasone tablets intervention 3: Melphalan tablets intervention 4: Cyclophosphamide tablets intervention 5: Thalidomide capsules intervention 6: Lenalidomide capsules

Protocol document:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL 
NCT Number: 
Study Title: 
Study Number: 
NCT01659658
A Phase 3, Randomized, Controlled, Open-label, Multicenter, Safety and 
Efficacy Study of Dexamethasone Plus MLN9708 or Physician’s Choice of 
Treatment Administered to Patients With Relapsed or Refractory Systemic 
Light Chain (AL) Amyloidosis
C16011
Protocol Version and Date: 
Amendment Version 6.0: 14 January 2020 
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MLN9708
Study No. C16011
Protocol Incorporating Amendment No. 6
Confidential
1
CLINICAL STUDY PROTOCOL C16011 AMENDMENT 6
MLN9708
A Phase 3, Randomized, Controlled, Open-label, Multicenter, Safety and Efficacy Study 
of Dexamethasone Plus MLN9708 or Physician’s Choice of Treatment Administered to
Patients With Relapsed or Refractory Systemic Light Chain (AL) Amyloidosis
Protocol Number:
C16011
Indication:
Amyloidosis
Phase:
3
Sponsor:
Millennium Pharmaceuticals, Inc
EudraCT Number:
2011-005468-10
Therapeutic Area:
Oncology
Protocol History
Region
Date
Original
Global
06 December 2011
Amendment 1
Global
01 June 2012
Amendment 2
Global
09 November 2012
Amendment 3
Global
20 November 2013
Amendment 4
Global
09 July 2015
Amendment 5 
For use in France only
09 July 2015
Amendment 6 (substantial)
Global
13 January 2020
Millennium Pharmaceuticals, Inc
40 Landsdowne Street
Cambridge, MA USA 02139
Telephone:  +1 (617) 679-7000
Approved by:
Note:  If this document was approved electronically, the electronic approval signatures may be 
found at the end of the document.
, MD
, Oncology 
Clinical Research; 
Global Clinical Lead
Signature
Date DD Month 
YYYY
, MD, PhD
, Oncology 
Clinical Research (or designee)
Signature
Date DD Month 
YYYY
, PhD
, Statistical and Quantitative 
Sciences (or designee)
Signature
Date DD Month
YYYY
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MLN9708
Study No. C16011
Protocol Incorporating Amendment No. 6
Confidential
2
Confidentiality Statement
The information contained herein is confidential and the proprietary property of Millennium 
Pharmaceuticals and any unauthorized use or disclosure of such information without the prior 
written authorization of Millennium Pharmaceuticals is expressly prohibited.
Rationale for Amendment 6
This document describes the changes to the protocol incorporating Amendment 6. The 
primary rationale for this amendment is to modify the study assessments. The first interim 
analysis (IA) was conducted (data cut-off date 20 February 2019) and the primary endpoint 
of overall hematologic response rate (complete response [CR] + very good partial response 
[VGPR] + partial response [PR]) did not reach statistical significance. However, patients in 
both treatment arms appeared to receive benefit. In light of the primary endpoint not being 
met, the sponsor has decided to remove the planned second IA and final analysis (FA) and 
discontinue the majority of study assessments to ease the burden of protocol-mandated 
assessments on patients. Ixazomib (MLN9708) and control drugs (if Takeda has been 
supplying them) will continue to be provided for patients who continue to derive benefit. 
Upon implementation of this amendment, data collection requirements will be limited to the 
following safety assessments: all serious adverse events (SAEs) (regardless of causality, 
including all deaths), any adverse event (AE) resulting in dose modification or 
discontinuation of any study drug, Grade ≥3 AEs, AEs of new primary malignancy, all 
reports of drug exposure during pregnancy and pregnancy outcomes, product complaints, 
and medication errors (including overdose). All other study assessments are no longer 
required. All central laboratory and investigator assessments of response and progression for 
protocol purposes are discontinued—Adjudication Committee (AC) review of response data 
will no longer be performed. Patients will not be followed for the progression-free survival 
(PFS) or overall survival (OS) follow-up periods, as PFS and OS are no longer being 
collected. Quality of Life (QOL) and pharmacokinetic (PK) assessments will no longer be 
performed or recorded.  Patients should otherwise be treated by the investigator according to 
standard of care. See the updated Schedule of Events—Amendment 6 and beyond for more 
detailed information.
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 15.18.
Purposes for Amendment 6
The purposes of this amendment are to:
1. Add primary study results from the first interim analysis (IA) and clarify details about 
subsequent analyses. 
2. Clarify the study objectives as of Amendment 6.
3. Clarify the study endpoints as of Amendment 6.
4. Define the ongoing safety assessments as of Amendment 6.
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Protocol Incorporating Amendment No. 6
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5. Discontinue all disease and efficacy response assessments, including central laboratory 
assessments of efficacy and safety, for protocol purposes because no further analyses 
will be performed.
6. Discontinue pharmacokinetic (PK) sampling for ongoing patients.
7. Discontinue Quality of Life (QOL) and Health Utilization assessments for ongoing 
patients.
8. Discontinue collection of concomitant medications and procedures.
9. Specify that no further Adjudication Committee (AC) reviews are needed as of 
Amendment 6.
10. Update the number of patients in the study.
11. Update the estimated study duration.
12. Discontinue the PFS and OS follow-up periods.
13. Clarify the exclusion criterion for patients diagnosed with or treated for another 
malignancy.
14. Define overdose.
15. Clarify the procedures for management of medication errors, including overdose.
16. Remove mention of the Safety Management Attachment (SMA).
17. Update the procedures for SAE reporting.
18. Specify that no further independent data monitoring committee reviews of safety and 
efficacy are needed as of Amendment 6.
For specific examples of changes in text and where the changes are located, see 
Section 15.18.
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Study No. C16011
Protocol Incorporating Amendment No. 6
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PROTOCOL SUMMARY
Study Title: A Phase 3, Randomized, Controlled, Open-Label, Multicenter, Safety and Efficacy 
Study of Dexamethasone Plus MLN9708 or Physician’s Choice of Treatment Administered to
Patients With Relapsed or Refractory Systemic Light Chain (AL) Amyloidosis
Study Phase: 3
Number of Patients:  Approximately 176 patients
Study Objectives
As of this amendment, the objectives are to provide continued access of MLN9708 and/or other 
study medications and to continue collecting relevant safety data to monitor patient safety. All other 
study objectives will no longer be assessed. However, the complete list of objectives is retained 
below for reference.
Primary Objectives

To determine whether dexamethasone plus MLN9708 improves hematologic response (PR + 
VGPR + CR) versus a physician’s choice of a chemotherapy regimen as selected from the 
list of offered treatment options in patients diagnosed with relapsed or refractory AL 
amyloidosis.

To determine whether dexamethasone plus MLN9708 improves 2-year vital organ (that is, 
heart or kidney) deterioration and mortality rate versus a physician’s choice of a 
chemotherapy regimen as selected from the list of offered treatment options in patients 
diagnosed with relapsed or refractory AL amyloidosis.  Cardiac deterioration is defined as 
the need for hospitalization for heart failure.  Kidney deterioration is defined as progression 
to end-stage renal disease (ESRD) with the need for maintenance dialysis or renal 
transplantation.
Key secondary objectives are:

To determine overall survival (OS).

To determine the complete hematologic response rate (CR).
Other secondary objectives are: 

To determine progression-free survival (PFS).  

To measure hematologic disease PFS.

To determine best response in the vital organs allowed at study entry (heart and kidney).

To determine time to vital organ deterioration or death.

To measure vital organ PFS.

To measure the duration of hematologic response (DOR).

To evaluate safety.

To measure time to treatment failure (TTF).

To measure time to subsequent anticancer therapy.

To describe the impact of treatment on quality of life (QOL) using the Medical Outcomes 
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Protocol Incorporating Amendment No. 6
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Study 36- item Short Form General Health Survey (SF-36 v2) (Section 15.3), FACT-
neurotoxicity subscale (FACT/GOG-Ntx) (Section 15.4) and a symptom scale questionnaire 
(Section 15.5).

To evaluate Health Utilization (HU) and to collect EuroQol 5-Dimensional (EQ-5D) 
(Section 15.9) data.

To collect PK data to contribute to population PK analyses.
Overview of Study Design:  
This is a phase 3, randomized, controlled, open-label, multicenter study of the oral formulation of 
dexamethasone plus MLN9708 compared with treatment chosen by the investigator from a 
prespecified list of regimens available in clinical practice.  Treatment options will include:  
dexamethasone alone, dexamethasone plus an alkylating agent (melphalan or cyclophosphamide), or 
dexamethasone plus an immunomodulatory drug (IMiD, thalidomide or lenalidomide) in patients 
with relapsed or refractory AL amyloidosis.  Crossover to the investigational treatment arm is not 
permitted during participation in this study.
Eligible patients must have:  1) biopsy-proven AL amyloidosis with relapsed or refractory disease 
despite 1 or 2 prior therapies; 2) disease requiring further treatment; 3) measureable disease as 
defined by serum differential free light chain concentration (dFLC); and 4) objective and measurable 
major organ involvement (ie, cardiac or renal) as defined by the standard International Society of 
Amyloidosis (ISA) criteria.  Patients must not have been previously treated with proteasome 
inhibitors. (The sponsor reserves the right to open the trial to proteasome inhibitor-exposed patients 
in the future, at some time point after the first interim analysis [IA].)
Physicians will choose a treatment regimen from a list of options provided by the sponsor.  Before 
randomization, physicians will declare which treatment regimen they plan to select for each screened 
patient; the selection will be recorded in the database.  To maintain a balanced representation of the 
disease characteristics, patients enrolled in this study will be stratified by:  1) Cardiac Risk Stage:  1 
versus 2 versus subgroup Cardiac Risk Stage 3 (ie, both NT-proBNP and troponin T over threshold 
[but NT-proBNP < 8000 pg/mL]); 2) relapsed versus refractory (relapsed is defined as PD 
documented more than 60 days after last dose; refractory is defined as documented absence of 
hematologic response or hematologic progression on or within 60 days after last dose of prior 
therapy); and 3) proteasome inhibitor naïve versus exposed.  
Eligible patients will be randomized in a 1:1 ratio into 1 of the 2 study arms:
Arm A:  dexamethasone plus MLN9708
Arm B:  physician’s choice 
In both treatment arms, each patient will continue to receive sequential cycles of therapy until 
disease progression, unacceptable toxicity, or until the study is terminated, whichever occurs first. 
Patients in Arm B receiving melphalan and dexamethasone will be treated to best response plus 2 
additional cycles (see Section 6.4.2). 
Response to therapy will be evaluated by an AC which will include the assessment of hematologic 
response and organ response according to the criteria outlined in the Revised Consensus Response 
Criteria of the ISA.  The AC will also review specific data elements and corresponding data 
documentation to support criteria of vital organ (that is heart or kidney) deterioration. An 
independent data monitoring committee (IDMC) will review safety and efficacy data at the IAs.  
Safety will be assessed through adverse events (AEs), clinical laboratory tests, and vital sign 
measurements.  In addition, QOL and HU will be assessed using questionnaires.
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Study No. C16011
Protocol Incorporating Amendment No. 6
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After disease progression, patients will be followed for survival, vital organ deterioration, and 
subsequent therapy at least every 12 weeks.
As of Amendment 6, however, the first IA has been conducted and the primary endpoint of overall 
hematologic response rate (CR + VGPR + PR) did not reach statistical significance. As such, the 
sponsor has decided to remove the planned second IA and final analysis and discontinue the majority 
of study assessments to ease the burden of protocol-mandated assessments on patients. Ixazomib 
(MLN9708) and control drugs (if Takeda has been supplying them) will continue to be provided for 
patients who continue to derive benefit. 
Upon implementation of this amendment, data collection requirements will be limited to the 
following safety assessments: all SAEs (regardless of causality, including all deaths), any AE 
resulting in dose modification or discontinuation of any study drug, Grade ≥3 AEs, AEs of new 
primary malignancy, all reports of drug exposure during pregnancy and pregnancy outcomes, 
product complaints, and medication errors (including overdose). All other study assessments are no 
longer required. Central laboratory and investigator assessments of response and progression for 
protocol purposes are discontinued—AC review of response data and IDMC review of efficacy and 
safety data will no longer be performed. Patients will not be followed for the PFS or OS follow-up 
periods, as PFS and OS are no longer being collected. Patients should otherwise be treated by the 
investigator according to standard of care. 
Study Population:  
Adult patients with biopsy-proven systemic AL amyloidosis with relapsed or refractory disease.
Duration of Study:
The duration of the study will be approximately 120 months (ie, 10 years), including 84 months of 
enrollment and 36 months of follow-up after the last patient is enrolled.  
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Protocol Incorporating Amendment No. 6
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STUDY OVERVIEW DIAGRAM
Screening
Stratification:
1.
Proteasome Inhibitor Naïve vs 
Exposed
2.
Cardiac Staging:  Cardiac Risk Stage 
1 versus 2 versus a subgroup of 
Cardiac Risk Stage 3
3.
Relapsed vs Refractory 
Randomization
Arm A:
MLN9708 + dexamethasone
(N = 124)
Arm B:  Physician’s choice 
•
Dexamethasone alone 
•
Dexamethasone + melphalan
•
Dexamethasone + cyclophosphamide 
•
Dexamethasone + thalidomide 
•
Dexamethasone + lenalidomide 
(N = 124)
Repeat every 28 days until progression or 
unacceptable toxicity*
All patients STOP due to 
unacceptable toxicity
End of Treatment Visit
Follow-up for Progression Free Survival:
•
Hematologic assessment every 6 
weeks
•
Organ assessment every 12 weeks
•
Vital organ deterioration
•
Death
Overall Survival follow-up every 12 
weeks:
•
Vital organ deterioration
•
Death
All patients STOP due to 
progression
End of Treatment Visit
Overall Survival follow-up every 12 
weeks:
•
Vital organ deterioration
•
Death
* Refer to Section 6.4.2  for treatment duration guidelines for patients in the melphalan + dexamethasone group 
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Study No. C16011
Protocol Incorporating Amendment No. 6
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SCHEDULE OF EVENTS—AMENDMENT 6 AND BEYOND
As of Amendment 6, the first IA has been conducted and the primary endpoint of overall 
hematologic response rate (CR + VGPR + PR) did not reach statistical significance. As 
such, the sponsor has decided to remove the planned second IA and final analysis (FA) and 
discontinue the majority of study assessments to ease the burden of protocol-mandated 
assessments on patients. Ixazomib (MLN9708) and control drugs (if Takeda has been 
supplying them) will continue to be provided for patients who continue to derive benefit. 
For ease of study conduct, the Schedule of Events now presented has been simplified to 
apply to the remainder of the study. Beyond the assessments noted here, patients should be 
treated by the investigator according to standard of care.
The full Schedule of Events prior to Amendment 6 has been moved to Section 15.11. The 
PK sampling schedule has been moved to Section 15.12, as PK sample collection is no 
longer applicable for ongoing patients.
Study Procedures
Treatment Period
28-Day Cycles
End of 
Treatmentb
Cycle
Cycle Xa and Beyond
Day
1
Window
± 3 days
+ 10 days
Complete Physical Examination
Xc
Symptom-Directed Physical Exam
Xc
Pregnancy Testd
X
X
Hematology
Xe
Xe
Clinical Chemistry
Xe
Xe
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Study Procedures
Treatment Period
28-Day Cycles
End of 
Treatmentb
Cycle
Cycle Xa and Beyond
Day
1
Window
± 3 days
+ 10 days
Adverse Event Reporting
Recorded from the first dose of study drug through 30 days after 
last dose of study drug. Only AEs leading to dose modification or 
discontinuation, Grade ≥3 AEs, AEs of new primary malignancy, 
all reports of drug exposure during pregnancy and pregnancy 
outcomes, product complaints, and medication errors are to be 
reported upon implementation of Amendment 6 through 30 days 
after the last dose of study drug.
Serious Adverse Event Reporting
Serious AEs will be reported from signing of the informed 
consent form through 30 days after the last dose of study drug.
Study Drug Administration
MLN9708
MLN9708 on Days 1, 8, and 15
Dexamethasone
Dexamethasone on Days 1, 8, 15, and 22
Dexamethasone and Melphalan 
Days 1-4
Dexamethasone and 
Cyclophosphamide
Cyclophosphamide Days 1, 8, and 15 and 
dexamethasone Days 1, 8, 15, and 22
Dexamethasone and Thalidomide
Thalidomide daily and dexamethasone Days 
1, 8, 15, and 22
Dexamethasone and Lenalidomide
Lenalidomide Days 1-21 and dexamethasone 
Days 1, 8, 15, and 22
AE=adverse event; eCRF=electronic case report form; IMiDs=immunomodulatory drugs. 
a Follow this Schedule of Events at the start of the next full treatment cycle upon implementation of 
Amendment 6.
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 Collect and record in the electronic case report form (eCRF) only in the event that they are needed to 
evaluate an AE. Otherwise, patients should be treated according to standard of care.
d Treatment with immunomodulatory drugs (IMiDs) requires pregnancy testing in female patients of child-
bearing age prior to each cycle.  A serum pregnancy test will be performed for all women of childbearing 
potential.  
e All central laboratory assessments are discontinued. Local hematology and chemistry panels to be collected 
and recorded in the eCRF only in the event that they are needed to evaluate an AE. Otherwise, patients 
should be treated according to standard of care and laboratory assessments to inform dosing decisions do not 
need to be recorded in the eCRF. 
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Protocol Incorporating Amendment No. 6
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TABLE OF CONTENTS
LIST OF TABLES.............................................................................................................13
LIST OF FIGURES............................................................................................................14
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS ..........................................15
1. BACKGROUND AND STUDY RATIONALE..............................................................19
1.1 Scientific Background ..............................................................................................19
1.1.1 Disease Under Treatment...................................................................................19
1.1.2 Treatment Approaches .......................................................................................23
1.1.3 MLN9708, A Next-Generation Proteasome Inhibitor .........................................29
1.2 Nonclinical Experience.............................................................................................30
1.2.1 Nonclinical Pharmacology:  In Vivo Studies......................................................30
1.3 Clinical Experience ..................................................................................................31
1.4 Study Rationale ........................................................................................................40
1.5 Rationale for MLN9708 Dose and Schedule Selection..............................................44
1.6 Potential Risks and Benefits .....................................................................................48
2. STUDY OBJECTIVES ..................................................................................................49
2.1 Primary Objectives ...................................................................................................49
2.2 Secondary Objectives ...............................................................................................49
3. STUDY ENDPOINTS....................................................................................................50
3.1 Primary Endpoints....................................................................................................51
3.2 Secondary Endpoints................................................................................................51
4. STUDY DESIGN...........................................................................................................53
4.1 Overview of Study Design........................................................................................53
4.2 Number of Patients...................................................................................................56
4.3 Duration of Study.....................................................................................................56
5. STUDY POPULATION.................................................................................................57
5.1 Inclusion Criteria......................................................................................................57
5.2 Exclusion Criteria.....................................................................................................60
6. DESCRIPTION OF TREATMENT................................................................................61
6.1 MLN9708 and Dexamethasone.................................................................................62
6.2 MLN9708 Administration ........................................................................................62
6.3 Dexamethasone Administration................................................................................62
6.4 Physician’s Choice ...................................................................................................63
6.4.1 Dexamethasone..................................................................................................63
6.4.2 Dexamethasone Plus Melphalan.........................................................................63
6.4.3 Dexamethasone Plus Cyclophosphamide ...........................................................64
6.4.4 Dexamethasone Plus Thalidomide......................................................................64
6.4.5 Dexamethasone Plus Lenalidomide....................................................................64
6.5 Dose Modification Guidelines ..................................................................................64
6.5.1 Criteria for Toxicity Recovery for a New Cycle of Therapy to Begin:  All 
Treatment Regimens ...................................................................................65
6.5.2 Dose-Modification Guidelines for MLN9708.....................................................65
6.5.3 Dexamethasone–Related Treatment Modification ..............................................68
6.5.4 Dose Modification for Melphalan ......................................................................69
6.5.5 Dose Modification for Cyclophosphamide .........................................................70
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6.5.6 Dose Modification for Thalidomide ...................................................................71
6.5.7 Dose Modification for Lenalidomide..................................................................73
6.6 Excluded Concomitant Medications and Procedures.................................................74
6.7 Permitted Concomitant Medications and Procedures.................................................75
6.8 Precautions and Restrictions .....................................................................................76
6.9 Contraception Requirements.....................................................................................77
6.10 Management of Clinical Events..............................................................................78
6.11 Blinding and Unblinding ........................................................................................81
6.12 Description of Investigational Agents .....................................................................81
6.12.1 MLN9708 Preparation, Reconstitution, and Dispensation.................................81
6.12.2 MLN9708 Packaging and Labeling..................................................................82
6.12.3 MLN9708 Storage, Handling, and Accountability............................................82
6.12.4 Other Protocol-Specified Materials ..................................................................84
7. STUDY CONDUCT ......................................................................................................84
7.1 Study Personnel and Organizations...........................................................................84
7.2 Arrangements for Recruitment of Patients ................................................................84
7.3 Treatment Group Assignments .................................................................................85
7.4 Study Procedures......................................................................................................85
7.4.1 Informed Consent ..............................................................................................86
7.4.2 Patient Demographics ........................................................................................86
7.4.3 Medical History.................................................................................................86
7.4.4 Physical Examination.........................................................................................86
7.4.5 Eastern Cooperative Oncology Group Performance Status.................................86
7.4.6 Vital Signs, Body Weight and Height.................................................................86
7.4.7 Pregnancy Test ..................................................................................................87
7.4.8 Electrocardiogram..............................................................................................87
7.4.9 Clinical Laboratory Evaluations.........................................................................87
7.4.10 Quality of Life Assessments.............................................................................89
7.4.11 Health Utilization.............................................................................................89
7.4.12 EQ-5D .............................................................................................................90
7.4.13 Disease Assessments........................................................................................90
7.4.14 Pharmacokinetic Measurements (Arm A Only) ................................................96
7.4.15 Concomitant Medications and Procedures........................................................97
7.4.16 Adverse Events................................................................................................97
7.4.17 Follow-Up Assessments (PFS and OS).............................................................97
7.5 Study Compliance ....................................................................................................98
7.6 Discontinuation of Treatment With Study Drug, and Patient Replacement................98
7.7 Withdrawal of Patients From Study..........................................................................99
8. STATISTICAL AND QUANTITATIVE ANALYSES ................................................100
8.1 Statistical Methods .................................................................................................100
8.1.1 Determination of Sample Size..........................................................................100
8.1.2 Randomization and Stratification .....................................................................102
8.1.3 Populations for Analysis ..................................................................................102
8.1.4 Procedures for Handling Missing, Unused, and Spurious Data.........................103
8.1.5 Demographic and Baseline Characteristics.......................................................103
8.1.6 Efficacy Analysis.............................................................................................104
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8.1.7 Analyses of Patient-Reported Outcomes and Health Economics.......................108
8.1.8 Pharmacokinetics, Pharmacodynamics, and Biomarkers...................................109
8.1.9 Safety Analysis ................................................................................................109
8.1.10 Interim Analyses............................................................................................111
9. STUDY COMMITTEES..............................................................................................112
9.1 Steering Committee................................................................................................112
9.2 Independent Data Monitoring Committee...............................................................112
9.3 Adjudication Committee.........................................................................................112
10. ADVERSE EVENTS .................................................................................................113
10.1 Definitions............................................................................................................113
10.1.1 Pretreatment Event Definition........................................................................113
10.1.2 Adverse Event Definition...............................................................................113
10.1.3 Serious Adverse Event Definition ..................................................................113
10.2 Procedures for Recording and Reporting Adverse Events and Serious 
Adverse Events...............................................................................................114
10.3 Monitoring of Adverse Events and Period of Observation.....................................116
10.4 Procedures for Reporting Drug Exposure During Pregnancy and Birth Events......117
11. ADMINISTRATIVE REQUIREMENTS ...................................................................117
11.1 Good Clinical Practice..........................................................................................117
11.2 Data Quality Assurance ........................................................................................117
11.3 Electronic Case Report Form Completion.............................................................118
11.4 Study Monitoring .................................................................................................118
11.5 Ethical Considerations..........................................................................................119
11.6 Patient Information and Informed Consent............................................................119
11.7 Patient Confidentiality..........................................................................................119
11.8 Investigator Compliance.......................................................................................119
11.9 On-site Audits ......................................................................................................120
11.10 Investigator and Site Responsibility for Drug Accountability..............................120
11.11 Product Complaints and Medication Errors (Including Overdose).......................120
11.12 Closure of the Study ...........................................................................................121
11.13 Record Retention................................................................................................122
12. USE OF INFORMATION..........................................................................................122
13. INVESTIGATOR AGREEMENT..............................................................................123
14. REFERENCES...........................................................................................................124
15. APPENDICES ...........................................................................................................134
15.1 Amyloid Typing ...................................................................................................134
15.2 Equation to Estimate Glomerular Filtration Rate (eGFR)......................................135
15.3 Short Form General Health Survey (SF-36 v2™)..................................................136
15.4 FACT/GOG-Ntx...................................................................................................143
15.5 Amyloidosis Symptom Scale ................................................................................144
15.6 New York Heart Association Classification of Cardiac Disease ............................145
15.7 Steroid Equivalent Doses......................................................................................145
15.8 Eastern Cooperative Oncology Group Scale for Performance Status.....................146
15.9 EuroQol 5-Dimensional (EQ-5D) .........................................................................147
15.10 Amyloid-Related Hematologic and Organ Criteria for Involvement, 
Stabilization, Response, and Progression.........................................................150
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15.11 Full Schedule of Events (Prior to Amendment 6)................................................153
15.12 Pharmacokinetic Sampling Schedule (Prior to Amendment 6) ............................158
15.13 Amendment 1 Rationale and Purposes................................................................159
15.14 Amendment 2 Rationale and Purposes................................................................160
15.15 Amendment 3 Rationale and Purposes................................................................161
15.16 Rationale for Amendment 4................................................................................163
15.17 Rationale for Amendment 5................................................................................164
15.18 Amendment 6 Detailed Summary of Changes.....................................................166
LIST OF TABLES
Table 1-1   
Ongoing Studies of Oral MLN9708.............................................................32
Table 1-2   
MLN9708 Potential Risks (Pooled PO Formulation), as of 30 April 2012 ...34
Table 1-3   
Study C16004:  Oral MLN9708, Single Agent Given Weekly Most 
Common TEAEs as of 30 April 12 (N = 52)................................................36
Table 1-4   
Study C16007:  Oral MLN9708, Single Agent Given Weekly Most 
Common TEAE as of 30 April 12 (N = 14).................................................37
Table 1-5   
Cardiac Risk Assessment Staging System ...................................................43
Table 1-6   
Best Confirmed Hematologic Response to VELCADE in Patients at the 
Recommended Dose on Each Schedule or at Lower Doses on Either 
Schedule .....................................................................................................47
Table 6-1   
MLN9708 Dose Adjustments......................................................................66
Table 6-2   
MLN9708 Dose Adjustments for Hematologic Toxicities ...........................66
Table 6-3   
MLN9708 Dose Adjustments for Nonhematologic Toxicities......................67
Table 6-4   
Dose Reduction Steps for Dexamethasone...................................................68
Table 6-5   
Dexamethasone–Related Treatment Modification (Delays, Reductions, 
and Discontinuations) Guidelines Due to Adverse Events ...........................69
Table 6-6   
Dose Reduction Steps for Melphalan...........................................................70
Table 6-7   
Melphalan–Related Treatment Modification (Delays, Reductions, and 
Discontinuations) Guidelines Due to Adverse Events..................................70
Table 6-8   
Dose Reduction Steps for Cyclophosphamide .............................................71
Table 6-9   
Cyclophosphamide–Related Treatment Modification (Delays, 
Reductions, and Discontinuations) Guidelines Due to Adverse Events ........71
Table 6-10   
Thalidomide–Related Treatment Modification (Delays, Reductions, and 
Discontinuations) Guidelines Due to Adverse Events..................................72
Table 6-11   
Dose Reduction Steps for Lenalidomide......................................................73
Table 6-12   
Lenalidomide–Related Treatment Modification (Delays, Reductions, 
and Discontinuations) Guidelines Due to Adverse Events ...........................74
Table 6-13   
MLN9708 Capsules ....................................................................................81
Table 7-1   
Cardiac Risk Assessment Staging System ...................................................93
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LIST OF FIGURES
Figure 1-1   
No Apparent Relationship Between MLN9708 Clearance and Body 
Surface Area ...............................................................................................45
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LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS
Abbreviation
Term
AC
Adjudication Committee
AE
adverse event
ACE
Angiotensin converting enzyme (ACE)
AL amyloidosis
primary systemic light chain amyloidosis
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
AUC
area under the plasma concentration versus time curve
AUC0-24hr
area under the plasma concentration versus time curve zero to 24 hours
AUC0-tau
area under the plasma concentration versus time curve zero to next dose
AV
atrioventricular
BIW
biweekly (ie, twice weekly)
BP
bodily pain
BSA
body surface area
BUN
blood urea nitrogen
CBC
complete blood count
CDF
cumulative distribution function
CHF
congestive heart failure
CI
confidence interval
CL
clearance, IV dosing
CLb
blood clearance
CLP
plasma clearance
Cmax
single-dose maximum (peak) concentration
CO2
carbon dioxide
CR
complete response
CT
computed tomography
CYP
cytochrome P450
DDI
drug-drug interaction
dFLC
serum differential free light chain concentration; difference between amyloid 
forming and non amyloid forming FLC
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
eGFR
estimated glomerular filtration rate; eGFR according to the recently 
recommended CKD-EPI equation
Emax
maximum effect
EMG
electromyography
EDC
electronic data capture
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Abbreviation
Term
eGRF
estimated glomerular filtration rate
EOT
End of Treatment (visit)
ESRD
end-stage renal disease
EQ-5D
EuroQol 5-Dimensional (questionnaire)
F
bioavailability
FA
final analysis
FISH
fluorescent in situ hybridization
FLC
free light chain
GADD34
Growth Arrest DNA Damage 34
GCP
Good Clinical Practice
G-CSF
granulocyte colony stimulating factor
GH 
general health
GI
gastrointestinal
GLP
Good Laboratory Practices
GM-CSF
granulocyte macrophage-colony stimulating factor
hERG
human ether-à-go-go related gene
HDT-SCT
high-dose therapy- stem cell transplantation
HIV
human immunodeficiency virus
HU
Health Utilization
MLN9708 IB
Investigator’s Brochure
IA
interim analysis
IC50
concentration producing 50% inhibition
ICF
informed consent form
ICH
International Conference on Harmonisation
IDMC
independent data monitoring committee
IEC
independent ethics committee
IEM
immunogold electron microscopy
IHC
immunohistochemistry 
IMiDs
immunomodulatory drugs
IRB
institutional review board
ISA
International Society of Amyloidosis
ITT
intent-to-treat (population)
IV
intravenous; intravenously
Ki
inhibition constant
K-M
Kaplan-Meier
LVEF
left ventricular ejection fraction
MCS
mental component summary
MedDRA
Medical Dictionary for Regulatory Activities
Millennium
Millennium Pharmaceuticals, Inc., and its affiliates
MM
multiple myeloma
MPD
maximum planned dose
MR
minimal response
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Abbreviation
Term
MRI
magnetic resonance imaging
msec
millisecond
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
NSAID
nonsteroidal anti-inflammatory drug
NT-proBNP
N-terminal proBNP
NYHA
New York Heart Association
OS
overall survival
PCS
physical component summary
PD
progressive disease (disease progression)
PF
physical function
PFS
progression free survival
P-gp
P-glycoprotein
PK
pharmacokinetic(s)
PN
peripheral neuropathy
PO
per os; by mouth (orally)
PR
partial response
PRO
patient-reported outcome
PT
prothrombin time
RRMM
relapsed and refractory multiple myeloma
QALYs
quality adjusted life years
QD
quaque die; each day; once daily
QLQ
Quality of Life Questionnaire
QLQ-C30
EORTC Core Quality of Life Questionnaire
QOL
quality of life
QTc
rate-corrected QT interval (millisecond) of electrocardiograph
Q3C
every 3 cycles
RBC
red blood cell
RE
role emotional
RP
role physical
RP2D
recommended phase 2 dose
RRAL
relapsed or refractory AL amyloidosis
SAE
serious adverse event
SCT
stem cell transplant
SF
social function
SMA
Safety Management Attachment
SPEP
serum protein electrophoresis
t1/2
terminal disposition half-life
TEAE
treatment-emergent adverse event ; may or may not be treatment related
TEmax
time of occurrence of Emax
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Abbreviation
Term
Tmax
single-dose first time of occurrence of maximum (peak) concentration
TTF
time to treatment failure
ULN
upper limit of the normal range
UPEP
urine protein electrophoresis
US
United States
VT
vitality 
VGPR
very good partial response
Vss
volume of distribution at steady state
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
Primary systemic light chain (AL) amyloidosis is a rare, progressive, lethal disease caused 
by proteotoxic light chain proteins produced by a small clonal plasma cell.(1, 2, 3)  This 
plasma cell dyscrasia is characterized by monoclonal plasma cells in the bone marrow and 
their production of excess errant monoclonal immunoglobulin light-chains that tend to 
misfold, form aggregates, and deposit as amyloid fibrils in visceral organs.  Tissue damage 
is caused when these toxic amyloid light chains interact with cells and when they 
accumulate in organs causing end-organ dysfunction.(4)  Murray, et al demonstrated that the 
monoclonal protein secreted by these neoplastic plasma cells is the pathogenetic protein 
causing the amyloid deposits.(5)  While the disease is a clonal plasma cell disease similar to 
multiple myeloma (MM), the clonal plasma cells are present at a low percentage in the bone 
marrow, the paraprotein is often not an intact immunoglobulin, but rather a free light chain, 
or fragment thereof, which is predominantly of the isotype rather than the (-to-ratio is 
1:4).(1, 6, 7)  Further, unlike multiple myeloma, the clinical picture and prognosis for patients 
with AL amyloidosis is determined by the organ dysfunction caused by the toxic 
amyloidogenic light chains.  Hence, hematologic response is fundamentally linked to organ 
response and survival, unlike multiple myeloma.(8)  Thus, if the plasma cell clone is not first 
substantially suppressed thereby abolishing the production of circulating amyloidogenic free 
light chains (FLC), important clinical outcomes such as improved organ function and 
survival are not possible.(9)
Early diagnosis and treatment of AL amyloidosis are key to patient outcomes.  
Unfortunately, late diagnosis remains a major problem.  Accumulation of extracellular 
amyloid fibril deposits disrupts normal tissue structure and function notably in the heart, 
kidneys, liver, peripheral nervous system, gastrointestinal tract, and soft tissues.(1)  This 
progressive accumulation leads to organ dysfunction, organ failure, and ultimately death, 
often due to cardiac causes.  The disease carries a grim prognosis which is predominantly 
influenced by the patient’s performance status and extent of organ involvement, particularly 
cardiac involvement, at diagnosis.  One-fourth of patients present with clinical involvement 
of 1 organ; however, the majority present with clinical involvement of more than 1 organ.(1, 
10)  Renal dysfunction is the most common clinical manifestation, while liver involvement is 
reported but is less common.  The severity of the cardiac involvement dictates the prognosis.  
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Notably, the majority of patients with AL amyloidosis die from cardiac complications, 
which is often sudden death.(11)
The incidence of systemic AL amyloidosis has been estimated globally at 8.9 to 10 patients 
per million per year an incidence similar to Hodgkin lymphoma or chronic myelogenous 
leukemia).(2, 12)  It is about one-fifth as common as multiple myeloma; however, median 
survival time is shorter (47 months for multiple myeloma, but ranging from 4.6 months-36.8 
months depending on cardiac involvement).(13, 14, 15)  Further, patients with hematologic 
refractory disease have a poor survival, approximately 14 months, while those that have 
relapsed after previous hematologic response have an overall survival of approximately 
32 months (personal communication, Prof. 
 and Dr. 
, 
July 7, 2011).  Overall, the natural history of AL amyloidosis includes progression to death 
within 2 years from diagnosis in about 80% of patients.(10)
The diagnosis of a systemic, as opposed to localized, amyloidosis relies on the identification 
of amyloid deposits in tissues, eg, abdominal adipose aspiration, salivary glands, and organ 
biopsy.(16)  Current practice involves Congo red staining of these tissues where a 
characteristic apple-green birefringence of the amyloid fibrils is seen under polarized light.  
Once amyloidosis has been confirmed, amyloid typing is necessary to distinguish clinically 
between different types of amyloidosis for prognosis, clinical management, and necessitates 
adequate techniques.  Combination methods such as Congo red staining plus 
immunoelectron microscopy, immunofluorescence, immunoperoxidase, 
immunohistochemistry, proteomic mass spectrometry-based methods, and genetic testing 
play a major role in tissue typing.(17)  The importance of these techniques is to enable 
differentiation of the various types of systemic amyloidosis, to identify specific mutation 
associated with hereditary forms,(16) and to confirm the diagnosis of AL amyloidosis in 
certain instances (Section 15.1)  The correct identification of the underlying amyloid 
precursor protein is critical as different therapies exist for different types of amyloid.  
Amyloidosis of the light chain derivation is the only type that is responsive to cytotoxic 
chemotherapy.(18, 19, 20, 21)  Given the rarity of systemic AL amyloidosis, diagnostic tests and 
response criteria have historically been based on multiple myeloma.  However, recent 
technical advances have now enabled the establishment of diagnostic and response criteria 
specifically relevant to AL amyloidosis.  The characterization of amyloidosis as light chain 
type requires the demonstration of the underlying plasma cell clone which produces the 
amyloidogenic immunoglobulin light chain.  Serum free light chain (FLC) assay in 
combination with serum and urine protein electrophoresis, immunofixation, 
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immunoglobulin quantification, and bone marrow examination are required tests.(20)  Once 
the diagnosis of AL amyloidosis has been established, prompt initiation of treatment is 
required to eliminate the malignant clone and to reduce the supply of the amyloidogenic free 
light chains.
The assessment of disease and response to therapy in AL amyloidosis is more complex than 
in multiple myeloma.  In AL amyloidosis, the disease involves both the persistence of the 
clonal plasma cell and its production of the amyloid-forming FLC that directly causes 
fibrillar aggregation, toxic damage, and organ failure.  Hence, hematologic response is 
fundamentally linked to organ response and survival unlike multiple myeloma.  However 
historically, hematologic response was defined using the same tests and criteria for reduction 
of bone marrow plasma cells and monoclonal proteins developed for multiple myeloma.  
Assessments of response to therapy in AL amyloidosis must reliably determine objective 
changes in the clonal hematologic disorder and in organ disease while acknowledging that 
organ responses can lag up to 12 months behind hematologic response.(8)  The serum FLC 
assay, a test that can quantify serum amyloidogenic FLC, is a recent advance that has 
significantly changed how patients with AL amyloidosis are diagnosed and monitored 
during therapy given its documented sensitivity and prognostic utility.(22, 23, 24, 25, 26, 27, 28)  
This assay is critical in this disease because, different than MM, patients with AL 
amyloidosis typically have modest plasma cell infiltrates in the bone marrow and small or 
no circulating intact immunoglobulin thus making accurate quantification of monoclonal 
protein with the typical assays from serum, urine, and bone marrow difficult and not useful 
for response evaluations.(9)  Since 2003, a growing number of clinical trials have reported 
that reducing the concentration of serum amyloidogenic FLC results in prolonged survival, 
thereby increasing the importance of the FLC evaluations.(26, 29, 30, 31, 32, 33)  
In 2010, the International Society of Amyloidosis (ISA) Panel, noting recent technical 
advances and the clinical observations that FLC responses correlated with survival better 
than traditional monoclonal protein responses, convened to develop better response criteria 
for the management of this complex disease.(34)  The panel aimed to identify criteria of 
hematologic response that would make a distinction in survival outcomes.  The absolute 
concentration of FLC, the difference between involved (that is, clonal amyloidogenic) and 
uninvolved FLC, and the currently used monoclonal protein response criteria established by 
the 2005 ISA Consensus were evaluated.  The Consensus Panel demonstrated that 
hematologic response criteria based on FLC correlated better with survival than did the 
monoclonal protein criteria of the 2005 Consensus Panel, underscoring the importance of 
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measuring the amyloidogenic precursor protein which is responsible for organ damage.(34)  
The panel also showed that in AL amyloidosis, the preferred method of quantifying changes 
in amyloidogenic FLC concentrations is to estimate the difference between involved and 
uninvolved immunologlobulin light chains.  This is accomplished by subtracting the 
uninvolved light chain from that of the involved light chain to obtain the FLC difference, 
known as dFLC.  The dFLC is preferred over absolute FLC concentration or even involved 
FLC (iFLC) concentration because dFLC compensates for altered FLC metabolism in 
patients with renal failure.(34, 35)  The value of the FLC component estimated as the dFLC 
has now been established and validated.(32, 36)
According to the ISA 2010 criteria, a 50% decrease in dFLC is considered a partial response 
(PR), a reduction in the absolute dFLC to less than 40 mg/L is a very good partial response 
(VGPR), and normal FLC levels with a normal kappa/lambda ratio and negative serum and 
urine immunofixation for the clonal FLC is an amyloid complete response [aCR].(19, 34)  Data 
now also supports that achievement of at least a 50% reduction in the serum amyloidogenic 
free light chain is often sufficient to lead to stabilization or regression of amyloid deposits in 
the organs with potential for improved organ function, improvements in performance status, 
the ability to carry out activities of daily living, the ability to return to work, improved QOL, 
and survival.(29, 37)
The 2010 ISA Consensus Panel also gave consideration to, validated, and updated 
definitions for organ involvement as well as response based upon recent technologic 
advances since the establishment of the first criteria in 2005.(20, 38)  Cardiac response was 
updated to include NT-proBNP and cardiac troponins, which are validated, accessible and 
reproducible cardiac biomarkers, diagnostic tools of cardiac failure, and prognostic factors 
in congestive heart failure (CHF), which are predictors of survival in AL amyloidosis.(34, 39, 
40, 41)  Additionally, an adequate decrease (defined as > 50%) in serum FLC can translate into 
a parallel decrease in the cardiac biomarker, NT-proBNP, and cardiac function and 
symptoms of heart failure can improve despite the amount of cardiac amyloid deposits 
remaining relatively unaltered by other measures such as echocardiograms.(26, 41)  Hence, 
ventricular wall thickness and left ventricular ejection fraction measured by echocardiogram 
as in the 2005 Consensus Opinion response criteria are not useful for response 
assessments.(39)  The Consensus Panel therefore determined that validated cardiac biomarker 
measurements are important in the overall monitoring of patients receiving treatment for AL 
amyloidosis and added them into the response criteria.  Renal response continued to focus 
on urinary protein excretion with consideration given to the patient’s estimated glomerular 
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filtration rate (eGFR) (Section 15.2).  Criteria for hepatic disease were not changed.  The 
Consensus Panel did not change criteria for peripheral and autonomic nervous system 
involvement given the lack of reliable, widely available methodologies.(38)
1.1.2   
Treatment Approaches
The goal of chemotherapy in AL amyloidosis is the prompt elimination of the plasma cells 
that produce the toxic light chain proteins that have an affinity for visceral organs, extension 
of survival, minimization of treatment toxicity, and support of end organ function.(19, 22, 34, 39, 
42, 43)  Treatment choices in AL amyloidosis have utilized advances made in the 
chemotherapy of MM and thus involve intensive regimens such stem cell transplant and 
various nonintensive chemotherapy regimens, including corticosteroids, alkylating agents, 
immunomodulatory drugs (IMiDs), and proteasome inhibitors.  However, unlike MM in 
which survival is determined by the plasma cell tumor mass, in AL amyloidosis, 
hematologic response based on FLC is of key importance with concomitant achievement of 
organ improvement, which lags significantly behind hematologic response, so unfortunately 
some patients may not survive long enough to enjoy this clinical benefit.(2, 44)  Moreover, 
there is a desperate need for alternative treatments for the significant proportion of patients 
not eligible for dose-intensive therapy, for those who decline dose-intensive therapy given 
its morbidity, or for those who have progressive disease (PD) despite such therapy.  
Furthermore, disease can recur or progress even after a response has been achieved, thereby 
necessitating subsequent effective therapies.  When the patient’s disease relapses or does not 
respond to therapy, there is no standard therapy, and data are limited even for those agents 
used in this setting.  Given the rarity of AL amyloidosis, there have not been any 
randomized controlled trials in the relapsed disease setting, but rather there have been
anecdotal case reports, retrospective series, and small, single-institution trials utilizing 
various single-agent or combination therapy regimens shown active in MM.  The National 
Comprehensive Cancer Network (NCCN) therefore recommends treatment in a clinical trial 
because data are insufficient to identify an optimal treatment.(4)  Treatment choices are thus 
based on the patient’s age, organ dysfunction, pace of disease, and regimen toxicities.(19)
Nonintensive Therapies
Intensive therapy such as high-dose therapy- stem cell transplantation (HDT-SCT) may be a 
preferable treatment option; however, only a quarter of newly diagnosed patients are eligible 
for this therapeutic option.(39, 45)
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Melphalan- dexamethasone was compared to HDT-SCT in a randomized trial of 
100 patients.  After a median follow up of 3 years, there was no significant difference in 
response rates and the median overall survival was better for patients treated with 
melphalan-dexamethasone than with HDT-SCT (56.9 months versus 22.2 months 
respectively).(46)  The response rate and its durability were similar in this study to others 
reported in the literature; (47) however, these authors reported that the HDT-SCT group had a 
lower than expected outcome because of a high mortality rate and possible differences in 
patient selection compared with other trials.  Lastly they hypothesized that a trial of these 
2 treatments in a tertiary referral center where the treatment-related mortality rate would 
likely be lower, might have a different outcome.(46)  Even so, the use of melphalan and 
dexamethasone appears at least comparable to HDT-SCT and is considered a standard 
frontline treatment option.(46)
There is no consensus on the optimal regimen for patients whose disease has relapsed or did 
not respond to therapy.  The choice of treatment depends on a balance between the 
perceived efficacy of the chosen regimen and the individual patient’s expected ability to 
tolerate the treatment’s toxicity considering their age, organ dysfunction, and pace of 
disease.  Given the limited treatment options, the treatment chosen may mean exposure to an 
agent from the same drug class or the use of an agent used previously.  As noted, clinical 
trial data are limited in patients previously treated and even the available data are from trials 
that include both previously untreated and treated patients. 
Conventional Agents:  Alkylating Agents and Corticosteroids
Corticosteroids
Dexamethasone is a versatile agent in the treatment of plasma cell dyscrasias.  Experience in 
MM using dexamethasone (dex) to reduce the plasma cell tumor burden led to the use of this 
drug, both as a single agent and in combination with melphalan, in the treatment of AL 
amyloidosis.  A Southwest Oncology Group (SWOG) phase 2 trial reported hematologic 
response rates of 53%, an organ response rate of 45%, and median survival of 31 months 
with single-agent pulse high-dose dexamethasone (40 mg/day on Days 1-4, 9-12, and 17-20 
every 35 days for 3 cycles) followed by dexamethasone plus alpha interferon 
maintenance.(48)  Though tolerated well in MM and despite the reported AL amyloidosis 
disease benefit, a 7% treatment-related mortality and Grade 3 or greater toxicities, including 
cardiovascular/fluid overload, hematologic, gastrointestinal, renal and infection AEs, 
necessitate dose reductions during the initiation of therapy.  Consequently, Palladini and 
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colleagues investigated a modified high-dose dexamethasone regimen (40 mg/day on 
Days 1-4 every 21 days) in patients both treatment naïve and previously treated.  This 
regimen was active with a 35% hematologic response rate, a median survival of 
20.6 months, and no significant toxicity.(49)  The authors concluded this modified regimen 
was an important treatment option as it could serve as a bridge for patients who do not 
tolerate intensive dexamethasone regimens or those who might benefit from combination 
therapy.  Recently, based on the results of low-dose dexamethasone (40 mg weekly on 
Days 1, 8, and 15 every 28 days) in MM, this dose and schedule is being incorporated into 
AL amyloidosis treatment combinations.(50)
Corticosteroids Plus Alkylating Agents
Subsequent phase 2 data have confirmed the activity of dexamethasone and melphalan, 
which is considered standard therapy for patients who have not undergone HDT-SCT.  In 
46 patients with newly diagnosed AL amyloidosis, the combination (dexamethasone 
40 mg/day plus melphalan 0.22 mg/kg each on Days 1-4 every 28 days) demonstrated a 67% 
hematologic response rate, 33% complete responses, a 48% organ response rate, and an 
actuarial survival at 6 years of approximately 50%.  Severe adverse events consisting of 
respiratory infections, reversible cytopenia, and 1 case of myelodysplastic syndrome were 
reported in 11% of patients.(47, 51)  Additionally, this trial demonstrated that in relapsing 
patients, the amyloid clone remains sensitive to the combination of melphalan and 
dexamethasone and hematologic response can still be achieved by repeating treatment.  
Thus, this combination represents an important option in the treatment of patients with AL 
amyloidosis.(51)  The melphalan-dexamethasone combination was also reported based on a 
retrospective review of 70 patients not eligible for HDT-SCT where the hematologic 
response rate was 38%, complete response was 13%, and the median overall survival had 
not been reached.  Though 2 different dexamethasone schedules (4-day pulse(49) and low-
dose weekly(50)) were used in the treatment of these patients, no difference in hematologic 
response was observed.  The authors noted that the difference in CR rate in this trial 
compared to others in the literature may be related to a difference in CR criteria, selection 
bias, referral bias, or other differences between the patients treated.(52)  Further, the authors 
acknowledged that 27% of patients who did not achieve a partial response or less received 
additional therapy, including HDT-SCT in 3 patients, which led to an improvement in 
survival.(52)  A retrospective review of 428 patients with AL amyloidosis treated in 3 major 
European centers reported outcomes including 204 patients treated with melphalan and 
dexamethasone.(51)  The overall hematologic response rate was 44% with 26% and 23% 
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achieving complete responses and organ response, respectively, again demonstrating the 
benefit of this combination.(51)  Dexamethasone has also been combined with 
cyclophosphamide in the treatment of AL amyloidosis.  Investigators from the United 
Kingdom (UK) report 2 series looking at cyclophosphamide in combination with 
dexamethasone and thalidomide.  The hematologic response rate ranged from 63% to 74%, 
the complete response rate was approximately 22%, and the organ response rate ranged from 
25% to 38%.(51, 53)  One of the series reported a median overall survival of 41 months.(51)  
This combination appears to have similar efficacy, similar toxicity while being non-stem cell 
toxic, and without necessary dose adjustments in renal failure as compared with melphalan 
and dexamethasone.  These data suggests that alkylating agents plus dexamethasone are 
active as upfront therapy and importantly in relapsing patients given that AL amyloidosis is 
an incurable disease.(51, 54)
Novel Agents:  Immunomodulatory Agents and Proteasome Inhibitors
Immunomodulatory Agents (IMiD)
Though the exact mechanism of action remains unclear, the immunomodulatory agents 
thalidomide and lenalidomide were introduced into the therapeutic landscape in MM and as 
a result were incorporated into investigator-initiated clinical trials given the anticipated 
activity in patients with advanced AL amyloidosis.  The first IMiD to be investigated in 
relapsed AL amyloidosis was thalidomide.  The activity of thalidomide with or without 
dexamethasone has been reported by several investigators.(9, 53, 55, 56)  In combination with 
dexamethasone, hematologic responses are reported in the range of 48% to 80% with 
approximately a 19% rate of organ response;(53, 57) however, toxicity at high doses is 
problematic with 50% of patients experiencing Grade 3 to 4 toxicity, specifically fatigue, 
sedation, fluid retention, constipation, orthostasis, peripheral neuropathy (PN), and 
worsening renal function.(9, 19, 53)  In these trials, the median maximum tolerated dose of 
thalidomide was 300 mg/day.  A risk-adapted dosing approach (thalidomide 100 mg/day 
increased to 200 mg/day after 4 weeks if tolerated or an even lower starting dose 
[50 mg/day] and slower escalation [50 mg/day every 4 weeks to a total dose of 200 mg/day] 
in elderly patients) plus dexamethasone and cyclophosphamide has been reported as active 
and well tolerated.(58)  Hematologic responses were seen in 74% of patients with a median 
survival of 41 months.(58)  The activity of thalidomide and dexamethasone in patients
refractory to frontline melphalan and dexamethasone was reported by Jaccard, et al.(57)  In 
this small retrospective review, hematologic responses were obtained in 4/5 patients treated 
with thalidomide plus sequential dexamethasone.(57)  Overall, the combination of 
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thalidomide and dexamethasone is an active option for patients with relapsed or refractory 
AL amyloidosis; however, reduced doses and careful monitoring for toxicity are required.(22)
Like thalidomide, data with full-dose lenalidomide demonstrate significant toxicity, but it is 
better tolerated at a dose of 15 mg/day for 21 days in a 28-day cycle.  Rash, fatigue, 
myelosuppression (neutropenia and thrombocytopenia), and, to a lesser extent, 
thromboembolic complications were mainly reported.(43, 59, 60)  Hematologic response rates 
of 40% to 60% and a median survival ranging from 2 to 3 years have been achieved.(22, 38, 39, 
43, 61, 62)  Single-agent lenalidomide provides limited activity, but response is improved when 
given in combination with dexamethasone.(60)  Sanchorawala and colleagues reported a 16% 
complete response rate of which 60% were durable for a median of 24 months in 69 patients 
(most were previously treated) who were treated with lenalidomide and dexamethasone.(63)  
The effectiveness of lenalidomide and dexamethasone in patients refractory to frontline 
melphalan and dexamethasone was reported by Jaccard and colleagues.(57)  In this small 
retrospective review, hematologic responses were obtained in 2/7 patients treated with the 
combination of lenalidomide and dexamethasone.(57)  Taken together, the data support the 
combination of lenalidomide and dexamethasone as a treatment option for patients with 
relapsed or refractory AL amyloidosis. 
Proteasome Inhibitors
The proteasome inhibitor was validated as an oncology target following the clinical success 
of VELCADE® (bortezomib) for Injection, the first-in-class, boronic acid-based proteasome 
inhibitor that is approved in the United States (US) by the Food and Drug Administration 
(FDA) for the treatment of patients with MM and mantle cell lymphoma (MCL).  Biological 
and clinical data suggest that proteasome inhibition is an attractive treatment approach for 
patients with AL amyloidosis. 
The biological rationale for the use of proteasome inhibitors stems from the clonal plasma 
cell and their secretion of a toxic light chain protein characteristic of this disease.  Normal 
plasma cells and MM cells have both been proposed to be especially sensitive to proteasome 
inhibition due to their extremely high proteasome workload of misfolded and newly 
synthesized light chain proteins.(64, 65, 66, 67, 68, 69, 70)  Under conditions of proteasome 
inhibition, even higher levels of proteins accumulate in the cells, placing great stress on the 
endoplasmic reticulum (ER), resulting in a terminal unfolded protein response (UPR) and 
cell death.(66, 67, 71, 72, 73)  The additional stress imposed on the ER system makes plasma cells 
hypersensitive to proteasome inhibition.  This same mechanism of cell death is expected to 
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apply to the errant plasma cells in AL amyloidosis.  In addition, evidence suggest that 
extracellular oligomers of amyloidogenic light-chains could inhibit proteasome activity, 
sensitizing amyloidogenic plasma cells in a sort of autocrine-inhibitory loop, thus creating a 
particularly compelling biological rationale for the research and development of proteasome 
inhibitors in this disease.(64, 68)
Pengo, et al(69, 74) have reported that differentiating plasma cells suffer from proteotoxicity 
with decreased proteasome capacity even with increased protein synthesis.  This imbalance 
of the ubiquitin proteasome system results in the accumulation of ubiquitin-conjugates and 
apoptotic sensitization to proteasome inhibitors.(69, 74)  Amyloidosis is a protein misfolding 
disease and as such may be particularly sensitive to proteasome inhibition.
Clinical rationale is based on small case studies and prospective trials of VELCADE with or 
without dexamethasone in relapsed and/or refractory AL amyloidosis.  Most of the patients 
enrolled in these studies had failed previous therapies or were ineligible for SCT.  Treatment 
with VELCADE with or without dexamethasone was characterized by rapid response and 
high rates of hematologic and organ responses.(75, 76)  Data across these small trials 
demonstrate hematologic response rates in the range of 60% to 90% with an organ response 
rate of approximately 25%.(75, 77, 78)  Although treatment-related mortality was uncommon in 
these studies, discontinuation of VELCADE due to adverse events was common.  Peripheral 
neurotoxicity, fatigue, nausea, vomiting, diarrhea, constipation, edema, and hypotension 
were reported and, at times, necessitated dose modification or discontinuation of therapy.  
The effectiveness of VELCADE and dexamethasone in patients who are refractory to 
frontline melphalan and dexamethasone was reported by Jaccard and colleagues.(57)  In this 
small retrospective review, hematologic responses were obtained in 17/20 patients treated 
with bortezomib-dexamethasone.(57)
Reece and colleagues reported on the first prospective study of single-agent VELCADE in 
relapsed amyloidosis.(79, 80)  The primary objective of this phase 1/2 study was to determine 
the maximum tolerated dose (MTD) and evaluate safety.  The determination of the 
hematologic response rate and duration of response at the MTD was a secondary objective, 
while assessment of organ response and overall survival were exploratory objectives.  In the 
phase 1 portion of the study, VELCADE was generally well tolerated at doses of up to 
1.6 mg/m2 on a weekly schedule and 1.3 mg/m2 on a twice-weekly schedule.  The MTD was 
not reached with either dosing schedule therefore the maximum planned dose (MPD) was 
evaluated in the phase 2 portion of the study.  A total of 70 patients were enrolled in this 
study, 18 at 1.6 mg/m2 weekly, 34 at 1.3 mg/m2 twice weekly, and 18 at lower doses during 
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dose-escalation.  Best hematologic response (CR/PR) rates were 68.8% and 66.7%, 
respectively, for the weekly and twice-weekly dosing schedules with 78% overall of 
responders with a durable (> 1 year) response.  Responses were more rapid with the twice-
weekly dosing schedule, but toxicity appeared lower with the weekly schedule.  The most 
common adverse events were fatigue, thrombocytopenia, vomiting, diarrhea, pneumonia, 
and syncope.  Together the biologic and clinical data support the use of a proteasome 
inhibitor in the treatment of AL amyloidosis.
Currently, no satisfactory therapy exists for patients with AL amyloidosis that has 
progressed despite previous chemotherapy including stem cell transplant.  Amyloidosis is a 
protein misfolding disease and therefore may be particularly sensitive to proteasome 
inhibition.  The retrospective review from 3 European centers provides the largest 
comparative review of treatment regimens in the literature.(51, 81)  Between 2003 and 2010, 
428 patients with AL amyloidosis were treated with melphalan-dexamethasone, 
cyclophosphamide-thalidomide-dexamethasone, cyclophosphamide-lenalidomide-
dexamethasone, bortezomib-dexamethasone with or without an alkylating agent, or 
HD-SCT.  The outcome of patients was comparable supporting the rationale for phase 3 
trials confirming the benefits of proteasome inhibition as compared to other regimens for the 
frontline treatment of patients with AL amyloidosis.  Two such trials are being conducted 
investigating the combination of melphalan plus dexamethasone, with or without 
bortezomib; 1 each in Europe (EMN-03/ NCT01277016) and the US (ECOG E4A08/ 
NCT01078454).  Therefore, the intention of this study in patients with hematologic relapsed 
or refractory disease is to compare a proteasome inhibitor (MLN9708) to other classes of 
agents that are currently used in clinical practice.
1.1.3   
MLN9708, A Next-Generation Proteasome Inhibitor
Like VELCADE, MLN9708 is a modified peptide boronic acid analog.  The drug substance 
MLN9708 refers to the citrate ester of MLN2238.  MLN2238 refers to the biologically 
active, boronic acid form of the drug substance, MLN9708.  In water or aqueous 
environments, the equilibrium shifts from MLN9708 to the biologically active boronic acid 
form, MLN2238.  All doses and concentrations are expressed as the boronic acid, 
MLN2238.  MLN9708 is the first oral proteasome inhibitor undergoing clinical 
investigation in humans with safety, tolerability, PK, pharmacodynamics, and disease 
response assessed in each study.
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As Millennium’s next-generation proteasome inhibitor, MLN9708 was designed to build 
upon the attributes of VELCADE while also providing an option for oral administration and 
increased activity in tumor types where VELCADE has shown activity, and improving the 
safety profile (refer to the MLN9708 Investigator’s Brochure).  Given the similarities 
between these 2 proteasome inhibitors, it is anticipated that MLN9708, which is directed 
against the same components of the ubiquitin-proteasome pathway (UPP) as VELCADE, 
will also prove useful in the treatment of AL amyloidosis.
1.2   
Nonclinical 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 
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.
In summary, the single- and repeat- dose studies of up to 5 cycles in duration in rats and 
dogs, using both the oral (PO) and intravenous (IV) routes of administration have been 
completed.  Compromise of the gastrointestinal (GI) systems led to dose-limiting toxicity in 
both rats and dogs.  At tolerated doses, alterations in leukocyte and coagulation parameters 
consistent with an inflammatory response were seen in both rats and dogs.  
The principal toxicologic effects of MLN2238 administration to rats in 2- and 5-cycle PO 
(each cycle consisted of twice-weekly dosing for 2 weeks; cycles were separated by a 
10-day nondosing period) and 2-cycle IV toxicology studies (following the same cycle 
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schedule) include inhibition of erythropoiesis, decreased thrombocyte counts, leukocyte and 
coagulation profile changes consistent with an inflammatory response, intestinal mucosal 
inflammation, as well as lymphoid depletion of lymph nodes and other lymphoid organs.  
Differences of note with IV administration included a trend toward decreased leukocyte 
counts with corresponding bone marrow hypocellularity. 
The IV administration of MLN9708 to beagles for a total of 5 cycles (each cycle consisted 
of twice weekly dosing for 2 weeks separated by a 10-day nondosing observation period) 
resulted in hematology parameters; neuronal degeneration of the sympathetic, dorsal root, 
and end organ ganglia with secondary axonal/nerve fiber degeneration of the peripheral 
nerves and ascending tracts in the spinal cord and medulla oblongata.  Similar 
neurodegenerative changes were also observed in oral studies in dogs of 2 or 5 cycle 
duration, and in the 2-cycle rat IV study.  The neurologic lesions in these studies are similar 
to what has been described after treatment with bortezomib and are believed to be the cause 
of the PN observed in patients treated with bortezomib.  All of the effects seen in PO 
toxicology studies in both rats and dogs at tolerated doses were shown to resolve or were 
trending toward resolution after a 14-day nondosing recovery period.  Recovery was not 
assessed in the 5-cycle IV study in dogs.  All findings are expected to be monitorable with 
routine clinical, clinical pathology, and/or neurologic assessments.
Detailed information regarding the nonclinical pharmacology and toxicology of MLN9708 
may be found in the MLN9708 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 phase 1 and 
phase 1/ 2 study.  As of 30 April 2012, 382 patients have been treated with MLN9708 across 
9 enrolling sponsor-led phase 1 or phase 1/2 studies with a twice-weekly and a weekly 
dosing schedule being evaluated.  MLN9708 is available as an intravenous and oral 
formulation. 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. To date, the development 
of oral MLN9708 has focused on multiple myeloma [relapsed and/or refractory and newly 
diagnosed] and a different yet related plasma cell dyscrasia, systemic light chain (AL) 
amyloidosis. A clinical pharmacology study looking at drug-drug interactions, the effect of 
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food, and bioavailability also uses the oral formulation. Details of these trials can be found 
in ClinicalTrials.gov and the MLN9708 Investigator’s Brochure (IB).
Clinical Trial Experience Using the Oral Formulation of MLN9708
In the 7 studies actively enrolling patients to investigate oral MLN9708 in patients with 
differing malignancies (multiple myeloma, AL amyloidosis, nonhematologic cancers, and 
lymphoma), a total of 242 patients have been treated as of 30 April 2012.  These patients 
have been treated with different doses of MLN9708 either as a single agent treatment or in 
combination with currently clinically available treatments.  Information regarding the 
ongoing studies, patient populations, and doses investigated are included in Table 1-1. 
Table 1-1   
Ongoing Studies of Oral MLN9708
Trial/
Population
Description
Doses Investigated
C16003
RRMM
N = 58
PO, twice weekly (TW), single agent
0.24-2.23 mg/m2 TW
MTD:  2.0 mg/m2
DLT:  rash,thrombocytopenia
C16004
RRMM
N = 52
PO, weekly (W), single agent
0.24-3.95 mg/m2 W
MTD:  2.97 mg/m2
DLT:  rash, nausea, vomiting, diarrhea
C16005
NDMM
N = 65
PO W, combination with LenDex 28 day 
cycle
1.68-3.95 mg/m2 W
MTD:  2.97 mg/m2
DLT:  nausea, vomiting, diarrhea, syncope
RP2D*: 4.0 mg fixed [switched to fixed dosing in 
Ph2, relevant to 2.23mg/m2]
C16006
NDMM
N = 20
PO TW (Arm A- 42 day cycle) and W 
(Arm B- 28 day cycle), combination 
with Melphalan and Prednisone
Arm A*:    3mg -3.7 mg fixed dose TW
DLT: rash, thrombocytopenia, subileus
Arm B*:   3 mg - 5.5 mg fixed dose, W
DLT: Esophageal ulcer
C16007
RRAL
N = 14
PO, W, single agent
4 mg-5.5 mg fixed dose* W
MTD:  4 mg
DLT:  thrombocytopenia, diarrhea, dyspnea, acute 
rise in creatinine, cardiac arrest
C16008
NDMM
N = 11
PO, TW, combination with LenDex 21 
day cycle
3.0-3.7 mg fixed dose* W
MTD:  4 mg
DLT:
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Table 1-1   
Ongoing Studies of Oral MLN9708
Trial/
Population
Description
Doses Investigated
C16009
Solid 
tumors,
Lymphomas
N = 22
PO, weekly, single agent
5.5 mg fixed dose* 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; RPh2D= recommended phase 2 dose.
* Approximate BSA and fixed dosing equivalence: 3 mg~ equivalent to 1.68 mg/m2 BSA dosing; 4.0 mg ~ 
equivalent to 2.23 mg/m2 BSA dosing; and 5.5 mg~ equivalent to 2.97 mg/m2 BSA dosing
In addition to the trials noted above and this study, there are currently 4 planned trials; each 
of which will use the oral formulation of MLN9708; these studies are being reviewed by 
IRB/ethic committees, but are expected to begin enrollment of patients in 2012:

Study C16010 is a phase 3 trial of lenalidomide and dexamethasone with MLN9708 or 
placebo given weekly in patients with relapsed or refractory MM.

Study C16012 is an open-label, phase 2 (with dose-finding lead-in) study of the oral 
MLN9708 formulation in adult patients with nonhematologic malignancies expressing 
elevated cytoplasmic p65/NFƙB.

Study C16013 is a phase 1 pharmacokinetic study of oral MLN9708 plus lenalidomide 
and dexamethasone in adult Asian patients with relapsed and/or refractory multiple 
myeloma.

Study TB-MC010034 is a phase 1 trial of MLN9708 in Japanese patients with relapsed 
and/or refractory multiple myeloma.
Overview of the Oral Formulation of MLN9708
The emerging safety profile indicates that oral MLN9708 is generally well tolerated with 
predominant toxicities largely reversible, able to be monitored by routine clinical 
examinations, and manageable by dose reductions, discontinuation, or standard supportive 
care. From experience from phase 1 through 2 studies the major toxicities can be managed 
to allow repeat treatment cycles over periods extending beyond 24 months. As noted in 
Table 1-2, the MTD has been established in most of the phase 1 trials with dose-escalation 
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continuing in 1 study (Study C16006, NDMM). The potential risks reported with MLN9708 
use, pooled from the enrolling 7 phase 1 and phase 1/2 clinical studies (N=242) using the 
oral formulation are shown in Table 1-2. As of 30 April 2012, one patient treated with the 
oral formulation of MLN9708 has reported Grade 3 PN; while 13% (32 patients) have 
reported Grade 1 or 2 PN; 11 of these patients reporting baseline Grade 1 neuropathy at 
study entry.
Table 1-2   
MLN9708 Potential Risks (Pooled PO Formulation), as of 30 April 2012
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 Dyspnea
Chills
Dizziness
Peripheral neuropathy
Arthralgia, back pain, abdominal pain
Peripheral edema
The clinical experience with MLN9708 also shows early signs of antitumor activity as 
evidenced by at least a 50% reduction in disease burden in some patients and prolonged 
disease stabilization in others across all ongoing trials. The antitumor activity has been seen 
with single-agent MLN9708, when combined with established therapies, and across the 
malignancies studied (advanced solid tumors, non-Hodgkin’s disease, Hodgkin’s disease, 
relapsed and/or refractory multiple myeloma [RRMM], relapsed or refractory systemic light 
chain amyloidosis [RRAL], and newly diagnosed multiple myeloma [NDMM]) to date. 
Though additional data are needed to characterize the clinical benefit of this drug, the 
emerging data supports the ongoing development of MLN9708.
Of particular relevance to this study (C16011) is the clinical experience from Studies 
C16004 and C16007  in which single-agent MLN9708 is administered weekly in patients 
with RRMM or RRAL, respectively. See section on Pharmacokinetics and Drug Metabolism 
and Figure 1-1 regarding MLN9708 dosing switch from BSA-based to fixed dose.
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C16004: Relapsed and/ or Refractory Multiple Myeloma
Study C16004 is an open-label, dose-escalation, phase 1 study of MLN9708 administered 
weekly on Days 1, 8, and 15 of a 28-day cycle in adult patients with RRMM.  Patients with 
MM enrolled in the dose-escalation component of the study have relapsed following at least 
2 lines of therapy, which must have included bortezomib, thalidomide (or lenalidomide), and 
corticosteroids. The dose-escalation phase of the trial has completed. In this study, 2 of 
3 patients experienced protocol-defined DLTs (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.
Once the MTD was established, cohorts of patients representing the heterogeneous patient 
population currently seen in clinical practice were enrolled in order to further evaluate the 
safety, tolerability, efficacy, PK, and pharmacodynamics of oral MLN9708.  The MTD 
expansion cohorts enrolling are:
1. Relapsed and Refractory expansion cohort [refractory is defined as disease 
progression while on therapy or within 60 days after the last dose of therapy]; 
2. Carfilzomib expansion cohort 
3. Proteasome Inhibitor-Naïve expansion cohort 
4. VELCADE-Relapsed expansion cohort 
Final study results are not available for this ongoing trial, but preliminary data suggest 
MLN9708 has antitumor activity in heavily pretreated MM patients, with durable 
responses/disease control, and is generally well tolerated.(82, 83)
As of the 30 April 2012 data cut, these patients are considered heavily pretreated as 
evidenced by a median number of 4 (range 1–13) prior lines of therapy, with 66% refractory 
to the last line of therapy. Patients have received a median of 2 cycles of therapy (range, 
1-11).  Five patients have achieved objective response: 1 patient achieved a VGPR and 
4 patients achieved a PR.  Additionally, 15 patients achieved durable disease stabilization 
for up to 9.5 months. At data cut-off, 15 patients remain on treatment; discontinuation of 
treatment was primarily due to progressive disease (69%).
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A summary of the safety profile of patients treated in Study C16004 is outlined in Table 1-3.  
Overall, 92% of patients experienced a TEAE of any grade and of any cause. Peripheral 
neuropathy was limited to Grade 1/ 2 in 6 patients, with 3 patients reporting baseline 
Grade 1 PN at study entry.
Table 1-3   
Study C16004:  Oral MLN9708, Single Agent Given Weekly Most 
Common TEAEs as of 30 April 12 (N = 52)
Most Common (> 20%)  
Any Grade and Irrespective of Cause
Thrombocytopenia (54%)
Fatigue (48%)
Nausea (44%), diarrhea (44%),
Vomiting (37%)
Decreased appetite (33%)
Rash* (31%)
Anemia (25%)
Neutropenia (23%)
Drug-Related Grade > 3 in> 5% of patients 
Thrombocytopenia 38%, diarrhea and neutropenia 
17% (each), fatigue and lymphopenia 10% (each), 
nausea and decreased appetite 8% (each), and 
vomiting 6%
*Rash includes preferred terms of rash macular, rash, maculo-papular, rash morbilliform, rash pruritic, 
pruritus, rash erythematous,  exfoliative rash, and rash popular.
Dose reductions required were due to AEs that included rash, neutropenia, 
thrombocytopenia, diarrhea, nausea, vomiting, dehydration, hypotension, increase in serum 
creatinine, abdominal pain, ileus, fatigue, and pneumonia. The AEs reported for the 
5 patients who were required to discontinue treatment included Grade 2 MLN9708-related 
nausea/vomiting in 1 patient treated above the MTD, Grade 3 MLN9708-related diarrhea in 
a second patient, related Grade 3 thrombocytopenia, related Grade 2 dyspnea, and 
not-related Grade 4 elevation in creatinine(1 patient each). There were no on-study deaths.
C16007:  Relapsed or Refractory Systemic Light Chain (AL) Amyloidosis
Study C16007 is evaluating single agent weekly, Day 1, 8, and 15 of a 28-day cycle, oral 
dosing in patients with RRAL after at least 1 prior therapy.  The objectives of this study are 
to determine the safety, tolerability, and MTD, as well as to determine hematologic and 
organ response rates in this patient population.  The starting dose level was selected from 
Study C16004 as previously described. In Study C16007 the dose was switched from the 
BSA-based dosing to the fixed dose, thereby the 4.0 mg fixed starting dose in Study C16007 
corresponds to the 2.23 mg/m2 dose (one dose level below MTD) from Study C16004.  This 
study is currently enrolling patients in the dose-expansion portion of the trial.
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As of 30 April 2012, 14 patients have been treated in this study. At the first dose level of 
4.0 mg, 1 of 6 patients experienced a protocol-defined DLT (that is, thrombocytopenia that 
lasted more than 2 weeks, which met the definition of a DLT due to the delay in starting 
Cycle 2).  As per protocol, the dose was escalated to 5.5 mg for the next cohort of patients 
where 2 of 5 patients experienced a DLT (Grade 3 diarrhea, n=1; and Grade 2 dyspnea, 
Grade 2 acute rise in serum creatinine, and Grade 4 cardiac arrest, n=1).  The latter patient 
did not appear to have cardiac AL amyloidosis by echocardiogram on study entry, but did 
have substantial renal involvement. After the occurrence of this DLT, diagnoses included 
cardiac involvement and CHF. The MTD of weekly oral MLN9708 was determined to be 
4.0 mg. Following the establishment of the MTD, patients are currently being enrolled in to 
1 of 2 cohorts: proteasome inhibitor naïve or proteasome inhibitor exposed.(84)
As of the 30 April 2012 data cut, the patients enrolled in the study are considered heavily 
pretreated, as evidenced by a median number of 3 prior lines of therapy (range 1–7), with 
38% and 46% of patients having been previously treated with bortezomib and lenalidomide, 
respectively. To be eligible for the study, patients must have amyloid involvement of the 
heart, kidney, or both; at the data cut the organ involvement distribution was 6, 4, and 
4 patients, respectively. Patients have received a median of 2.5 cycles of therapy (range, 
1-12).  Eight patients remain on treatment. Early signs of activity have been reported. There 
were 11 patients who have received at least 1 cycle of therapy with completed response 
assessments (9 in the 4.0 mg [MTD] cohort and 2 in the 5.5 mg cohort). The overall 
hematologic response rate at MTD is 56% (5 patients achieved a hematologic response 
[4 VGPR and 1 PR]; 3 patients showed no change, and 1 patient had an early progression.  
A summary of the safety profile of patients treated in Study C16007 is outlined in Table 1-4.  
Overall, 86% of patients experienced a TEAE of any grade and of any cause.
Table 1-4   
Study C16007:  Oral MLN9708, Single Agent Given Weekly Most 
Common TEAE as of 30 April 12 (N = 14)
Most Common (> 20%)  
Any Grade and Irrespective of Cause
Nausea (50%)
Fatigue (36%)
Thrombocytopenia (29%)
Diarrhea (29%)
Decreased appetite (21%)
Peripheral edema (21%)
Dyspnea (21%)
Abdominal pain (21%)
Drug-Related Grade ≥ 3 in  ≥ 2 patients 
Thrombocytopenia 5 patients, rash 3 patients, 
dehydration 2 patients, fatigue 2 patients
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One patient discontinued study drug administration due to a TEAE (patient with DLT of 
acute rise in serum creatinine, dyspnea, and cardiac arrest treated at 5.5 mg, as noted above). 
No death has been reported.
The potential risks reported with MLN9708 use, pooled from all studies using the oral 
formulations, were anticipated based on preclinical data and previous experience with 
VELCADE and are noted in the MLN9708 IB and ICF documents. Regardless of whether 
MLN9708 is administered on the once weekly or twice weekly dosing schedule, there is 
consistency among the type of TEAEs reported, despite 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 MLN9708 IB for further information.
Pharmacokinetics and Drug Metabolism
Clinical IV and PO pharmacokinetic (PK) data show that MLN9708 (measured as the 
biologically active boronic acid form of MLN9708 [MLN2238]) has multi-exponential 
disposition with a rapid initial phase that is largely over by 4 hours.  Oral MLN9708 is 
rapidly absorbed with a median time to single-dose first time of occurrence of maximum 
(peak) concentration (Tmax) of approximately 0.5 to 2.0 hours and terminal disposition 
half-life (t1/2) after multiple dosing of approximately 5 to 7 days.(85)  Results of a population 
PK analysis (N = 137) show that there is no relationship between body surface area (BSA) 
or body weight and clearance, IV dosing (CL).  Also, based on stochastic simulations for 
fixed dose, exposures are independent of the individual patient’s BSA.(86)  Based on these 
data, a recommendation was made for fixed dosing in clinical trials.  An absolute 
bioavailability of 67% was determined for MLN9708 using the population PK analysis.  
Please refer to the MLN9708 IB for information on the PK for IV doses of MLN9708.
Metabolism appears to be the major route of elimination for MLN9708, and urinary 
excretion of the parent drug is negligible (< 3% of dose).  In vitro studies indicate that 
MLN9708 is metabolized by multiple cytochrome P450s (CYPs) and non-CYP 
enzymes/proteins.  These data indicate that at clinically relevant concentrations of ixazomib, 
no specific CYP isozyme predominantly contributes to ixazomib clearance. At 
concentrations exceeding those observed clinically (10 µM), ixazomib was metabolized by 
multiple CYP isoforms with estimated relative contributions of 3A4 (42.3%), 1A2 (26.1%), 
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2B6 (16.0%), 2C8 (6.0%), 2D6 (4.8%), CYP2C19 (4.8%) and 2C9 (<1%). These studies 
were conducted at supra-therapeutic concentrations (10 µM ixazomib) that are >90 fold 
higher than the geometric mean clinical Cmax (0.11 μM) at the 4 mg oral once weekly dose. 
At 0.1 µM and 0.5 µM substrate concentrations, which are closer to clinical concentrations 
of ixazomib following oral administration of 4 mg ixazomib, non-CYP mediated clearance
was observed and seemed to play a major role in ixazomib clearance in vitro. The rate of 
ixazomib disappearance and the rate of formation of measurable metabolites were similar in 
control incubations that contained no active CYP isozymes and ones that had active CYP 
isozymes present when the same protein amounts were used. These data indicate that at 
clinically relevant concentrations of ixazomib, non-CYP proteins contribute to the clearance 
of ixazomib and no specific CYP isozyme predominantly contributes to the clearance of 
ixazomib. Therefore, at clinically relevant concentrations of ixazomib, minimal CYP-
mediated drug-drug interactions (DDIs) with a selective CYP inhibitor would be expected.
MLN9708 is not an inhibitor of CYPs 1A2, 2C9, 2C19, 2D6, or 3A4 nor a time-dependent 
inhibitor of CYP3A4/5.
The PK of ixazomib (Cmax and AUC0-last) was similar with and without coadministration of 
clarithromycin, a strong CYP3A inhibitor, and hence no dose adjustment is necessary when 
ixazomib is administered with strong CYP3A inhibitors. These findings are explained by the 
in vitro metabolism data indicating the lack of a discernible contribution of CYP-mediated 
metabolism at clinically relevant ixazomib concentrations. As discussed earlier, no CYP 
isoforms have been identified to contribute meaningfully to ixazomib metabolism at 
clinically relevant concentrations and CYP3A contribution to total metabolism was highest 
across all CYP isoforms when characterized at a supra-therapeutic concentration of 10 µM. 
Therefore, based on the totality of information from the clinical clarithromycin DDI study 
and the in vitro CYP phenotyping data, it can be concluded that ixazomib PK is not likely to 
be altered upon co-administration of any CYP isoform-selective inhibitor, including strong 
CYP1A2 inhibitors. Consistently, in the population PK analysis, co-administration of strong 
CYP1A2 inhibitors did not affect ixazomib clearance. Therefore, no dose adjustment is 
required for patients receiving strong inhibitors of CYP1A2. MLN2238 may be a weak 
affinity substrate of P glycoprotein (P-gp) but not of breast cancer resistance protein (BCRP) 
and multidrug resistance associated protein (MRP2) efflux pump transporters. MLN2238 is
not an inhibitor of P-gp, BCRP, and MRP2. The potential for DDIs with substrates or 
inhibitors of P-gp, BCRP, and MRP2 is, therefore, inferred to be low.
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1.4   
Study Rationale
Primary light chain (AL) amyloidosis is a rare, lethal plasma cell dyscrasia in which fibril
deposits containing toxic monoclonal immunoglobulin light chains infiltrate tissues causing 
their dysfunction and failure.  Unlike patients with MM, patients with AL amyloidosis not 
only have a hematologic malignancy, but also direct progressive involvement of 1 or more 
visceral organs.  Given the rarity of AL amyloidosis, there have not been any randomized 
controlled trials in the relapsed disease setting, but rather there have been anecdotal case 
reports, retrospective series, and small single institution trials utilizing differing single-agent 
or combination therapy regimens shown active in a similar yet different plasma cell 
dyscrasia multiple myeloma.  The National Comprehensive Cancer Network (NCCN) 
therefore recommends treatment in a clinical trial because there are no regulatory approved 
treatments and data are insufficient to identify an optimal therapy.(4)  The treatment of 
patients with relapsed and/or refractory systemic light-chain (AL) amyloidosis is an area of 
unmet need.  The current therapeutic approach to systemic amyloidosis is based on the 
observation that amyloid deposits can be reabsorbed and organ function restored if the 
concentration of the amyloidogenic protein precursor (known as the involved free light 
chains [FLC]) is reduced.  Therefore, the aim of therapyin AL amyloidosis is to rapidly 
decrease the supply of errant amyloid-forming FLC by suppressing the underlying clonal 
plasma cell while using supportive measures to sustain and possibly preserve organ 
functions.  The clinical course of the disease is improved by arresting progressive organ 
damage and allowing functional improvement of affected organs, thereby providing clinical 
benefit.
While reduction in the amyloidogenic-involved free light chains can improve the clinical 
course of the disease, the therapies that achieve these results are not curative adding to the 
uniformly fatal prognosis for this disease with the currently available approaches.  When the 
patient’s disease relapses or does not respond to first-line therapy, there is no standard 
therapy, and data are limited even for those agents used in this setting.(4)  Unfortunately, the 
current choice of treatment is primarily based on nonrandomized studies and investigator 
personal experience, which accounts for discrepancies in the treatment strategies proposed 
by different investigators.  Because there is no consensus, the choice of treatment depends 
on a fine balance between the perceived efficacy of the chosen regimen and the individual
patient’s expected ability to tolerate the treatment’s toxicity considering their age, organ 
dysfunction, and pace of disease, and given the limited treatment options, may mean 
exposure to an agent from the same drug class.  Available treatment options in AL 
amyloidosis have used advances made in the chemotherapy of MM, including the use of 
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corticosteroids, alkylating agents, proteasome inhibitors, and immunomodulatory agents 
(IMiDs), more frequently as combination regimens but also as single agents. 
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, 
improving drug administration, while building on the efficacy seen with VELCADE.  This 
study has been designed based on the results of VELCADE in previously treated AL 
amyloidosis,(80, 87) the emerging activity seen with MLN9708 in the treatment of previously 
treated and untreated MM and AL amyloidosis (see Section 1.3), and the urgent need for 
better treatment options for this rare disease, especially in the relapsed setting where no 
standard treatment exists.
Amyloidosis is a protein misfolding disease and may therefore be particularly sensitive to 
proteasome inhibition.  The hypothesis of this study, therefore, is to compare a proteasome 
inhibitor, oral MLN9708, to oral agents of other drug classes that are currently used in 
clinical practice.  Given that the AL amyloidosis population is predominantly a frail and 
elderly patient population, the convenience of an oral regimen is expected to increase 
compliance and possibly duration of treatment, which in turn should result in more durable 
hematologic responses. This study is designed to determine the safety and efficacy of oral 
MLN9708 with dexamethasone compared with treatment as chosen by the investigator from 
a selected list of oral regimens routinely available in clinical practice, dexamethasone alone 
or with an alkylating agent (melphalan or cyclophosphamide) or dexamethasone with an 
IMiD (thalidomide or lenalidomide) in patients with relapsed AL amyloidosis.  Inclusion of 
patients with amyloid involvement of heart and kidney was selected because these organs 
represent the major organs most commonly involved in AL amyloidosis, but more 
importantly, the criteria for involvement, response, and progression are based on objective 
clinical laboratory and imaging tests which can be analyzed by central laboratories to reduce 
variability and bias.  The primary objective of this study is to determine the overall 
hematologic response based on dFLC (difference between the involved and uninvolved 
FLC) assessment and to determine the rate of vital organ (that is heart and kidney) 
deterioration at 2 years. An improvement in hematologic response, as measured by reduction 
in FLC, and a reduction in the rate of vital organ deterioration in patients with relapsed or 
refractory systemic light chain amyloidosis would represent clinical benefit. 
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Rationale for Stratification Factors
Much of the variability in outcomes in the literature is related to the different proportion of 
patients with advanced cardiac disease in each clinical trial.  Additionally, the patient’s 
response to the prior therapy is important.  To maintain a balanced representation of the 
disease characteristics, patients enrolled in this study will be stratified by:  1) Cardiac Risk 
Stage:  1 versus 2 versus subgroup Cardiac Risk Stage 3 (ie, both NT-proBNP and 
troponin T over threshold [but NT-proBNP < 8000 pg/mL]); 2) relapsed versus refractory 
(relapsed is defined as PD documented more than 60 days after last dose; refractory is 
defined as documented absence of hematologic response or hematologic progression on or 
within 60 days  after last dose of prior therapy); and 3) proteasome inhibitor naïve versus 
exposed.
Because no approved therapy exists for patients with AL amyloidosis, experts, including the 
NCCN, recommend treatment of patients on clinical studies.  At relapse, given the limited 
treatment options, patients seek subsequent treatment even if it means exposure to an agent 
from the same drug class.(4)  MLN9708 is a modified peptide boronic acid analog similar to 
the first-in-class proteasome inhibitor VELCADE, which in some parts of the world, is used 
to treat relapsed AL amyloidosis and is also being evaluated in 2 frontline phase 3 trials 
comparing melphalan plus dexamethasone with or without VELCADE.  It is unlikely that 
there will be significant differences in safety, based on the emerging safety data from 
ongoing phase 1 studies in patients with relapsed or refractory MM who have been 
previously treated with proteasome inhibitors; however, there may be differences in activity.  
Therefore, patients are eligible for this study regardless of prior exposure to proteasome 
inhibition therapy; however, patients will be stratified based on this past exposure (naïve 
versus exposed) in order to characterize the activity of oral MLN9708 as compared to other 
oral regimens routinely used in clinical practice.
Amyloid heart involvement is predominantly due to infiltration of the heart by amyloid 
aggregates.  Patients with cardiac AL amyloidosis and evidence of active disease have a 
poor prognosis.(56)  Cardiac biomarkers, such as cardiac troponins and NT-proBNP, are now 
validated as a sensitive, reliable, quantitative assessment of cardiac damage and 
cardiomyocyte stress; in the context of AL amyloidosis, are the most important predictors of 
outcome; and serve as the basis of a staging system used to stratify patients.(19, 26, 56)  Cardiac 
troponin T is a highly specific and sensitive marker of cardiac injury, while NT-proBNP is 
considered a sensitive indicator of cardiac dysfunction.(88, 89)  Baseline levels of cardiac 
biomarkers predict for OS.(56, 90, 91)  As reported by the Mayo Clinic, median survival for 
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three risks groups (as defined in Table 1-5) were 26.4 (1-low risk), 10.5 (2-intermediate 
risk), and 3.5 months (3-high risk) (p < 0.0001).(56)  Additionally, the serum concentration of 
NT-proBNP drops if the reduction of circulating FLC is adequate (at least 50%)(26, 29, 45, 92)
even without changes based on echocardiogram,(19) translating into improvement in cardiac 
symptoms,(19, 26, 93) and prolonged survival.(26, 28, 45, 94, 95, 96)  Several reports confirm that the 
deeper the reduction in circulating amyloidogenic FLC by chemotherapy, the greater the 
improvement in cardiac function.(26, 81, 91)  Together the troponin plus NT-proBNP risk 
staging system adds objective, reproducible, biochemical information beyond the clinical 
and echocardiographic diagnostic determination of presence or absence of cardiac 
involvement and divides patients into 3 groups with different outcomes.(97, 98, 99)  These 
criteria provide a prognostic guide for staging and stratifying patients; therefore in order to 
balance patients between the 2 treatment groups, patients in this study will be stratified by 
Cardiac Risk Stage 1, 2, or a subgroup of Stage 3 based on the cardiac biomarkers NT-
proBNP and troponin T.  Most studies exclude patients with severe (Stage 3) cardiac 
disease, because these patients usually die quickly from cardiac failure, arrhythmias, and 
organ failure, often before they have had a chance to respond to therapy.(90, 100)  According to 
Chee, et al patients with this worst outcome were characterized by NT-proBNP values 
greater than 9000 pg/mL.(100)  This clinical trial proposes to include (and stratify) patients 
with Cardiac Risk Stage 3 disease with NT-proBNP levels less than 8000 ng/L as a means to 
include patients with a significant unmet medical need while ensuring the ability to 
comprehensively characterize of the safety and efficacy of MLN9708.  This will allow for 
similarities between treatment arms and thus consistent and reliable comparisons of the 
therapeutic outcomes. 
Table 1-5   
Cardiac Risk Assessment Staging System 
Stage
Criteria:  Threshold levels NTpro-BNP > 332 pg/mL and troponin 
T < 0.035 ng/mL
1 (low risk)
Both troponin or NT-proBNP under threshold
2 (intermediate risk)
Either troponin or NT-proBNP [but not both] over threshold
3 (high risk)
Both troponin or NT-proBNP  over threshold
Source:  Dispenzieri A, Gertz MA, Kyle RA, Lacy MQ, Burritt MF, Therneau TM, et al. Serum cardiac 
troponins and N-terminal pro-brain natriuretic peptide: a staging system for primary systemic 
amyloidosis. Journal of Clinical Oncology 2004;22(18):3751-7.(97)
Abbreviations:  NT-pro BNP = N-terminal pro-brain natriuretic peptide.
If troponin T not available at local institution, troponin I may be used, but threshold is < 0.1 µg/mL.
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Given the lack of randomized trials, this study proposes to include both patients whose 
disease has not responded to prior therapy as well as those whose disease has relapsed based 
on hematologic criteria.  Treatment of AL amyloidosis is not curative and the 
pathophysiology of AL amyloidosis is complex.  Patients with refractory disease, defined as 
no improvement in FLC and NT-proBNP after 3 cycles of therapy, are at high risk of early 
death from cardiac failure, arrhythmias, and organ failure.(26, 100)  Patients may develop a late 
relapse in organ reserve even though there has been a reduction in measurable FLC 
prompting the need for subsequent therapy.(26, 39, 101)  The depth of free light chain reduction 
(hematologic response) along with the tempo of organ improvement or failure influence the 
need for further treatment and depending on adequacy of organ function may reduce the 
therapeutic choices and have an effect on response to subsequent therapy.(26, 39, 101)  
Therefore, in order to balance patients between the 2 treatment groups, patients will be 
stratified by based on whether they are refractory to their prior therapy or if they have 
relapsed disease.  
1.5   
Rationale for MLN9708 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.  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. In clinical studies, single-agent weekly MLN9708 has 
been administered to patients with RRMM and to patients with RRAL.  Study C16004, a 
phase 1 study in adult patients with RRMM, was the first trial to investigate single-agent 
MLN9708 in this weekly schedule. In this study, the estimated MTD is 2.97 mg/m2 with 
DLTs of transient rash, nausea, vomiting, and diarrhea. The most common related > Grade 3 
AEs included thrombocytopenia, diarrhea, nausea, neutropenia, and fatigue. Current data 
suggest weekly administration of oral MLN9708 is generally well tolerated with infrequent 
PN, and shows early signs of antitumor activity as evidenced by at least a 50% reduction in 
disease burden and prolonged disease stabilization in some heavily pretreated patients with 
RRMM.(83)  See Section 1.3 for additional details. 
At initiation of clinical development of MLN9708, early phase 1 clinical studies empirically 
used a body surface area-based (BSA) 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 5 early trials (Studies C16001, C16002, 
C16003, C16004, and C16005).  However, the clearance of small molecule drugs is 
typically not a linear function of BSA and the appropriateness of traditional BSA-scaled 
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approaches for dosing anticancer agents has been questioned.  Based on PK modeling of 
MLN9708 as shown in Figure 1-1 and described in Section 1.3 it was determined that BSA 
did not affect single-dose maximum (peak) concentration (Cmax) or area under the plasma 
concentration versus time curve (AUC), and thus fixed dosing was appropriate. The clinical 
development of MLN9708 therefore transitioned from use of BSA-based dosing to fixed 
dosing in all subsequent studies, including the phase 1 trial C16007 that serves as the basis 
for the dose in this phase 3 trial.
Figure 1-1   
No Apparent Relationship Between MLN9708 Clearance and Body 
Surface Area
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 the linear regression line.
Study C16007:  Phase 1 Study in Relapsed or Refractory AL Amyloidosis:  Dose, 
Schedule, Safety, and Early Activity
Study C16007 also evaluated single-agent oral MLN9708 weekly in patients with RRAL on 
Days 1, 8, and 15 of a 28-day cycle. Based on the data from the RRMM study C16004, there 
were 2 planned dose escalations in Study C16007: fixed doses of 4.0 mg (equivalent to 
2.23 mg/m2 dosing, 1 dose level below the MTD in C16004) and 5.5 mg (equivalent to 
2.97 mg/m2 dosing, the MTD in C16004).  As of 30 April 2012, 14 patients have been 
treated.  At the first dose level of 4.0 mg, 1 of 6 patients experienced a protocol-defined 
DLT (that is, thrombocytopenia that lasted more than 2 weeks, which delayed the start of 
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Cycle 2 and thus met the criteria for DLT).  At the next dose level of 5.5 mg, 2 of 5 patients 
experienced a DLT (Grade 3 diarrhea, n=1; and Grade 2 dyspnea, Grade 2 acute rise in 
serum creatinine, and Grade 4 cardiac arrest, n=1).  The latter patient did not appear to have 
cardiac AL amyloidosis by echocardiogram at study entry, but did have substantial renal 
involvement; however, the differential diagnoses at the time of the DLT included cardiac 
amyloid involvement and CHF. This patient discontinued therapy due to this AE.  As per 
protocol, with 2/5 patients experiencing DLTs at the 5.5 mg dose level, the MTD of weekly 
oral MLN9708 was determined to be 1 dose level lower (ie, a fixed dose of 4.0 mg). With 
the MTD now established, patients are being enrolled to 1 of 2 cohorts: proteasome inhibitor 
naïve or proteasome inhibitor exposed.(84)
Early signs of activity were documented with single agent MLN9708 in these patients.  
Eleven patients received at least 1 cycle of therapy and had completed response assessments 
(9 in the 4.0 mg [MTD] cohort and 2 in the 5.5 mg cohort). The overall hematologic 
response rate at the 4.0 mg dose level is 56% (5 achieved a hematologic response [4 VGPR 
and 1 PR]); 3 patients showed no change, and 1 patient had an early progression.  Notably, 
the hematologic and organ response criteria used in Study C16007 is the same criteria to be 
used in Study C16011. More data will be gained from the 2 MTD expansion cohorts of 
Study C16007, in which up to an additional 25 patients will receive MLN9708 at dose of 
4.0 mg administered weekly Days 1, 8, and 15 of a 28-day cycle.
There is a similarity and consistency among the type of AEs reported with weekly oral 
MLN9708, regardless of whether the patient population is MM or systemic light chain 
amyloidosis. Millennium considers the MM safety data clinically relevant as MM and AL 
amyloidosis are related plasma cell disorders.  As of 30 April 2012, 6 clinical studies using 
the oral formulation as outlined in Table 1-1 have enrolled 220 patients with MM or AL 
amyloidosis. It is important to note that the doses used in the MM trials and the current and 
proposed AL amyloidosis trials are similar.  Therefore, based on the available clinical data, 
including data from Study C16007 in a patient population similar to that eligible for this 
study (C16011), the recommended dose of MLN9708 in this study is a fixed dose of 4.0 mg. 
VELCADE:  First-in-Class Proteasome Inhibitor in AL amyloidosis
In addition to the clinical trials of weekly MLN9708, the weekly schedule used in this trial 
was based on a trial reported by Reece and colleagues. (78);(79) The CAN-2007 study, the 
first prospective phase 1/ 2 study of single-agent VELCADE, enrolled 70 patients with 
previously treated (relapsed) systemic AL amyloidosis who required further treatment (a 
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population similar to that for Study C16011 with MLN9708). The primary objectives of the 
study were to determine the MTD and safety of single-agent VELCADE in this patient 
population; the secondary objectives were to determine the hematologic response rate (CR 
and PR) and the duration of response at the MTD. The MTD was not defined for either 
schedule, rather the maximum planned doses of 1.6 mg/m2 (once weekly) and 1.3 mg/m2
(twice weekly) were used in phase 2 evaluation.(102)  It is important to note that these 
doses/schedules represent the same dose and schedule as used to treat patients with MM:  
1.6 mg/m2 once weekly (Days 1, 8, 15, and 22 in a 35-day cycle) and 1.3 mg/m2 twice 
weekly (Days 1, 4, 8, and 11 in a 21-day cycle). Hematologic response rates were similar 
between the weekly and twice weekly treatment groups (68.8% and 66.7% [37.5% and 
24.3% complete responses]), respectively (Table 1-6). Response durations of > 1 year were 
achieved in 78.8% and 75.5% of patients, respectively. Organ responses, across all 
70 patients treated, were reported in 29% of those with renal involvement and 13% of those 
with cardiac involvement. The weekly dose schedule was better tolerated than the twice 
weekly when considering rates of Grade > 3 toxicities (50% vs 79%) and 
discontinuation/dose reductions (28/22% vs 38/53%). The hematologic CR rate and organ 
response rates were better with the weekly dose schedule than the twice weekly schedule; 
thus, the results of this study were also used to guide the dose and weekly schedule planned 
in Study C16011 with MLN9708. 
Table 1-6   
Best Confirmed Hematologic Response to VELCADE in Patients at 
the Recommended Dose on Each Schedule or at Lower Doses on 
Either Schedule
Recommended Dose Groups
1.6 mg/m2 QW
1.3 mg/m2 BIW
Lower Doses
Best confirmed hematologic response, n (%) 
(95% CI)
N = 16
N = 33
N = 18
Overall Response Rate (CR + PR)
11 (68.8)
(41.3, 89.0)
22 (66.7)
(48.2, 82.0)
7 (38.9)
(17.3,64.3)
CR
6 (37.5)
(15.2, 64.6)
8 (24.2)
(11.1,42.3)
2 (11.1)
(1.4, 34.7)
SD
4 (25.0)
(7.3, 52.4)
10 (30.3)
(15.6, 48.7)
11 (61.1)
(35.7, 82.7)
PD
1 (6.3)
(0.2,30.2)
1 (3.0)
(0.1, 15.8)
0
Source:  Reece et al., 2011(78); VELCADE, IND 56,515, Sep. 2, 2010, Serial No. 1416.
Abbreviations:  BIW = twice weekly; QW = once weekly.
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In summary and as outlined above, Millennium believes that the dose of MLN9708 to be 
used in the proposed Study C16011 is supported by several key data sets.  The dose and 
schedule for MLN9708 proposed for Study C16011 has been derived from the MTD in a 
phase 1 trial in patients with relapsed and/or refractory MM using the same schedule as the 
proposed clinical trial.  Millennium considers the MM clinical safety data relevant as MM 
and AL amyloidosis are related plasma cell disorders.  Importantly, the applicability of the 
clinical data in a MM patient population to the AL amyloidosis setting is supported by 
clinical data from a phase 1/2 trial of another boronic acid proteasome inhibitor, VELCADE, 
where the dose and schedule in AL amyloidosis was the same as the approved clinical dose 
and schedule in MM.
1.6   
Potential Risks and Benefits
As of the clinical cut-off date of 30 April 2012, 242 patients across 7 ongoing sponsor-led 
studies have been treated with oral MLN9708.  Clinical safety data includes experience from 
patients who received multiple cycles followed by treatment-free periods and from patients 
who reduced or discontinued treatment.  The emerging safety profile (as noted in 
Section 1.3, the MLN9708 IB, and the SMA) indicates that the adverse events reported with 
MLN9708 are generally consistent with the class-based effects of proteasome inhibition and 
are similar to what has been previously reported with bortezomib though the frequency may 
slightly differ.  While some of these potential toxicities may be severe, they can be managed 
by clinical monitoring and standard medical intervention.  It is possible that MLN9708 will 
have toxicities that were not previously observed in or predicted from its evaluation in 
nonclinical studies and from ongoing clinical studies given the current human experience 
with MLN9708.  To mitigate the inherent risks in clinical studies of MLN9708, patients are 
monitored closely for anticipated toxicities.  Guidance for the management of AEs and 
procedures for reducing doses are provided in the protocols, and drug dosage can be reduced 
by either reducing the dose administered or by interruption of the scheduled treatment within 
a cycle.  MLN9708 shows early signs of antitumor activity as evidenced by at least a 50% 
reduction in disease burden in some patients and prolonged disease stabilization in others 
across all ongoing trials.  Weekly dosing appears to enable delivery of higher MLN9708 
doses.  VELCADE’s proven utility in the treatment of MM and mantle cell lymphoma and 
MLN9708’s increased tissue distribution and activity in several xenograft models against the 
same components of the ubiquitin proteasome system support the further clinical 
investigation of MLN9708.  The emerging data also support the expanded development of 
MLN9708 for the treatment of patients with plasma cell dyscrasias such as AL amyloidosis.  
See the MLN9708 Investigator’s Brochure for more information. This trial will be 
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conducted in compliance with the protocol, good clinical practice (GCP), applicable 
regulatory requirements, and International Conference on Harmonization (ICH) guidelines. 
2.   
STUDY OBJECTIVES
As of this amendment, the objectives are to provide continued access of MLN9708 and/or 
other study medications and to continue collecting relevant safety data to monitor patient 
safety. All other study objectives will no longer be assessed. However, the complete list of 
objectives is retained below for reference.
2.1   
Primary Objectives
The 2 primary objectives are:

To determine whether dexamethasone plus MLN9708 improves hematologic 
response (PR + VGPR + CR) versus a physician’s choice of a chemotherapy regimen 
as selected from the list of offered treatment options in patients diagnosed with 
relapsed or refractory AL amyloidosis.

To determine whether dexamethasone plus MLN9708 improves 2-year vital organ 
(that is, heart or kidney) deterioration and mortality rate versus a physician’s choice 
of a chemotherapy regimen as selected from the list of offered treatment options in 
patients diagnosed with relapsed or refractory AL amyloidosis.  Cardiac deterioration 
is defined as the need for hospitalization for heart failure.  Kidney deterioration is 
defined as progression to end-stage renal disease (ESRD) with the need for 
maintenance dialysis or renal transplantation.
2.2   
Secondary Objectives
The key secondary objectives are:

To determine OS.

To determine the complete hematologic response rate (CR).
Other secondary objectives are:

To determine progression-free survival (PFS).  
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
To measure hematologic disease PFS.

To determine best response in the vital organs allowed at study entry (heart and 
kidney).

To determine time to vital organ deterioration or death.

To measure vital organ PFS.

To measure the duration of hematologic response (DOR).

To evaluate safety.

To measure time to treatment failure (TTF).

To measure time to subsequent anticancer therapy.

To describe the impact of treatment on quality of life (QOL) using the Medical 
Outcomes Study 36- item Short Form General Health Survey (SF-36 v2) 
(Section 15.3), FACT-neurotoxicity subscale (FACT/GOG-Ntx) (Section 15.4) and a 
symptom scale questionnaire (Section 15.5).

To evaluate Health Utilization (HU) and to collect EuroQol 5-Dimensional (EQ-5D) 
(Section15.9) data.

To collect PK data to contribute to population PK analyses.
3.   
STUDY ENDPOINTS
As of this amendment, evaluation of the safety profile of MLN9708 and/or other study 
medication is the only endpoint being assessed. All other study endpoints will no longer be 
assessed. However, the complete list of endpoints is retained below for reference.
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3.1   
Primary Endpoints
The primary endpoints are:

Overall hematologic (CR + VGPR + PR) response rate based on central laboratory 
results and the 2010 International Society of Amyloidosis (ISA) Consensus Criteria 
as evaluated by an Adjudication Committee (AC)

2-year vital organ (that is, heart or kidney) deterioration and mortality rate.  Cardiac 
deterioration is defined as the need for hospitalization for heart failure.  Kidney 
deterioration is defined as progression to end-stage renal disease (ESRD) with the 
need for maintenance dialysis or renal transplantation.   Vital organ deterioration will 
be evaluated by an AC.
3.2   
Secondary Endpoints
The key secondary endpoints are:

Complete hematologic response rate (CR) according to central laboratory results and 
ISA criteria as evaluated by an AC.

OS, measured as the time from randomization to the date of death.
Other secondary endpoints are:

PFS, defined as the time from the date of randomization to the date of first 
documentation of disease progression (hematologic PD or major organ progression 
[specifically involvement of heart or kidney] whichever occurs first) according to 
central laboratory results and ISA criteria as evaluated by an AC, or death due to any 
cause, whichever occurs first.

Hematologic disease PFS, defined as the time from the date of randomization to the 
date of first documented hematologic disease progression according to central 
laboratory results and ISA criteria, as evaluated by an AC, or death due to any cause, 
whichever occurs first.

Time to vital organ (that is, heart or kidney) deterioration and mortality rate. Cardiac 
deterioration is defined as the need for hospitalization for heart failure.  Kidney 
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deterioration is defined as progression to ESRD with the need for maintenance 
dialysis or renal transplantation.

Best response in the vital organs allowed at study entry (heart and kidney) according 
to central laboratory results and International Society of Amyloidosis criteria as 
evaluated by an AC.  

Vital organ PFS, defined as the time from the date of randomization to the date of 
first documentation of progression of  vital  organ (that is, heart or kidney) according 
to central laboratory results and ISA criteria, as evaluated by an AC, or death due to 
any cause, whichever occurs first.

Duration of hematologic response, measured as the time from the date of first 
documentation of hematologic response to the date of first documented hematologic 
disease progression, respectively according to central laboratory results and ISA 
criteria as determined by an AC.

Adverse events (AEs), serious adverse events (SAEs), and assessments of clinical 
laboratory values.

TTF, defined as the time from the date of randomization to the date of first 
documented treatment failure.  Treatment failure is defined as:  1) death due to any 
cause; 2) hematologic progression or major organ progression according to central 
laboratory results and ISA criteria as evaluated by an AC; 3) clinically morbid organ 
disease requiring additional therapy; or 4) withdrawn for any reason.

Time to subsequent anticancer treatment, defined as the time from the date of 
randomization to the start date of subsequent anticancer treatment.

QOL from patient-reported outcomes instruments (changes from baseline in health 
status based on SF-36 v2 survey, the FACT/GOG-Ntx, and a symptom scale 
questionnaire.

Collection of Health Utilization (HU) related to the disease and the therapy in both 
treatment arms and the EQ-5D questionnaire data. 

Plasma concentration-time data to contribute to future population PK analysis.
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4.   
STUDY DESIGN
4.1   
Overview of Study Design
This is a phase 3, randomized, controlled, open-label, multicenter study of the oral 
formulation of MLN9708 in combination with dexamethasone compared with treatment as 
chosen by the physician from a prespecified list of regimens available in clinical practice:  
dexamethasone alone, dexamethasone with an alkylating agent (melphalan or 
cyclophosphamide), or dexamethasone with an IMiD (thalidomide or lenalidomide) in 
patients with relapsed or refractory AL amyloidosis.  Crossover to the investigational 
treatment arm is not permitted during participation in this study.
Patients must have biopsy-proven AL amyloidosis with relapsed or refractory disease 
despite 1 or 2 prior therapies and require further treatment.  Patients cannot be refractory to 
proteasome inhibitor therapy.  To be eligible for enrollment, patients must also have 
measurable disease as defined by dFLC and objective, measurable major organ involvement 
(ie, cardiac, renal), as defined by standard ISA criteria (Section 5.1).  Patients may also have 
other organ involvement as outlined in Section 7.4.13.2.
The primary objectives of this study are hematologic response and 2-year vital organ (that is, 
heart or kidney) deterioration and mortality rate.  Cardiac deterioration is defined as the need 
for hospitalization for heart failure.  Kidney deterioration is defined as progression to 
end-stage renal disease (ESRD) with the need for maintenance dialysis or renal 
transplantation.
To maintain a balanced representation of the disease subtypes, enrollment to this study will 
be stratified by:  1) Cardiac Risk Stage:  1 versus 2 versus subgroup Cardiac Risk Stage 3 
(ie, both NT-proBNP and troponin T over threshold [but NT-proBNP < 8000 pg/mL]); 
2) relapsed versus refractory (relapsed is defined as PD documented more than 60 days after 
last dose; refractory is defined as documented absence of hematologic response or 
hematologic progression on or within 60 days  after last dose of prior therapy); and 
3) proteasome inhibitor naïve versus exposed.  In all treatment arms, each patient will 
continue to receive sequential cycles of therapy until disease progression, unacceptable 
toxicity, or termination of the study (See Section 6.4.2 for duration of treatment in the 
melphalan/dexamethasone group).  Dose adjustments are possible based on toxicities 
experienced.  Throughout the study, adverse events (AEs), laboratory values, and vital sign 
measurements will be collected and assessed to evaluate the safety of therapy.  Clinical 
laboratory tests and clinically indicated disease assessments (to include but not limited to 
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serum free light chain, cardiac biomarkers, 24-hour urine analyses, echocardiograms, and 
CT scan/MRIs) will be analyzed at the appropriate central laboratory/imaging center.
Response to therapy will be evaluated by an AC assessment, which will include the 
assessment of hematologic response and organ response according to the criteria outlined in 
the Revised Consensus Response Criteria of the International Society of Amyloidosis 
(ISA).(36)  Hematologic and organ disease assessments will be done within 28 days before 
the first dose.  Hematologic response will be assessed every cycle from the date of first dose 
until end of treatment, and every 6 weeks thereafter until documented progression or 
initiation of subsequent therapy.  Organ response will be assessed after the completion of 
Cycles 3, 6, 9, and 12 and then every 3 cycles thereafter until disease progression or the 
initiation of subsequent therapy.  Vital organ deterioration will be evaluated by an AC to 
provide a determination of the events of this composite endpoint. Vital organ deterioration is 
characterized as cardiac deterioration, that is the need for hospitalization for heart failure, 
and kidney deterioration, that is progression to ESRD with the need for maintenance dialysis 
or renal transplantation. Quality of life questionnaires will be administered to patients 
before each cycle, at the end of treatment, and every 6 weeks until disease progression or 
initiation of subsequent therapy.  After disease progression, the patients will be followed for 
survival and subsequent therapy at least every 12 weeks.
The sponsor will designate the central laboratory and independent central safety and efficacy 
review, including the IDMC and AC. 
Prior to randomization, the physician will choose a treatment regimen from the list of 
options provided by the sponsor for each screened patient.  The physician’s choice will be 
collected and recorded in the database.  Eligible patients will be randomized to 1 of 2 study 
arms in a 1:1 ratio.  Once randomized, patients should start therapy within 7 business days.
Arm A:  Patients will receive MLN9708 (4.0 mg) PO on Days 1, 8, and 15 plus 
dexamethasone 20 mg/day PO weekly on Days 1, 8, 15, and 22 of each 28-day cycle; 
dexamethasone may be increased up to 40 mg/day after 4 weeks, if tolerated.  Patients may 
continue to receive treatment until PD or unacceptable toxicity, whichever comes first.
Arm B:  Patients will receive one of the following treatment options as selected by the 
physician:

Dexamethasone:  Dexamethasone 20 mg/day PO on Days 1 through 4, 9 through 
12, and 17 through 20 of each 28-day cycle; dexamethasone may be increased up to 
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40 mg/day after 4 weeks, if the lower dose is tolerated without any > Grade 2 
dexamethasone-related toxicities.  Dose adjustments are possible based on toxicities 
experienced.

Dexamethasone plus melphalan:  Dexamethasone 20 mg/day PO on Days 1 
through 4 of each 28-day cycle dexamethasone may be increased up to 40 mg/day 
after 4 weeks if the lower dose is tolerated without any > Grade 2 dexamethasone-
related toxicities, plus melphalan 0.22 mg/kg PO on Days 1 through 4 every 28 days.  
Melphalan has to be dose adjusted in patients with renal function impairment (see 
Section 6.4.2).  Dose adjustments are possible based on toxicities experienced.

Dexamethasone plus cyclophosphamide:  Dexamethasone 20 mg/day PO weekly 
on Days 1, 8, 15, and 22 of each 28-day cycle; dexamethasone may be increased up 
to 40 mg/day after 4 weeks, if the lower dose is tolerated without any > Grade 2 
dexamethasone-related toxicities, plus cyclophosphamide 500 mg PO Days 1, 8, and 
15 every 28 days.  Dose adjustments are possible based on toxicities experienced.

Dexamethasone plus thalidomide:  Dexamethasone 20 mg/day PO weekly Days 1, 
8, 15, and 22 of each 28-day cycle; dexamethasone may be increased up to 
40 mg/day after 4 weeks, if the lower dose is tolerated without any > Grade 2 
dexamethasone-related toxicities, plus thalidomide total dose 200 mg/day PO 
(starting dose 50 mg/day, increased as tolerated to a maximum of 200 mg/day).  
Dose adjustments are possible based on toxicities experienced.

Dexamethasone plus lenalidomide:  Dexamethasone 20 mg/day PO weekly on 
Days 1, 8, 15, and 22 of each 28-day cycle; dexamethasone may be increased up to 
40 mg/day after 4 weeks, if the lower dose is tolerated without any > Grade 2 
dexamethasone-related toxicities, plus lenalidomide 15 mg/day for 21 days every 
28 days.  Dose adjustments are possible based on toxicities experienced.
Patients may continue to receive treatment until PD or unacceptable toxicity.  
The study includes 2 primary endpoints: assessment of hematologic response (PR + VGPR 
+ CR), and 2-year vital organ deterioration and mortality rate; each of these endpoints will 
be assessed by an AC. Two formal interim analyses (IAs) have been planned for this study, 
the first to occur when approximately 176 patients enrolled have had an opportunity to 
complete 6 cycles of treatment. An independent statistician will perform the IAs. An IDMC 
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will meet regularly to evaluate safety results, and at the appropriate IAs to evaluate efficacy 
results.  
Health-related QOL will also be evaluated using the patient self-reported symptom scale 
questionnaire, FACT/GOG-Ntx, SF-36 v2, the symptom scale questionnaire, and EQ-5D.  In 
addition to assessing selected symptoms, these instruments elucidate the effects of disease 
on physical, social, psychological/emotional, and cognitive functioning.
As of Amendment 6, the first IA has been conducted (data cut-off: 20 February 2019) and 
the primary endpoint of overall hematologic response rate (CR + VGPR + PR) did not reach 
statistical significance. However, patients in both treatment arms appeared to receive 
benefit. In light of the primary endpoint not being met, the sponsor has decided to remove 
the planned second IA and final analysis (FA) and discontinue the majority of study 
assessments to ease the burden of protocol-mandated assessments on patients. Ixazomib 
(MLN9708) and control drugs (if Takeda has been supplying them) will continue to be 
provided for patients who continue to derive benefit. Upon implementation of this 
amendment, data collection requirements will be limited to the following safety 
assessments: all SAEs (regardless of causality, including all deaths), any AE resulting in 
dose modification or discontinuation of any study drug, Grade ≥3 AEs, AEs of new primary 
malignancy, all reports of drug exposure during pregnancy and pregnancy outcomes, 
product complaints, and medication errors (including overdose). All other study assessments 
are no longer required. All central laboratory and investigator assessments of response and 
progression for protocol purposes are discontinued—AC review of response data and IDMC 
review of efficacy and safety data will no longer be performed. Patients will not be followed 
for the PFS or OS follow-up periods, as PFS and OS are no longer being collected. Patients 
should otherwise be treated by the investigator according to standard of care.
4.2   
Number of Patients
Approximately 176 patients are anticipated to be enrolled into this study at approximately 
75 centers in North America, Europe, and the rest of the world.
4.3   
Duration of Study
The duration of the study will be approximately 120 months (ie, 10 years), including 
84 months of enrollment and 36 months of follow-up after the last patient is enrolled.  
Delayed treatment-related AEs will be followed for 30 days after last dose of study drug.  
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The first IA was conducted when 168 patients enrolled had the opportunity to receive at 
least 6 cycles of treatment or discontinue study. The planned second IA will no longer be 
conducted. The analyses from the first IA will be used to write the clinical study report. 
Minimal descriptive analyses will be done on patient data collected after the first IA.
5.   
STUDY POPULATION
Adult patients with biopsy-proven systemic AL amyloidosis with relapsed or refractory 
disease will be enrolled.
5.1   
Inclusion Criteria
To be eligible for this study, a prospective patient must meet EACH of the following 
primary criteria:
1. Male or female patients 18 years or older.
2. Biopsy-proven diagnosis of AL amyloidosis according to the following standard criteria:
a.
Histochemical diagnosis of amyloidosis, as based on tissue specimens with Congo 
red staining with exhibition of an apple-green birefringence.
b. If clinical and laboratory parameters insufficient to establish AL amyloidosis or in 
cases of doubt, amyloid typing may be necessary (see Section 15.1).
3. Measurable disease as defined by serum differential free light chain concentration 
(dFLC, difference between amyloid forming [involved] and nonamyloid forming 
[uninvolved] free light chain [FLC]) ≥ 50 mg/L.
4. Objective, measurable major (cardiac or renal ) organ amyloid involvement as defined as 
follows (amyloid involvement of at least 1 required).(20)
a.
Cardiac involvement is defined as the presence of a mean left ventricular wall 
thickness on echocardiogram greater than 12 mm in the absence of other 
potential causes of left ventricular hypertrophy (controlled hypertension is 
allowed) with a noncardiac biopsy showing amyloid, or a positive cardiac biopsy 
in the presence of clinical or laboratory evidence of involvement.  If there is 
isolated cardiac involvement, then typing of amyloid deposits is recommended. 
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b.
Renal involvement is defined as proteinuria (predominantly albumin) >0.5 g/day 
in a 24-hour urine collection.
Note:  Amyloid involvement of other organ systems is allowed, but not required.
5. Must be relapsed or refractory after 1 or 2 prior therapies.  
For this protocol, relapsed is defined as PD documented more than 60 days after last 
dose; refractory is defined as documented absence of hematologic response or 
hematologic progression on or within 60 days after last dose of prior therapy.
a.
Patient must not have been previously treated with proteasome inhibitors. (The 
sponsor reserves the right to open the study to proteasome inhibitor-exposed 
patients in the future, at some time point after the first IA. In that case, the patient 
may not be refractory to proteasome inhibitor therapy.)
b. Given that the physician may select from an offered list of regimens to treat a 
specific patient, the patient may be refractory to an agent/s listed within the list of 
offered treatment choices.
c.
Must have recovered (ie, Grade ≤1 toxicity or patient’s baseline status) from the 
reversible effects of prior therapy.
d. If a patient has received a transplant as his/her first-line therapy, he/she must be 
at least 3 months posttransplantation and recovered from the side effects of the 
stem cell transplant.
6. Patient must meet criteria for 1 of the following AL Amyloidosis Risk Stages (as defined 
by NT-proBNP cut-off of < 332 pg/mL and troponin T cut-off of 0.035 ng/mL as 
thresholds):
a.
Stage 1: both NT-proBNP and troponin T under threshold.
b. Stage 2: either NT-proBNP or troponin T (but not both) over threshold.
c.
Stage 3: both NT-proBNP and troponin T over threshold (but NT-proBNP 
< 8000 pg/mL).
7. ECOG Performance Status ≤ 2.
8. Clinical laboratory values:
a.
Absolute neutrophil count 1000/µL.
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b. Platelet count 75,000/µL.
c.
Total bilirubin ≤ 1.5 ULN, except for patients with Gilbert’s syndrome as defined 
by > 80% unconjugated bilirubin and total bilirubin 6 mg/dL.
d. Alkaline phosphatase ≤ 5 ULN.
e.
ALT or AST ≤3 ULN.
f.
Calculated creatinine clearance ≥ 30 mL/min.
9. Female patients who:
a.
If they are of childbearing potential, agree to practice 2 effective methods of 
contraception, at the same time, from the time of signing the informed consent 
through 90 days after the last dose of study treatment, AND
b. Must also adhere to the guidelines of any treatment-specific pregnancy prevention 
program, if applicable, OR
c.
Agree to practice true abstinence when this is line with the preferred and usual 
lifestyle of the subject.  (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
post-ovulation methods] and withdrawal are not acceptable methods of 
contraception.)(103)
Male patients, even if surgically sterilized (ie, status post vasectomy), who:
a.
Agree to practice effective barrier contraception during the entire study treatment 
period and through 90 days after the last dose of study drug, AND
b.
Must also adhere to the guidelines of any treatment-specific pregnancy prevention 
program, if applicable, OR
c.
Agree to practice true abstinence when this is line with the preferred and usual 
lifestyle of the subject.  (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
post-ovulation methods] and withdrawal are not acceptable methods of 
contraception.)
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 
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withdrawn by the patient at any time without prejudice to future medical care.
5.2   
Exclusion Criteria
Prospective patients will be excluded from this study if they meet ANY of the following 
criteria: 
1. Amyloidosis due to mutations of the transthyretin gene or presence of other 
non-AL amyloidosis. 
2. Female patients who are lactating, breastfeeding, or pregnant.
3. Medically documented cardiac syncope, uncompensated NYHA Class 3 or 4 congestive 
heart failure (Section 15.6), myocardial infarction within the previous 6 months, unstable 
angina pectoris, clinically significant repetitive ventricular arrhythmias despite anti-
arrhythmic treatment, or severe orthostatic hypotension or clinically important 
autonomic disease.
4. Clinically overt multiple myeloma,  according to the IMWG criteria(103) with at least 1 of 
the following:
a.
Bone lesions.
b. Hypercalcemia, defined as a calcium of > 11 mg/dL.
5. Inability to swallow oral medication, inability or unwillingness to comply with the drug 
administration requirements, or GI procedure that could interfere with the oral 
absorption or tolerance of treatment.
6. Requirement for other concomitant chemotherapy, immunotherapy, radiotherapy, or any 
ancillary therapy considered to be investigational or which would be considered as a 
treatment of AL amyloidosis.  However, patients may be on chronic steroids (maximum 
dose 20 mg/day prednisone or equivalent [Section 15.7]) if they are being given for 
disorders other than amyloidosis (eg, adrenal insufficiency, rheumatoid arthritis, etc.).
7. 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.
8. Ongoing or active infection, known HIV positive, active hepatitis B or C infection.
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9. Psychiatric illness/social situations that would limit compliance with study requirements.
10. Known allergy to boron, MLN9708, any of the study treatments, their analogues, or 
excipients. 
11. Systemic treatment with strong CYP3A inducers (rifampin, rifapentine, rifabutin, 
carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John’s wort 
within 14 days before the first dose of study treatment.
12. Diagnosed or treated for another malignancy within 3 years (or 5 years for patients in 
France) before study enrollment 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.   
DESCRIPTION OF TREATMENT 
All protocol-specific criteria for administration of study drug must be met and documented 
before drug administration.  Study drug will be administered only to eligible patients under 
the supervision of the investigator or identified subinvestigator(s).  Patients should be 
monitored for toxicity as necessary and doses of the appropriate treatment drug should be 
modified as needed to accommodate patient tolerance to treatment; this may include 
symptomatic treatment, dose interruptions, and adjustments in the dose.  
All doses must be taken as outlined in the Schedule of Events.  Dosing should be performed 
on schedule, but occasional changes in patient scheduling are allowable (± 3 days) for 
holidays and other administrative reasons and (± 1 week) for patient vacations.  See Section 
7.4 for information about corresponding study procedures if dosing is delayed for reasons as 
noted.  Refer to the Study Manual for additional instructions regarding study drug 
administration.
Patients will be given a diary to record study drug dosing.  If a dose is missed entirely, the 
missed dose will be recorded as “not taken.”
Study drug compliance will be calculated for each patient by taking into account whether a 
patient takes all study drug as instructed.  Patients will be instructed to bring study drug to 
each patient visit for reconciliation.  The number of tablets taken will be calculated by 
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subtracting the number of tablets returned from the number of tablets dispensed.  The dosing 
diary will provide supporting information if necessary.
6.1   MLN9708 and Dexamethasone
Patients randomized to Arm A will receive dexamethasone plus MLN9708.  The 
investigator should refer to the current package insert/summary of product characteristics 
(SmPC) where available, for the most recent instructions on the handling, administration, 
and risks and potential side-effects of dexamethasone.
6.2   MLN9708 Administration
MLN9708 will be given as a once-daily oral dose.  The study drug should be taken at 
approximately the same time each day, on an empty stomach, at least 1 hour before or no 
sooner than 2 hours after a meal.  The capsules should not be chewed, broken, or opened for 
administration.  Each dose of MLN9708 will be taken orally with approximately 8 ounces 
(ie, 240 mL) total of water consumed. 
MLN9708 will be administered on Days 1, 8, and 15 of a 28-day cycle.  Missed doses can 
be taken as soon as the patient remembers as long as the next scheduled dose is 72 hours or 
more away.  Patients who vomit after ingestion will not receive an additional dose, but 
should resume dosing at the time of the next scheduled dose.  Dosing windows of ± 3 days 
are allowed occasionally (unless otherwise specified) as are occasional changes for holidays, 
vacations, and other administrative reasons (see Section 6).
6.3   Dexamethasone Administration
When used in the MLN9708 combination treatment arm, dexamethasone will be given as a 
single, oral dose of 20 mg/day PO weekly on Days 1, 8, 15, and 22 of each 28-day cycle; 
dexamethasone may be increased by 20 mg/day (up to 40 mg/day) after 4 weeks if the lower 
dose is tolerated without any > Grade 2 dexamethasone-related toxicities.
Dexamethasone should be taken at approximately the same time each day.  Each dose of 
dexamethasone should be taken with food or milk, and should be taken after MLN9708 
unless an alternative timing is needed to maximize patient tolerance (refer to Section 6.5.3). 
If a dose of dexamethasone is missed, the dose should be taken as soon as the patient 
remembers it.  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 
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dosing at the time of the next scheduled dose.  Dosing windows of ± 3 days are allowed 
occasionally (unless otherwise specified) as are occasional changes for holidays, vacations, 
and other administrative reasons (see Section 6 and 6.5.3).
6.4   
Physician’s Choice
Before randomization, physicians will declare which treatment regimen from the list of 
options they plan to select for each patient.  The selection will be collected and recorded in 
the database.  Patients will then be randomized in a 1:1 ratio to 1 of 2 treatment arms:  
Arm A) dexamethasone plus MLN9708; or Arm B) the physician’s preselected choice of 
treatment.  Dosing windows of ± 3 days are allowed occasionally (unless otherwise 
specified) as are occasional changes for holidays, vacations, and other administrative 
reasons (see Section 6).  The investigator should refer to the current package insert/SmPC, 
where available, for the most recent instructions on the handling, administration, and risks 
and potential side-effects of each drug.  
6.4.1   
Dexamethasone
Dexamethasone 20 mg/day PO on Days 1 through 4, 9 through 12, 17 through 20 every 
28 days; dexamethasone may be increased by 20 mg/day (up to 40 mg/day) after 4 weeks if 
the lower is tolerated without any > Grade 2 dexamethasone-related toxicities.  Dose 
adjustments are possible based on toxicities experienced.
6.4.2   
Dexamethasone Plus Melphalan
Dexamethasone 20 mg/day PO on Days 1 through 4 of each 28-day cycle; dexamethasone 
may be increased by 20 mg/day (up to 40 mg/day) after 4 weeks, if the lower dose is 
tolerated without any > Grade 2 dexamethasone-related toxicities, plus melphalan 
0.22 mg/kg PO on Days 1 through 4 every 28 days.  Melphalan can be dose adjusted for 
renal function:  

Creatinine clearance 20 to 40 mL/min:  0.18 mg/ kg of melphalan; 

Creatinine clearance < 20 mL/min:  0.15 mg/kg melphalan.  
Note that at study entry, calculated creatinine clearance must be ≥ 30 mL/min; patients are 
not eligible if the results are lower.  However, if renal function is lower during treatment, the 
melphalan dose may be adjusted as noted.  
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Treatment cycles continue until best response plus 2 additional cycles or to a maximum of 
18 months of therapy or 600 mg total dose given increased risk of second primary 
malignancies with prolonged melphalan use as noted in the melphalan package insert/ 
SmPC.  Best response would be defined as a plateau in deepest response achieved (eg, an 
achievement of PR which did not improve over 3 cycles total [the onset of PR plus 2 
additional cycles]).
6.4.3   
Dexamethasone Plus Cyclophosphamide 
Dexamethasone 20 mg/day PO weekly on Days 1, 8, 15, and 22; dexamethasone may be 
increased by 20 mg/day (up to 40 mg/day) after 4 weeks if the lower dose is tolerated 
without any > Grade 2 dexamethasone-related toxicities, plus cyclophosphamide 500 mg PO 
on Days 1, 8, and 15 of each 28-day cycle. 
6.4.4   
Dexamethasone Plus Thalidomide
Dexamethasone 20 mg/day PO weekly Days 1, 8, 15, and 22 of each 28-day cycle; 
dexamethasone may be increased by 20 mg/day (up to 40 mg/day) after 4 weeks, if the 
lower dose is tolerated without any > Grade 2 dexamethasone-related toxicities, plus 
thalidomide total dose 200 mg/day PO (starting dose 50 mg/day, increased as tolerated to a 
maximum of 200 mg/day).
6.4.5   
Dexamethasone Plus Lenalidomide 
Dexamethasone 20 mg/day PO weekly on Days 1, 8, 15, and 22 of each 28-day cycle; 
dexamethasone may be increased by 20 mg/day (up to 40 mg/day) after 4 weeks, if the 
lower dose is tolerated without any > Grade 2 dexamethasone-related toxicities, plus 
lenalidomide 15 mg/day for 21 days every 28 days.
6.5   
Dose Modification Guidelines
Toxicity will be evaluated according to the NCI CTCAE, version 4.03, effective 
14 June 2010.(104)
Dose modifications or delays will be made based on the toxicity experienced during the 
previous cycle of treatment.  Each AE should be attributed to a specific drug, if possible, so 
that the dose modifications can be made accordingly.  Reduction or discontinuation of 
1 agent and not the other is appropriate if toxicity is related primarily to 1 of the agents.  If 
multiple toxicities are noted, the dose adjustments and/or delays should be made once per 
cycle according to the most severe toxicity guidelines.  Further clarification can be obtained 
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in consultation with the Millennium project clinician (or designee).  Guidelines for dosing 
modifications and handling dexamethasone, melphalan, cyclophosphamide, thalidomide, 
and lenalidomide are provided here; however, it is recommended that the investigator refer 
to the most current prescribing information/SmPC for these therapies.
To manage excessive toxicity, reduction of the total drug dose can be done by reducing the 
daily dose administered and/or by interruption of the scheduled treatment within a cycle.  A 
dose reduction to a lower dose level will be made either based on criteria within a cycle or at 
the start of the subsequent cycle, but not for both.  For example, if a dose was reduced 
during a cycle, that lower dose would be carried forward into the next cycle; the dose would 
not be lowered again for the same toxicity at the beginning of the subsequent cycle.  If 
medically appropriate, additional hematology and clinical assessment may be considered to 
determine if the dosing period should be interrupted for the remainder of that cycle or if 
additional monitoring is needed. 
6.5.1   
Criteria for Toxicity Recovery for a New Cycle of Therapy to Begin:  All 
Treatment Regimens

Absolute neutrophil count (ANC) must be ≥ 1 109/L

Platelet count must be ≥ 75 109/L

All other nonhematologic toxicity (except for alopecia) must have resolved to 
≤Grade 1 or to the patient’s baseline condition
If the patient fails to meet the above-cited criteria for retreatment, hold treatment.  The 
patient should be re-evaluated weekly or more frequently to determine whether the criteria 
for retreatment have been met and a new cycle can begin.  If the criteria for retreatment have 
been met refer to appropriate drug modification guidelines to resume therapy.  The 
maximum delay before treatment should be discontinued will be 3 weeks (except in the case 
of investigator-determined clinical benefit and discussion with the Millennium project 
clinician or designee).  After 2 dose reductions due to toxicity in prior cycles, should 
treatment need to be again delayed for more than 2 weeks because of incomplete recovery 
from treatment-related toxicity, treatment may need to be discontinued. 
6.5.2   
Dose-Modification Guidelines for MLN9708
Patients experiencing adverse events attributed to MLN9708 may continue in the study but 
will have doses of MLN9708 reduced by at least 1 dose level as shown in Table 6-1.  
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Grade 4 nonhematologic toxicities will, in general, require that treatment with MLN9708 be 
permanently discontinued.  If, in the opinion of the investigator and the Millennium 
clinician, it is in the patient’s best interest to continue treatment with MLN9708, then the 
dose of MLN9708 will be reduced by at least 1 dose level in subsequent cycles of treatment 
after recovery of the toxicity or toxicities in question to Grade 1 or to baseline values.  When 
a dose reduction of MLN9708 is required due to toxicity, no dose re-escalation will be 
permitted.  The investigator and project clinician (or designee) may discuss considerations 
for dose modifications.
Table 6-1   
MLN9708 Dose Adjustments 
Dose Level
Dose (mg)
Starting Dose
4.0 mg
-1
3.0 mg
-2
2.3 mg
-3
Discontinue
6.5.2.1   
MLN9708 Dose Adjustments for Hematologic Toxicity
Dosage adjustments for hematologic toxicity are outlined in Table 6-2.  Note: Dose level 
reductions should be made in accordance with those outlined in Table 6-1.
Table 6-2   
MLN9708 Dose Adjustments for Hematologic Toxicities
Criteria
Action
Within-Cycle Dose Modifications
If platelet count 30 109/L or ANC ≤ 0.75 109/L 
on a MLN9708 dosing day (other than Day 1).
MLN9708 dose should be withheld.  Complete 
blood count (CBC) with differential should be 
repeated at least weekly or more frequently until the 
ANC and/or platelet counts have exceeded the 
prespecified values (see Section 6.5.2).  Upon 
recovery, MLN9708 may be reinitiated and reduced 
by 1 dose level in accordance with reductions 
outlined in Table 6-1.
Dose Modifications for Subsequent Treatment 
Cycles
Delay of > 2 weeks in the start of a subsequent cycle 
due to lack of toxicity recovery as defined in 
Section 6.5.1:  

ANC < 1.0 109/L, platelet count < 75 109/L.

Or other nonhematologic toxicities > Grade 1 or 
not to the patient’s baseline condition.
Hold MLN9708 until resolution per criteria Section 
6.5.1.
Reduce MLN9708 by 1 dose level as outlined in 
Table 6-1.
The maximum delay before treatment should be 
discontinued (except in the case of investigator-
determined clinical benefit and discussion with the 
project clinician/designee) should be 3 weeks.
Dose Modifications for Subsequent Treatment 
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Table 6-2   
MLN9708 Dose Adjustments for Hematologic Toxicities
Criteria
Action
Cycles
All hematologic toxicities.
If dose reduced within a cycle and toxicity recovers 
to meet criteria in Section 6.4.1 at the planned start 
of the next cycle, maintain that dose at the start of 
the cycle.
If dose was not reduced within a cycle and the next 
cycle was delayed because of criteria in Section 
6.4.1, upon recovery, decrease the dose of 
MLN9708 by 1 dose level as outlined in Table 6-1 at 
the start of the cycle.
Abbreviations:  ANC = absolute neutrophil count; CBC = complete blood count.
6.5.2.2   
MLN9708 Dose Adjustments for Nonhematologic Toxicity
Dosage adjustments for nonhematologic toxicity are outlined in Table 6-3.  Note:  Dose 
level reductions should be made in accordance with those outlined in Table 6-1.
Table 6-3   
MLN9708 Dose Adjustments for Nonhematologic Toxicities
Criteria
Action
Peripheral Neuropathy:
Grade 1 peripheral neuropathy 
No action
Grade 1 signs & symptoms: 
asymptomatic; without pain 
or loss of function; clinical 
or diagnostic observations 
only(104)
Worsening Grade 1 peripheral 
neuropathy (ie, Grade 1 with pain) or 
Grade 2
Hold study drug until resolution to 
Grade ≤ 1 without pain or baseline
Grade 2 signs & symptoms: 
Moderate symptoms; 
limiting instrumental 
activities of daily living 
(ADL)(104)
New or worsening Grade 2 peripheral 
neuropathy with pain or Grade 3
Hold study drug until resolution to 
Grade ≤ 1 or baseline
Reduce study drug to next lower  
dose upon recovery as outlined in 
Table 6-1
Grade 3 signs & symptoms: 
severe symptoms; limiting 
self care ADL; assistive 
device indicated(104)
New or worsening Grade 4 peripheral 
neuropathy
Discontinue study drug
Grade 2 Rash
Symptomatic recommendations as per section 6.10. The 
investigator and project clinician may discuss considerations for 
dose modifications and symptom management.
All Other Grade ≥ 3 
Nonhematological Toxicities:
Hold MLN9708 until resolution to Grade < 1 or baseline.
Reduce MLN9708 by 1 dose level as outlined in Table 6-1.
Note: A dose level reduction will be made either based on within-
cycle criteria or for a subsequent cycle criteria, but not for 
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Table 6-3   
MLN9708 Dose Adjustments for Nonhematologic Toxicities
Criteria
Action
both for a same cycle.
Grade 4 Nonhematologic Toxicities 
(except alopecia)
Consider permanently discontinuing MLN9708.  Exception, in the 
case where the investigator determines the patient is obtaining a 
clinical benefit and has discussed this with the project clinician or 
designee.
Criteria for Retreatment and Cycle 
Delays
Both hematologic & nonhematologic 
recovery required.
Delay therapy 1 week.
Re-evaluate patient; if still not resolved, delay therapy 
1 additional week.
If not resolved:
If initiation of subsequent therapy needs to be delayed for more 
than 2 weeks because of incomplete recovery from treatment-
related toxicity, the dose of MLN9708 will be reduced by 1 dose 
level as outlined in Table 6-1 when treatment resumes.
The maximum delay before treatment should be discontinued 
(except in the case of investigator-determined clinical benefit and 
discussion with the project clinician or designee) will be 3 weeks.
6.5.3   
Dexamethasone–Related Treatment Modification 
Dosage adjustments for dexamethasone are outlined in Table 6-4.  Dexamethasone dose 
modifications are outlined in Table 6-5.  The investigator and project clinician (or designee) 
may discuss considerations for dose modifications.
Table 6-4   
Dose Reduction Steps for Dexamethasone
Permitted Dose Increase
+1
Starting Dose
1
Dose Level
-1
Dose Level
-2
Dose Level
-3
40 mg QD
20 mg QD
8 mg QD
4 mg
Discontinue 
dexamethasone
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Table 6-5   
Dexamethasone–Related Treatment Modification (Delays, Reductions, 
and Discontinuations) Guidelines Due to Adverse Events
Adverse Event (Severity)
Action on Study Drug
Gastrointestinal
Dyspepsia, gastric, or duodenal ulcer, 
gastritis Grades 1-2 (requiring 
medical management)
Treat with histamine-2 blockers, sucralfate, or omeprazole.  If 
symptoms persist despite these measures, decrease dexamethasone 
by 1 dose reduction as outlined in Table 6-4.
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 as outlined in Table 6-4.  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 as outlined in Table 6-4.  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 as outlined in Table 
6-4.  If weakness persists despite these measures, decrease dose by 
1 dose level as outlined in Table 6-4.  Discontinue dexamethasone 
and do not resume if symptoms persist.  
Metabolic
Hyperglycemia > Grade 3 or higher
Treatment with insulin or oral hypoglycemics as needed.  If 
uncontrolled despite these measures, decrease dose by 1 dose level 
as outlined in Table 6-4 until levels are satisfactory.  The 
investigator and project clinician may discuss considerations for 
dose modifications.
Source:  Package insert for DEXAMETHASONE Tablets USP, DEXAMETHASONE Oral Solution September 2007, Roxane Laboratories, Inc, a division 
of Boehringer Ingelheim.(105)
6.5.4   
Dose Modification for Melphalan
After initiation of melphalan therapy, melphalan dose modification should be based on 
individual patient treatment tolerance as described in the package insert/SmPC.  The 
investigator and project clinician (or designee) may discuss considerations for dose 
modifications.
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Table 6-6   
Dose Reduction Steps for Melphalan
Starting Dose
Dose Level
-1
Dose Level
-2
Dose Level
-3
Dose Level
-4
0.22 mg/kg
0.20 mg/kg
0.18 mg/kg
0.15 mg/kg
Discontinue
Table 6-7   
Melphalan–Related Treatment Modification (Delays, Reductions, and 
Discontinuations) Guidelines Due to Adverse Events
Adverse Event (Severity)
Action on Melphalan
Hematologic:  ˃ Grade 3 ANC 
associated with fever 
(temperature 38.5C) or 
Grade 4 neutropenia lasting for 
7 days
Days 2-14 of cycle
Follow CBC weekly.
Next cycle, decrease 1 dose level as outlined in 
Table 6-6
Days 15-28 of cycle
Begin melphalan next cycle on schedule at 
1 dose level as outlined in Table 6-6 once ANC 
has recovered to Grade 1 or better.
Thrombocytopenia > Grade 3 
(platelet count < 50,000/mm3) 
lasting for 7 days
Days 2-14 of cycle
Follow CBC weekly.
Next cycle, decrease 1 dose level as outlined in 
Table 6-6.
Days 15-28 of cycle
Begin melphalan next cycle on schedule at 
1 dose level as outlined in Table 6-6 once 
platelets have recovered to Grade 2 or better.
Renal function:
Creatinine clearance 20-40 
mL/min after start of 
treatment 
Reduce dose to 0.18-mg/kg of melphalan.
Creatinine clearance 
< 20 mL/min after start of 
treatment
Reduce dose to 0.15-mg/kg melphalan.
Nonhematologic > Grade 3, 
attributable
Days 2-14 of cycle
Next cycle, decrease 1 dose level.
Days 15-28 of cycle
Begin melphalan next cycle on schedule at 
1 dose level lower once recovered to Grade 1 or 
better.
Abbreviations:  ANC = absolute neutrophil count; CBC = complete blood count.
6.5.5   
Dose Modification for Cyclophosphamide
After initiation of cyclophosphamide therapy, cyclophosphamide dose modification should 
be based on individual patient treatment tolerance, as described in the package insert/SmPC.
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Table 6-8   
Dose Reduction Steps for Cyclophosphamide
Starting Dose
Dose Level
-1
Dose Level
-2
Dose Level
-3
500 mg
300 mg
100 mg
Discontinue
Table 6-9   
Cyclophosphamide–Related Treatment Modification (Delays, 
Reductions, and Discontinuations) Guidelines Due to Adverse Events
Adverse Event (Severity)
Action on Cyclophosphamide
Hematologic :  ˃ Grade 3 ANC 
associated with fever 
(temperature 38.5C) or 
Grade 4 neutropenia lasting for 
7 days
Days 2-14 of cycle
Hold. Follow CBC weekly.
Next cycle, decrease 1 dose level as outlined in 
Table 6-8
Days 15-28 of cycle
Hold. Begin next cycle at 1 dose level lower 
(giving consideration to any reductions already 
done within the previous cycle) as outlined in 
Table 6-6 once ANC has recovered to Grade 1 or 
better.
Thrombocytopenia > Grade 3 
(platelet count < 50,000/mm3) 
lasting for 7 days
Days 2-14 of cycle
Hold. Follow CBC weekly.
Next cycle, decrease 1 dose level as outlined in 
Table 6-6.
Days 15-28 of cycle
Hold.  Begin next cycle at 1 dose level lower 
(giving consideration to any reductions already 
done within the previous cycle) as outlined in 
Table 6-6 once platelets recovered to Grade 2 or 
better.
Genitourinary
Cystitis Grade 1-2
Decrease cyclophosphamide by 1 dose level.
Cystitis Grade 3
Discontinue cyclophosphamide for remainder of 
study cycle.
Nonhematologic > Grade 3, 
attributable
Days 2-14 of cycle
Hold. Next cycle, decrease by 1 dose level as 
outlined in Table 6-6.
Days 15-28 of cycle
Hold. Begin next cycle at 1 dose level lower 
(giving consideration to any reductions already 
done within the previous cycle) as outlined in 
Table 6-6 once recovered to Grade 1 or better.
Abbreviations:  ANC = absolute neutrophil count; CBC = complete blood count.
6.5.6   
Dose Modification for Thalidomide
After initiation of thalidomide therapy, thalidomide dose modification should be based on 
individual patient treatment tolerance, as described in the package insert/SmPC.  The 
investigator and project clinician (or designee) may discuss considerations for dose 
modifications.
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Table 6-10   Thalidomide–Related Treatment Modification (Delays, Reductions, 
and Discontinuations) Guidelines Due to Adverse Events
Adverse Event (Severity)
Action on Thalidomide
Hematologic:  Grade 3 
ANC associated with 
fever (temperature 
38.5C) or Grade 3 
neutropenia (ANC 
< 750/mcL)
Days 2-14 of cycle
Hold. Follow CBC weekly. Restart within cycle 
with a decrease by 50 mg/day once ANC 
recovered to Grade 1 or better.  Continue this dose 
into next cycle.
Days 15-28 of cycle
Hold. Begin next cycle on schedule and decrease 
dose by 50 mg/day once ANC has recovered to 
Grade 1 or better giving consideration to any 
reductions already done within the cycle.
Thrombocytopenia 
> Grade 3 (platelet count 
< 50,000/mm3)
Days 2-14 of cycle
Hold. Follow CBC weekly. Restart within cycle 
with a dose decrease of 50 mg/day once ANC 
recovered to Grade 1 or better. Continue this dose 
into next cycle.
Days 15-28 of cycle
Hold. Begin next cycle on schedule and decrease 
dose by 50 mg/day once platelets recovered to 
Grade 2 or better, giving consideration to any 
reductions already done within the cycle.
Other hematologic 
toxicity, attributable 
Grade 3
Hold treatment and restart at a dose 50 mg/day 
below previous one when toxicity has resolved to 
Grade 2.
Grade 4
Consider discontinuing.
Hypersensitivity (eg, 
angioedema, Stevens-
Johnson syndrome, toxic 
epidermal necrolysis)
Grade 2-3 skin rash
Interrupt until resolved.
Grade 4 rash, angioedema, 
exfoliative or bullous rash 
or SJS or TEN
Discontinue thalidomide.
Drowsiness/somnolence
Grade 2
Hold treatment and restart at a dose 50 mg/day 
below previous when toxicity has resolved to 
Grade 1 or to patient’s baseline.
Dizziness, syncope, or 
orthostatic hypotension
Grade 3
Hold treatment and restart at a dose 50 mg/day 
below previous when toxicity has resolved to 
Grade 1 or to patient’s baseline.
Constipation 
Grade 2
Hold treatment and restart at a dose 50 mg/day 
below previous when toxicity has resolved to 
Grade 1 or to patient’s baseline.
Peripheral Neuropathy
Grade 2
Hold treatment and restart at a dose 50 mg/day 
below previous when toxicity has resolved to 
Grade 1 or to patient’s baseline.
Nonhematologic 
Grade 3, attributable
Days 2-14 of cycle
Hold treatment until recovery to Grade 1 or 
baseline, and restart at a dose 50 mg/day below 
previous.
Grade 4, attributable
Days 15-28 of cycle
Hold treatment.  Begin next cycle on schedule at a 
dose of 50 mg/day below previous once recovered 
to Grade 1 or better.
Consider discontinuing thalidomide.
Abbreviations:  ANC = absolute neutrophil count; CBC = complete blood count; SJS = Stevens-Johnson 
syndrome; TEN = toxic epidermal necrolysis.
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6.5.7   
Dose Modification for Lenalidomide
After initiation of lenalidomide therapy, lenalidomide dose modification should be based on 
individual patient treatment tolerance, as described in the package insert/SmPC.  The 
investigator and project clinician (or designee) may discuss considerations for dose 
modifications.
Table 6-11   Dose Reduction Steps for Lenalidomide
Starting Dose
Dose Level
-1
Dose Level
-2
Dose Level
-3
15 mg
10 mg
5 mg
Discontinue
Because lenalidomide is primarily excreted unchanged by the kidney, adjustments to the 
initial dose of lenalidomide are recommended to provide appropriate drug exposure in 
patients with moderate or severe renal impairment and in patients on dialysis.  See package 
insert/SmPC for details.
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Table 6-12   Lenalidomide–Related Treatment Modification (Delays, Reductions, 
and Discontinuations) Guidelines Due to Adverse Events
Adverse Event (Severity)
Action on Lenalidomide
Hematologic:  Platelets
Fall to < 30,000/mcL
Interrupt lenalidomide; Follow CBC weekly. 
Return to 30,000/mcL
Restart lenalidomide, decrease 5 mg less than 
previous dose.  Do not dose below 5 mg daily.
For each subsequent drop 
< 30,000/mcL
Interrupt lenalidomide treat; upon recovery to 
30,000/mcL.  Resume at 5 mg less than previous 
dose.  Do not dose below 5 mg daily.
Hematologic:  ANC
Fall to < 1000/mcL lasting 
for 7 days
Interrupt lenalidomide treatment, add G-CSF, 
follow CBC weekly.
With return to ≥ 1000/mcL and neutropenia is the 
only toxicity:  resume lenalidomide at previous 
dose. 
Return to ≥ 1000/mcL  
and if other toxicity
Resume lenalidomide at 5 mg less than previous 
dose.  Do not dose below 5 mg daily.
For each subsequent drop 
< 1000/mcL
Interrupt lenalidomide treatment.
Return to > 1000/mcL.  Resume lenalidomide at 
5 mg less than the previous dose.  Do not dose 
below 5 mg daily.
Other Grade 3/4 
hematologic toxicity 
Hold treatment and restart at next lower dose level 
as outlined in Table 6-11 when toxicity has 
resolved to Grade 2.
Hypersensitivity (eg, 
angioedema, Stevens-
Johnson syndrome, toxic 
epidermal necrolysis)
Grade 2-3 skin rash
Interrupt until resolved
Grade 4 rash, angioedema, 
exfoliative or bullous rash 
or SJS or TEN
Discontinue lenalidomide
Nonhematologic 
Grade 3
Days 2-14 of cycle
Next cycle, decrease 1 dose level as outlined in 
Table 6-11.
Days 15-28 of cycle
Begin next cycle on schedule at 1 dose level lower 
as outlined in Table 6-11 once recovered to Grade 
1 or better.
Abbreviations:  ANC = absolute neutrophil count; CBC = complete blood count; SJS = Stevens-Johnson 
syndrome; TEN = toxic epidermal necrolysis.
6.6   
Excluded Concomitant Medications and Procedures
The following medications and procedures are prohibited during the study:

Angiotensin converting enzyme (ACE) inhibitors should be used with caution and 
their use requires consultation with the Millennium clinician or designee.  Patients 
with AL amyloidosis usually poorly tolerate ACE inhibitors not due to possible 
interaction with MLN9708, but because of symptomatic hypotension due to an 
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underlying involvement of the autonomic nervous system.  Therefore, ACE 
inhibitors should be excluded in patients with eGFR < 60 mL/min and in those 
whom orthostatic systolic blood pressure is < 100 mmHg.

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.  
The rationale for this (unlike with inhibitors) is that in the event of a drug-drug 
interaction with a strong inducer, MLN9708 exposure would be decreased.
o
Strong CYP3A inducers:  rifampin, rifapentine, rifabutin, carbamazepine, 
phenytoin, and phenobarbital
o
Excluded foods and dietary supplements include St. John’s wort and Ginkgo 
biloba
The following procedures are prohibited during the study:

Radiation therapy (note that, in general, the requirement for local radiation therapy 
indicates disease progression)

Platelet transfusions to help patients meet eligibility criteria are not allowed within 
3 days before study drug dosing
6.7   
Permitted Concomitant Medications and Procedures
All necessary supportive care consistent with optimal patient care shall be available to 
patients as necessary.  All blood products and concomitant medications received from the 
first day of study treatment administration until 30 days after the final dose will be recorded 
in the CRFs. 
The following are examples of those permitted during the study:  

Antiemetics, including 5-HT3 serotonin receptor antagonists, may be used at the 
discretion of the investigator.

Loperamide or other antidiarrheal should be used for symptomatic diarrhea at 
discretion of the investigator.  The dose and regimen will be according to 
institutional guidelines.  IVF should be given to prevent volume depletion.
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
Growth factors (eg, granulocyte colony stimulating factor [G-CSF], granulocyte 
macrophage-colony stimulating factor [GM-CSF], recombinant erythropoietin) are 
permitted.  Their use should follow published guidelines and/or institutional practice; 
however, alternative usage may be reviewed with the Millennium project clinician or 
designee.  Granulocyte stimulating factors should be used in this patient population 
with caution given risk for fluid retention.

Patients should be transfused with red cells and platelets as clinically indicated 
according to institutional guidelines.

Antiviral therapy such as acyclovir may be administered if medically appropriate. 

DVT/pulmonary embolism (for patients receiving thalidomide or lenalidomide).  
Prophylactic anticoagulation is permitted according to published guidelines.  The 
decision to take prophylactic measures should be done carefully after an assessment 
of an individual patient’s underlying risk factors. 

Concomitant treatment with bisphosphonates will be permitted.

Patients who experience worsening neuropathy from baseline may be observed for 
recovery, and any supportive therapy or intervention may be initiated as appropriate 
at the discretion of the investigator.  
Standard amyloid supportive guidelines that should be considered include:

Patients who experience fluid retention or CHF may be treated with intravenous 
diuretics. 

Patients who experience life-threatening ventricular arrhythmias or atrial arrhythmias 
with hemodynamic instability should be treated according to standard clinical 
practice guidelines.

Compression garments and midodrine for patients with symptomatic orthostasis.
6.8   Precautions and Restrictions 

Fluid deficits should be corrected before initiation of treatment.  
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
Nonsteroidal anti-inflammatory drugs (NSAIDs)  induced prevalence of 
nephrotoxicity is relatively low; however, given the wide use of these agents many 
persons are at risk, including for example, patients with cardio-renal disease, 
dehydration, and the aging kidney.  NSAIDs should be avoided with impaired renal 
function given reported NSAID-induced renal failure in patients with decreased renal 
function.
6.9   Contraception Requirements
Patients treated with IMiDs must adhere to the contraceptive and pregnancy testing 
guidelines of the appropriate IMiD (thalidomide or lenalidomide) safety management 
program (eg, pregnancy testing in female patients of child-bearing age prior to each cycle).  
It is not known what effects MLN9708 has on human pregnancy or development of the 
embryo or fetus.  Therefore, female patients participating in this study should avoid 
becoming pregnant, and male patients should avoid impregnating a female partner.  
Nonsterilized female patients of reproductive age group and male patients should use 
effective methods of contraception through defined periods during and after study treatment 
as specified below.
Female patients must meet 1 of the following criteria: 

Postmenopausal for at least 1 year before the screening visit, OR

Surgically sterile, OR

If they are of childbearing potential, agree to practice 2 effective methods of 
contraception, at the same time, from the time of signing the informed consent form 
through 90 days after the last dose of study drug, AND

Must also adhere to the guidelines of any treatment-specific pregnancy prevention 
program, if applicable, OR 

Agree to practice true abstinence when this is line with the preferred and usual 
lifestyle of the subject.  (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
post-ovulation methods] and withdrawal are not acceptable methods of 
contraception.)
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Male patients, even if surgically sterilized (ie, status postvasectomy), must agree to 1 of the 
following:

Agree to practice effective barrier contraception during the entire study treatment 
period and through 90 days after the last dose of study drug, OR

Must also adhere to the guidelines of any treatment-specific pregnancy prevention 
program, if applicable, OR

Agree to practice true abstinence when this is line with the preferred and usual 
lifestyle of the subject.  (Periodic abstinence (eg, calendar, ovulation, symptothermal, 
post-ovulation methods] and withdrawal are not acceptable methods of 
contraception.)
6.10   
Management of Clinical Events 
Adverse drug reactions such as thrombocytopenia, diarrhea, fatigue, nausea, vomiting, and 
rash have been associated with MLN9708 treatment.  Management guidelines regarding 
these events are outlined below.  Further details of management of MLN9708 AEs are 
described in Section 6 of the MLN9708 IB.  Please refer to the appropriate package 
insert/SmPC for information relating to adverse events related to melphalan, 
cyclophosphamide, thalidomide, lenalidomide, and dexamethasone.
Prophylaxis Against Risk of Reactivation of Herpes Infection
Patients may be at an increased risk of infection including reactivation of herpes zoster and 
herpes simplex viruses.  Antiviral therapy such as acyclovir, valacyclovir, or other antivirals 
may be initiated as clinically indicated.  Other antivirals are also acceptable.
Nausea and/or Vomiting
Standard anti-emetics including 5-hydroxytryptamine 3 serotonin receptor antagonists are 
recommended for emesis if it occurs once treatment is initiated; prophylactic anti-emetics 
may also be considered at the physician’s discretion. Dexamethasone should not be 
administered as an anti-emetic. Fluid deficit should be corrected before initiation of study 
drug and during treatment.
Diarrhea
Prophylactic antidiarrheals will not be used in this protocol. However, diarrhea should be 
managed according to clinical practice, including the administration of antidiarrheals once 
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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
As with bortezomib, rash with or without pruritus has been reported with MLN9708, 
primarily at the higher doses tested and when given with agents where rash is an overlapping 
toxicity.  The rash may range from limited erythematous areas, macular and/or small papular 
bumps that may or may not be pruritic over a few areas of the body, to a more generalized 
eruption that is predominately on the trunk or extremities.  Rash has been most commonly 
characterized as maculopapular or macular.  To date, when it does occur, rash is most 
commonly reported within the first 3 cycles of therapy.  The rash is often transient, 
self-limiting, and is typically Grade 1 to 2 in severity. 
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) is 
permitted.  Management of a Grade 3 rash may require intravenous 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).  A rare risk is Stevens-Johnson 
Syndrome, a severe and potentially life-threatening rash with skin peeling and mouth sores, 
which should be managed symptomatically according to standard medical practice.  Punch 
biopsies for histopathological analysis are encouraged at the discretion of the investigator.
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. 
MLN9708 administration should be modified as noted as per dose modification 
recommendations in the protocol when thrombocytopenia occurs (see Section 6.5). Therapy 
can be reinitiated at a reduced level upon recovery of platelet counts. A rare risk is 
thrombotic thrombocytopenic purpura (TTP), a rare blood disorder where blood clots form 
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in small blood vessels throughout the body characterized by thrombocytopenia, petechiae, 
fever, or possibly more serious signs and symptoms. TTP should be managed 
symptomatically according to standard medical practice.
Neutropenia
Blood counts should be monitored regularly as outlined in the protocol with additional 
testing obtained according to standard clinical practice.  Neutropenia may be severe but has 
been manageable.  Growth factor support is not required but may be considered according to 
standard clinical practice.  MLN9708 administration should be modified as noted as per 
dose modification recommendations in the protocol when neutropenia occurs (see Section 
6.5).  Therapy can be reinitiated at a reduced level upon recovery of ANCs.
Fluid Deficit
Dehydration should be avoided since 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 and as needed during 
treatment to avoid dehydration (see Section 6.5).
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 anorexia.  Patients taking 
medications and/or diuretics to manage their blood pressure (for either hypo- or 
hypertension) should be managed according to standard clinical practice, including 
considerations for dose adjustments of their concomitant medications during the course of 
the trial.  Fluid deficit should be corrected before initiation of study drug and as needed 
during treatment to avoid dehydration.
Posterior Reversible Encephalopathy Syndrome
One case of posterior reversible encephalopathy syndrome, which ultimately resolved, has 
been reported with MLN9708.  This condition is characterized by headache, seizures and 
visual loss, as well as abrupt increase in blood pressure.  Diagnosis may be confirmed by 
magnetic resonance imaging (MRI).  If the syndrome is diagnosed or suspected, symptom-
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directed treatment should be maintained until the condition is reversed by control of 
hypertension or other instigating factors.
Overdose
An overdose is defined as a known deliberate or accidental administration of investigational 
drug, to or by a study patient, at a dose above that which is assigned to that individual 
patient 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
This is an open-label study; investigators and patients will know the individual treatment 
assignments.
6.12   
Description of Investigational Agents
MLN9708 Capsules
The MLN9708 drug product is provided in strengths of 4.0-, 3.0-, and 2.3-mg capsules as 
the active boronic acid.  
The 3 different dose strengths are differentiated by both capsule size and color as described 
in Table 6-13:  
Table 6-13   MLN9708 Capsules
Dose Strength
Capsule Size
Capsule Color
4.0 mg
Size 4
Ivory
3.0 mg
Size 3
Light Gray
2.3 mg
Size 2
Light Pink
For additional details, please see the MLN9708 IB and Pharmacy Manual.
6.12.1   MLN9708 Preparation, Reconstitution, and Dispensation
For blistered material, the capsules are packaged in cold-form foil-foil blisters in a 
child-resistant carton.
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MLN9708 is an anticancer drug and, as with other potentially toxic compounds, caution 
should be exercised when handling MLN9708 capsules.
6.12.2   MLN9708 Packaging and Labeling
The study drug MLN9708 capsules will be provided by Millennium.  The study drug will be 
labeled and handled as open-label material, and packaging labels will fulfill all requirements 
specified by governing regulations.  The formulation consists of 2.3-, 3.0-, and 4.0-mg 
capsules for oral administration. 
The capsules are individually packaged using cold-form foil-foil blisters that are in a 
child-resistant carton.  There are 3 capsules in each wallet/carton. 
6.12.3   MLN9708 Storage, Handling, and Accountability
Upon receipt at the investigative site, MLN9708 should remain in the blister and carton 
provided until use or until it is dispensed.  The container should be stored at the investigative 
site refrigerated (36°F-46°F, 2°C-8°C).  All excursions should be brought to the sponsor’s 
attention for assessment and authorization for continued use.  Ensure that the drug is used 
before the retest expiry date provided by Millennium.  Expiry extensions will be 
communicated accordingly with updated documentation to support the extended shelf life.
MLN9708 capsules dispensed to the patient for take-home dosing should remain in the 
blister packaging and carton and refrigerated as noted above until the point of 
use. Comprehensive instructions should be provided to the patient in order to ensure 
compliance with dosing procedures.  Patients who are receiving take-home medication 
should be given only 1 cycle of medication at a time.  Under certain circumstances, 
additional cycles may be dispensed to a patient following discussion between the 
investigator and MPI project clinician/designee; approval may be granted on a case-by-case 
basis. Patients should be instructed to store the medication refrigerated (36°F-46°F, 2°C-
8°C) for the duration of each cycle.  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 take-home medication.  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 investigational agent, it should be handled with due care.  Patients 
should be instructed not to chew, break, or open capsules.  In case of contact with broken 
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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.
Patients are to be instructed on proper storage, accountability, and administration of 
MLN9708, including that MLN9708 is to be taken as intact capsules.
Please refer to the Pharmacy Manual for additional instructions.
6.12.3.1   Dexamethasone 
Dexamethasone is a standard agent.  Dexamethasone may be supplied by the sponsor or 
sourced locally by the clinical sites when arrangements have been made and agreed to by 
Millennium and the clinical site and when regulations allow for clinical site sourcing, 
appropriate labeling, and compliance with local and regional regulations. Additional details 
are provided in the package insert/SmPC. 
6.12.3.2   Melphalan
Melphalan is a standard agent.  Melphalan may be supplied by the sponsor or sourced 
locally by the clinical sites when arrangements have been made and agreed to by 
Millennium and the clinical site and when regulations allow for clinical site sourcing, 
appropriate labeling, and compliance with local and regional regulations. Additional details 
are provided in the package insert/SmPC. 
6.12.3.3   Cyclophosphamide
Cyclophosphamide is a standard agent. Cyclophosphamide may be supplied by the sponsor 
or sourced locally by the clinical sites when arrangements have been made and agreed to by 
Millennium and the clinical site and when regulations allow for clinical site sourcing, 
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appropriate labeling, and compliance with local and regional regulations. Additional details 
are provided in the package insert/SmPC.
6.12.3.4   Thalidomide
Thalidomide is a standard agent.  Thalidomide will be sourced locally by the clinical sites 
when arrangements have been made and agreed to by Millennium and the clinical site and 
when regulations allow for clinical site sourcing, appropriate labeling, and compliance with 
local and regional regulations.  Additional details are provided in the package insert/SmPC.
6.12.3.5   Lenalidomide 
Lenalidomide is a standard agent.  Lenalidomide will be sourced locally by the clinical sites 
when arrangements have been made and agreed to by Millennium and the clinical site and 
when regulations allow for clinical site sourcing, appropriate labeling, and compliance with 
local and regional regulations.  Additional details are provided in the package insert/SmPC.
6.12.4   Other Protocol-Specified Materials
No other drugs or ancillary material are supplied for use in this study.
7.   
STUDY CONDUCT
7.1   
Study Personnel and Organizations
The contact information for the Millennium clinician or designee for this study, the central 
laboratory(ies) and any additional laboratories, the coordinating investigator for each
member state/country, and a full list of investigators will be available in the sponsor’s or 
designee’s database.
7.2   
Arrangements for Recruitment of Patients
Recruitment and enrollment strategies for this study may include recruitment from the 
investigator’s local practice or referrals from other physicians.  If advertisements become 
part of the recruitment strategy, they will be reviewed by the institutional review board 
(IRB)/independent ethics committee (IEC).  It is not envisioned that prisoners (or other 
populations that might be subject to coercion or exploitation) will be randomized into this 
study.
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7.3   
Treatment Group Assignments 
All patients who meet the inclusion and exclusion criteria will be stratified (as detailed in 
Section 4.1) and then randomized in a 1:1 ratio.  Before randomization, physicians will 
declare which standard available regimen from the list of options they would select for each 
enrolling patient.  The physician’s selection will be collected and recorded in the database.  
Patients will then be randomized between dexamethasone plus MLN9708 (Arm A) or the 
Physician’s Choice arm (Arm B) in a 1:1 fashion.  If the patient is randomized to the 
Physician’s Choice arm, the patient should receive the regimen initially selected by the 
physician.  The procedures for enrollment using the IVRS system are described in the Study 
Manual.  Patients should begin therapy within 7 business days after randomization.
7.4   
Study Procedures
Patients are being evaluated at scheduled visits over 4 study periods:  Screening, Treatment, 
End of Treatment (EOT), and Follow-Up (PFS and OS).  The first IA was conducted (data 
cut-off date 20 February 2019) and the primary endpoint of overall hematologic response 
rate (complete response [CR] + very good partial response [VGPR] + partial response [PR]) 
did not reach statistical significance. However, the primary endpoint of hematologic 
response was not met at the first IA. However, patients in both treatment arms appeared to 
receive benefit. In light of the primary endpoint not being met, the sponsor has decided to 
remove the planned second IA and FA and discontinue the majority of study assessments to 
ease the burden of protocol-mandated assessments on patients. Ixazomib (MLN9708) and 
control drugs (if Takeda has been supplying them) will continue to be provided for patients 
who continue to derive benefit. Patients will not be followed for the PFS or OS follow-up 
periods, as PFS and OS are no longer being collected. Ixazomib (MLN9708) and control 
drugs (if Takeda has been supplying them) will continue to be provided for patients who 
continue to derive benefit.
Refer to the Schedule of Events for the timing of study procedures. (Note that for 
Amendment 6, for ease of study conduct, the Schedule of Events has been simplified to 
apply only to the remainder of the study. The full Schedule of Events as of global 
Amendment 4 has been moved to Section 15.11.)  Tests and procedures should be done on 
schedule, but visit windows are allowed as follows:  All baseline evaluations/procedures are 
to be conducted at Cycle 1, Day 1 (C1D1) before dosing or within 3 days before the first 
dose of drug unless otherwise specified.  Evaluations/procedures for subsequent cycles 
(CXD1) are to be conducted within 3 days before the drug dosing unless otherwise 
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specified.  Occasional changes are allowable (± 3 days) for holidays and other 
administrative reasons and (± 1 week) for vacations.  If the study schedule is shifted, then 
both assessment and dosing schedules should be shifted accordingly to ensure that collection
of assessments is completed prior to dosing.  The cycle of therapy begins with the first dose 
of study drug.  See Section 6.1 for corresponding dosing schedule.
Additional details are provided as necessary in the sections that follow.
7.4.1   
Informed Consent
Informed consent must be obtained before any study-specific procedures for research 
purposes are performed.
7.4.2   
Patient Demographics
The age, 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.  
A complete medical history is to be obtained, including AL amyloidosis diagnosis, staging 
(cardiac biomarkers and NYHA classification), AL amyloidosis organ involvement, 
treatment history, neurologic medical history, and cardiac medical history.  The history 
should include a review of all current medications and the patient’s 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.  A neurologic exam is to be conducted 
as part of the symptom-directed physical exam.  Assessment of AL amyloidosis symptoms 
will be conducted at the time points specified in the Schedule of Events.
7.4.5   
Eastern Cooperative Oncology Group Performance Status
Performance status will be assessed using the ECOG scale (see Section 15.8) at the time 
points specified in the Schedule of Events.
7.4.6   
Vital Signs, Body Weight and Height
Measurement of vital signs will include temperature, blood pressure, and heart rate.  
Consideration should be given to determining orthostatic hypotension in patients with 
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amyloid nerve involvement or those who might have become volume depleted or 
experienced dizziness or syncope.
Body weight and height will be determined at the Screening visit and the time points 
specified in the Schedule of Events.  Height will be measured at the Screening visit only.
7.4.7   
Pregnancy Test
A serum pregnancy test will be performed for all women of childbearing potential at the 
Screening visit and the time points specified in the Schedule of Events and as required by 
any treatment-specific pregnancy prevention programs, if applicable.  Patients treated with 
IMiDs must adhere to the contraceptive and pregnancy testing guidelines of the appropriate 
IMiD (thalidomide or lenalidomide) safety management program (eg, pregnancy testing in 
female patients of child-bearing age prior to each cycle).  
The Cycle 1, Day 1 pregnancy test may be collected up to 3 days before dosing.  The results 
must be available and negative before the first dose.  
Pregnancy tests may also be repeated during the study as per request of IEC/IRBs or if 
required by local regulations.
7.4.8   
Electrocardiogram
A 12-lead ECG will be conducted at screening and at the times outlined in the Schedule of 
Events.  It may be repeated as clinically indicated during the study at the discretion of the 
investigator.  ECG data to be obtain include intervals RR, PR, QRS, QT, and QTc and 
waveforms.
7.4.9   
Clinical Laboratory Evaluations
Handling of central clinical laboratory samples will be outlined in the Study Manual.  For 
dosing decisions, local hematology and chemistry laboratory results may be used.  
Hematology and chemistry panels may be collected up to 3 days before Day 1 dosing, and 
24 hours before Day 15 dosing (see Schedule of Events for details).  Laboratory tests may be 
done more frequently at the investigator’s discretion.  Criteria for retreatment are provided 
in Section 6.5.1.
Per Amendment 6, centralized clinical laboratory evaluations of efficacy and safety will no 
longer be performed. Local laboratory evaluations should be entered into the eCRF only if 
required to understand a TEAE. For dosing decisions, response assessment, and all other 
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safety assessments for the patient, local hematology and chemistry laboratory results should 
be used and do not need to be entered into the eCRF. Local laboratory evaluations may be 
done more frequently at the investigator’s discretion (ie, for acute management of TEAEs), 
per the investigator’s judgement of standard of care. 
Clinical Chemistry and Hematology
Blood samples for analysis of the following clinical chemistry and hematological parameters 
will be obtained as specified in the Schedule of Events.
Hematology

Hemoglobin

Hematocrit

Platelet count 

WBC count with differential
Serum Chemistry

Blood Urea Nitrogen 
(BUN)

Creatinine

Total bilirubin

Uric acid

Lactate dehydrogenase

Alkaline phosphatase 

AST

ALT 

Albumin

Glucose 

Sodium

Potassium 

Chloride

CO2

Magnesium

Calcium

Phosphate

PT
Urinalysis

Appearance and color

pH

Specific gravity

Protein

Ketones

Bilirubin

Blood 

Nitrite

Urobilinogen

Glucose

Leukocytes

Microscopic 
assessment
24-Hour Urine Collection

Total protein 

Creatinine
Other

Cardiac Markers: 
BNP, NT-ProBNP, and troponin T (site may perform troponin I locally, but troponin 
T is required for the protocol)

2-Microglobulin
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7.4.10   Quality of Life Assessments 
The FACT/GOG-Ntx (Functional Assessment of Cancer Therapy/Gynecologic Oncology 
Group-Neurotoxicity [FACT/GOG-Ntx]; Section 15.4) comprises 11 individual items 
evaluating symptoms of neurotoxicity on a scale of 0 (not at all) to 4 (very much).  It will be 
completed by the patient at screening and at the time points specified in the Schedule of 
Events. 
SF-36 v2 is a multipurpose, short-form health survey with only 36 questions.  It yields an 
8-scale profile of functional health and well-being scores as well as psychometrically-based 
physical and mental health summary measures.  Physical component summary (PCS) is 
mostly contributed by physical function (PF), role physical (RP), bodily pain (BP), and 
general health (GH).  Mental component summary (MCS) is mostly contributed by mental 
health (MH), role emotional (RE), social function (SF), and vitality (VT).  It will be 
completed by the patient at screening and at the time points specified in the Schedule of 
Events.
The symptom scale questionnaire contains 3 items, each rated on an 11-point numerical 
rating scale of symptom severity. Items were generated from published literature, clinical 
experts, and amyloidosis patients. The psychometric properties of the measure will be 
evaluated using the clinical trial data. The questionnaire yields individual symptom scores.
The patient-reported symptom questionnaire (see Section 15.5) will be completed by the 
patient at screening and the time points specified in the Schedule of Events.  The symptom 
questionnaire is to be completed before other assessments are performed or study drug is 
administered.
Upon implementation of Amendment 6, QOL assessments will no longer be collected.
7.4.11   Health Utilization
During the treatment and the follow-up portions of the study, 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 of medical care 
encounters, such as inpatient/outpatient admissions, homecare, time of work loss, etc.  
Upon implementation of Amendment 6, Health Utilization assessments will no longer be 
collected.
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7.4.12   EQ-5D
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, anxiety/depression).  Each dimension has 5 levels:  no problems, 
slight problems, moderate problems, severe problems, and extreme problems.  The EQ 
visual analogue scale (VAS) records the respondent’s self-rated health on a 20-cm vertical 
VAS that ranges from 0 (worst imaginable health state) to 100 (best imaginable health state).  
The EQ-5D will be completed by the patient at screening and at the time points specified in 
the Schedule of Events.  
Upon implementation of Amendment 6, the EQ-5D will no longer be collected.
7.4.13   Disease Assessments
Patients with AL amyloidosis not only have a hematologic malignancy, but also progressive 
dysfunction of 1 or more organs.  The primary determinant of response for continuing 
treatment is the hematologic response as defined by dFLC according to published criteria.(20, 
34, 36)  A bone marrow aspirate and/or core biopsy are to be obtained at the Screening visit, 
and may be repeated at the discretion of the investigator as clinically indicated. 
Immunohistochemistry of dominant clonal plasma cells is recommended.  
The clinical laboratory tests and imaging for hematologic and organ response/progression 
will be analyzed/read at a central laboratory.  The investigator will evaluate each patient for 
response to therapy according to the response criteria presented in Section 15.10 (only 
1 parameter is required to satisfy the organ response criteria).  At each staging evaluation, 
response will be assessed relative to baseline. 
Upon implementation of Amendment 6, disease assessment for progressive disease will no 
longer be confirmed by the CRO Medical Monitor or Takeda Medical Monitor designee. 
Disease assessment will be performed and assessed by the investigator, according to 
standard of care treatment.
7.4.13.1   Hematologic Disease Assessments
The response assessments will be performed at screening and at the time points specified in 
the Schedule of Events.  The tests for hematologic response/progression will be conducted at 
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a central laboratory. Upon implementation of Amendment 6, the tests for hematologic 
response/progression will be conducted at a local laboratory.
Quantitative Immunoglobulins, Serum M-protein, Urine M-protein, and Serum Free 
Light Chains
Serum specimens will be analyzed for quantitative immunoglobulins at screening, and if 
needed at the time points specified in the Schedule of Events.  
Analysis for serum and urine M-protein and immunofixation is to be performed at screening 
and at the time points specified in the Schedule of Events.  Serum and urine immunofixation 
must be repeated if CR is documented by other criteria. 
Serum free light chain assay, ratio, and difference between involved and uninvolved (dFLC) 
is to be performed at screening and at the time points specified in the Schedule of Events.  If 
the patient comes off treatment, but has not yet progressed, the dFLC assay should be 
conducted every 6 weeks until disease progression.  An abnormal kappa-lambda FLC ratio 
(normal range 0.26-1.65) indicates an excess of 1 light chain type versus the other, and thus 
indicating clonal expansion.  The excess monoclonal light chain isotype is considered the 
involved FLC isotype and the opposite light chain type as the uninvolved FLC type.  The 
definition of hematologic response to treatment is based on the difference between the 
concentration of amyloid forming light chains (involved) and uninvolved free light chain 
(dFLC).  To be measurable, dFLC must be at least 50 mg/L.(68)
Upon implementation of Amendment 6, all central laboratory and investigator assessments 
of response and progression for protocol purposes are discontinued. Disease assessment will 
be performed and assessed by the investigator, according to standard of care treatment.
7.4.13.2   Amyloid-Related Organ Assessments
The extent of amyloid-related organ involvement according to standard criteria (see 
Section 15.10) is to be performed for all patients at screening and at the time points specified 
in the Schedule of Events.  Eligible patients must have objective measurable involvement of 
at least 1 major (heart or kidney) organ.  Organ involvement of additional organ system is 
allowed, as defined in Section 15.10.
The clinical laboratory tests and imaging for major (heart or kidney) organ 
response/progression will be analyzed/read at a central laboratory/imaging center.  At each 
staging evaluation, the organ involvement will be assessed according to standard criteria 
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(see Section 15.10) as response, no change, or progressed based on the characteristics of 
their disease at study entry.(20, 34, 36)
Disease assessments include relevant AEs and patient-reported symptoms, physical findings, 
and special laboratory tests for individual organ sites.  In addition, radiographic, CT, MRI, 
and ultrasound techniques may be performed as indicated to assess organ involvement.  In 
some cases, tissue sampling may be necessary.  
The following procedures/tests should be included at a minimum to assess amyloid-related 
organ involvement.  If clinically indicated, additional assessments may be performed at the 
discretion of the investigator.(18, 20, 34, 36, 68)
Heart:  NT-proBNP, troponin-T, echocardiography, physical examination

Echocardiogram to estimate mean left ventricular wall thickness and LVEF

NYHA criteria assessment (Section 15.6)

Cardiac troponin T is required and will be conducted at the central laboratory; 
however, troponin I may be done at the site at the physician’s discretion

BNP may be analyzed but is not specific to the organ response criteria.
Kidney:  24-hour urine proteinuria, serum creatinine, serum albumin, and calculated 
creatinine clearance. eGFR will also be calculated.
Evaluation and special testing based on other organ system involvement (see Section 15.10) 
may include:
Liver:  alkaline phosphatase, CT scan/MRI (ultrasound if indicated).  Serum albumin, 
prothrombin time, and ALT will be assessed as part of overall organ function, but are 
not specific to the organ response criteria.
Peripheral nervous system:  patient reported symptoms, physical examination and 
neurologic assessment by an investigator, nerve conduction studies or EMG (if 
indicated for clinically significant peripheral neuropathy)
Autonomic nervous system:  patient reported symptoms, determination of postural 
hypotension
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Soft tissue:  physical examination, imaging as indicated
GI tract:  physical findings, stool guaiacs or other special testing based on patient 
symptomatology as needed.
Lung:  physical examination and radiographic changes usually by CT scan
Cardiac Assessments
Cardiac assessments are to be performed for all patients as outlined in the Schedule of 
Events. 
Detailed cardiac evaluations are planned.  The assessments include, but are not limited to:

Relevant AEs and clinical findings, such as dyspnea, fluid retention, fatigue, and 
CHF 

Hospitalization 

Cardiac markers (NT-proBNP and troponin T [required; central laboratory]).  
Cardiac troponin I may be done at local hospital for investigator information

Blood pressure

NYHA classification determination (see Section 15.6)

Cardiac Risk Assessment Staging
Table 7-1   
Cardiac Risk Assessment Staging System
Stage
Criteria:  Threshold Levels NTpro-BNP < 332 pg/mL and Troponin T< 0.035 
ng/mL
1 
Both troponin or NT-proBNP under threshold
2 
Either troponin or NT-proBNP (but not both)over threshold
3 
Both troponin or NT-proBNP over threshold
NOTE: To be eligible NT-proBNP must be < 8000 pg/mL at study entry
Source:  Dispenzieri A, Gertz MA, Kyle RA, Lacy MQ, Burritt MF, Therneau TM, et al. Serum cardiac 
troponins and N-terminal pro-brain natriuretic peptide: a staging system for primary systemic 
amyloidosis. Journal of Clinical Oncology 2004;22(18):3751-7. (97)
Abbreviations:  NT-pro BNP = N-terminal pro-brain natriuretic peptide.
If troponin T is not available at local institution, troponin I may be used, but threshold is < 0.1 µg/mL.
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
In the setting of sustained hematologic response, but with an increase in NT-proBNP 
that is both >30% and >300 pg/mL, the following criteria will be used to confirm 
heart progression: 
o
Echo: interventricular septal thickness increased by 2 mm over 
baseline, or
o
An increase in NYHA class by 1 grade with decreasing LVEF of 
>10%

Echocardiogram at screening and at the time points specified in the Schedule of 
Events.  The following data may be collected:  2D-guided M-Mode (wall thickness 
and chamber diameters), short-axis, long-axis, apical 4-chamber and 2-chamber 
video clips (5 beats each), transmitral, transaortic, transtricuspidal, and pulmonary 
vein Doppler studies, mitral and tricuspidal annulus longitudinal excursion, and 
tissue Doppler imaging for systolic and diastolic wall velocities.  Strain and strain 
rate analyses may also be analyzed off-line from the short-axis and 4-chamber video 
clips at the discretion of the investigator. 
Note:  Mean left ventricular wall thickness is derived as the mean of the end diastolic 
ventricular septal wall (IVS) thickness + end diastolic posterior wall (PW) thickness.
Note:  If CT or MRI cardiac assessments are clinically indicated, then a record of the 
findings will be made.
Renal Assessments

24-hour urine collection (total protein, calculated creatinine clearance, M-protein 
quantification, and immunofixation)

eGFR assessment

Serum creatinine

Serum albumin

Hospitalization

Dialysis
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
Transplant 
Renal assessments are to be performed in all patients as outlined in the Schedule of Events.
Special Testing Based on Patient’s Other Organ System Involvement at Study Entry:
Hepatic Assessments

Alkaline phosphatase

CT or MRI scan

Clinical examination, or

Abdominal ultrasound at the discretion of the investigator if clinically indicated 

Assessment of hepatomegaly according to standard criteria if clinically indicated

Hepatic assessments are to be performed in all patients as outlined in the Schedule of 
Events.  The same evaluation (physical examination or radiography [and the same 
imaging modality]) must be used consistently in individual patients throughout the 
study for all follow-up assessments.
Neurologic Assessments
Assessments are to be performed as outlined in the Schedule of Events based on the 
involvement and characteristics of the patient’s disease at study entry.

Patient-reported gastrointestinal and neurologic symptoms

Clinical examination

Neurologic examination by the patient’s investigator, including sensory and/or motor 
findings

Detection and measures of postural hypotension

Nerve conduction studies, if indicated (including EMG, if necessary)
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Soft Tissue or Lymph Node Assessments
Assessments are to be performed as outlined in the Schedule of Events based on the 
involvement and characteristics of the patient’s disease at study entry.

CT or MRI scans at the discretion of the investigator as clinically indicated.  The 
same imaging modality used at screening (CT/MRI) should be used for all follow-up 
assessments

Recording of any abnormalities on physical examination

Patient reported symptoms
Gastrointestinal Tract Assessments

Assessments are to be performed as outlined in the Schedule of Events based on the 
involvement and characteristics of the patient’s disease at study entry.

Recording of any abnormalities on physical examination

Patient reported symptoms, ie, reduction of diarrhea 
Upon implementation of Amendment 6, all amyloid-related organ assessments for protocol 
purposes are discontinued.   
7.4.14
Pharmacokinetic Measurements (Arm A Only)
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 PK samples are provided in 
the Study Manual.  The sampling scheme is indicated in the Pharmacokinetic Sampling 
Schedule immediately following the Schedule of Events.
Blood samples (3 mL) for the determination of plasma concentrations of MLN2238 will be 
collected during Cycles 1 through 10.  Blood samples are to be collected at the time points 
specified in the Schedule of Events aligning with the dosing schedule if an occasional 
change has been made for holidays, vacations, and other administrative reasons (see 
Section 6).
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Upon implementation of Amendment 6, blood samples for PK measurements will no longer 
be collected.
7.4.15   Concomitant Medications and Procedures
Concomitant medications and therapy will be recorded as specified in 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.  
Upon implementation of Amendment 6, concomitant medications and procedures will not be 
recorded in the eCRF.   
7.4.16
Adverse Events
Monitoring of AEs, both nonserious and serious, will be conducted throughout the study as 
specified in the Schedule of Events.  Upon implementation of this amendment, data 
collection requirements will be limited to the following safety assessments: all SAEs 
(regardless of causality, including all deaths), any AE resulting in dose modification or 
discontinuation of any study drug, Grade ≥3 AEs, AEs of new primary malignancy, all 
reports of drug exposure during pregnancy and pregnancy outcomes, product complaints, 
and medication errors (including overdose).
See Section 10 for details regarding definitions, documentation, and reporting of 
pretreatment events, AEs, and SAEs. 
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.  Refer to Section 
10 for details regarding definitions, documentation, and reporting of SAEs.
7.4.17   Follow-Up Assessments (PFS and OS) 
Patients who do not develop PD will continue to have progression-free follow-up visits.  The 
hematologic PFS follow-up should occur every 6 weeks from the EOT visit until the 
occurrence of progression or the start of subsequent anticancer therapy.  The amyloid-organ 
PFS follow up should occur every 12 weeks from the EOT visit until the occurrence of 
progression or the start of subsequent anticancer therapy.  During these follow-up periods, 
data will be collected regarding hospitalizations, development of CHF, and progression to 
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ESRD requiring maintenance dialysis or renal transplantation. Refer to the Schedule of 
Events and Section 7.4.13 for appropriate assessments.
After the occurrence of PD or the initiation of subsequent anticancer therapy, patients will 
continue to have OS follow-up visits.  The OS follow-up visits should be conducted every 
12 weeks after documented PD.  Data may be collected by methods that include, but are not 
limited to, telephone, e-mail, mail, and social security indexes.  During these follow-up 
periods, data will be collected regarding hospitalizations, development of CHF, and 
progression to ESRD requiring maintenance dialysis or renal transplantation.  See the 
Schedule of Events for appropriate assessments.  The duration of follow-up for OS will be at 
least 2 years after the last patient enters OS follow-up. 
Upon implementation of Amendment 6, patients will no longer be followed during any of 
the follow-up periods, as PFS and OS are not being collected.
7.5   
Study Compliance
Study drug will be administered or dispensed only to eligible patients under the supervision 
of the investigator or identified sub-investigator(s).  Patients will be given a diary to record 
study drug dosing.  The appropriate study personnel will maintain records of study drug 
receipt and dispensing.  The dosing diary will provide supporting information, if necessary.
Compliance regarding adherence to study visit schedule and sharing of medical information 
is important throughout the duration of the study.  Various measures of contact utilized will 
include but are not limited to clinic visits, telephone calls, e-mail contact, contact of 
family/significant other, and contact with referring physicians will be utilized by site staff to 
obtain medical information important to the study endpoints.  The sponsor and/or its 
designees will work with site investigators and study staff to manage follow-up visit 
reminders, to stress the importance of patient retention and to obtain data points key to the 
study endpoints. 
7.6   
Discontinuation of Treatment With Study Drug, and Patient Replacement
Treatment with study drug must be discontinued for pregnancy.  Treatment may be 
discontinued permanently if any of the other following criteria are met:

AE (including SAE)

Protocol violation
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
Study terminated by sponsor

Withdrawal by patient

Lost to follow-up

PD

Initiation of subsequent therapies (including initiation of hematopoietic stem cell 
transplant)

Symptomatic deterioration 

Pregnancy (patient must be discontinued)

Other
Once study drug has been discontinued, all study procedures for the EOT visit as specified 
in the Schedule of Events will be completed.  The primary reason for study drug 
discontinuation will be recorded on the electronic case report form (eCRF).  
7.7   
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

Initiation of hematopoietic stem cell transplant

Other
The consequence of study withdrawal is that no new information will be collected from the 
withdrawn patient and added to the existing data or any database.  However, every effort 
will be made to follow all patients for safety and survival.
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8.   
STATISTICAL AND QUANTITATIVE ANALYSES
8.1   
Statistical Methods
In general, summary tabulations will be presented by treatment arm and will display the 
number of observations, mean, standard deviation, median, minimum, and maximum for 
continuous variables, and the number and percent per category for categorical data.  The 
Kaplan-Meier survival curves and 25th, 50th (median), and 75th percentiles will be provided 
along with their 2-sided 95% confidence intervals (CIs) for time-to-event data.  
The SAP will be written by Millennium and will be finalized before any formal 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.
The first IA has been performed (data cut-off date: 20 February 2019) and the primary 
endpoint of hematologic response was not met. Therefore, the sponsor has decided not to 
conduct any subsequent formal statistical analyses. The analysis of efficacy and safety has 
been completed on data from the first IA. As of this decision, no additional patients will be 
enrolled in the study and the number of study patients is reduced from 248 to 176 (note that 
8 patients had not completed a minimum of 6 cycles of treatment or discontinued before the 
data cut-off date required for inclusion in the IA). Minimal descriptive analyses will be done 
on patient data collected after the first IA. The description of statistical methods presented 
below reflects the original design of the study so to retain the statistical considerations up to 
the first IA.  
8.1.1   
Determination of Sample Size 
Two primary endpoints, hematological response and 2-year vital organ deterioration and 
mortality rate, along with key secondary endpoints of OS and complete hematologic 
response rate, will be sequentially tested in this study. 
The total sample size was calculated based on maintaining 80% power to test the OS key 
secondary endpoint.  There are 2 planned IAs and 1 FA.  The study is also adequately 
powered to test both primary endpoints: hematologic response rate and 2-year vital organ 
deterioration and mortality rate.
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Assuming a hazard ratio of 0.625 (median survival of 26 months in control arm versus 
41.6 months in the active arm), the number of events needed was 145 (80% power and 
2-sided alpha of 0.05).  A total of approximately 248 patients will need to be randomized in 
a 1:1 ratio into those 2 arms, assuming an average enrollment rate of 3 patients for the first 
5 months, approximately 3 to 5 patients per month thereafter, and an additional 28 months 
follow up for all patients after last patient is enrolled, and approximately 10% drop out rate.  
The FA of OS is estimated to occur approximately 112 months from the enrollment of first 
patient.  This period includes an approximate 84 months accrual period and 28 months 
follow-up period. 
The first IA was performed when 168 patients enrolled had the opportunity to complete 6 
cycles of treatment or discontinue treatment before receiving 6 cycles of treatment.  This 
was the FA for hematological response.  To maintain the overall strong control of Type I 
error rate at a 2-sided alpha level of 0.05, hematological response and organ deterioration 
and mortality rate was tested sequentially at the first and second IA using the fall-back 
approach to adjust for multiple testing.  At the first IA, hematologic response was tested at a 
2-sided alpha level of 0.04. With 176 patients as the planned sample size for the first IA, the 
hematological response endpoint was powered at 90% at a 2-sided alpha level of 0.04 with 
the assumption of 40% response rate in the control arm and 65% response rate in the 
MLN9708 arm.  If the test was statistically significant, the study was to continue to test 2-
year vital organ deterioration and mortality rate at a 2-sided alpha of 0.05; otherwise 2-year 
vital organ deterioration and mortality rate will be tested at the second IA with a 2-sided 
alpha of 0.01. The primary endpoint was not met at the first IA and the sponsor has decided 
not to conduct the second IA. If the second IA had been conducted, below would have been 
the steps for the IA and the justification for the sample size for the second IA.
The second IA was originally planned to be performed when approximately 218 patients 
enrolled have had the opportunity to complete 2 years of treatment or to be followed up for 
at least 2 years if discontinuing treatment before receiving 2 years of treatment. This will be 
the FA for 2-year vital organ deterioration and mortality rate. With a statistically significant 
response for the primary endpoint at the first IA, the endpoint of 2-year vital organ 
deterioration and mortality rate is powered at 90% at a 2-sided alpha level of 0.05 with the 
assumption of 80% deterioration and mortality rate in the control arm and 60% rate in the 
MLN9708 arm. If the test for the primary endpoint at the first IA is not significant, the 
endpoint of 2-year vital organ deterioration and mortality rate is powered at 74% at a 2-sided 
alpha level of 0.01. If the test for 2-year vital organ deterioration and mortality rate is not 
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significant, the study will continue to FA without any formal testing; otherwise, OS will be 
tested with the total alpha to be the same as testing the 2-year vital organ deterioration and 
mortality rate. If the test for OS is statistically significant, the complete hematologic 
response rate will be tested at the same alpha level as that for OS and the study may be 
stopped for evidence of efficacy; if the test for OS is not statistically significant, the study 
will continue to the FA to test OS again. 
The O’Brien and Fleming stopping boundary (the Lan-DeMets method) will be used to 
assign alpha level to the second IA and FA on OS.
8.1.2   
Randomization and Stratification  
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 1 of the 2 two treatment arms, 
stratified by:  1) Cardiac Risk Stage:  1 versus 2 versus subgroup Cardiac Risk Stage 3 (ie, 
both NT-proBNP and troponin T over threshold [but NT-proBNP < 8000 pg/mL]); 
2) relapsed versus refractory; and 3: proteasome inhibitor naïve versus exposed.   
8.1.3   
Populations for Analysis
The populations used for analysis will include the following:
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.  
Hematologic Response-Evaluable population:  The hematologic response-evaluable 
population is defined as patients who have measurable disease at baseline, who receive at 
least 1 dose of any study treatment, and have at least 1 postbaseline hematologic response 
assessed by an AC.
Safety population:  The safety population is defined as all patients who receive at least 
1 dose of any study treatment.  Patients will be analyzed according to the treatment actually 
received. 
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8.1.4   
Procedures for Handling Missing, Unused, and Spurious Data
All available efficacy and safety data will be included in data listings and tabulations.  Data 
that are potentially spurious or erroneous will be examined 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 patient reported outcomes data, primarily missing data 
imputation will be based on published instrument specific methods.  Other missing data 
imputation method such as Last Observation Carry Forward (LOCF), random slope model, 
and pattern mixture model may be explored as sensitivity analyses for patient reported 
outcomes data.
For the hematologic response rate, a missing value is defined as no post-baseline 
hematologic response assessment due to either lost to follow-up or withdrawal by patient.  In 
the primary analysis, if the hematologic response assessment in either arm is missing upon 
comparison of hematologic response rates, it will be counted as a failure (non-responder) 
instead of a missing value.
For the 2-year organ deterioration and mortality rate, a missing value is defined as no 
documented vital organ deterioration or death event within the first 2 years and no further 
information available regarding vital organ deterioration or death event on or after 2-years 
from the date of first dosing of the study drug [Arm A] or standard drug [Arm B].  If there is 
any vital organ (heart or kidney) deterioration or death event within the first 2 years during 
the study, whichever occurred first, this event will be counted as one event at 2-year time 
point. In addition, at the time for the analysis, all patients will have the opportunity to be 
followed up for a minimum of 2-years. In the primary analysis, if the 2-year vital organ 
deterioration assessment or death information is missing in either arm, it will be counted as a 
failure instead of a missing value; that is, patient who has a missing event will be counted as 
an event towards vital organ deterioration or death. 
8.1.5   
Demographic and Baseline Characteristics
The demographic and baseline characteristics will be summarized in a descriptive fashion.  
Data to be evaluated will include age, sex, race, weight, baseline disease characteristics, and 
other parameters, as appropriate. 
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8.1.6   
Efficacy Analysis
8.1.6.1   
Analyses of Primary Efficacy Endpoints
There are 2 primary efficacy endpoints:  hematologic response and 2-year vital organ 
deterioration and mortality rate.
Hematologic Response
Hematologic response rate is defined as the proportion of patients who achieved PR or better 
relative to ITT population according to central laboratory results and ISA criteria as 
evaluated by an AC.  The unstratified Cochran-Mantel-Haenszel (CMH) test will be used to 
compare hematologic response rate 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.  
2-year Vital Organ Deterioration and Mortality Rate  
Cardiac deterioration is defined as the need for hospitalization for heart failure.  Kidney 
deterioration is defined as progression to ESRD with the need for maintenance dialysis or 
renal transplantation.  Vital organ deterioration will be assessed by an AC.
A patient enrolled in either arm of the study will be counted as a failure instead of a missing 
value if the 2-year vital organ deterioration assessment or death information is missing for 
the primary analysis upon comparison 2-year vital organ deterioration and mortality rates.
The unstratified CMH test will be used to make comparisons between the 2 treatment arms 
when approximately 218 patients enrolled have had the opportunity to complete 2 years of 
treatment or to be followed up for at least 2 years if discontinuing treatment before receiving 
2 years of treatment.  If the 2-year organ deterioration and mortality rate is statistically 
significantly lower in the dexamethasone plus MLN9708 arm (Arm A) by using the 2-sided 
CMH test, null hypothesis will be rejected.  
A logistic regression model will be used to estimate the treatment effect in terms of odds 
ratio.  The odds ratio and its associated 95% confidence intervals (CIs) will be presented. 
Sensitivity Analyses for Primary Endpoints
It is expected that the missing values will be limited and therefore, the primary analysis on 
both primary endpoints will not be driven by the handling of the missing data. To further 
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assess the impact of missing values and potential other factors, a range of sensitivity 
analyses are proposed as below:
1. Hematologic response and vital organ deterioration assessed by investigator will be 
analyzed in the ITT population.
2. Stratified CMH method 
3. Binomial test with the standard error for the estimated difference in rates adjusted by 
the number of missing values in each arm ( further elaborated in the SAP) 
4. Subgroup analyses including the stratification factors, and other baseline prognostic 
factors to be determined before database lock
In addition, hematologic response assessed by an AC will be analyzed in the hematologic 
response-evaluable population.
8.1.6.2   
Analyses of Key Secondary Efficacy Endpoints
In addition to the primary comparison of hematologic response and 2-year vital organ 
deterioration and mortality rate, there are 2 key secondary endpoints: OS ; complete 
hematologic response rate.  Key secondary endpoints will be tested sequentially. That is, 
complete hematologic response rate will be tested at the same alpha level as the OS analysis 
when the test of OS is statistically significant either at the IA or at the FA. The secondary 
endpoints will be tested on the ITT population, and the response data will be based on 
central laboratory results and ISA criteria by an AC.  Investigator-assessed response data 
will be used as sensitivity analysis.
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 analysis will be censored at the date 
last known to be alive.  Overall survival 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 second IA and FA is decided by the O’Brien and 
Fleming alpha spending function.  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 
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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. 
Complete Hematologic Response Rate 
Complete hematologic response rate is defined as the proportion of patients who achieved 
CR in the ITT population.  Complete hematologic response will be assessed by an AC using 
central laboratory results and ISA criteria. 
The complete hematologic response rate will be analyzed using the similar method as 
hematological response rate. 
8.1.6.3   
Analyses of Other Secondary Efficacy Endpoints 
Other secondary efficacy parameters include PFS, duration of hematologic response, 
hematologic disease PFS, time to vital organ deterioration or death, vital organ response, 
vital organ PFS, TTF, and time to subsequent anticancer therapy.  These endpoints will be 
tested on the ITT population and the data will be based on central laboratory results and ISA 
criteria by an AC.
PFS
Progression-free disease is defined as the time from the date of randomization to the date of 
first documentation of hematologic disease progression, or organ (cardiac or renal) 
progression, or death due to any cause, whichever occurs first.
Patients without documentation of hematologic PD and organ progression will be censored 
at the date of last hematologic response assessment that is SD or better, or the date of last 
organ assessment SD or better, whichever occurs last.  Progression-free survival will be 
analyzed using a method similar to that used for the analysis of OS.
Hematologic Disease PFS 
Hematologic disease PFS is defined as the time from the date of randomization to the date of 
first documentation of hematologic PD, or death due to any cause, whichever occurs first. 
Patients without documentation of hematologic PD will be censored at the date of last 
hematologic response assessment that is SD or better.  Hematologic disease PFS will be 
analyzed based on the ITT population using a method similar to that used for the analysis of 
OS.
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Time to Vital Organ Deterioration or Death 
Time to vital organ deterioration or death defined as the time from randomization to vital 
organ (heart or kidney) deterioration or death, whichever occurs first. 
Patients without documentation of organ deterioration or death will be censored at the date 
of the last assessment. Time to vital organ deterioration or death will be analyzed based on 
the ITT population using a method similar to that used for the analysis of OS.
Vital Organ Response Rate
Vital organ (heart and kidney) response rate is defined as the proportion of patients who 
achieved vital organ response in the ITT population. Changes from baseline in the vital 
organs will be documented as "response", "no change", or "progressed". An overall 
determination of vital organ response will then be documented for the given time point:

Progression of 1 of the 2 vital organs will equate to organ progression

Response of 1 or 2 of the involved vital organs with no change from baseline in the 
rest of  involved vital organs will equate to vital organ response

No change from baseline in any involved vital organs will equate to stable organ 
disease
Vital organ PFS 
Vital organ PFS is defined as the time from the date of randomization to the date of first 
documentation of progression of these two vital organs (heart or kidney), or death due to any 
cause, whichever occurs first.
Patients without documentation of vital organ progression will be censored at the date of last 
vital organ assessment SD or better. Vital organ PFS will be analyzed using the similar 
method as OS.
Duration of Hematologic Response
Duration of hematologic response (DOR) is defined as the time from the date of first 
documentation of a hematologic PR or better to the date of first documentation of 
hematologic PD for hematologic responders.  
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Hematologic responders without documentation of hematologic PD will be censored at the 
date of last hematologic response assessment that is SD or better.  DOR will be summarized 
descriptively using the Kaplan-Meier method. 
Time to Treatment Failure
Time to treatment failure (TTF) is defined as the time from randomization to the date of first 
documented treatment failure.  Treatment failure is defined as:  1) death due to any cause; 2) 
hematologic progression or major organ progression according to central laboratory results 
and ISA criteria as evaluated by an AC; 3) a hematologic response with stable but clinically 
morbid organ disease requiring additional therapy; or 4) or withdrawn for any reason. 
Patients without documentation of treatment failure will be censored at the date of last 
response assessment.  Time to treatment failure will be analyzed based on the ITT 
population using a method similar to that used for the analysis of OS.
Time to Subsequent Anticancer Therapy
Time to subsequent anticancer therapy is defined as the time from randomization to the first 
date of subsequent anticancer therapy.  
Patients without subsequent anticancer therapy will be censored at the date of death or last 
known to be alive.  Time to subsequent anticancer therapy will be analyzed based on the ITT 
population using a method similar to that used for the analysis of OS.
8.1.7   
Analyses of Patient-Reported Outcomes and Health Economics  
8.1.7.1   
Patient-reported Outcomes Analysis
Patient-reported outcome assessments using FACT/GOG-NTX, the symptom scale 
questionnaire, and SF-36 v2, will be analyzed to determine if response to therapy and side 
effects of therapy are accompanied by measurable changes in the PROs.  The analysis will 
be performed on summary scores as well as on subscales and individual symptoms.
To compare the 2 treatment groups with respect to maximum improvement from baseline in 
SF-36 v2, as well as the symptom scale questionnaire, an analysis of covariance (ANCOVA) 
model will be fitted.  Summaries from ANCOVA with baseline and other relevant clinical or 
demographic variables as covariates will include F-test p values, mean change scores, and 
95% CI for the differences between the treatment groups.
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Per the recommendations outlined in the FDA Guidance (2009), it will be informative to 
examine the cumulative distribution function (CDF) of responses between treatment groups 
to characterize the treatment effects.  A graphical display of this cumulative distribution, 
showing a continuous plot of the change from baseline on the X-axis and the percent of 
patients experiencing that change on the Y axis, will be presented.  The CDF will be 
performed on the PCS and MCS for the SF-36 v2, FACT/GOG-NTx, and individual and 
total symptom score on the symptom scale questionnaire.
Missing items in a scale will be handled by the individual scales or subscales on the basis of 
each individual assessment and according to the developer’s guidelines.  Investigation of 
missing patterns and details of imputation will be discussed in the SAP.
8.1.7.2   
Health Economics Analysis 
EQ-5D scores will be summarized in descriptive statistics for treatment arms. 
Health utilization data will be summarized in descriptive statistics of medical encounters 
(length of stay, inpatient, outpatient, and reason), number of missing days from work or 
other activities by patient and care-giver for treatment arms. 
8.1.8   
Pharmacokinetics, Pharmacodynamics, and Biomarkers
Pharmacokinetic Analysis
PK data collected 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. 
8.1.9   
Safety Analysis
Safety will be evaluated by the incidence of AEs, severity and type of AEs, and by changes 
from baseline in the patient’s vital signs, weight, and clinical laboratory results using the 
safety population.  Exposure to study drug and reasons for discontinuation will be tabulated.
Treatment-emergent AEs will be tabulated.  Treatment-emergent AEs are AEs that occur 
after administration of the first dose of study drug and through 30 days after the last dose of 
study drug.  AEs will be tabulated according to the Medical Dictionary for Regulatory 
Activities (MedDRA) and will include the following categories:

Treatment-emergent AEs
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
Drug-related treatment-emergent AEs

Grade 3 or higher treatment-emergent AEs

Grade 3 or higher drug-related treatment-emergent AEs

The most commonly reported treatment-emergent AEs (ie, those events reported by 
10% of patients in any treatment group)

SAEs
A listing of treatment-emergent AEs resulting in study drug discontinuation will be 
provided.
Descriptive statistics for the actual values of clinical laboratory parameters (and/or change 
from baseline in clinical laboratory parameters) will be presented for all scheduled 
measurements over time.  Mean laboratory values over time will be plotted for key 
laboratory parameters.
Descriptive statistics for the actual values and changes from baseline of vital signs, weight, 
ECOG scores will be tabulated by scheduled time point.  
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 screening 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.  Additional safety analyses may be 
done at a time as requested by health care authorities.
Upon implementation of this amendment, safety assessments will be limited to the 
following: all SAEs (regardless of causality, including all deaths), any AE resulting in dose 
modification or discontinuation of any study drug, Grade ≥3 AEs, AEs of new primary 
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malignancy, all reports of drug exposure during pregnancy and pregnancy outcomes, 
product complaints, and medication errors (including overdose).
8.1.10   Interim Analyses
There were 2 planned IAs.  The first IA was performed when 168 patients enrolled had the 
opportunity to complete 6 cycles of treatment or discontinued study treatment before 
receiving 6 cycles of treatment.  At that time, relevant safety and efficacy data from those 
patients was queried and cleaned; all analyses at this IA will be based on these patients 
whose data have been cleaned.  This will be the FA for hematologic response.  At the first 
IA, hematologic response was tested at a 2-sided alpha level of 0.04.  If the test was 
statistically significant, the study would have continued to test organ deterioration and 
mortality rate at a 2-sided alpha of 0.05 at the second IA; otherwise organ deterioration and 
mortality rate would have been tested at the second IA with a 2-sided alpha of 0.01. 
Therefore, by using this fall-back approach(106), the type I error would have been strongly 
controlled for 2 primary endpoints: hematologic response and 2-year vital organ 
deterioration and mortality rate. This first IA has occurred (data cut-off date: 20 February 
2019) and the primary endpoint of hematologic response was not met. Therefore, the 
sponsor has decided not to conduct the second IA.  The text below describes the sample size 
and steps originally planned for the second IA.
The second IA will be performed when approximately 218 patients enrolled have had the 
opportunity to complete 2 years of treatment or followed up for at least 2 years if 
discontinuing treatment before receiving 2 years of treatment.  This IA is expected to occur 
approximately 98 months from the first patient is enrolled.  At that time, relevant safety and 
efficacy data from those patients will be queried and cleaned; all analyses at this IA will be 
based on these patients whose data have been cleaned.
If the test for 2-year vital organ deterioration and mortality rate is significant at the second 
IA, the analyses on OS will be performed and the test for significance on OS for the second 
IA and FA will be determined using O’Brien-Fleming boundaries.(107)  If the alpha allocated 
to OS is 0.05, the trial will be stopped for overwhelming efficacy if the observed p value is 
less than 0.027 at the second IA assuming there are exactly 120 death events.  The FA will 
be tested at 2-sided alpha level of 0.0423 (corresponding to nominal alpha of 0.023). If the 
alpha allocated to OS is 0.01, OS will be tested using a similar approach as above.
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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 advise on the conduct of the study and development of 
publications and presentations (see also Section 12).
9.2   Independent Data Monitoring Committee
An IDMC will monitor safety and efficacy and perform the  interim analyses.  As part of the 
IDMC safety monitoring, this committee will receive reports of all cases of new primary 
malignancies occurring during the trial.
As of Amendment 6, the primary efficacy and safety analyses have been completed for this 
study, and no further independent data monitoring committee reviews of safety and efficacy 
data will take place for patients still receiving study therapy. The sponsor will continue to 
monitor all cases of new primary malignancies occurring during the trial. 
9.3   Adjudication Committee
Response to therapy will be assessed by an AC. Assessment of hematologic response and 
organ response will be based central laboratory results and will follow the criteria outlined 
in the Revised Consensus Response Criteria of the International Society of Amyloidosis 
(ISA).(20, 34, 36)  Vital organ deterioration will be evaluated in a blinded manner by the AC to 
provide a determination of the events of this composite endpoint. The AC will also review 
specific data elements and corresponding data documentation to support criteria of vital 
organ (that is heart or kidney) deterioration. Vital organ deterioration is characterized as 
cardiac deterioration, that is the need for hospitalization for heart failure, and kidney 
deterioration, that is progression to ESRD with the need for maintenance dialysis or renal 
transplantation). Such criteria will be applied consistently to both treatment arms.
Upon implementation of Amendment 6, AC review of response data will no longer be 
performed.
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10.    ADVERSE EVENTS
10.1   
Definitions
10.1.1   Pretreatment Event Definition
A pretreatment event is any untoward medical occurrence in a patient or subject who has 
signed informed consent to participate in a study but before administration of any study 
medication; it does not necessarily have to have a causal relationship with study 
participation.
10.1.2   Adverse Event Definition
Adverse event (AE) means any untoward medical occurrence in a patient or subject 
administered a pharmaceutical product; the untoward medical occurrence does not 
necessarily have a causal relationship with this treatment.  An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product whether 
or not it is related to the medicinal product.  This includes any newly occurring event, or a 
previous condition that has increased in severity or frequency since the administration of 
study drug.
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is 
considered by the investigator to be a clinically significant change from baseline.  
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.)
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
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.(104)  Clarification should be 
made between a serious AE (SAE) and an AE that is considered severe in intensity (Grade 3 
or 4), because the terms serious and severe are NOT synonymous.  The general term severe 
is often used to describe the intensity (severity) of a specific event; the event itself, however, 
may be of relatively minor medical significance (such as a Grade 3 headache).  This is NOT 
the same as serious, which is based on patient/event outcome or action criteria described 
above and is usually associated with events that pose a threat to a patient’s life or ability to 
function.  A severe AE (Grade 3 or 4) does not necessarily need to be considered serious.  
For example, a white blood cell count of 1000/mm3 to less than 2000 is considered Grade 3 
(severe) but may not be considered serious.  Seriousness (not intensity) serves as a guide for 
defining regulatory reporting obligations.
10.2   
Procedures for Recording and Reporting 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.
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Regardless of causality, SAEs and serious pretreatment events (as defined in Section 10.1) 
must be reported (see Section 10.3 for the period of observation) by the investigator to the 
Millennium Department of Pharmacovigilance or designee (contact information provided 
below).  This should be done by faxing the SAE Form within 24 hours after becoming aware 
of the event.  The SAE Form, created specifically by Millennium, will be provided to each 
clinical study site.  A sample of the SAE Form may be found in the Study Manual.  Follow-
up information on the SAE or serious pretreatment event may be requested by Millennium.  
SAE report information must be consistent with the data provided on the eCRF.
The paper SAE forms should be submitted via fax (see fax numbers below) within 24 hours 
of awareness. In case of fax, site personnel need to confirm successful transmission of all 
pages and include an e-mail address on the fax cover sheet so that an acknowledgment of 
receipt can be returned via e-mail within 1 business day. E-mail submission of paper SAE 
forms with a PDF attachment should only be used in the case where fax is not possible 
within 24 hours of receiving the event.  In case of e-mail, site personnel need to confirm 
successful transmission by awaiting an acknowledgment of the receipt via e-mail within 1 
business day. If SAEs are reported via fax or by e-mail, EDC/RAVE must be updated as 
soon as possible with the appropriate information
SAE Reporting Contact Information*
Cognizant
US and Canada
Toll-Free Fax #:  1-800-963-6290
E-mail:  takedaoncocases@cognizant.com
All other countries (Rest of World)
Fax #:  1 202 315-3560
E-mail:  takedaoncocases@cognizant.com
Planned hospital admissions or surgical procedures for an illness or disease that existed 
before the patient was enrolled in the 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 
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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.(104) 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?
Upon implementation of this amendment, data collection requirements will be limited to the 
following safety assessments: all SAEs (regardless of causality, including all deaths), any 
AE resulting in dose modification or discontinuation of any study drug, Grade ≥3 AEs, AEs 
of new primary malignancy, all reports of drug exposure during pregnancy and pregnancy 
outcomes, product complaints, and medication errors (including overdose).  
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 or the start of subsequent anticancer 
therapy, whichever occurs first, and recorded in the eCRFs.  That is, if a patient 
begins a new anticancer therapy, the AE reporting period for nonserious AEs ends at 
the time the new treatment is started. Upon implementation of Amendment 6, only 
AEs resulting in dose modification or discontinuation of any study drug, Grade ≥3 
AEs, AEs of new primary malignancy, all reports of drug exposure during pregnancy 
and pregnancy outcomes, product complaints, and medication errors (including 
overdose) are to be reported.

Serious pretreatment events will be reported to Millennium Department of 
Pharmacovigilance or designee from the time of the signing of the informed consent 
form (ICF) up to first dose of study drug, but will not be recorded in the eCRF.

Related and unrelated SAEs will be reported to Millennium Pharmacovigilance or 
designee from the first dose of study drug through 30 days after administration of the 
last dose of study drug and recorded in the eCRF.  All SAEs should be monitored 
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until they are resolved or are clearly determined to be due to a patient’s stable or 
chronic condition or intercurrent illness(es).  In addition, all new primary 
malignancies that occur during the follow-up periods must be reported, irrespective 
of causality to study regimen, starting from the first dose of study drug.  All cases of 
new primary malignancy will be immediately reported to the appropriate regional 
pharmacovigilance system according to the governing regulations.  The IDMC will 
also receive reports of all cases of new primary malignancies occurring during the 
trial. (Upon implementation of Amendment 6, the IDMC will no longer review 
safety data from the study; the sponsor will review all cases of new primary 
malignancy.)
10.4   
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events
If a woman becomes pregnant or suspects that she is pregnant while participating in this 
study, she must inform the investigator immediately and permanently discontinue study 
drug.  The sponsor must also be contacted immediately by faxing a completed Pregnancy 
Form to the Millennium Department of Pharmacovigilance (see Section 10.2).  The 
pregnancy must be followed for the final pregnancy outcome.
If a female partner of a male patient becomes pregnant during the male patient’s 
participation in this study, the sponsor must also be contacted immediately by faxing a 
completed Pregnancy Form to the Millennium Department of Pharmacovigilance (see 
Section 10.2).  Every effort should be made to follow the pregnancy for the final pregnancy 
outcome.
11.   
ADMINISTRATIVE REQUIREMENTS
11.1   
Good Clinical Practice
The study will be conducted in accordance with the ICH-GCP and the appropriate regulatory 
requirement(s).  The investigator will be thoroughly familiar with the appropriate use of the 
study drug as described in the protocol and the MLN9708 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, 
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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.
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 study, the study monitor will make study site visits to 
review protocol compliance, verify eCRFs against source documentation, assess drug 
accountability, and ensure that the study is being conducted according to pertinent 
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regulatory requirements.  The review of medical records will be performed in a manner that 
ensures that patient confidentiality is maintained.  
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, ICF, 
advertisements (if applicable), written information given to the patients (including diary 
cards), safety updates, annual progress reports, and any revisions to these documents will be 
provided to the IRB/IEC by the investigator or the sponsor, as allowed by local regulations.
11.6   
Patient Information and Informed Consent
After the study has been fully explained, written informed consent will be obtained from 
either the patient or his/her guardian or legal representative before study participation.  The 
method of obtaining and documenting the informed consent and the contents of the consent 
must comply with the ICH-GCP and all applicable regulatory requirements.
11.7   
Patient Confidentiality
To maintain patient privacy, all eCRFs, study drug accountability records, study reports, and 
communications will identify the patient by initials where permitted and/or by the assigned 
patient number.  The patient’s confidentiality will be maintained and will not be made 
publicly available to the extent permitted by the applicable laws and regulations.
11.8   
Investigator Compliance
The investigator will conduct the study 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 
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circumstances permit, to discuss the planned course of action.  Any departures from the 
protocol must be documented.
11.9   
On-site Audits
Regulatory authorities, the IEC/IRB, and/or Millennium may request access to all source 
documents, eCRFs, and other study documentation for on-site audit or inspection.  Direct 
access to these documents must be guaranteed by the investigator, who must provide support 
at all times for these activities.
11.10   Investigator and Site Responsibility for Drug Accountability
Accountability for the study drug at the study site is the responsibility of the investigator.  
Drug accountability records indicating the drug’s delivery date to the site, inventory at the 
site, use by each patient, and amount returned to Millennium, or a designee (or disposal of 
the drug, if approved by Millennium) will be maintained by the clinical site.  Millennium or 
its designee will review drug accountability at the site on an ongoing basis.
All material containing study drug will be treated and disposed of in accordance with 
governing regulations.
11.11   Product Complaints and Medication Errors (Including Overdose)
A product complaint is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product.  Individuals 
who identify a potential product complaint situation should immediately contact MedComm 
Solutions (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 Overdose for MLN9708), 
Call PPD at
Phone: 1-877-TAKEDA7 (1-877-825-3327)
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E-mail: medicalinformation@tpna.com
FAX: 1-800-247-8860
Hours: Mon-Fri, 8 a.m. to 6 p.m. ET 
(US and International)
Product complaints in and of themselves are not AEs.  If a product complaint is an SAE, an 
SAE form should be completed and sent to PPD (refer to section 10.2).
11.12   Closure of the Study
Within 90 days of the end of the study, the sponsor will notify the competent authorities and 
the IECs in all member states where the study is being carried out that the study has ended.
Within 1 year of the end of the study, a summary of the clinical 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.
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Within 15 days of premature closure, Millennium must notify the competent authorities and 
IECs of any member state where the study is being conducted, providing the reasons for 
study closure.
11.13   Record Retention
The investigator will maintain all study records according to the ICH-GCP and applicable 
regulatory requirement(s).  Records will be retained for at least 2 years after the last 
marketing application approval or 2 years after formal discontinuation of the clinical 
development of the investigational product or according to applicable regulatory 
requirement(s).  If the investigator withdraws from the responsibility of keeping the study 
records, custody must be transferred to a person willing to accept the responsibility and 
Millennium notified.
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 C16011, Amendment 6:  A Phase 3, Randomized, Controlled, Open-
Label, Multicenter, Safety and Efficacy Study of Dexamethasone Plus MLN9708 or 
Physician’s Choice of Treatment Administered to Patients With Relapsed or Refractory 
Systemic Light Chain (AL) Amyloidosis
I agree to conduct the study as detailed herein and in compliance with International 
Conference on Harmonisation Guidelines for Good Clinical Practice and applicable 
regulatory requirements and to inform all who assist me in the conduct of this study of their 
responsibilities and obligations.
Principal investigator printed name
Principal investigator signature
Date
Investigational site or name of institution and 
location (printed)
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14.   
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bortezomib in systemic AL amyloidosis with relapsed/refractory clonal disease. 
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Efficacy and safety of once-weekly and twice-weekly bortezomib in patients with 
relapsed systemic AL amyloidosis: results of a phase 1/2 study. Blood 
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Wechalekar A, Kastritis E, Merlini G, Hawkins P, Dimopoulos M, Gillmore J, et al. 
A European Collaborative Study of Treatment Outcomes In 428 Patients with 
Systemic AL Amyloidosis. American Society of Hematology Annual Meeting
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Patients with Relapsed and/or Refractory Multiple Myeloma: Results From a Phase 1 
Dose-Escalation Study [package insert]. San Diego, CA: 2011.
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Kumar S, Bensinger W, Reeder C, Zimmerman T, Berenson J, Liu G, et al. Weekly 
dosing of the investigational oral proteasome inhibitor MLN9708 in patients (pts) 
with relapsed/refractory multiple myeloma (MM): A phase I study. Journal of 
Clinical Oncology 2012 ASCO Annual Meeting Proceedings 2012:Abstract 8034.
84.
Sanchorawala V, Zonder J, Comenzo R, Schönland S, Dispenzieri A, Berg D, et al. 
Poster Presentation: Phase 1 study of MLN9708, a novel, investigational oral 
proteasome inhibitor, in patients with relapsed or refractory light-chain amyloidosis. 
XIII International Symposium on Amyloidosis, Groningen, The Netherlands 2012.
85.
Gupta N, Liu G, Berg D, Kalebic T, Gomez-Navarro J. Clinical Pharmacokinetics of 
Intravenous and Oral MLN9708, An Investigational Proteasome Inhibitor: An 
Analysis of Data From Four Phase 1 Monotherapy Studies. Blood 
2010;116(21):abstr 1813.
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Gupta N, Saleh M, Venkatakrishnan K. Flat-Dosing Versus BSA-Based Dosing for 
MLN9708, An Investigational Proteasome Inhibitor: Population Pharmacokinetic 
(PK) Analysis of Pooled Data From 4 Phase-1 Studies Blood 2011;118(21):abstr 
1433.
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Reece DE, Sullivan D, Lonial S, Mohrbacher AF, Chatta G, Shustik C, et al. 
Pharmacokinetic and pharmacodynamic study of two doses of bortezomib in patients 
with relapsed multiple myeloma. Cancer Chemotherapy & Pharmacology 
2011;67(1):57-67.
88.
Saltarelli F, Bianchi M, Moscetti A, Ferranti G, Capogreco F, Corsetti M, et al. 
Correlation between serum levels of free light chain and circulating cytokines in a 
patient with AL cardiac amyloidosis. Amyloid 2010;17(suppl 1):abstr P-196; 193-4.
89.
Kristen AV, Giannitsis E, Lehrke S, Hegenbart U, Konstandin M, Lindenmaier D, et 
al. Assessment of disease severity and outcome in patients with systemic light-chain 
amyloidosis by the high-sensitivity troponin T assay. Blood 2010;116(14):2455-61.
90.
Witteles W, Witteles R, Arai S, Lafayette R, Schrier S. AL Amyloidosis: Prognosis 
of Cardiac Involvement Reconsidered. Blood (ASH Annual Meeting Abstracts) 
2009;114(22):abstr 4872.
91.
Wechalekar AD, Gillmore JD, Wassef N, Lachmann HJ, Whelan C, Hawkins PN. 
Abnormal N-terminal fragment of brain natriuretic peptide in patients with light 
chain amyloidosis without cardiac involvement at presentation is a risk factor for 
development of cardiac amyloidosis. Haematologica 2011;96(7):1079-80.
92.
Gertz MA, Lacy MQ, Dispenzieri A, Hayman SR, Kumar SK, Leung N, et al. Effect 
of hematologic response on outcome of patients undergoing transplantation for 
primary amyloidosis: importance of achieving a complete response. Haematologica 
2007;92(10):1415-8.
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93.
Merlini G, Palladini G, Bosoni T. Circulating free light chain concentration 
correlates with degree of cardiac dysfunction in AL amyloidosis [abstract]. Clinical 
Chemistry 2004;50(A69).
94.
Wechalekar A, Merlini G, Gillmore J, Russo P, Lachmann H, Obici L, et al. Role of 
NT-ProBNP to Assess the Adequacy of Treatment Response in AL Amyloidosis. 
Blood (ASH Annual Meeting Abstracts) 2008;112:abstr 1689.
95.
Gibbs S, Gillmore J, Sattianayagam P, Offer M, Lachmann H, Hawkins P, et al. In 
AL amyloidosis, both oral melphalan and dexamethasone (Mel-Dex) and risk-
adapted cyclophosphamide, thalidomide and dexamethasone (CTD) have similar 
efficacy as upfront treatment. Blood (ASH Annual Meeting Abstracts) 
2009;114:abstr 745.
96.
Madan S, Dispenzieri A, Lacy M, Buadi F, Hayman S, Detweiler K, et al. Clinical 
Features and Treatment Response of Light Chain (AL) Amyloidosis Diagnosed in 
Patients with Previous Diagnosis of Multiple Myeloma (MM). Blood (ASH Annual
Meeting Abstracts) 2009;114:Abstract 4867.
97.
Dispenzieri A, Gertz MA, Kyle RA, Lacy MQ, Burritt MF, Therneau TM, et al. 
Serum cardiac troponins and N-terminal pro-brain natriuretic peptide: a staging 
system for primary systemic amyloidosis. Journal of Clinical Oncology 
2004;22(18):3751-7.
98.
Kumar SK, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK, Zeldenrust SR, et al. 
Changes in serum-free light chain rather than intact monoclonal immunoglobulin 
levels predicts outcome following therapy in primary amyloidosis. American Journal 
of Hematology 2011;86(3):251-5.
99.
Gertz MA. The classification and typing of amyloid deposits. American Journal of 
Clinical Pathology 2004;121(6):787-9.
100.
Chee CE, Lacy MQ, Dogan A, Zeldenrust SR, Gertz MA. Pitfalls in the diagnosis of 
primary amyloidosis. Clinical lymphoma, myeloma & leukemia 2010;10(3):177-80.
101.
Palladini G, Barassi A, Sarais G, Capra R, Milani P, Albertini R, et al. High-
sensitivity cardiac troponin is the most powerful prognostic determinant and predicts 
progression of cardiac dysfunction in AL amyloidosis. Amyloid 2010;17(suppl 
1):160; abstr P-137.
102.
Reece DE, Trieu Y, Chen C, Kukreti V, Xu W, Anglin P, et al. Sequencing novel 
agents in relapsed/refractory multiple myeloma:  Use of bortezomib-based therapy 
after lenalidomide + dexamethasone. Blood 2009;114(51st ASH Annual Meeting 
(Dec 5 - 8)):abstract 1853.
103.
Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and 
response assessment of multiple myeloma. Leukemia 2009;23(1):3-9.
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104.
Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03. 2010 14 
June 2010.
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DEXAMETHASONE Tablets USP, DEXAMETHASONE Oral Solution [package 
insert]. Columbus (OH): Roxane Laboratories, Inc, a division of Boehringer 
Ingelheim; 2007.
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Wiens BL. A fixed sequence Bonferroni procedure for testing multiple endpoints. 
Pharmaceutical Statistics 2003;2:211-215.
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O'Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics 
1979;35(3):549-56.
108.
Lachmann HJ, Booth DR, Booth SE, Bybee A, Gilbertson JA, Gillmore JD, et al. 
Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis. New England 
Journal of Medicine 2002;346(23):1786-91.
109.
Comenzo RL, Zhou P, Fleisher M, Clark B, Teruya-Feldstein J. Seeking confidence 
in the diagnosis of systemic AL (Ig light-chain) amyloidosis: patients can have both 
monoclonal gammopathies and hereditary amyloid proteins. Blood 
2006;107(9):3489-91.
110.
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, 3rd, Feldman HI, et al. 
A new equation to estimate glomerular filtration rate. Annals of Internal Medicine 
2009;150(9):604-12.
111.
Knoben J, Anderson P. Handbook of Clinical Drug Data, 6th ed.: Drug Intelligence 
Pub, Inc.; 1988.
112.
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. 
Toxicity and response criteria of the Eastern Cooperative Oncology Group. 
American Journal of Clinical Oncology 1982;5(6):649-55.
113.
Common Terminology Criteria for Adverse Events (CTCAE) version 4.02. 2009 28 
May 2009.
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15.   
APPENDICES
15.1   
Amyloid Typing
Because clinical presentations are similar for the common types of systemic amyloidosis, the 
stigmata of organ involvement do not enable one to deduce the type of amyloid in a given 
patient.(108)
Two potential precursor proteins can coexist in a patient, making it perplexing as to which 
type the patient has, a happenstance particularly relevant to 3 situations: 
1. African-Americans who have higher rates of monoclonal gammopathies and a 4% 
incidence of an hereditary ATTR variant (Val122Ile);(108, 109)
2. Patients presenting with peripheral neuropathy as the only clinical feature of organ 
involvement and a monoclonal gammopathy; peripheral nervous system involvement 
is a common presentation of hereditary disease;(109)
3. Elderly men who also have higher rates of both monoclonal gammopathies and 
wild-type ATTR.(109)
For diagnosis, tissue biopsy, either of an involved organ or a surrogate site (eg, abdominal 
fat), must demonstrate amyloid deposition by classic Congo red staining or electron 
microscopy. 
For typing, immunohistochemical staining is frequently unreliable and inaccurate, and 
immunogold electron microscopy (IEM) reliable but limited by serologic dependence.(109)  
DNA sequencing of genes related to hereditary variants is useful for typing, particularly in 
African-Americans and patients with peripheral neuropathy as above (situations 1 and 2 
where sequencing the transthyretin gene is indicated), or if adequate biopsy material for 
proteomic studies cannot be obtained.  DNA sequencing is also useful for confirming 
proteomic findings and for subsequent screening of kin.(109)
Proteomics employing mass spectrometry with customized bioinformatic assessment of the 
constituents of the Congophilic deposits is now the gold standard for typing amyloid, 
enabling precise identification of type.  It is specifically indicated for typing in cases where 
2 potential amyloid precursor proteins may be present in a patient as in situation 3 above.  
Given the population in this study has relapsed or refractory AL amyloidosis, the sponsor 
believes that if needed amyloid typing would have been done at initial diagnosis and thus is 
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not required for entry to this study. However, amyloid typing may be repeated at the 
investigators discretion if there is a question.
15.2   
Equation to Estimate Glomerular Filtration Rate (eGFR)
Race and Sex
Serum Creatinine Level
mol/L (mg/dL)
Equation
Black
Female
62 (0.7)
GFR = 166 (SCR/0.7) - 0.329 (0.993)age
> 62 (> 0.7)
GFR = 166 (SCR/0.7) - 1.209 (0.993)age
Male
80 (0.9)
GFR = 163 (SCR/0.9) - 0.411 (0.993)age
> 80 (> 0.9)
GFR = 163 (SCR/0.9) - 1.209 (0.993)age
White or Other
Female
62 (0.7)
GFR = 144 (Scr/0.7) - 0.329 (0.993)age
> 62 (> 0.7)
GFR = 144 (Scr/0.7) - 1.209 (0.993)age
Male
80 (0.9)
GFR = 141 (Scr/0.9) - 0.411 (0.993)age
> 80 (> 0.9)
GFR = 141 (Scr/0.9) - 1.209 (0.993)age
Source:  Levey et al, 2009.(110)
Abbreviations:  CKD-EPI = Chronic Kidney Disease Epidemiology Collaboration; GFR – glomerular filtration 
rate.
Expressed for specified race, sex, and serum creatinine level.  To convert GFR from mL/min/1.73 m2 to 
mL/sec/1.73 m2, multiply by 0.0167.  The equation coefficients were derived from pooled development and 
internal validation sets.  The CKD-EPI equation, expressed as a single equation, is GFR = 141 
min(Scr/,1)max(Scr/,1)-1.209 0.993age 1.018 (if female) 1.159 (if black), where Scr is serum 
creatinine, is 0.7 for females and 0.9 for males, is -0.329 for females and -0.411 for males, and min 
indicates the minimum of Scr/or 1, and max indicates the maximum of Scr/or 1.  In this table, the 
multiplication factors for race and sex are incorporated into the intercept, which results in different 
intercepts for age and sex combinations.
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15.3   
Short Form General Health Survey (SF-36 v2™)
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15.4   
FACT/GOG-Ntx
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15.5   
Amyloidosis Symptom Scale
Amyloidosis Symptom Scale
For each symptom below, please circle the one number that best describes how severe that symptom was for 
you AT ITS WORST IN THE LAST 24 HOURS.

How severe was the swellingin your lower body (feet, ankles, or legs)at its worst in the last 24
hours?
No swelling
Very severe
swelling
0
1
2
3
4
5
6
7
8
9
10

How severe was your   shortness of breathat its worst in the last 24 hours ? 
No
shortness of 
breath
Very severe
shortness of 
breath
0
1
2
3
4
5
6
7
8
9
10
3. How severe was your dizziness or lightheadednessat its worst in the last 24 hours?
No
dizziness or 
lightheadedness
Very severe
dizziness or 
lightheadedness
0
1
2
3
4
5
6
7
8
9
10
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15.6   
New York Heart Association Classification of Cardiac Disease
The following table presents the New York Heart Association classification of cardiac 
diseases.
Class
Functional Capacity
Objective Assessment
I
Patients with cardiac disease but without resulting limitations of 
physical activity.  Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea, or anginal pain.
No objective evidence of 
cardiovascular disease.
II
Patients with cardiac disease resulting in slight limitation of physical 
activity.  They are comfortable at rest.  Ordinary physical activity 
results in fatigue, palpitation, dyspnea, or anginal pain.
Objective evidence of 
minimal cardiovascular 
disease.
III
Patients with cardiac disease resulting in marked limitation of 
physical activity.  They are comfortable at rest.  Less than ordinary 
activity causes fatigue, palpitation, dyspnea, or anginal pain.
Objective evidence of 
moderately severe 
cardiovascular disease.
IV
Patients with cardiac disease resulting in inability to carry on any 
physical activity without discomfort.  Symptoms of heart failure or 
the anginal syndrome may be present even at rest.  If any physical 
activity is undertaken, discomfort is increased.
Objective evidence of 
severe cardiovascular 
disease.
Note:  A classification of 0 will be assigned to patients without cardiac disease or no evidence thereof.
15.7   
Steroid Equivalent Doses
Approximately equivalent doses:
Steroid
Glucocorticoid
Anti-inflammatory
(mg)
Mineralocorticoid
(mg)
Half-life
(hours)
Cortisone
100
100
812
Hydrocortisone
80
80
812
Prednisone
20
100
1236
Prednisolone
20
100
1236
Methylprednisolone
16
no effect
1236
Dexamethasone
2
no effect
3672
Source:  Knoben JE, Anderson PO.  Handbook of Clinical Drug Data, 6th ed.  Drug Intelligence Pub, Inc.  
1988.(111)
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15.8   
Eastern Cooperative Oncology Group Scale for Performance Status
Grade
Description
0
Normal activity.  Fully active, able to carry on all predisease performance without 
restriction
1
Symptoms but ambulatory.  Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (eg, light 
housework, office work)
2
In bed < 50% of the time.  Ambulatory and capable of all self-care, but unable to 
carry out any work activities.  Up and about more than 50% of waking hours.
3
In bed > 50% of the time.  Capable of only limited self-care, confined to bed or 
chair more than 50% of waking hours.
4
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  Totally 
confined to bed or chair
5
Dead
Source:  Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET et al. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5 (6):649-
55.(112)
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15.9   
EuroQol 5-Dimensional (EQ-5D)
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15.10   Amyloid-Related Hematologic and Organ Criteria for Involvement, 
Stabilization, Response, and Progression
Organ 
System
Involvement
Stablea
Response
Progression
Hematologic
Measurable disease 
defined as serum 
differential free light chain 
concentration (dFLC) 
50mg/L
dFLC is the difference 
between the amyloid 
forming (involved) and 
nonamyloid forming 
(uninvolved) free light 
chain.
A nephelometric assay 
measures both kappa and 
lambda light chains and  
identifies an excess 
production of  FLC isotype 
produced from the clonal 
plasma cell.  This FLC 
isotype is involved in the 
pathogenic process of 
misfolding into the 
amyloid fibrils. 
No CR, VGPR, PR, no 
progression
Complete Response 
(CR):
Negative serum & urine 
immunofixation, normal 
kappa:lambda FLC ratio 
Very Good Partial 
Response (VGPR):
dFLC <40 mg/L
Partial Response (PR):
dFLC decrease > 50%
Progression from CR: 
any detectable 
monoclonal protein or 
abnormal FLC ratio; 
involved free light chain 
must double.
Progression from VGPR, 
PR or stable disease: 
Involved free light chain 
increase of 50% to > 10 
mg/dL (100 mg/L) from 
its lowest measured level 
50% increase in serum 
M-protein to > 0.5 g/dL 
from nadir/baseline, or 
50% increase in urine M-
protein to > 200 mg/24 
hours with a visible peak 
present; 
Involvement of Heart or Kidney (at least one) required for study entry
Cardiac
Echo: mean 
interventricular septal wall 
thickness >12mm, no other 
cardiac cause with a non-
cardiac biopsy showing 
amyloid, or positive 
cardiac biopsy in the 
presence of clinical or 
laboratory evidence of 
involvment, e.g.
NT-proBNP > 332 
pg/mL in the absence of 
renal failure.
Note: a baseline NT-
proBNP 650 pg/mL
was required for NT-
proBNP response to be 
evaluable
Stable disease is defined 
when none of the criteria 
for response or for 
worsening disease are met.
NT-proBNP >30% and 
>300 pg/mL decrease if 
baseline NT-proBNP 
≥650 pg/mL)
Echo: mean 
interventricular septal 
wall thickness decrease 
by 2mm, or
20% improvement in 
LVEF, or
Improvement by > 2 
NYHA classes without 
an increase in diuretic 
use and no increase wall 
thickness
Increase in NT-proBNP 
that is both >30% and 
>300 pg/mL, or
Echo: interventricular 
septal thickness increased 
by 2mm over baseline, or
An increase in NYHA 
class by 1 grade with 
decreasing LVEF of 
>10%, 
Renal
24- hour protein > 0.5 
g/day, predominantly 
albumin
Stable disease is defined 
when none of the criteria 
for response or for 
worsening disease are met.
At least a 50% reduction 
in 24-hour urine protein 
(must be at least 0.5 
g/day) without worsening 
of creatinine or creatinine 
clearance by 25% 
compared to baseline
50% increase in urinary 
protein loss (at least 1 
g/24 hours) or 25% 
worsening of creatinine 
or creatinine clearance
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Organ 
System
Involvement
Stablea
Response
Progression
Involvement of any of the below allowed in addition to the requirement for involvement of one or more of the above organs
Liver 
Alkaline phosphatase 
value > 1.5 ULN, or 
liver span > 15 cm 
radiographically in the 
absence of heart failure,.  
Stable disease is defined 
when none of the criteria 
for response or for 
worsening disease are met.
>50% decrease in 
alkaline phosphatase 
from baseline
Decrease in liver size by 
at least 2 cm 
(radiographic 
determination
>50% increase of 
alkaline phosphatase 
above lowest level.
Gastro-
intestinal
Direct biopsy verification 
with symptoms such as 
diarrhea, frank bleeding, 
early satiety, 
malabsorption, GI motility 
disturbances, and weight 
loss (BJH 2004)
Stable disease is defined 
when none of the criteria 
for response or for 
worsening disease are met. 
Clinical changes based on 
NCI CTC Version 4.02 
criteria may be useful
Reliable, quantitative 
methods for defining 
response do not to 
exist.
Improvement in clinical 
findings such as 
diarrhea, motility 
disturbances and 
weight loss may be 
usefulb
Progression of signs and 
symptoms not 
attributable to therapy 
under study
Nerve, 
Peripheral 
Evidence of amyloid 
involvement alternative 
site plus clinical symptoms 
such as symmetric lower 
extremity sensory 
peripheral neuropathy 
(often with pain) on 
neurologic examination, 
parasthesiae, numbness or 
muscle weakness. Motor 
neuropathy is rare. (BJH 
2004)
Note: EMG and nerve 
conduction velocity are 
relatively insensitive in 
detecting involvement.
Stable disease is defined 
when none of the criteria 
for response or for 
worsening disease are met. 
Clinical changes based on 
NCI CTC Version 4.02 
criteria may be useful.
Reliable, quantitative 
methods for defining 
response do not to 
exist..
Improvement in clinical 
findings with decrease 
in the Ntx score, signs 
and/or symptoms of 
peripheral neuropathy, 
and decrease in 
neuropathic pain may 
be usefulb
Progressive neuropathy 
not attributable to 
therapy under study.
Progressive neuropathy 
by EMG or nerve 
conduction velocity may 
show progression.
Nerve, 
Autonomic 
Based on clinical history 
of autonomic dysfunction 
and symptoms such 
orthostasis, gastric 
emptying disorder, early 
satiety, impotence/ erectile 
dysfunction, bowel or 
bladder dysfunction not 
related to direct organ 
infiltrate, anhidrosis or 
gustatory sweating (BJH 
2004) 
Stable disease is defined 
when none of the criteria 
for response or for 
worsening disease are met. 
Clinical changes based on 
NCI CTC Version 4.02 
criteria may be useful
Reliable, quantitative 
methods for defining 
response do not to 
exist.
Improvement in clinical 
examination findings 
including such 
symptoms as 
improvement in 
orthostasis and other 
signs and/or symptoms 
related to autonomic 
dysfunctionb
Progression neuropathy 
not attributable to 
therapy under study
Soft tissue 
and 
lymphatic
Based on classic physical 
findings such as:

Macroglossia 
(enlarged tongue),

Arthropathy,

Claudication, 
presumed vascular 
amyloid

Shoulder pad sign, 

Periorbital purpura 
(Raccoon eyes), 

Carpal tunnel 
Stable disease is defined 
when none of the criteria 
for response or for 
worsening disease are met. 
Clinical changes based on 
NCI CTC Version 4.02 
criteria may be useful
Reliable, quantitative 
methods for defining 
response do not to 
exist.
Clinical changes based 
on NCI CTC Version 
4.02 criteria may be 
useful
Progression of signs and 
symptoms not 
attributable to therapy 
under study
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Organ 
System
Involvement
Stablea
Response
Progression
syndrome, 

Synovial 
enlargement, 

Lymphadenopathy, 
biopsy verification.

Skin thickening

Myopathy by biopsy 
or 
pseudohypertrophy
Lung
Direct biopsy verification 
with symptoms. Diffuse 
interstitial radiographic 
pattern usually by CT scan
Stable disease is defined 
when none of the criteria 
for response or for 
worsening disease are met. 
Clinical changes based on 
NCI CTC Version 4.02 
criteria may be useful
Reliable, quantitative 
methods for defining 
response do not to 
exist.
Radiographic 
improvement
Progression of 
radiographic findings not 
attributable to therapy 
under study
Sources:  (4, 19, 20, 34, 36, 38)
a
Unless clinically indicated to check sooner, stabilization of organ function must be confirmed visit in the absence of worsening of 
any other organs unless worsening is considered a treatment-emergent adverse event.
b
Based on NCI CTC Version 4.02 criteria.(113)
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15.11   Full Schedule of Events (Prior to Amendment 6)
This full Schedule of Events is no longer in effect, as of Amendment 6, because the first IA has been conducted and the primary 
endpoint of overall hematologic response rate (CR + VGPR + PR) did not reach statistical significance. As such, the sponsor has 
decided to discontinue the majority of study assessments for protocol purposes; study drug will continue to be provided
Study Procedures
Screening
Treatment Period
28-Day Cycles
End of Treatmentn
Follow-up
PFS
PFS Organ 
Assessment
OS
Cycle
C1
C1
C2
C2
C3
C3
After 
C3 until 
PD
Every 
6 weeks
Every 
12 weeks
Every 
12 weeks
Days
-28 
to -1
1
14
1
14
1
14
1
Window
± 3 days
+ 10 
days
± 1 wk
Informed Consenta
X
Inclusion/Exclusion Criteria
X
Demographics
X
Complete Medical History, including 
AL amyloidosis treatment history, 
neurologic history and cardiac medical 
history
X
12-lead ECG
X
X
X
Complete Physical Examination
X
X
Q3C
X
X
Symptom-Directed Physical Exam
X
X
X
Assessment of AL Amyloidosis 
Symptomsb
X
X
X
X
X
X
X
ECOG Performance Status
X
X
X
X
X
X
X
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Study Procedures
Screening
Treatment Period
28-Day Cycles
End of Treatmentn
Follow-up
PFS
PFS Organ 
Assessment
OS
Cycle
C1
C1
C2
C2
C3
C3
After 
C3 until 
PD
Every 
6 weeks
Every 
12 weeks
Every 
12 weeks
Days
-28 
to -1
1
14
1
14
1
14
1
Window
± 3 days
+ 10 
days
± 1 wk
Vital Signs
X
X
X
X
X
X
Height (cm)  
X
Weight (kg)
X
X
X
X
X
X
X
Pregnancy Testc
X
X
X
Hematologyd
X
X
X
X
X
X
X
X
X
Prothrombin Time
X
X
X
X
Clinical Chemistryd
X
X
X
X
X
X
Urinalysise
X
X
24-hour Urine Collection for 
Creatininef
X
Xf
X
Select Physician’s Choice Treatment 
X
SF-36 v2g
X
X
X
Q3C
X
X
Symptom Scale Questionnaireg
X
X
X
X
X
X
X
EQ-5Dg
X
X
X
X
X
X
X
X
HU  Assessmentg
X
X
X
X
X
X
FACT/GOG-Ntxg
X
X
X
X
X
X
X
Bone marrow core biopsy and/or 
aspirateh
X
Hematologic Disease Response
2-microglobulin
X
M-protein measurements (SPEP)
X
X
X
X
X
X
X
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Study Procedures
Screening
Treatment Period
28-Day Cycles
End of Treatmentn
Follow-up
PFS
PFS Organ 
Assessment
OS
Cycle
C1
C1
C2
C2
C3
C3
After 
C3 until 
PD
Every 
6 weeks
Every 
12 weeks
Every 
12 weeks
Days
-28 
to -1
1
14
1
14
1
14
1
Window
± 3 days
+ 10 
days
± 1 wk
M-protein Measurements (UPEP [24-
hour urine collection]i,j
X
Xe
X
Xe
Serum Free Light Chain Assayi
X
X
X
X
X
X
Immunofixation - Serum and Urine e,i,j
X
X 
Quantification of Igi,j
X
X
Skeletal Surveye,k
X
Amyloid-related Organ Assessment
24-hour Urine Collection for Total 
Protein
X
X
Q3C
X
X
Serum Albumin, calculated creatinine 
clearance, and eGFR
X
X
Q3C
X
X
CT or MRI Scans, alkaline 
phosphatase, and ALT as indicated to 
assess organ involvement (eg, liver)l
X
X
Q3C
X
X
Echocardiogram
X
X
Q3C
X
X
Serum Cardiac Markers (NT-proBNP, 
BNP, troponin T)
X
X
X
X
X
X
NYHA Classification
X
X
X
X
X
X
Concomitant Medications/Procedures
Recorded from the first dose of study drug through 30 
days after last dose of  any study drug 
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Study Procedures
Screening
Treatment Period
28-Day Cycles
End of Treatmentn
Follow-up
PFS
PFS Organ 
Assessment
OS
Cycle
C1
C1
C2
C2
C3
C3
After 
C3 until 
PD
Every 
6 weeks
Every 
12 weeks
Every 
12 weeks
Days
-28 
to -1
1
14
1
14
1
14
1
Window
± 3 days
+ 10 
days
± 1 wk
Adverse Event Reporting
Recorded from the first dose of study drug through 
30 days after last dose of study drug
Serious adverse eventsm will be reported from signing of 
the informed consent form through 30 days after the last 
dose of study drug.
Survival
X
Drug Administration
MLN9708
MLN9708 on Days 1, 8, and 15
Dexamethasone
Dexamethasone on Days 1, 8, 15, and 22
Comparator Administration:
Dexamethasone Alone
Daily on Days 1-4, 9-12, & 17-20
Dexamethasone and Melphalan 
Days 1-4
Dexamethasone and 
Cyclophosphamide
Cyclophosphamide Days 1, 8, and 15 and 
dexamethasone Day 1, 8, 15, and 22
Dexamethasone and Thalidomide
Thalidomide daily and dexamethasone Days 1, 
8, 15, and 22
Dexamethasone and Lenalidomide
Lenalidomide Days 1-21 and dexamethasone 
Day 1, 8, 15, and 22
Abbreviations:  ALT = alanine aminotransferase; β = Beta; BNP = B-type natriuretic peptide; C = Cycle; CT = computed tomography; ECG = 
electrocardiogram; ECOG = Eastern Cooperative Oncology Group; eGRR = estimated glomerular filtration rate; Ig = immunoglobulin; MRI = 
magnetic resonance imaging; NT-pro BNP = N-terminal pro-brain natriuretic peptide; NYHA = New York Heart Association; OS = overall 
survival; PD=progressive disease; PFS = progression-free survival; QOL = quality of life; Q3C = every 3 cycles; SPEP = serum protein 
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Study Procedures
Screening
Treatment Period
28-Day Cycles
End of Treatmentn
Follow-up
PFS
PFS Organ 
Assessment
OS
Cycle
C1
C1
C2
C2
C3
C3
After 
C3 until 
PD
Every 
6 weeks
Every 
12 weeks
Every 
12 weeks
Days
-28 
to -1
1
14
1
14
1
14
1
Window
± 3 days
+ 10 
days
± 1 wk
electrophoresis; UPEP = urine protein electrophoresis.
a Informed consent must be obtained before any study-specific procedures for research purposes are performed. Evaluations during the Screening 
period are to be conducted within 28 days prior to randomization, unless otherwise noted or with permission from the MPI clinician /designee in 
extenuating circumstances.  Bone marrow examinations may be performed within 42 days of randomization. One complete cycle is 28 days.  
Occasional changes are allowable for holidays, vacations, and other administrative reasons (see Sections 6 and 7.4).
b The Cardiac Assessment (CA) and Neurological Assessment (NA) forms can be used, or should serve as a guide for to the level of detail required 
for these assessments in the medical note. The CA and NA forms must be used if the medical notes do not document the level of detail specified in 
these forms.
c Treatment with IMiDs requires pregnancy testing in female patients of child-bearing age prior to each cycle.  A serum pregnancy test will be 
performed for all women of childbearing potential.  The Cycle 1, Day 1 pregnancy test may be collected up to 3 days before dosing and the results 
must be available and negative before the first dose.
d Hematology and chemistry panels may be collected up to 3 days before dosing on Day 1.  Day 14 hematology (Cycle 1-3) can be done locally to 
make a dosing decision, but a central hematology also needs to be drawn.  Criteria for retreatment are provided in Section 6.5.1.
e Repeat as clinically indicated. 
f
Repeat as clinically indicated by change in serum creatinine. 
g All questionnaires should be completed before any other study procedures are performed.  The SF-36 v2, FACT/GOG-Ntx and the symptom scale 
questionnaire must be completed at PD and PFS follow up.  The EQ-5D and HU questionnaires may be collected by phone during the OS follow-up 
period.
h Bone marrow biopsy and/or aspirate should be repeated at the discretion of the investigator as clinically indicated.  Immunohistochemistry of 
dominant clonal plasma cells is recommended.
i
Serum and urine immunofixation required in patients suspected of CR based on FLC criteria of complete response.  
j
Must be obtained at PD.  Serum and urine immunofixation to be obtained at the end-of-treatment visit.
k Skeletal surveys may be performed within 8 weeks of randomization.  To be performed at screening and at any time the physician believes there are 
symptoms or signs that suggest increased or new bone lesions.  If results are interpreted as abnormal, then repeat at the discretion of the investigator 
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Study Procedures
Screening
Treatment Period
28-Day Cycles
End of Treatmentn
Follow-up
PFS
PFS Organ 
Assessment
OS
Cycle
C1
C1
C2
C2
C3
C3
After 
C3 until 
PD
Every 
6 weeks
Every 
12 weeks
Every 
12 weeks
Days
-28 
to -1
1
14
1
14
1
14
1
Window
± 3 days
+ 10 
days
± 1 wk
as clinically indicated.  The same imaging modality used at screening should be used for all follow-up assessments.
l
If results are interpreted as abnormal, then repeat at the discretion of the investigator as clinically indicated.  The same imaging modality used at 
screening (CT/MRI) should be used for all follow-up assessments. 
m Including serious pretreatment events; see Section 11.2.
n Patients who do not continue treatment must complete the EOT assessments, which should occur at least 30 days after the last dose of study drug or 
prior to the initiation of subsequent antineoplastic therapy.
15.12   Pharmacokinetic Sampling Schedule (Prior to Amendment 6)
Cycle
1
2
3-10
Days
1
14
1
14
1
Window
1 hour postdose
(0.25)
4 hours postdose
(0.75)
At any time 
during clinic 
visit
Predose 
At any time 
during clinic 
visit
Predose
X
X
Xa
X
Xa
X
a PK samples will be collected from patients visiting the clinic for other study-related activities.  PK samples are optional for patients who do not 
have an onsite visit on Cycle 1 Day 14 or Cycle 2 Day 14.
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15.13   
Amendment 1 Rationale and Purposes
Rationale for Amendment 1
The primary purpose of this amendment is to revise the second primary endpoint, key 
secondary endpoints, and regular secondary endpoints. 
Consideration has been given to the fact that the current treatment paradigm of patients with 
systemic light chain (AL) amyloidosis is complex and presents unique challenges.  As such, 
while overall survival (OS) is a standard regulatory endpoint, it may be difficult to 
demonstrate in this patient population, particularly because physicians change treatment 
regimens in an effort to obtain more robust clinical benefits than those achieved with the 
previous treatment that the patient received.  This change in treatment makes it difficult to 
determine which therapy has the greatest impact on survival.  As is standard in nononcology 
settings when investigating agents for conditions such as congestive heart failure (CHF) or 
diabetic nephropathy, deterioration of vital organs (heart and kidney, respectively) and 
mortality is an acceptable regulatory endpoint to demonstrate clinical benefit.  The 2 organs 
most commonly involved in AL amyloidosis are heart and kidney; thus, congestive heart 
failure and renal nephropathy are conditions that frequently affect patients with light chain 
amyloid involvement of the heart and kidney, respectively. 
Originally, the second primary endpoint in this study was OS.  However, considering the 
methods by which patients are treated and the intention to demonstrate a meaningful 
measure of clinical benefit, this endpoint has been replaced by 2-year vital organ (that is, 
heart and kidney) deterioration and mortality rate.  The definitions of heart and kidney 
deterioration are in alignment with those used in nononcology settings (ie, cardiac 
deterioration is defined as hospitalization for CHF, and kidney deterioration is defined as 
progression to end-stage renal disease [ESRD] with the need for maintenance dialysis or 
renal transplantation).  In and of itself, OS remains an important endpoint and has therefore 
been included as a key secondary endpoint.  Also, the key secondary endpoint of organ 
response and stabilization rate is now revised to vital organ response and is included as a 
regular secondary endpoint.
Purposes for Amendment 1
The purposes of this amendment are to:

Change the second primary endpoint from overall survival (OS) to 2-year vital organ 
(that is, heart or kidney) deterioration and mortality rate

Include OS as a key secondary endpoint

Change the key secondary endpoint of organ response and stabilization rate to a regular 
secondary endpoint 

Remove liver from the list of vital organs with amyloid involvement required at study 
entry

Revise definitions of relapsed and refractory disease

Update the Study Schema to accurately reflect the study design

Update Schedule of Events to more accurately reflect conduct of study procedures
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
Replace reference to Medical Resource Utilization (MRU) with Health Utilization 
(HU) to reflect the Sponsor’s updated terminology

Replace reference to Independent Review Committee with Adjudication Committee to 
accurately reflect how hematologic and organ response and vital organ deterioration 
will be assessed 

Update Section 1.3, Clinical Experience to provide data as of 30 April 2012

Update Section 1.5, Rationale for MLN9708 Dose and Schedule Selection

Revise the duration of study from 7.6 years to 6.7 years

Update the Management of Clinical Events section to include Stevens-Johnson 
Syndrome and hypotension

Revise Table 6-2, MLN9708 Dose Adjustments for Hematologic Toxicities to reflect 
sponsor’s current dose adjustment recommendations 

Revise Table 6.3, MLN9708 Dose Adjustments for Nonhematologic Toxicities to 
reflect sponsor’s current dose adjustment recommendations

Revise Sections 6.12.3,  Dexamethasone, 6.12.3.2, Melphalan, and 6.12.3.3, 
Cyclophosphamide,  to clarify that these drugs may be supplied by the sponsor

Add note to Section 7.4.17, Adverse Events, to indicate that related SAEs must be 
reported to the Millennium Department of Pharmacovigilance or designee 

Update the description of the investigational agents

Add paragraph to Section 7.5, Compliance, to describe the methods of contact the 
sponsor or sponsor designee may utilize to obtain follow-up information on patients 

Revise Section 8, Statistical and Quantitative Analyses, to reflect changes to the 
statistical analysis plan

Revise the Amyloid Symptom Scale (Section 15.5) to replace diarrhea with 
dizziness/lightheadedness

Correct typographical errors, punctuation, grammar, and formatting
15.14   
Amendment 2 Rationale and Purposes
The primary reason for this protocol amendment is to address regulatory feedback received 
from several competent authorities and to clarify inconsistencies identified in the protocol.  
Additionally, the sponsor has decided not to collect or test any gene polymorphism samples.  
Of the numerous signaling pathways constitutively activated in primary multiple myeloma 
cells, the nuclear factor-κB (NF-κB) pathway has recently emerged as one of the most 
important drivers of the tumor-promoting machinery, ie, cell proliferation, metastasis, tumor 
promotion, inflammation, and suppression of apoptosis.  In multiple myeloma, many studies 
have suggested the link between activation of NF-kB and response to bortezomib.  This has 
not been tested in AL amyloidosis.  The original protocol was designed to evaluate this 
hypothesis in patients with AL amyloidosis given it is a similar plasma cell dyscrasia; 
however, given that the assessment was exploratory in addition to other business reasons, 
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references to collection and testing of this sample have been removed from the protocol.  
Protocol-specified samples given by the patients in this study will not be used for genetic 
testing.

Remove the screening blood sample for assessment of gene polymorphism

Add the definition of cardiac deterioration to the primary objective to be consistent 
with other sections of the protocol

Clarify the definition of abstinence “to be in line with the preferred and usual lifestyle 
of the patient” per country-specific regulations

Update the duration of contraception to 90 days following last dose of study treatment

Exclude patients diagnosed with another malignancy or with a history of malignancy 
from participating in the study 

Clarify reference to hepatitis B and C virus infections in the exclusion criteria

Outline conditions for the dosing schedule changes for holidays, administrative 
reasons, vacations, and extenuating circumstances

Clarify dose modification procedures

Clarify the precautions and restrictions section regarding nonsteroidal anti-
inflammatory drugs (NSAIDs)

Update the management of clinical events section to add information on thrombotic 
thrombocytopenic purpura (TTP), neutropenia, and posterior reversible encephalopathy 
syndrome (PRES)

Add SAE and pregnancy to the criteria for discontinuation of treatment

Update the independent data monitoring committee section to include reporting of all 
cases of new primary malignancies

Delete redundant serious adverse event reporting language 

Modify the reporting period for SAEs to Millennium Department of 
Pharmacovigilance or designee from 1 working day to 24 hours per current company 
standards

Update language regarding follow-up of AEs to current company standards 

Add reporting requirements for all new primary malignances

Clarify that initiation of hematopoietic stem cell transplant is a reason for 
discontinuation from the study

Update MedComm Solutions contact information for reporting product complaints

Correct typographical errors, punctuation, grammar, and formatting
15.15   Amendment 3 Rationale and Purposes
Rationale for Amendment 3
The primary reason for this protocol amendment is to clarify details regarding the duration 
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of treatment in the melphalan/dexamethasone group given the risk of second malignancy 
with prolonged use as noted in the melphalan package insert/summary of product 
characteristics (SmPC).  Additionally, further clarification has been added to the definition 
of cardiac involvement in the setting of a cardiac biopsy.
This amendment also provides additional revisions and corrections made to clarify the initial 
intent of sections as detailed in the following.
Purposes for Amendment 3
The purposes of this amendment are to:

Clarify the guidelines regarding the duration of treatment in the 
melphalan/dexamethasone group given the published risk of second malignancy with 
prolonged use

Clarify language regarding the definition of cardiac involvement in the setting of a 
positive cardiac biopsy

Revise the timing of the bone marrow screening window to 42 days

Revise the pharmacokinetic sampling schedule to eliminate the 2-hour predose 
requirement 

Provide clarification regarding dexamethasone dose modifications to maximize patient 
tolerance as initially intended

Simplify wording regarding overt multiple myeloma as outlined in the exclusion 
criteria to align with published International Myeloma Working Group (IMWG) 
guidelines

Clarify that informed consent must be obtained before performing any study-specific 
procedures for research purposes

Update guidance regarding the management of prophylaxis against risk of reactivation 
of herpes infection, erythematous rash with or without pruritus, neutropenia, 
hypotension, fluid deficit, and posterior reversible encephalopathy syndrome to reflect 
the sponsor’s current recommendations

Clarify that the investigator’s selection of a Physician’s Choice regimen within Arm B 
only occurs prior to randomization

Revise treatment window language to align with sponsor’s current guidelines

Clarify that in some instances, a patient may receive more than 1 cycle of take-home 
medication following approval of the Millennium clinician/designee

Clarify that if the study schedule is shifted, then both assessment and dosing schedules 
should be shifted accordingly

Clarify how mean ventricular wall thickness is calculated on echocardiogram

Update all units of measurement for NT-proBNP (pg/mL) and troponin T (ng/mL) for 
consistency throughout the protocol

Correct typographical errors, punctuation, grammar, and formatting
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15.16   Rationale for Amendment 4
The rationale for Amendment 4 is: 1) to enrich the study population for proteasome 
inhibitor-naïve patients so that it will better reflect the global population of patients with 
relapsed or refractory amyloidosis; 2) to delay the first interim analysis (IA), which is also 
the final analysis (FA) for hematologic response, to allow time for proteasome inhibitor-
naïve patients to enroll; and 3) instead of using the closed sequential approach for the first 
primary endpoint of hematologic response and second primary endpoint of 2-year organ 
deterioration and mortality rate, the fall-back approach is used to strongly control type I 
error.
Purposes for Amendment 4
The purposes of this amendment are to:

Revise inclusion criterion #5 to allow enrichment of proteasome inhibitor-naïve 
patients by holding enrollment of proteasome inhibitor-exposed patients.

Delay the timing of the first interim analysis (IA) to allow time for proteasome 
inhibitor-naïve patients to enroll and increase the number of patients in the analysis.

Extend the duration of the study as a result of enriching for proteasome inhibitor-naïve 
patients and delaying the timing of the first IA.

Revise the statistical analysis to allow splitting of alpha at the first IA and second IA 
for the 2 primary endpoints by using the fall-back alpha spending approach, and 
remove the requirement to terminate the study at the second IA if the test for the 
primary endpoint is not statistically significant. 

Clarify the analysis of the second primary efficacy endpoint.

Revise inclusion criterion #8 to allow patients with Gilbert’s syndrome to be eligible 
for enrollment despite a total bilirubin > 1.5 x ULN.

Revise exclusion criterion #11 to remove the concomitant use of strong inhibitors of 
CYP1A2 and CYP3A.

Revise exclusion criterion #12 to shorten the time period from previous diagnosis or 
treatment for another malignancy from 5 years to 3 years.

Remove the requirement for bone marrow analysis to establish complete hematological 
response.

Increase the flexibility around the timing of Day 14 PK sampling to ease patient 
burden.

Clarify the requirement for assessment of AL amyloidosis symptoms.

Clarify when the second IA will be performed.

Clarify that 2-year follow-up refers to patients included in the analysis for the second 
primary endpoint.

Remove details regarding the safety population analysis from the protocol, as the 
analysis will be clarified in the Statistical Analysis Plan (SAP).

Update the background PK and drug metabolism text for the rationale for the revisions 
to exclusion criterion #11.
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
Update the number of study centers from 50 to 75.

Add a reference for the statistical analysis fall-back approach.

Clarify when the Independent Data Monitoring Committee (IDMC) will meet to 
evaluate safety and efficacy results.

Clarify that additional safety analyses may be done at a time as requested by health 
authorities.

Update the serious adverse event reporting contact information.

Update the Product Complaint contact information to reflect that inquiries will now be 
handled by the Takeda US call center, run by Pharmaceutical Product Development 
(PPD).

Make minor corrections to the amyloid-related hematologic and organ criteria for 
involvement, stabilization, response, and progression.

Update the Global Clinical Lead for the study to 
, MD, PhD.

Correct typographical errors, punctuation, grammar, and formatting.
15.17   Rationale for Amendment 5
(France-specific protocol Amendment 5 contains the same changes in global protocol 
Amendment 4, with the exception of the revision to exclusion #12.)
The rationale for Amendment 5 is: 1) to enrich the study population for proteasome 
inhibitor-naïve patients so that it will better reflect the global population of patients with 
relapsed or refractory amyloidosis; 2) to delay the first interim analysis (IA), which is also 
the final analysis (FA) for hematologic response, to allow time for proteasome inhibitor-
naïve patients to enroll; and 3) instead of using the closed sequential approach for the first 
primary endpoint of hematologic response and second primary endpoint of 2-year organ 
deterioration and mortality rate, the fall-back approach is used to strongly control type I 
error.
Purposes for Amendment 5
The purposes of this amendment are to:

Revise inclusion criterion #5 to allow enrichment of proteasome inhibitor-naïve 
patients by holding enrollment of proteasome inhibitor-exposed patients.

Delay the timing of the first interim analysis (IA) to allow time for proteasome 
inhibitor-naïve patients to enroll and increase the number of patients in the analysis.

Extend the duration of the study as a result of enriching for proteasome inhibitor-naïve 
patients and delaying the timing of the first IA.

Revise the statistical analysis to allow splitting of alpha at the first IA and second IA 
for the 2 primary endpoints by using the fall-back alpha spending approach, and 
remove the requirement to terminate the study at the second IA if the test for the 
primary endpoint is not statistically significant. 

Clarify the analysis of the second primary efficacy endpoint.
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
Revise inclusion criterion #8 to allow patients with Gilbert’s syndrome to be eligible 
for enrollment despite a total bilirubin > 1.5 ULN.

Revise exclusion criterion #11 to remove the concomitant use of strong inhibitors of 
CYP1A2 and CYP3A.

Remove the requirement for bone marrow analysis to establish complete hematological 
response.

Increase the flexibility around the timing of Day 14 PK sampling to ease patient 
burden.

Clarify the requirement for assessment of AL amyloidosis symptoms.

Clarify when the second IA will be performed.

Clarify that 2-year follow-up refers to patients included in the analysis for the second 
primary endpoint.

Remove details regarding the safety population analysis from the protocol, as the 
analysis will be clarified in the Statistical Analysis Plan (SAP).

Update the background PK and drug metabolism text for the rationale for the revisions 
to exclusion criterion #11.

Update the number of study centers from 50 to 75.

Add a reference for the statistical analysis fall-back approach.

Clarify when the Independent Data Monitoring Committee (IDMC) will meet to 
evaluate safety and efficacy results.

Clarify that additional safety analyses may be done at a time as requested by health 
authorities.

Update the serious adverse event reporting contact information.

Update the Product Complaint contact information to reflect that inquiries will now be 
handled by the Takeda US call center, run by Pharmaceutical Product Development 
(PPD).

Make minor corrections to the amyloid-related hematologic and organ criteria for 
involvement, stabilization, response, and progression.

Update the Global Clinical Lead for the study to 
, MD, PhD.

Correct typographical errors, punctuation, grammar, and formatting.
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15.18   Amendment 6 Detailed Summary of Changes
The primary section(s) of the protocol affected by the changes in Amendment 6 are 
indicated. The corresponding text has been revised throughout the protocol.
Change 1: Add primary study results from the first interim analysis (IA) and clarify details 
about subsequent analyses.
The primary change occurs in Section 8.1 Statistical Methods.
Initial 
wording:
Details for the FA will be provided in the statistical analysis plan (SAP).  The 
SAP will be written by Millennium and will be finalized before any formal 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.
Amended 
or new 
wording:
Details for the FA will be provided in the statistical analysis plan (SAP).  The 
SAP will be written by Millennium and will be finalized before any formal 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. 
The first IA has been performed (data cut-off date: 20 February 2019) and 
the primary endpoint of hematologic response was not met. Therefore, the 
sponsor has decided not to conduct any subsequent formal statistical 
analyses. The analysis of efficacy and safety has been completed on data 
from the first IA. Minimal descriptive analyses will be done on patient data 
collected after the first IA. The description of statistical methods presented 
below reflects the original design of the study so to retain the statistical 
considerations up to the first IA.  
Rationale for Change:
The first IA was conducted and the primary endpoint of hematologic response rate (at the 
primary analysis) did not reach statistical significance. However, patients in both treatment 
arms appeared to receive benefit. In light of the primary endpoint not being met, the sponsor 
has decided to remove the planned second IA and FA and discontinue the majority of study 
assessments to ease the burden of protocol-mandated assessments on patients.
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The following sections also contain this change:

Protocol Summary

Schedule of Events

Section 4.1 Overview of Study Design

Section 4.3 Duration of Study

Section 7.4 Study Procedures

Section 8.1.10 Interim Analyses
Change 2: Clarify the study objectives as of Amendment 6.
The primary change occurs in Section 2 STUDY OBJECTIVES.
Added 
text:
As of this amendment, the objectives are to provide continued access of 
MLN9708 and/or other study medications and to continue collecting 
relevant safety data to monitor patient safety. All other study objectives will 
no longer be assessed. However, the complete list of objectives is retained 
below for reference.
Rationale for Change:
In light of the primary endpoint not being met, the sponsor has decided to remove the 
planned second IA and FA and discontinue the majority of study assessments to ease the 
burden of protocol-mandated assessments on patients.
The Protocol Summary also contains this change. 
Change 3: Clarify the study endpoints as of Amendment 6.
The primary change occurs in Section 3 STUDY ENDPOINTS.
Added 
text:
As of this amendment, evaluation of the safety profile of MLN9708 and/or 
other study medication is the only endpoint being assessed. All other study 
endpoints will no longer be assessed. However, the complete list of 
endpoints is retained below for reference.
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Rationale for Change:
In light of the primary endpoint not being met, the sponsor has decided to remove the 
planned second IA and FA and discontinue the majority of study assessments to ease the 
burden of protocol-mandated assessments on patients.
The Protocol Summary also contains this change. 
Change 4: Define the ongoing safety assessments as of Amendment 6.
The primary change occurs in Section 7.4.16 Adverse Events.
Added 
text:
Monitoring of AEs, both nonserious and serious, will be conducted throughout 
the study as specified in the Schedule of Events.  Upon implementation of this 
amendment, data collection requirements will be limited to the following 
safety assessments: all SAEs (regardless of causality, including all deaths), 
any AE resulting in dose modification or discontinuation of any study drug, 
Grade ≥3 AEs, AEs of new primary malignancy, all reports of drug 
exposure during pregnancy and pregnancy outcomes, product complaints, 
and medication errors (including overdose).
Rationale for Change:
A comprehensive safety analysis was conducted using data from the first IA. As of 
Amendment 6, no further formal efficacy or safety analyses are planned and select safety 
assessments are retained to ensure patient safety. 
The following sections also contain this change:

Protocol Summary

Schedule of Events

Section 4.1 Overview of Study Design

Section 7.4.9 Clinical Laboratory Evaluations

Section 8.1.9 Safety Analysis

Section 10.2 Procedures for Recording and Reporting Adverse Events and Serious 
Adverse Events
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Change 5: Discontinue all disease and efficacy response assessments, including central 
laboratory assessments of efficacy and safety, for protocol purposes because no further 
analyses will be performed.
The primary change occurs in Section 7.4.9 Clinical Laboratory Evaluations.
Added 
text:
Per Amendment 6, centralized clinical laboratory evaluations of efficacy 
and safety will no longer be performed. Local laboratory evaluations should 
be entered into the eCRF only if required to understand a TEAE. For 
dosing decisions, response assessment, 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.
Rationale for Change:
To clarify that no further efficacy or formal safety analyses will be performed for this study.
The following sections also contain this change:

Protocol Summary

Schedule of Events

Section 4.1 Overview of Study Design

Section 7.4.13 Disease Assessments

Section 7.4.13.1 Hematologic Disease Assessments

Section 7.4.13.2 Amyloid-Related Organ Assessments
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Change 6: Discontinue pharmacokinetic (PK) sampling for ongoing patients.
The primary change occurs in Section 7.4.14 Pharmacokinetic Measurements (Arm A 
Only).
Added 
text:
Upon implementation of Amendment 6, blood samples for PK 
measurements will no longer be collected.
Rationale for Change:
To clarify that no further PK sampling will be done for patients in the study.
The Pharmacokinetic Sampling Schedule (now moved to Section 15.12) also contains this
change. 
Change 7: Discontinue Quality of Life (QOL) and Health Utilization assessments for 
ongoing patients.
The primary change occurs in Section 7.4.10 Quality of Life Assessments.
Added 
text:
Upon implementation of Amendment 6, QOL assessments will no longer be 
collected.
Rationale for Change:
In light of the primary endpoint not being met, the sponsor has decided to discontinue the 
majority of study assessments to ease the burden of protocol-mandated assessments on 
patients.
The following sections also contain this change:

Section 7.4.11Health Utilization

Section 7.4.12 EQ-5D
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Change 8: Discontinue collection of concomitant medications and procedures.
The primary change occurs in Section 7.4.15 Concomitant Medications and Procedures.
Added 
text:
Upon implementation of Amendment 6, concomitant medications and 
procedures will not be recorded in the eCRF.   
Rationale for Change:
To reflect that no further analysis of concomitant medications or procedures will be 
performed for patients in the study. 
Change 9: Specify that no further Adjudication Committee (AC) reviews are needed as of 
Amendment 6.
The primary change occurs in Section 9.3 Adjudication Committee.
Added 
text:
Upon implementation of Amendment 6, AC review of response data will no 
longer be performed.
Rationale for Change:
To reflect that no further efficacy or formal safety analyses will be performed for this study.
The following sections also contain this change:

Protocol Summary

Section 4.1 Overview of Study Design
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Change 10: Update the number of patients in the study.
The primary change occurs in Section 4.2 Number of Patients Duration of Study,
Initial 
wording:
Approximately 248 patients are anticipated to be enrolled into this study at 
approximately 75 centers in North America, Europe, and the rest of the world.
Amended 
or new 
wording:
Approximately 248176 patients are anticipated to be enrolled into this study at 
approximately 75 centers in North America, Europe, and the rest of the world.
Rationale for Change:
To reflect that no new patients will be enrolled in the study after analysis of patient data 
from the first IA. 
The following sections also contain this change:

Protocol Summary

Section 4.3 Duration of Study

Section 8.1.1 Determination of Sample Size

Section 8.1.10 Interim Analyses
Change 11: Update the estimated study duration.
The primary change occurs in Section 4.3 Duration of Study.
Initial 
wording:
The duration of the study will be approximately 112 months (ie, 9.3 years), 
including 84 months of enrollment and 28 months of follow-up after the last 
patient is enrolled.  All patients included in the analysis for the second primary 
endpoint will have the opportunity to be followed for a minimum of 2 years.
Amended 
or new 
wording:
The duration of the study will be approximately 112120 months (ie, 9.310
years), including 84 months of enrollment and 2836 months of follow-up after 
the last patient is enrolled.  All patients included in the analysis for the second 
primary endpoint will have the opportunity to be followed for a minimum of 2 
years.
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Rationale for Change:
To reflect the new planned duration of follow-up after the last patient was enrolled. 
The Protocol Summary also contains this change. 
Change 12: Discontinue the PFS and OS follow-up periods.
The primary change occurs in Section 7.4.17 Follow-Up Assessments (PFS and OS).
Added 
text:
As of Amendment 6, patients will no longer be followed during any of the 
follow-up periods, as PFS and OS are not being collected.
Rationale for Change:
To clarify that patients no longer need to be followed once they come off study treatment, as 
no further efficacy or formal safety analyses will be performed for this study.
The following sections also contain this change:

Protocol Summary

Schedule of Events

Section 4.1 Overview of Study Design

Section 7.4 Study Procedures

Section 7.6 Discontinuation of Treatment With Study Drug, and Patient 
Replacement
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Change 13: Clarify the exclusion criterion for patients diagnosed with or treated for another 
malignancy.
The primary change occurs in Section 5.2 Exclusion Criteria.
Added 
text:
12. Diagnosed or treated for another malignancy within 3 years (or 5 years for 
patients in France) before study enrollment 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.
Rationale for Change:
To incorporate the France-specific requirement for prior malignancies. 
Change 14: Define overdose.
The primary change occurs in Section 6.10 Management of Clinical Events. 
Added 
text:
Overdose
An overdose is defined as a known deliberate or accidental administration 
of investigational drug, to or by a study patient, at a dose above that which 
is assigned to that individual patient 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.
Rationale for Change:
To define overdose and outline the clinical management of overdose should it occur. 
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Change 15: Clarify the procedures for management of medication errors, including 
overdose.
The primary change occurs in Section 11.11 Product Complaints and Medication Errors 
(Including Overdose).
Added 
text:
11.11   Product Complaints Product Complaints and Medication Errors 
(Including Overdose)
…..
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.
[Added ‘Medication Errors including Overdose for MLN9708’ to contact table]
Rationale for Change:
To provide an update to the procedures for product complaints, including instruction for 
medication errors and overdose.
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Change 16: Remove mention of the Safety Management Attachment (SMA).
The primary change occurs in Section 1.1.3 MLN9708, A Next-Generation Proteasome 
Inhibitor.
Deleted 
text:
As Millennium’s next-generation proteasome inhibitor, MLN9708 was designed 
to build upon the attributes of VELCADE while also providing an option for oral 
administration and increased activity in tumor types where VELCADE has 
shown activity, and improving the safety profile (refer to the MLN9708 
Investigator’s Brochure and Safety Management Attachment [SMA]).
Rationale for Change:
To remove reference to the SMA, as this document no longer exists. All applicable safety 
data are included in the MLN9708 IB.
Change 17: 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 should be submitted via fax (please see fax numbers 
below) within 24 hours of awareness. In case of fax, site personnel need to 
confirm successful transmission of all pages and include an e-mail address 
on the fax cover sheet so that an acknowledgment of receipt can be returned 
via e-mail within 1 business day. E-mail submission of paper SAE forms 
with a PDF attachment should only be used in the case where fax is not 
possible within 24 hours of receiving the event.  In case of e-mail, site 
personnel need to confirm successful transmission by awaiting an 
acknowledgment of the receipt via e-mail within 1 business day. If SAEs are 
reported via fax or by e-mail, EDC/RAVE must be updated as soon as 
possible with the appropriate information.
Rationale for Change:
To provide an update to the procedures for SAE reporting.
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Change 18: Specify that no further independent data monitoring committee reviews of 
safety and efficacy are needed as of Amendment 6.
The primary change occurs in Section 9.2 Independent Data Monitoring Committee.
Added 
text:
As of Amendment 6, the primary efficacy and safety analyses have been 
completed for this study, and no further independent data monitoring 
committee reviews of safety and efficacy data will take place for patients 
still receiving study therapy. The sponsor will continue to monitor all cases 
of new primary malignancies occurring during the trial. 
Rationale for Change:
To provide an update to the procedures for monitoring efficacy and safety. 
Section 10.3 Monitoring of Adverse Events and Period of Observation also contains this 
change.
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ELECTRONIC SIGNATURES 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm ‘UTC’) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
090101d680cbaeb9
A Phase 3, Randomized, Controlled, Open-label, Multicenter, Safety and Efficacy Study of Dexamethasone Plus
MLN9708 or Physician's Choice of Treatment Administered to Patients with Relapsed or Refractory Systemic
Light Chain (AL) Amyloidosis
Clinical Science Approval
13-Jan-2020 20:08 UTC
Biostatistics Approval
14-Jan-2020 02:31 UTC
Clinical Science Approval
14-Jan-2020 04:54 UTC
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SAP_001.pdf: 
CLINICAL STUDY PROTOCOL 
NCT Number: 
Study Title: 
Study Number: 
NCT01659658
A Phase 3, Randomized, Controlled, Open-label, Multicenter, Safety and 
Efficacy Study of Dexamethasone Plus MLN9708 or Physician’s Choice of 
Treatment Administered to Patients With Relapsed or Refractory Systemic 
Light Chain (AL) Amyloidosis
C16011
Statistical Analysis Plan 
Amendment Version 2.0: 15-July-2015 
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Statistical Analysis Plan, Study C16011
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1
STATISTICAL ANALYSIS PLAN
A Phase 3 Randomized, Controlled, Open-label, Multicenter, Safety and Efficacy Study 
of Dexamethasone plus MLN9708 or Physician’s Choice of Treatment Administered to 
Patients With Relapsed or Refractory Systemic Light Chain (AL) Amyloidosis
Protocol #:  C16011
SAP Version:
Date of Statistical Analysis Plan:
Final
7 December 2011
Amendment 1
05 June 2012
Amendment 2 
14 July 2015
Approval Signatures
Date
Prepared by: 
, Ph D
, Global Biostatistics
Date
Reviewed by: 
, PhD
, Global Biostatistics
Date
Approved by: 
, MD, PhD
, Global Biostatistics
Date
Approved by: 
, MD, PhD
, Oncology Clinical Research
Date
Approved by: 
, Oncology Clinical 
Research
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Statistical Analysis Plan, Study C16011
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Rationale for Amendment 2 
The main purpose of this amendment is to incorporate the statistically-relevant changes in 
Protocol C16011, amendment 4, dated 09 July 2015.  
Purposes for amendment 2 are to:

Enrich the study population for proteasome inhibitor-naïve patients to better reflect 
the global population of patients with relapsed or refractory AL amyloidosis

Delay the first interim analysis (IA), which is also the final analysis (FA) for 
hematologic response, to allow time for proteasome inhibitor-naïve patients to enroll

The fall-back alpha spending approach is used to strongly control type I error 
between the testing of hypothesis in the first family (hematologic response) and 
those in the second family which consists of 2-year organ deterioration and mortality 
rate, overall survival and complete hematologic response. The closed sequential 
approach is used to control type I error of the testing of hypothesis within the second 
family.

Remove the requirement to terminate the study at the second IA if the test for the 
primary endpoint is not statistically significant.
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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 Hematologic Response-Evaluable Population...........................................................11
2.3 Safety Population .....................................................................................................11
3. HYPOTHESES AND DECISION RULES.....................................................................11
3.1 Statistical Hypotheses...............................................................................................11
3.2 Statistical Decision Rules .........................................................................................12
4. INTERIM ANALYSIS...................................................................................................15
4.1 Interim Analysis .......................................................................................................15
4.2 Independent Data Monitoring Committee (IDMC)....................................................16
4.3 Adjudication Committee (AC)..................................................................................16
5. STATISTICAL METHODOLOGY ...............................................................................16
5.1 Sample Size Justification..........................................................................................16
5.2 Randomization and Stratification..............................................................................17
5.3 Unblinding ...............................................................................................................18
5.4 Data Handling ..........................................................................................................18
5.4.1 Methods for Handling Missing Data...................................................................18
5.4.2 Definition of Baseline Values ............................................................................21
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.................................................22
5.6.1 Demographics....................................................................................................22
5.6.2 Medical History.................................................................................................22
5.6.3 Baseline Disease Status......................................................................................22
5.7 Treatments and Medications .....................................................................................23
5.7.1 Concomitant Medications ..................................................................................23
5.7.2 Study Treatments...............................................................................................24
5.8 Efficacy Analyses.....................................................................................................26
5.8.1 Primary Efficacy Endpoint.................................................................................26
5.8.2 Key Secondary Efficacy Endpoints....................................................................28
5.8.3 Other Secondary Efficacy Endpoints and Analyses ............................................30
5.9 Pharmacokinetic, Pharmacodynamic, and Biomarker Analysis .................................33
5.9.1 Pharmacokinetic Analyses .................................................................................33
5.9.2 Pharmacodynamic Analyses...............................................................................33
5.9.3 Biomarker Analysis ...........................................................................................33
5.10 Resource Utilization and Patient Reported Outcome Analysis ................................34
5.10.1 Patient Reported Outcomes (PROs)..................................................................34
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5.10.2 Health Economics (Health Care Resource Use)................................................35
5.11 Safety Analyses ......................................................................................................36
5.11.1 Adverse Events................................................................................................36
5.11.2 Laboratory Data...............................................................................................37
5.11.3 Electrocardiograms ..........................................................................................38
5.11.4 Vital Signs .......................................................................................................39
5.11.5 Eastern Cooperative Oncology Group (ECOG) Performance Status .................39
5.11.6 Other Safety Assessments ................................................................................39
6. CHANGES TO PLANNED ANALYSES FROM PROTOCOL .....................................39
7. PROGRAMMING CONSIDERATIONS .......................................................................39
7.1 Statistical Software...................................................................................................39
7.2 Rules and Definitions ...............................................................................................39
8. APPENDIX....................................................................................................................40
8.1 Appendix 1: Amyloid-Related Hematologic and Organ Criteria ...............................40
8.2 Appendix 2: Proof of Strong Control of Type I Error Rate for Key Secondary 
Endpoints..........................................................................................................42
8.3 Appendix 3: Amendment 2 Detailed Summary of Changes.......................................45
8.4 Rationale for Amendment 1......................................................................................54
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LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS
Abbreviation
Term
AC
Adjudication Committee
AE
adverse event
ACE
Angiotensin converting enzyme (ACE)
AL amyloidosis
primary systemic light chain amyloidosis
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
AUC
area under the plasma concentration versus time curve
AUC0-24hr
area under the plasma concentration versus time curve zero to 24 hours
AUC0-tau
area under the plasma concentration versus time curve zero to next dose
AV
atrioventricular
BIW
biweekly (ie, twice weekly)
BP
bodily pain
BSA
body surface area
BUN
blood urea nitrogen
CBC
complete blood count
CDF
cumulative distribution function
CHF
congestive heart failure
CI
confidence interval
CL
clearance
CLb
blood clearance
CLP
plasma clearance
Cmax
maximum plasma concentration
CO2
carbon dioxide
CR
complete response
CT
computed tomography
CYP
cytochrome P450
DDI
drug-drug interaction
dFLC
serum differential free light chain concentration; difference between amyloid 
forming and non amyloid forming FLC
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
eGFR
estimated glomerular filtration rate; eGFR according to the recently 
recommended CKD-EPI equation
Emax
maximum effect
EMG
electromyography
EDC
electronic data capture
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Abbreviation
Term
eGRF
estimated glomerular filtration rate
EOT
End of Treatment (visit)
ESRD
end-stage renal disease
EQ-5D
EuroQol 5-Dimensional (questionnaire)
F
bioavailability
FA
final analysis 
FISH
fluorescent in situ hybridization
FLC
free light chain
GADD34
Growth Arrest DNA Damage 34
GCP
good clinical practice
G-CSF
granulocyte colony stimulating factor
GH 
general health
GI
gastrointestinal
GM-CSF
granulocyte macrophage-colony stimulating factor
hERG
human ether-à-go-go related gene
HDT-SCT
high-dose therapy- stem cell transplantation
HIV
human immunodeficiency virus
HU
health utilization
HemR
hematologic response
MLN9708 IB
investigator’s brochure
IA
interim analysis
ICF
informed consent form
ICH
International Conference on Harmonisation
IDMC
independent data monitoring committee
IEC
independent ethics committee
IEM
immunogold electron microscopy
IHC
immunohistochemistry 
IMiDs
immunomodulatory drugs
IRB
institutional review board
ISA
international society of amyloidosis
ITT
intent-to-treat (population)
K-M
Kaplan-Meier
LVEF
left ventricular ejection fraction
MCS
mental component summary
MedDRA
Medical Dictionary for Regulatory Activities
Millennium
Millennium Pharmaceuticals, Inc., and its affiliates
MM
multiple myeloma
MPD
maximum planned dose
MR
minimal response
MRI
magnetic resonance imaging
msec
Millisecond
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
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Abbreviation
Term
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NDMM
newly-diagnosed multiple myeloma
NSAID
nonsteroidal anti-inflammatory drug
NT-proBNP
N-terminal proBNP
NYHA
New York Heart Association
ODM
organ deterioration and mortality
OS
overall survival
PCS
physical component summary
PD
progressive disease (disease progression)
PF
physical function
PFS
progression free survival
P-gp
P-glycoprotein
PK
pharmacokinetic(s)
PN
peripheral neuropathy
PO
per os; by mouth (orally)
PR
partial response
PRO
patient-reported outcome
RRMM
relapsed and refractory multiple myeloma
QALYs
quality adjusted life years
QOL
quality of life
QTc
rate-corrected QT interval (millisecond) of electrocardiograph
Q3C
every 3 cycles
RBC
red blood cell
RE
role emotional
RP
role physical
RRAL
relapsed or refractory AL amyloidosis
SAE
serious adverse event
SAP
statistical analysis plan
SCT
stem cell transplant
SF
social function
SMA
safety management attachment
SPEP
serum protein electrophoresis
TEAE
treatment-emergent adverse event ; may or may not be treatment related
TTF
time to treatment failure
ULN
upper limit of the normal range
UPEP
urine protein electrophoresis
US
United States
VT
vitality 
VGPR
very good partial response
Vss
volume of distribution at steady state
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 
addresses 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, controlled, open-label, multicenter study of the oral 
formulation of dexamethasone plus MLN9708 compared with treatment chosen by the 
investigator from a prespecified list of regimens available in clinical practice.  Treatment 
options will include: dexamethasone alone, dexamethasone plus an alkylating agent 
(melphalan or cyclophosphamide), or dexamethasone plus an immunomodulatory drug 
([IMiD] thalidomide or lenalidomide) in patients with relapsed or refractory AL 
amyloidosis.  Crossover to the investigational treatment arm is not permitted during 
participation in this study.
Eligible patients must have: 1) biopsy-proven AL-amyloidosis with relapsed or refractory 
disease despite 1 or 2 prior therapies; 2) disease requiring further treatment; 3) measureable 
disease as defined by serum differential free light chain concentration (dFLC); and 4) 
objective and measurable vital organ involvement (ie, cardiac or renal) as defined by 
the standard International Society of Amyloidosis (ISA) criteria. Patients enrolled based on 
protocol amendment 4 must not have been previously treated with proteasome inhibitors. 
(The Sponsor reserves the right to open the trial to proteasome inhibitor-exposed patients in 
the future, at some time point after the first interim analysis [IA].) The definition of relapsed 
is documented hematologic progressive disease (PD) after a response to prior therapy [PD 
more than 60 days of last dose].  The definition of refractory is documented absence of 
hematologic response or hematologic progression on or within 60 days of last dose of prior 
therapy.
Physicians will choose a treatment regimen from a list of options provided by the sponsor.   
Before randomization, physicians will declare which treatment regimen they plan to select 
for each screened patient; the selection will be recorded in the database.  To maintain a 
balanced representation of the disease characteristics, patients enrolled in this study will be 
stratified by:  1) Cardiac Risk Stage: 1 versus 2 versus subgroup Cardiac Risk Stage 3(ie, 
both NT-proBNP and troponin T over threshold , but NT-proBNP < 8000 pg/mL); 2) 
relapsed versus refractory to last prior therapy; and 3) proteasome inhibitor naïve versus 
exposed.   
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Eligible patients will be randomized in a 1:1 ratio into 1 of the 2 study arms:
Arm A: dexamethasone plus MLN9708
Arm B: Physician’s choice 
In both treatment arms, each patient will continue to receive sequential cycles of therapy 
until disease progression/death, unacceptable toxicity, or until the study is terminated, 
whichever occurs first.
Response to therapy will be evaluated by an adjudication committee (AC) which will 
include the assessment of hematologic response and organ response according to the criteria 
outlined in the Revised Consensus Response Criteria of the ISA (Appendix 1), and vital 
organ (that is, heart and kidney) deterioration.   An independent data monitoring committee 
(IDMC) will review safety and efficacy data at the interim analyses.  
Safety will be assessed through adverse events (AEs), clinical laboratory tests, and vital sign 
measurements. In addition, quality of life (QOL) and health utilization (HU) will 
be assessed using questionnaires.
After disease progression, patients will be followed for survival, vital organ deterioration,
and subsequent therapy at least every 12 weeks.
1.2   
Study Objectives
The 2 primary objectives are:

To determine whether dexamethasone plus MLN9708 improves hematologic 
response (PR + VGPR + CR) versus a Physician’s choice of a chemotherapy 
regimen as selected from the list of offered treatment options in patients diagnosed 
with relapsed or refractory AL amyloidosis

To determine whether dexamethasone plus MLN9708 improves 2-year vital organ 
(that is, heart or kidney) deterioration and mortality rate versus a Physician’s choice 
of a chemotherapy regimen as selected from the list of offered treatment options in 
patients diagnosed with relapsed or refractory AL amyloidosis.  Cardiac deterioration 
is defined as the need for hospitalization for heart failure.  Kidney deterioration is 
defined as progression to end-stage renal disease (ESRD) with the need for 
maintenance dialysis or renal transplantation.
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The key secondary objectives are:

To determine overall survival (OS)

To determine the complete hematologic response rate (CR)
Other secondary objectives are:

To determine progression-free survival (PFS) 

To measure hematologic disease PFS

To measure time to vital organ deterioration or death 

To measure vital organ response 

To measure vital organ PFS

To measure the duration of hematologic response (DOR)

To evaluate safety

To measure time to treatment failure (TTF)

To measure time to subsequent anticancer therapy

To describe the impact of treatment on quality of life (QOL) using the Medical 
Outcomes Study 36- item Short Form General Health Survey (SF-36 v2), 
FACT-neurotoxicity subscale (FACT/GOG-Ntx) and a symptom scale questionnaire

To evaluate health utilization (HU) and collect EuroQol 5-Dimensional (EQ-5D)
data

To collect PK data to contribute to population PK analyses

To assess the association between clinical outcomes and gene polymorphisms that 
may relate to MLN9708 activity, such as NF-kB pathway-related genes NFKB2 and 
TRAF-3 in blood samples.
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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, secondary efficacy analyses, and resource 
utilization and patient reported outcome analysis.
2.2   
Hematologic Response-Evaluable Population
The hematologic response-evaluable population is defined as patients who have measurable 
disease at baseline, who receive at least 1 dose of any treatment drug (study drug[Arm A] or 
standard drug [Arm B]), and have at least 1 postbaseline hematologic response assessment
by an AC
Hematologic response-evaluable population will be used for sensitivity analysis of 
hematologic response rate. 
2.3   
Safety Population
The safety population is defined as all patients who receive at least 1 dose of any treatment 
drug.  
Safety population will be used for all safety related analyses such as AE, concomitant 
medication, laboratory tests, and vital signs.
3.   
HYPOTHESES AND DECISION RULES
3.1   
Statistical Hypotheses
There are two primary endpoints in this study. 
The null and alternative hypothesis for hematologic response is:
H0: Hematologic Response rate in Arm A = Hematologic Response Rate in Arm B
Ha: Hematologic Response rate in Arm A > Hematologic Response Rate in Arm B
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The null and alternative hypothesis for 2-year vital organ deterioration and mortality rate is:
H0: 2-year vital organ deterioration and mortality rate in Arm A = 2-year vital organ 
deterioration and mortality rate in Arm B
Ha: 2-year vital organ deterioration and mortality rate in Arm A < 2-year vital organ 
deterioration and mortality rate in Arm B
There are two key secondary efficacy endpoints in this study.
The null and alternative hypothesis for OS is:
H0: OS in Arm A = OS in Arm B
Ha: OS in Arm A > OS in Arm B
The null and alternative hypothesis for complete hematologic response rate (CR) is:
H0: CR in Arm A = CR in Arm B
Ha: CR in Arm A > CR in Arm B
3.2   
Statistical Decision Rules
Hematological response will be tested using unstratified Cochran-Mantel-Haenszel (CMH) 
test at 0.04 significance level at the first IA; if p value is ≤ 0.04, then at the second IA, 2-
year vital organ deterioration and mortality rate will be tested at 0.05 level; otherwise it will 
be tested at 0.01 level.
Hypothesis for 2-year vital organ deterioration and mortality rate will be tested at the second 
IA. If the test is not significant, the study may still continue, however no formal testing will 
be conducted. If the test is significant, the null hypothesis will be rejected, and the key 
secondary endpoint OS will be tested at the second IA. Using O’Brien-Fleming boundaries, 
if the alpha allocated to OS is 0.05, the trial may be stopped for overwhelming efficacy if the 
observed p value is less than 0.027 at the second IA assuming there are exactly 120 death 
events.  The final analysis (FA) will be tested at 2-sided alpha level of 0.0423 
(corresponding to nominal alpha of 0.023). If the alpha allocated to OS is 0.01, OS will be 
tested using a similar approach as above.
Hypothesis for the second key secondary endpoint, complete hematologic response rate, will 
be tested sequentially when OS hypothesis is rejected either at second IA or at FA.  The 
testing level of significance will be the same as those used for OS.  For instance if OS is 
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significant at 0.023 level at the FA, complete hematologic response rate will also be tested at 
2-sided alpha level of 0.023 at the FA.  
The type I error for all primary endpoints and key secondary endpoints using the testing 
procedure presented in Figure 1 is strongly controlled.   Those endpoints are grouped into 
two ordered families 1) hematologic response, and 2) organ deterioration and mortality, OS 
and CR. The closed sequential testing approach will be used for strong type I error rate 
control in the second family. That is, OS will be only tested using the same alpha level 
assigned to 2-year organ deterioration and mortality rate if the test on 2-year organ 
deterioration and mortality rate is statistically significant, and then the alpha assigned to OS 
is allocated using O’Brien-Fleming boundaries for OS tests at second IA and FA; and CR 
will be only tested at the same alpha level of OS at second IA or FA if the test on OS is 
significant at second IA or FA. For testing the two families, the fall-back approach (Wiens 
B.L., 2003) is used to control type I error rate. 
This approach for the key secondary endpoints is similar to strategy 2 from Hung, Wang, 
and O’Neill (2007) for family-wise Type I error control; that is, testing the second endpoint 
conservatively using the same rejection boundary as the first endpoint to be tested. In 
Hung’s paper, they assume that the correlation (information fraction) for the second 
endpoint between the IA and FA is the same as that for the first endpoint. However, this 
might not be the case in our study since complete hematologic response rate is gated by OS. 
By the time of the second IA, all patients will have been enrolled and contributed to the
complete hematologic response assessment, which leads to the fact that the correlation
between test statistics for the second endpoint is much higher than that of the first endpoint 
OS. Therefore, instead of using the same rejection boundary as the first endpoint, it is 
proposed to use the same alpha level for the second endpoint. The proof of strong control of 
family-wise error rate for both first and second endpoints is provided in Appendix 2 of this 
document.   
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Figure 1. Statistical Testing Procedure and Alpha Spending Schema
The rejection boundary for the secondary endpoints at the FA will be calculated based on the
actual correlation between the test statistics at the second IA and FA. Examples of critical
values at the FA based on different correlations between the test statistics at IA and FA 
using a 2- sided alpha of 0.023 are presented below. The formula to calculate the critical 
values is also shown in the proof of strong control of error rate in Appendix 2. 
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Information fraction(  
⁄
)
Correlation (	 
⁄
) 
Critical value 
2/3
0.82
2.09
5/6
0.91
2.03
1
1
1.96
where n1 and n2 are the size of patient population at the second IA and FA, respectively
Since in the family 2, the testing of key secondary endpoints is gated by the significance of 
the second primary endpoint, and between family 1 and family 2, the type I error rate is 
controlled at 2-sided alpha level by using the fall-back approach, the overall type I error rate
for all endpoints, i.e. both primary and all key secondary endpoints, is also controlled 
strongly at 2-sided 0.05 level.
4.   
INTERIM ANALYSIS
4.1   
Interim Analysis
There are two planned formal IAs.  The first IA will be performed when approximately 
176 patients have been enrolled and have had the opportunity to complete 6 cycles of 
treatment or have discontinued study treatment before receiving 6 cycles of treatment.  At 
that time, relevant safety and efficacy data from these patients will be queried and cleaned; 
all analyses at this IA will be based on these patients whose data have been cleaned. This 
will be the FA for hematologic response.  At the first IA, hematologic response will be 
tested using unstratified CMH at a 2-sided alpha level of 0.04.  If the test is statistically 
significant, the study will continue to test organ deterioration and mortality rate at a 2-sided 
alpha of 0.05 at the second IA; otherwise organ deterioration and mortality rate will be 
tested at the second IA with a 2-sided alpha of 0.01. This IA is expected to occur 
approximately 54 months after the first patient is enrolled.  During this IA, enrollment to the 
study will continue.                                             
The second IA will be performed when approximately 218 patients enrolled have had the 
opportunity to complete 2 years of treatment or followed up for at least 2 years if 
discontinuing treatment before receiving 2 years of treatment.  This IA is expected to occur 
approximately 98 months from the first patient is enrolled.  At that time, relevant safety and 
efficacy data from those patients will be queried and cleaned; all analyses at this IA will be 
based on these patients whose data have been cleaned.
If the test for 2-year vital organ deterioration and mortality rate is significant at the second 
IA, the analyses on OS will be performed and the test significance level on OS for the 
second IA and FA will be determined using O’Brien-Fleming boundaries. Assuming there 
are exactly 120 death events at second IA, the trial will be stopped for overwhelming 
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efficacy if the observed p value is less than 0.027.  The FA will be tested at 2-sided alpha 
level of 0.0423 (corresponding to nominal alpha of 0.023). If the alpha allocated to OS is 
0.01, OS will be tested using a similar approach as above using O’Brien-Fleming 
boundaries. 
4.2   
Independent Data Monitoring Committee (IDMC)
An IDMC will periodically review safety and efficacy data at regularly scheduled meetings 
pre-specified in the IDMC charter.  A detailed charter outlining all activities of the IDMC 
(eg, type of data reviewed, frequency of meetings, location of meetings, etc.) will be 
finalized during its initial meeting. At the time of the interim analyses, the IDMC will be 
responsible to provide a recommendation regarding study continuation based on the safety 
and efficacy parameters.  
4.3   
Adjudication Committee (AC)
Hematologic response/progression and organ response/progression will be assessed by an 
Adjudication Committee (AC) who are blinded to the treatment assignment.  Assessment of 
hematologic response and organ response will be based on central laboratory results and will 
follow the criteria outlined in the Revised Consensus Response Criteria of the international
Society of Amyloidosis (ISA). The detailed criteria are included in Appendix 1. Vital organ 
deterioration will also be assessed by the AC.  
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 percent (of nonmissing) per category for categorical data, unless specified 
otherwise.  
5.1   
Sample Size Justification
Two primary endpoints, hematologic response and 2-year vital organ deterioration and 
mortality rate, along with key secondary endpoints of OS and complete hematologic 
response rate, will be sequentially tested in this study.
The total sample size was calculated to provide 80% power for the assessment of OS with 
the allocated alpha 0.05.  The study is also adequately powered to test both primary 
endpoints: hematologic response rate and 2-year vital organ deterioration and mortality rate. 
There are two planned IAs and one FA.
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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 26 months, and testing arm
median OS of 41.6 months (assuming exponential distribution, hazard ratio 0.625).  With 
1 IA (second) and 1 FA occurring at information time of 0.89 and 1, an average enrollment 
rate of 3 patient /month for the first 5 months, and 3-5 patient/month thereafter, an additional 
28 months follow up for all patients after last patient is enrolled, and approximately 10% 
drop out rate, a total of 248 patients will need to be randomized in a 1:1 ratio into 
2 treatment arms in order to achieve 145 death events.    The O’Brien-Fleming stopping 
boundary (Lan-DeMets method) will be used to assign alpha level to the second IA and FA.
The parameters used for hematologic response endpoint are a 2-sided test at the significance 
level of α = 0.04, power of 90%, a null hypothesis hematologic response rate 40%, and an 
alternative hypothesis hematologic response rate 65%.  Approximately 176 patients are 
needed for two-sample test of the difference of proportions.   Testing for hematologic 
response hypothesis will be performed when approximately 176 patients enrolled have had 
opportunity to either complete 6 cycles of treatment or discontinue treatment before 
receiving 6 cycles of treatment.  This is the first IA for the study, also the FA for 
hematologic response for statistical testing purpose, with the opportunity to claim 
hematologic response rate benefit.  If the test is statistically significant in favor of the 
dexamethasone plus MLN9708 arm, the second IA for organ deterioration and mortality will 
be tested at 2-sided α = 0.05 based on fallback approach, otherwise it’ll be tested at 2-sided 
α = 0.01.
The second IA will be performed when approximately 218 patients enrolled have had the 
opportunity to complete 2 years of treatment or discontinue treatment before receiving
2 years of treatment. This will be the FA for 2-year vital organ deterioration and mortality 
rate. With 218 patients, the endpoint of 2-year vital organ deterioration and mortality rate is 
powered at 90% at a 2-sided alpha level of 0.05 with the assumption of 80% deterioration 
and mortality rate in the control arm and 60% rate in the MLN9708 arm. If first IA result is 
not significant, power of 2-year vital organ deterioration and mortality rate will be 74% at a 
2-sided alpha level of 0.01. If the test for 2-year vital organ deterioration and mortality rate 
is not significant, there will not be any formal testing; otherwise, OS will be tested. If the 
test for OS is statistically significant, the complete hematologic response rate will be tested 
at the same alpha level as that for OS and the study may be stopped for evidence of efficacy; 
if the test for OS is not statistically significant, the study will continue to the FA.
5.2   
Randomization and Stratification 
Randomization scheme will be generated by an independent biostatistician 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).
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Eligible patients will be randomized in a 1:1 ratio into 1 of the 2 treatment arms, stratified 
by: 1) Cardiac Risk Stage: 1 versus 2 versus subgroup Cardiac Risk Stage 3(ie, both 
NT-proBNP and troponin T over threshold, but NT-proBNP < 8000 pg/mL); 2) relapsed 
versus refractory to last prior therapy; and 3) proteasome inhibitor naïve versus exposed.
5.3   
Unblinding
This is an open-label study; investigators and patients will know the individual treatment 
assignments.  However, the Millennium and CRO study team, investigators, and patients 
will be blinded to the aggregate efficacy results.  Efficacy data will be masked with dummy 
patient identification number during the study conduct for data review/cleaning purposes.  
Only limited Millennium and CRO personnel will have access to un-blinded individual 
patient level data in the electronic data capture system.  The periodic safety analyses will be 
generated for the IDMC by CRO’s statistical group.  Two formal interim efficacy analyses 
will be conducted by an independent statistical center (ISC) for the IDMC.  
Refer to section 4 for the roles and responsibilities of IDMC and AC.
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 patient reported outcomes data, primarily missing data imputation will be based on 
published instrument specific methods.  Other missing data imputation method such as Last 
Observation Carry Forward (LOCF), random slope model, and pattern mixture model may 
be explored as sensitivity analyses for patient reported outcomes data.
For the primary analysis on the first primary endpoint (hematologic response rate), missing 
value is defined as no post-baseline hematologic response assessment either due to lost to 
follow-up or withdrawal by patients. If the hematologic response assessment in either arm is 
missing on comparing hematologic response rates, it will be counted as a failure (non-
responder) instead of a missing value. 
For the primary analysis on the second primary endpoint (2-year organ deterioration and 
mortality rate), missing value is defined as no documented vital organ deterioration or death 
event within the first 2 years and no further information available regarding vital organ 
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deterioration or death event on or after 2 years from the date of first dosing of the treatment 
drug (study drug [Arm A] or standard drug [Arm B]). All event (vital organ deterioration or 
death) occurred within the first 2 years will be counted as one event.  If the 2-year vital 
organ deterioration assessment or death information is missing in either arm, it will be 
counted as a failure instead of a missing value; that is, patient who has a missing event will 
be counted as an event towards vital organ deterioration or death. 
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 treatment 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 treatment 
drug, the 15th of January will be used unless it is later than the first dose, in which 
case the date of the first of January will be used, unless other data indicates that the 
date is earlier. 

If only a year is present, and it is not the same as the year of the first dose of 
treatment drug, the 15th of June will be used, unless other data indicates that the date 
is earlier. 
5.4.1.2   Missing/Partial Dates in Adverse Events/Concomitant Therapies/Subsequent 
Therapies
Every effort will be made to avoid missing/partial dates in on-study data. 
Adverse events with stop dates that are completely or partially missing will be imputed as 
follows:

If the stop date has month and year but day is missing, the last day of the month will 
be imputed

If the stop date has year, but day and month are missing, the 31th of December will 
be imputed
After the imputation, the imputed dates will be compared against the date of death, if 
available.  If the date is later than the date of death, the date of death will be used as the 
imputed date instead.
Adverse events with start dates that are completely or partially missing will be imputed as 
follows:
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
If the start date has month and year but day is missing, the first day of the month will 
be imputed
o
If this date is earlier than the first dose date, then the first dose date will be 
used instead
o
If this date is later than the stop date (possibly imputed), then the stop date 
will be used instead

If the start date has year, but day and month are missing, the 15th of June will be 
imputed
o
If this date is earlier than the first dose date, then the first dose date will be 
used instead
o
If this date is later than the stop date (possibly imputed), then the stop date 
will be used instead
If the start date of an event is completely missing, then it is imputed with the first dose date.
Concomitant therapies with start dates that are completely or partially missing will be 
analyzed as follows:

If the start date has month and year but day is missing, the therapy will be included 
in the summary table if the month and year of the start date of the event are: 
o
On or after the month and year of the date of the first dose of treatment drug
and 
o
On or before the month and year of the date of the last dose of treatment drug
plus 30 days.

If the start date has year, but day and month are missing, the therapy will be included 
in the summary table if the year of the start date of the event is:
o
On or after the year of the date of the first dose of treatment drug
and 
o
On or before the year of the date of the last dose of treatment 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:
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
When month and year are present and the day of the month is missing, 
o
If the onset month and year are the same as the month and year of last dose 
with treatment drug, the day of last dose + 1 will be imputed.  
o
If the onset month and year are not the same as the month and year of last 
dose with treatment drug, the first day of the month is imputed. 

When only a year is present, 
o
If the onset year is the same as the year of last dose with treatment drug, the 
date of last dose + 1 will be imputed.  
o
If the onset year is not the same as the year of last dose with treatment drug, 
the first day of the year is imputed. 

If no components of the onset date are present the date of last dose + 1 will be 
imputed.
5.4.2   
Definition of Baseline Values
Unless otherwise specified, the baseline value is defined as the value collected at the time 
closest to, but prior to, the start of treatment drug administration.  
5.4.3   
Windowing of Visits
All data will be categorized based on the scheduled visit at which it was collected.  These 
visit designators are predefined values that appear as part of the visit tab in the eCRF.  
5.4.4   
Justification of Pooling
All data from all sites will be pooled.  Study center or treatment-by-center interaction will 
not be included in any statistical analysis.
5.4.5   
Withdrawals, Dropouts, Loss to Follow-up
Time to event parameters will be censored if patients withdraw, drop out, or are lost to 
follow-up before documentation of the events (progressive disease / death).  Rules for 
censoring are detailed in section 5.8.
5.5   
Patient Disposition
A disposition of patients includes the number and percentage of patients for the following 
categories:  patients in each of the study population, patients discontinued from the 
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treatment, primary reason to discontinue from the treatment, patients discontinued from the 
study, and primary reason to discontinue from the study.  All percentages will be based on 
the number of patients in the ITT population.  
A listing will present data concerning patient disposition.
5.6   
Demographics and Baseline Disease Characteristics
5.6.1   
Demographics
Demographics will be summarized by treatment arms in a descriptive fashion in the ITT 
population.  Baseline demographic data to be evaluated will include age, sex, race, height, 
weight, and other parameters as appropriate.  Patient enrollment by region and country will 
also be summarized by treatment arms.
5.6.2   
Medical History
Medical history will be presented in a by-patient listing.  Specific neurologic (11 questions 
with grade) and cardiac (7 questions with grade) medical history information will be 
summarized by treatment group in the ITT population.  Smoking history will also be 
summarized similarly in the ITT population.
5.6.3   
Baseline Disease Status
Disease status at initial diagnosis will be summarized by the treatment arms in the ITT 
population, including cardiac biomarker stage, NYHA classification, and sites of amyloid 
involvement, 
Baseline disease status will be summarized by the treatment arms in the ITT population, 
including time since initial diagnosis (months), type and number of organ involvement, type 
and quantity of involved free light chain, dFLC, serum κ/λ ratio, serum and urine m-protein 
quantity, serum and urine immunofixation results, skeletal survey results, cardiac biomarker 
stage, Eastern Cooperative Oncology Group (ECOG) performance status, ß2-microglobulin, 
serum creatinine, serum creatinine clearance, total urine creatinine, urine creatinine 
clearance, serum albumin, alkaline phosphatase, ALT, AST, serum cardiac markers (NT-
proBNP, BNP, troponin T), NYHA classification, and other parameters as appropriate.  
Separate by-patient listings will also be presented.
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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





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 organ and/or 
hematologic responses to prior systemic therapy, relapse/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. By-patient listing will also be 
presented for prior systemic therapy.
Months since diagnosis 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 screening 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.  
By-patient listing will also be presented for concomitant medications.
Concomitant procedures will not be coded, but will be presented in a data listing in the 
safety population.
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5.7.2   
Study Treatments
Prior to randomization, the physician will choose a treatment regimen from the list of 
options provided by the sponsor for each screened patient. The physician’s choice will be 
collected and recorded in the database. Eligible patients will be randomized to 1 of 2 study 
arms in a 1:1 ratio.  Once randomized, patients must start therapy within 5 business days.
Arm A: Patients will receive MLN9708 (4.0 mg) PO on Days 1, 8, and 15 plus 
dexamethasone 20 mg/day PO weekly on Days 1, 8, 15, 22 of each 28-day cycle; 
dexamethasone may be increased up to 40 mg/day after 4 weeks, if tolerated. Patients may 
continue to receive treatment until PD or unacceptable toxicity, whichever comes first.
Arm B:  Patients will receive one of the following treatment options as selected by the 
physician:

Dexamethasone: Dexamethasone 20 mg/day PO on Days 1-4, 9-12, 17-20 of each 
28-day cycle; dexamethasone may be increased up to 40 mg/day after 4 weeks, if the 
lower dose is tolerated without any > Grade 2 dexamethasone-related toxicities.
Dose adjustments are possible based on toxicities experienced.

Dexamethasone plus melphalan: Dexamethasone 20 mg/day PO on Days 1-4 of 
each 28-day cycle; dexamethasone may be increased up to 40 mg/day after 4 weeks 
if the lower dose is tolerated without any > Grade 2 dexamethasone-related 
toxicities, plus melphalan 0.22 mg/kg PO on Days 1-4 every 28 days. Melphalan has 
to be dose adjusted in patients with renal function impairment. Dose adjustments are 
possible based on toxicities experienced.

Dexamethasone plus cyclophosphamide: Dexamethasone 20 mg/day PO weekly 
on Days 1, 8, 15, and 22 of each 28-day cycle; dexamethasone may be increased up 
to 40 mg/day after 4 weeks, if the lower dose is tolerated without any > Grade 2 
dexamethasone-related toxicities, plus cyclophosphamide 500 mg PO Days 1, 8, and 
15, every 28 days. Dose adjustments are possible based on toxicities experienced.

Dexamethasone plus thalidomide: Dexamethasone 20 mg/day PO weekly Days 1, 
8, 15, and 22 of each 28-day cycle; dexamethasone may be increased up to 
40 mg/day after 4 weeks, if the lower dose is tolerated without any > Grade 2 
dexamethasone-related toxicities, plus thalidomide total dose 200 mg/day PO 
(starting dose 50 mg/day, increased as tolerated to a maximum of 200 mg/day). Dose 
adjustments are possible based on toxicities experienced.

Dexamethasone plus lenalidomide: Dexamethasone 20 mg/day PO weekly on 
Days 1, 8, 15, and 22 of each 28-day cycle; dexamethasone may be increased up to 
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40 mg/day after 4 weeks, if the lower dose is tolerated without any > Grade 2 
dexamethasone-related toxicities, plus lenalidomide 15 mg/day for 21 days every 
28 days. Dose adjustments are possible based on toxicities experienced.
Patients may continue to receive treatment until PD or unacceptable toxicity.  
5.7.2.1   Extent of Exposure
An overall summary of drug exposure will be presented including number of treated cycles, 
numbers and percentages of patients who had ≥1, ≥2, …, and ≥12 treated cycles, for each 
treatment group in the safety population.  Aggregate summary of numbers and percentages 
of patients who had 1-6, 7-12, ≥13 treated cycles will also be presented in the same table.  
For patients in arm B, summarization will be based on the actual treatment option received.
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 ≥12 treated cycles, and relative dose intensity (%) for each 
treatment group in the safety population. Aggregate summary of numbers and percentages 
of patients who had 1-6, 7-12, ≥13 treated cycles will also be presented in the same table.  
For patients in arm B, summarization will be based on the actual treatment option received.
MLN9708, melphalan, cyclophosphamide, thalidomide, and lenalidomide exposure will be 
summarized similarly as dexamethasone for the applicable treatment group/option.
A treated cycle is defined as a cycle in which the patient received any amount of any 
treatment drug. 
A treated cycle for a specific drug is defined as a cycle in which the patient received any 
amount of the specific drug.
Prescribed dose for MLN9708, melphalan, cyclophosphamide, and lenalidomide is 
determined by the dose level to which a patient is enrolled at the onset of the study.  
Prescribed dose for dexamethasone will be increased up to 40 mg/day after 4 weeks if a dose 
increase is applicable for a patient.  Prescribed dose for thalidomide will be increased up to 
200 mg/day according to the actual dose increase schedule for a patient.
Relative dose intensity (%) is defined as 100 x (total dose received in mg) / (sum of 
prescribed dose over all treated cycles). 
Dosing data will also be presented in a by-patient listing.
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5.7.2.2   Treatment Modifications
Action on each treatment drug will be summarized by each of the Cycle 1 through 12, sum 
of the remainder Cycles, Cycles 1-6, Cycles 7-12, and total for each treatment group in the 
safety population. For patients in arm B, summarization will be based on the actual 
treatment option received.
5.8   
Efficacy Analyses
All efficacy evaluations will be conducted using the ITT population. At the IAs, relevant 
safety and efficacy data from these patients for the primary analyses will be queried and 
cleaned; all analyses at this IA will be based on these patients whose data have been cleaned.
Hematologic response-evaluable population will be used for sensitivity analyses for 
hematologic response as specified below.
5.8.1   
Primary Efficacy Endpoint
There are 2 primary endpoints: hematologic response and 2-year vital organ (that is, heart or 
kidney) deterioration and mortality rate.
Hematologic Response
Hematologic response rate is defined as the proportion of patients who achieved PR or better 
in the ITT population.  Hematologic response is assessed by AC using central laboratory 
results and ISA criteria.  
2-year vital organ (that is, heart or kidney) deterioration and mortality rate 
Cardiac deterioration is defined as the need for hospitalization for heart failure.  Kidney 
deterioration is defined as progression to end-stage renal disease (ESRD) with the need for 
maintenance dialysis or renal transplantation. Vital organ deterioration is assessed by AC as 
well. 
5.8.1.1   Primary Efficacy Analysis
Two primary efficacy endpoints will be tested sequentially in the order of 1) hematologic 
response; 2) 2-year vital organ (that is, heart or kidney) deterioration and mortality rate.
Hematologic Response
If the hematologic response assessment in either arm is missing on comparing hematologic 
response rates, it will be counted as a failure (non-responder) instead of a missing value.
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The unstratified CMH test will be used to compare hematologic response rate between the 
2 treatment arms when 176 ITT patients have had the opportunity to receive 6 cycles of 
treatment, or discontinued treatment prior to 6 cycles.  If the hematologic response rate is 
higher in the dexamethasone plus MLN9708 arm (arm A), and the 2-sided CMH test p value 
is ≤ 0.04, null hypothesis will be rejected.  Therefore statistical significance will be claimed 
for dexamethasone plus MLN9708.  
A logistic regression model will be used to estimate the treatment effect in terms of odds 
ratio.  The odds ratio and its associated 95% confidence intervals (CIs) will be presented. 
2-year vital organ deterioration and mortality rate 
If the 2-year vital organ deterioration assessment or death information is missing in either 
arm, it will be counted as a failure instead of a missing value; that is, patient who has a 
missing event will be counted as an event towards vital organ deterioration or death.
The unstratified CMH test will be used to make comparisons between the 2 treatment arms 
at the second IA when approximately 218 patients enrolled have had the opportunity to 
complete 2 years of treatment or have discontinued treatment before receiving 2 years of 
treatment.  If the 2-year organ deterioration and mortality rate is lower in the dexamethasone 
plus MLN9708 arm (arm A), and the 2-sided CMH test p value is ≤ 0.05 when hematologic 
response endpoint is significant or ≤ 0.01 when hematologic response endpoint is not 
significant, null hypothesis will be rejected.  Therefore statistical significance will be 
claimed for dexamethasone plus MLN9708.
A logistic regression model will be used to estimate the treatment effect in terms of odds 
ratio.  The odds ratio and its associated 95% confidence intervals (CIs) will be presented. 
5.8.1.2   Sensitivity Analyses for Primary Endpoints
It is expected that the missing values will be limited and therefore, the primary analysis on 
both primary endpoints will not be driven by the handling of the missing data. To further 
assess the impact of missing values and potential other factors, a range of sensitivity 
analyses are proposed as below:
1) Hematologic response and vital organ deterioration assessed by investigator in the 
ITT population
2) Stratified CMH method 
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3) Binomial test with standard error estimate for the difference in rates for both primary 
endpoints 
Let  and ! be the total number of subjects for the respective arms and  
∗ and 
!
∗ are the total number of known outcomes (missing values will be excluded) for the 
respective arms; and #̂  and #̂!are the proportion of successes (known as no vital 
organ deterioration or death within 2-years) used in the analysis based on all subjects 
in the respective arms. Then the test statistics will be: 
(#̂ −#̂!)
' #̂ (1 −#̂ )
( 
∗)(
+ !#̂!(1 −#̂!)
(!
∗)(
*
4) Subgroup analyses for hematologic response and 2-year vital organ deterioration and 
mortality rate will include the stratification factors, and other baseline prognostic 
factors to be determined before database lock.
5) Hematologic response assessed by AC in the hematologic response-evaluable 
population
5.8.2   
Key Secondary Efficacy Endpoints
There are 2 key secondary endpoints: OS and complete hematologic response rate.
Overall Survival
OS is defined as 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.
Complete Hematologic Response Rate
Complete hematologic response rate is defined as the proportion of patients who achieved 
CR in the ITT population.  Complete hematologic response is assessed by AC using central 
laboratory results and ISA criteria.  
5.8.2.1   Key Secondary Efficacy Analysis
Two key secondary efficacy endpoints will be tested sequentially in the order of 1) OS; 2) 
complete hematologic response rate when the test of 2-year vital organ deterioration and 
mortality rate is statistically significant at the second IA. The alpha level for complete 
hematologic response rate will be the same alpha level as that for the OS analysis either at 
the second IA or at the FA.
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Overall Survival
OS will only be tested after statistical significance is achieved for dexamethasone plus 
MLN9708 in 2-year vital organ deterioration and mortality rate analysis.  A 2-sided, 
stratified log-rank test will be used to compare the treatment arms with respect to OS.  OS 
will be tested at the second IA and FA if necessary.  O’Brien-Fleming boundaries will be 
calculated using the Lan-DeMets method.  The information fraction at the second IA is 
calculated as (number of death events/145).  In addition, an unadjusted stratified Cox 
regression 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.  If the log-rank test statistics cross the efficacy boundary at the second IA 
in favor of the dexamethasone plus MLN9708 arm (arm A), statistical significance will be 
claimed and the study will be stopped at the second IA. Otherwise, the study will continue 
until 145 death events are observed.  At the FA if the log-rank test statistics crosses the 
efficacy boundary in favor of the dexamethasone plus MLN9708 arm (arm A), statistical 
significance will be claimed.
Complete Hematologic Response Rate
The unstratified CMH test will be used to compare complete hematologic response rates
between the 2 treatment arms in the ITT population.  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.  If the complete hematologic response rate is higher in the 
dexamethasone plus MLN9708 arm (arm A), and the 2-sided CMH test statistics cross the 
efficacy boundary, null hypothesis will be rejected. Statistical significance will be claimed 
for dexamethasone plus MLN9708.  
5.8.2.2   Sensitivity Analyses for Key Secondary Endpoints
Complete hematologic response assessed by investigator will be summarized in the ITT 
population.  Complete hematologic response rate will also be summarized in the 
hematologic response-evaluable population. In addition, the binomial test described in 
section 5.8.1.2 as the sensitivity analysis method for primary endpoints will be performed if 
necessary. 
Sensitivity analyses for OS include: 1) adjustment for prognostic factors in Cox regression 
model; 2) unstratified log-rank test and unstratified Cox regression model; 3) Subgroup 
analysis based on prognostic factors. 
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5.8.3   
Other Secondary Efficacy Endpoints and Analyses
Other secondary efficacy parameters include PFS, duration of hematologic response, 
hematologic disease PFS, time to vital organ deterioration or death, vital organ response 
rate, vital organ PFS, TTF, and time to subsequent anticancer therapy. In addition, organ 
response rate and organ PFS will be presented for any involved organ at the baseline.
PFS
PFS is defined as the time from the date of randomization to the date of first documentation 
of hematologic disease progression, or organ (cardiac and renal) progression, or death due to 
any cause, whichever occurs first.
Patients without documentation of hematologic PD and vital organ progression will be 
censored at the date of last hematologic response assessment that is SD or better, or the date
of last vital organ assessment SD or better, whichever occurs last.  
PFS will be analyzed using the similar method as OS.
Duration of Hematologic Response
Duration of hematologic response is defined as the time from the date of first documentation 
of a hematologic PR or better to the date of first documentation of hematologic PD for 
hematologic responders.
Hematologic responders without documentation of hematologic PD will be censored at the 
date of last hematologic response assessment that is SD or better.  
Duration of hematologic response will be summarized descriptively using the Kaplan-Meier 
method.
Hematologic Disease PFS
Hematologic disease PFS is defined as the time from the date of randomization to the date of 
first documentation of hematologic PD, or death due to any cause, whichever occurs first.
Patients without documentation of hematologic PD will be censored at the date of last 
hematologic response assessment that is SD or better.
Hematologic disease PFS will be analyzed using the similar method as OS.
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Time to Vital Organ Deterioration or Death 
Time to vital organ deterioration or death defined as the time from randomization to vital
organ (heart or kidney) deterioration or death, whichever occurs first. Cardiac deterioration 
is defined as the need for hospitalization for heart failure. Kidney deterioration is defined as 
progression to ESRD with the need for maintenance dialysis or renal transplantation.
Patients without documentation of organ deterioration or death will be censored at the date 
of last assessment.
Time to vital organ deterioration or death will be analyzed using the similar method as OS.
Vital Organ Response Rate
Vital organ (heart and kidney) response rate is defined as the proportion of patients who 
achieved vital organ response in the ITT population.  Vital organ response will be assessed 
by the AC using central laboratory results and ISA criteria. Changes from baseline in the 
vital organs will be documented as “response”, “no change”, or “progression”. An overall 
determination of vital organ response will then be documented for the given time point. 

Progression of one of the two vital organs will equate to organ progression

Response of one or two of the involved vital organs with no change from baseline in 
the rest of other involved vital organs will equate to vital organ response

No change from baseline in all involved vital organs will equate to stable organ 
disease. 
The vital organ response rate will be analyzed using the similar method as hematologic 
response rate. 
Vital Organ PFS
Vital organ PFS is defined as the time from the date of randomization to the date of first 
documentation of vital organ progression, or death due to any cause, whichever occurs first.
Patients without documentation of vital organ progression will be censored at the date of last
vital organ assessment SD or better.  
Vital organ PFS will be analyzed using the similar method as OS.
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Time to Treatment Failure
TTF is defined as the time from randomization to the date of first documented treatment 
failure.  The following events are considered as treatment failure:

Death due to any cause

Hematologic progression by AC

Vital organ (cardiac and renal) progression by AC

Hematologic response with stable but clinically morbid organ disease requiring 
additional therapy

Withdrawn from study for any reason
Patients without documentation of treatment failure will be censored at the date of last 
response assessment.
TTF will be analyzed using the similar method as OS.
Time to Subsequent Anticancer Therapy
Time to subsequent anticancer therapy is defined as the time from randomization to the first 
date of subsequent anticancer therapy.
Patients without documented subsequent anticancer therapy will be censored at the date of 
death or last known to be alive. 
Time to subsequent anticancer therapy will be analyzed using the similar method as OS.
Organ Response Rate
Organ response rate is defined as the proportion of patients who achieved organ response in 
the ITT population.  Organ response will be assessed by the AC using central laboratory 
results and ISA criteria. Changes from baseline in any involved organs will be documented 
as “response”, “no change”, or “progression”. An overall determination of organ response 
will then be documented for the given time point. 

Progression of any involved organs will equate to organ progression

Response of any involved organs with no change from baseline in the rest of 
involved organs will equate to vital organ response
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
No change from baseline in all involved organs will equate to stable organ disease. 
The organ response rate will be analyzed using the similar method as hematologic response 
rate. 
Organ PFS
Organ PFS is defined as the time from the date of randomization to the date of first 
documentation of organ progression, or death due to any cause, whichever occurs first.
Patients without documentation of organ progression will be censored at the date of last 
organ assessment SD or better.  
Organ PFS will be analyzed using the similar method as OS.
5.9   
Pharmacokinetic, Pharmacodynamic, and Biomarker Analysis
5.9.1   
Pharmacokinetic Analyses
Plasma concentration-time data will be presented in listings.  PK data will be used to 
perform population PK analysis using a nonlinear mixed effects modeling approach and to 
assess the effect of various covariates on PK after including data from other studies, if 
possible.  The analysis plan for the population PK analysis will be separately defined and the 
results of these analyses will be reported separately.
5.9.2   
Pharmacodynamic Analyses 
Not applicable.
5.9.3   
Biomarker Analysis
Germline DNA Polymorphisms Analysis
Exploratory analysis may examine the association between polymorphisms in the major 
NFκB pathway-related genes and hematologic response and OS.  Characterization of the 
potential effects of genetic variation in these genes on the activity of MLN9708 in 
amyloidosis may require analysis of data from this study in combination with the data from 
other clinical studies of MLN9708.
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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 FACT/GOG-NTX, the symptom questionnaire,
and SF-36, will be analyzed to determine if response to therapy and side effects of therapy 
are accompanied by measurable changes in the PROs.  
The FACT/GOG-NTX (Functional Assessment of Cancer
Therapy/Gynecologic Oncology Group-Neurotoxicity [FACT/GOG-Ntx]) comprises 
11 individual items evaluating symptoms of neurotoxicity on a scale of 0 (not at all) to 
4 (very much).
The symptom scale questionnaire contains 3 items, each rated on an 11-point numerical 
rating scale of symptom severity.  The questionnaire yields individual symptom scores such 
as swelling, shortness of breath, dizziness and lighted headedness, as well as a total 
symptom score.
SF-36 v2 is a multi-purpose, short-form health survey with only 36 questions.  It yields an 
8-scale profile of functional health and well-being scores as well as psychometrically-based 
physical and mental health summary measures.  Physical component summary (PCS) is 
mostly contributed by physical function (PF), role physical (RP), bodily pain (BP), and 
general health (GH).  Mental component summary (MCS) is mostly contributed by mental 
health (MH), role emotional (RE), social function (SF), and vitality (VT). 
ITT population will be used for patient reported outcomes related analyses.
Missing data pattern will be examined by the proportion of missing responses for each 
individual scale, as well as summary scores, over time.
Item-level missing data will be handled based on the instrument developer’s guideline.
SF36 v2 scores will be calculated by software provided by the instrument developer. 
For FACT/GOG-NTX, if there are missing items, subscale scores can be prorated.  This is 
done by multiplying the sum of the subscale by the number of items in the subscale, then 
dividing by the number of items actually answered.  When there are missing data, prorating 
by subscale in this way is acceptable as long as at least 50% of the items were answered.  If 
more than 50% of the items in the subscale are missing, the subscale score will be missing.
Summary statistics of observed values will be presented over time for FACT/GOG-NTX 
(including 11 individual subscales, sensory scale (sum of NTX1-4), and the summary score), 
the symptom questionnaire (including 3 individual symptom scores, and the total symptom 
score) and SF-36 (including PF, RP, BP, GH, MH, RE, SF, VT, PCS, and MCS).  Graphical 
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display will include plot of mean and standard deviation over time for each score by
treatment arms.  
To compare the 2 treatment arms with respect to maximum improvement from baseline in
SF-36 (including PF, RP, BP, GH, MH, RE, SF, VT, PCS, and MCS), as well as symptom 
questionnaire (including 3 individual symptom scores, and the total symptom score), an 
analysis of covariance (ANCOVA) model will be fitted.  Maximum improvement is defined 
as the difference between the best value on study and the baseline value.  Summaries from 
ANCOVA with baseline and other relevant clinical or demographic variables as covariates 
will include F-test p values, mean change scores, and 95% CI for the differences between 
the treatment arms. 
As a sensitivity analysis, a longitudinal model that accounts for repeated measures over 
time, such as mixed model with repeated measures, will be fitted to compare the SF-36 
scores change, as well as the symptom scale questionnaire score change from baseline
between the 2 treatment arms. Different imputation methods for missing data including Last 
Observation Carry Forward (LOCF), random slope model, and pattern mixture model may
be evaluated if appropriate after examining missing data patterns.  
For PCS, MCS, FACT/GOG-NTX, and individual and total symptom score, a graphical 
display with maximum improvement from baseline on the x-axis, and the percent of patients 
experiencing that change on the y-axis will be presented by treatment arms.  These plots will 
be informative to examine the cumulative distribution function (CDF) of responses between 
treatment arms to characterize the treatment effects.  Similar figures will also be presented 
for change from baseline at each planned data collection time point if there are sufficient 
data available.
In addition, patient reported outcome assessments may be analyzed to determine if response 
to therapy and side effects of therapy (such as AE, change from baseline of vital signs and 
key laboratory parameters) are accompanied by measurable changes in the PROs. 
5.10.2   Health Economics (Health Care Resource Use)
EQ-5D scores will be summarized in descriptive statistics for treatment arms. 
HU data will be summarized in descriptive statistics of medical encounters (length of stay, 
inpatient, outpatient, and reason), number of missing days from work or other activities by 
patient and care-giver for treatment arms.
Further modeling will be performed separately at post hoc analyses
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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, 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.
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 treatment drug and through 30 days after the last dose 
of any treatment drug.
AEs will be tabulated according to the MedDRA by system organ class, high level terms and 
preferred terms and will include the following categories:

Treatment-emergent AEs

Drug-related treatment-emergent AEs

Grade 3 or higher treatment-emergent AEs

Grade 3 or higher drug-related treatment-emergent AEs

The most commonly reported treatment-emergent AEs (ie, those events reported by 
10% of patients in either treatment group) 
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.
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An overall summary AE table will include numbers and percentages of patients who had any 
AE, drug-related AE, grade 3 or higher AE, grade 3 or higher drug-related AE, serious AE 
(SAE), drug-related SAE, AE resulting in discontinuation, and on-study deaths.  On-study 
death is defined as the death that occurs between the first dose of any treatment drug and 30 
days of the last dose of any treatment drug.  
5.11.1.2   Serious Adverse Events
The number and percentage of patients experiencing at least one treatment-emergent SAE 
will be summarized by MedDRA primary system organ class, high level term, and preferred 
term. Drug-related SAE will be summarized similarly.
In addition, a by-patient listing of the SAEs will be presented (the patient listing will contain 
all SAEs regardless of treatment-emergent AE status).
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.
Laboratory test results from the central laboratory will be used when they are available.  
Laboratory test results from local laboratory will only be used when no central laboratory 
test results exist at the same scheduled sample collection time point.
If a patient has repeated laboratory values for a given time point, the value from the last 
evaluation will be used.
Laboratory test results will be summarized according to the scheduled sample collection 
time point.  Change from baseline will also be presented. Unscheduled laboratory test 
results will be listed and included in laboratory shift tables.  The parameters to be analyzed 
are as follows:
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
Hematology:  hemoglobin, hematocrit, ANC, ALC, monocytes, eosinophils, 
basophils, platelets, and white blood cell (WBC) count

Serum chemistry:  blood urea nitrogen, creatinine, total bilirubin, uric acid, LDH, 
albumin, alkaline phosphatase, AST, ALT, glucose, calcium, sodium, potassium, 
chloride, CO2, magnesium, phosphate, and PT.
Shift tables will be constructed for laboratory parameters to tabulate changes in NCI 
CTCAE for toxicity (version 4.03) from baseline to post baseline worst CTC grade.  
Parameters to be tabulated will include:

Hematology: ALC, ANC, hemoglobin, platelets, WBC

Serum chemistry: ALT, AST, alkaline phosphatase, creatinine, total bilirubin, 
calcium, CO2, magnesium, potassium, sodium, and phosphate.
Summary statistics will also be presented for shift from baseline urinalysis values.
Box plots over time through Cycle 12 for key lab parameters will be produced, including but 
not limited to ANC, platelets, and liver function tests (ALT/SGPT, AST/SGOT, alkaline 
phosphatase, and total bilirubin).
By-patient listings to be presented include hematology, serum chemistry, urinalysis, urine 
total protein, and urine creatinine.
5.11.3   Electrocardiograms
Descriptive statistics for the actual values and changes from baseline in ECGs will be 
tabulated by time point including any unscheduled measurements.
QTc interval will be calculated using Bazett’s correction and Fridericia’s correction.  The 
formulas are:
QTc (Bazett) = QT / (RR0.5)
QTc (Fridericia) = QT / (RR0.33)
where RR = 60 / heart rate (bpm)
In addition, a categorical analysis of QTc intervals will be performed for each time point.  
The number and percentage of patients in each QTc interval (< 450 msec, 450-480 msec, 
481-500 msec, and > 500msec) will be summarized at baseline and each of the subsequent 
time points.  Categories of changes from baseline (≥ 30 msec and ≥ 60 msec) will be 
summarized as well. 
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Maximum QTc intervals and maximum changes from baseline will also be summarized 
similarly in a separate display.
ECG abnormalities will be presented in a data listing.
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 MLN9708.
6.   
CHANGES TO PLANNED ANALYSES FROM PROTOCOL
Reference materials for this statistical plan include Clinical Study Protocol C16011
(Protocol Amendment 4 dated 09 July 2015).
7.   
PROGRAMMING CONSIDERATIONS
7.1   
Statistical Software 
SAS version 9.1 (or higher) will be used for all analyses.  
7.2   
Rules and Definitions
Patient populations are defined in Section 2.
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Baseline values are defined in Section 5.4.2.
8.   
APPENDIX
8.1   
Appendix 1: Amyloid-Related Hematologic and Organ Criteria 
Amyloid-Related Hematologic and Organ Criteria for Involvement, Stabilization, Response, and 
Progression
Organ 
System
Involvement
Stablea
Response
Progression
Hematologic
Measurable disease 
defined as serum 
differential free light chain 
concentration (dFLC) > 
50mg/dL
dFLC is the difference 
between the amyloid 
forming (involved) and 
nonamyloid forming 
(uninvolved) free light 
chain.
A nephelometric assay 
measures both kappa and 
lambda light chains and  
identifies an excess 
production of  FLC isotype 
produced from the clonal 
plasma cell.  This FLC 
isotype is involved in the 
pathogenic process of 
misfolding into the 
amyloid fibrils. 
No CR, VGPR, PR, no 
progression
Complete Response 
(CR):
Negative serum & urine 
immunofixation, normal 
kappa:lambda FLC ratio, 
Very Good Partial 
Response (VGPR):
dFLC <40 mg/dL
Partial Response (PR):
dFCL decrease > 50%
Progression from CR: 
any detectable 
monoclonal protein or 
abnormal FLC ratio;
involved free light chain 
must double.
Progression from VGPR, 
PR or stable disease: 
Involved free light chain 
increase of 50% to > 10 
mg/dL (100 mg/L) from 
its lowest measured level 
50% increase in serum 
M-protein to > 0.5 g/dL 
from nadir/baseline, or 
50% increase in urine M-
protein to > 200 mg/24 
hours with a visible peak 
present; 
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Involvement of Heart or Kidney (at least one) required for study entry
Cardiac
Echo: mean 
interventricular septal wall 
thickness >12mm, no other 
cardiac cause, or 
NT-proBNP > 332 ng/L in 
the absence of renal failure
Note: a baseline NT-
proBNP 650 ng/L was 
required for NT-proBNP 
response to be evaluable
Stable disease is defined 
when none of the criteria 
for response or for 
worsening disease are met.
NT-proBNP >30% and 
>300 ng/L decrease if 
baseline NT-proBNP 
≥650 ng/L)
Echo: mean 
interventricular septal 
wall thickness decrease 
by 2mm, or
20% improvement in 
LVEF, 
Improvement by > 2 
NYHA classes without 
an increase in diuretic 
use and no increase wall 
thickness, or
Increase in NT-proBNP 
that is both >30% and 
>300 ng/L, or
Echo: interventricular 
septal thickness increased 
by 2mm over baseline, or
An increase in NYHA 
class by 1 grade with 
decreasing LVEF of 
>10%, 
Note: Worsening wall 
thickness and LVEF 
while harbinger of poor 
outcome, not useful 
clinical endpoint
Renal
24- hour protein > 0.5 
g/day, predominantly 
albumin
Stable disease is defined 
when none of the criteria 
for response or for 
worsening disease are met.
At least a 50% reduction 
in 24-hour urine protein 
(must be at least 0.5 
g/day) without worsening 
of creatinine or creatinine 
clearance by 25% over 
baseline
50% increase in urinary 
protein loss (at least 1 
g/24 hours) or 25% 
worsening of creatinine 
or creatinine clearance
Involvement of any of the below allowed in addition to the requirement for involvement of one or more of the above organs
Liver 
Alkaline phosphatase 
value > 1.5 ULN, or 
liver span > 15 cm 
radiographically in the 
absence of heart failure,.  
Stable disease is defined 
when none of the criteria 
for response or for 
worsening disease are met.
>50% decrease in 
alkalaline phosphatase 
from baseline
Decrease in liver size by 
at least 2 cm 
(radioagraphic 
determination
>50% increase of 
alkaline phosphatase 
above lowest level.
Gastrointesti
nal
Direct biopsy verification 
with symptoms such as 
diarrhea, frank bleeding, 
early satiety, 
malabsorption, GI motility 
disturbances, and weight 
loss (BJH 2004)
Stable disease is defined 
when none of the criteria 
for response or for 
worsening disease are met. 
Clinical changes based on 
NCI CTC Version 4.02 
criteria may be useful
Reliable, quantitative 
methods for defining 
response do not to exist.
Improvement in clinical 
findings such as diarrhea, 
motility disturbances and 
weight loss may be 
usefulb
Progression of signs and 
symptoms not 
attributable to therapy 
under study
Nerve, 
Peripheral 
Evidence of amyloid 
involvement alternative 
site plus clinical symptoms 
such as symmetric lower 
extremity sensory 
peripheral neuropathy 
(often with pain) on 
neurologic examination, 
parasthesiae, numbness or 
muscle weakness. Motor 
neuropathy is rare. (BJH 
2004)
Note: EMG and nerve 
conduction velocity are 
relatively insensitive in 
detecting involvement.
Stable disease is defined 
when none of the criteria 
for response or for 
worsening disease are met. 
Clinical changes based on 
NCI CTC Version 4.02 
criteria may be useful.
Reliable, quantitative 
methods for defining 
response do not to exist..
Improvement in clinical 
findings with decrease in 
the Ntx score, signs 
and/or symptoms of 
peripheral neuropathy, 
and decrease in 
neuropathic pain may be 
usefulb
Progressive neuropathy 
not attributable to 
therapy under study.
Progressive neuropathy 
by EMG or nerve 
conduction velocity may 
show progression.
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Nerve, 
Autonomic 
Based on clinical history 
of autonomic dysfunction 
and symptoms such 
orthostasis, gastric 
emptying disorder, early 
satiety, impotence/ erectile 
dysfunction, bowel or 
bladder dysfunction not 
related to direct organ 
infiltrate, anhidrosis or 
gustatory sweating (BJH 
2004) 
Stable disease is defined 
when none of the criteria 
for response or for 
worsening disease are met. 
Clinical changes based on 
NCI CTC Version 4.02 
criteria may be useful
Reliable, quantitative 
methods for defining 
response do not to exist.
Improvement in clinical 
examination findings 
including such symptoms 
as improvement in 
orthostasis and other 
signs and/or symptoms 
related to autonomic 
dysfunctionb
Progression neuropathy 
not attributable to 
therapy under study
Soft tissue 
and 
lymphatic
Based on classic physical 
findings such as:

Macroglossia 
(enlarged tongue),

Arthropathy,

Claudication, 
presumed vascular 
amyloid

Shoulder pad sign, 

Periorbital purpura 
(Raccoon eyes), 

Carpal tunnel 
syndrome, 

Synovial 
enlargement, 

Lymphadenopathy, 
biopsy verification.

Skin thickening

Myopathy by biopsy 
or 
pseudohypertrophy
Stable disease is defined 
when none of the criteria 
for response or for 
worsening disease are met. 
Clinical changes based on 
NCI CTC Version 4.02 
criteria may be useful
Reliable, quantitative 
methods for defining 
response do not to exist.
Clinical changes based
on NCI CTC Version 
4.02 criteria may be 
useful
Progression of signs and 
symptoms not 
attributable to therapy 
under study
Lung
Direct biopsy verification 
with symptoms. Diffuse 
interstitial radiographic 
pattern usually by CT scan
Stable disease is defined 
when none of the criteria 
for response or for 
worsening disease are met. 
Clinical changes based on 
NCI CTC Version 4.02 
criteria may be useful
Reliable, quantitative 
methods for defining 
response do not to exist.
Radiographic 
improvement
Progression of 
radiographic findings not 
attributable to therapy 
under study
a
Unless clinically indicated to check sooner, stabilization of organ function must be confirmed visit in the absence of worsening of 
any other organs unless worsening is considered a treatment-emergent adverse event.
b
Based on NCI CTC Version 4.02 criteria.
8.2   
Appendix 2: 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 
complete hematologic response rate):
With the proposed testing procedure of the two key secondary endpoints (OS and complete 
hematologic response rate), this is to prove the strong control of overall Type I error rate for 
both endpoints at one-sided 0.025 level. 
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To facilitate the probability presentation, we introduce the following notations. Let P, S 
indicate the first and second key secondary, OS and complete hematologic response rate 
(CR). Denote the family of null hypotheses of interest as: 
0
  
:
H
P
P
0


(OS is not 
efficacious); 
0
:
H S
0

S

(CR 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 square root of the CMH chi-square 
test statistics for CR 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 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.
)
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 
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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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8.3
Appendix 3: Amendment 2 Detailed Summary of Changes
THE PRIMARY SECTION(S) OF THE SAP AFFECTED BY THE CHANGES IN 
AMENDMENT 2 ARE INDICATED.  THE CORRESPONDING TEXT HAS BEEN 
REVISED THROUGHOUT THE SAP.
Purpose:  Enroll only proteasome inhibitor naïve patients.
The primary change occurs in Section 1.1, Study Design:
Formerly 
read:
Eligible patients must have: 1) biopsy-proven AL-amyloidosis with relapsed 
or refractory disease despite 1 or 2 prior therapies; 2) disease requiring further 
treatment; 3) measureable disease as defined by serum differential free light 
chain concentration (dFLC); and 4) objective and measurable vital organ 
involvement (ie, cardiac or renal) as defined by the standard International 
Society of Amyloidosis (ISA) criteria.  Patients may be proteasome inhibitor-
exposed or naïve, but cannot be refractory to proteasome inhibitor therapy.  
The definition of relapsed is documented hematologic progressive disease
(PD) after a response to prior therapy [PD more than 60 days of last dose].  
The definition of refractory is documented absence of hematologic response 
or hematologic progression on or within 60 days of last dose of prior therapy.
Now 
reads:
Eligible patients must have: 1) biopsy-proven AL-amyloidosis with relapsed 
or refractory disease despite 1 or 2 prior therapies; 2) disease requiring further 
treatment; 3) measureable disease as defined by serum differential free light 
chain concentration (dFLC); and 4) objective and measurable vital organ 
involvement (ie, cardiac or renal) as defined by the standard International 
Society of Amyloidosis (ISA) criteria.  Patients enrolled based on protocol 
amendment 4 must not have been previously treated with proteasome 
inhibitors. (The Sponsor reserves the right to open the trial to 
proteasome inhibitor-exposed patients in the future, at some time point 
after the first interim analysis [IA].) The definition of relapsed is 
documented hematologic progressive disease (PD) after a response to prior 
therapy [PD more than 60 days of last dose].  The definition of refractory is 
documented absence of hematologic response or hematologic progression on 
or within 60 days of last dose of prior therapy.
Purpose:  Revise statistical decision rules to split alpha between the first and second 
families and remove stopping rule.
The primary change occurs in Section 3.2, Statistical Decision Rules:
Formerly 
read:
Closed sequential testing procedure will be used to strongly control type I 
error rate at 2-sided 0.05 for the primary endpoints and key secondary 
endpoints.  The hypothesis for hematologic response will be tested at the first 
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interim analysis (IA).  If the unstratified Cochran-Mantel-Haenszel (CMH) 
test p value is < 0.05, the null hypothesis will be rejected, and study will 
continue to full enrollment.  Otherwise the study will be deemed unsuccessful 
and terminated.
Hypothesis for 2-year vital organ deterioration and mortality rate will be 
tested at the second IA. If the unstratified CMH test p value is >0.05, no 
further analysis will be conducted and the study will be terminated. If the 
unstratified CMH test p value is <0.05, the null hypothesis will be rejected, 
and the key secondary endpoint OS will be tested at the second IA with 
approximately 120 death events and again at the final analysis (FA) with 
approximately 145 events if necessary.  O’Brien-Fleming boundary will be 
calculated using the Lan-DeMets method.  The information fraction for 
second IA is equal to the number of death events observed divided by 145.  If 
there are exactly 120 death events at second IA, null hypothesis for OS will 
be rejected if the observed p value of the stratified log-rank test is less than 
0.027.  Otherwise OS hypothesis will be tested again at FA.  If the observed p 
value of the stratified log-rank test is less than 0.0423 at FA (corresponding to 
nominal alpha of 0.023); the null hypothesis for OS will be rejected.  
Hypothesis for the second key secondary endpoint, complete hematologic 
response rate, will be tested sequentially when OS hypothesis is rejected 
either at second IA or at FA.  The testing level of significance will be the 
same as those used for OS.  For instance if OS is significant at 0.023 level at 
the FA, complete hematologic response rate will also be tested at 2-sided 
alpha level of 0.023 at the FA.
Now 
reads:
Hematological response will be tested using unstratified Cochran-
Mantel-Haenszel (CMH) test at 0.04 significance level at the first IA; if p 
value is ≤ 0.04, then at the second IA, 2-year vital organ deterioration 
and mortality rate will be tested at 0.05 level; otherwise it will be tested 
at 0.01 level.
Hypothesis for 2-year vital organ deterioration and mortality rate will be 
tested at the second IA. If the test is not significant, the study may still 
continue, however no formal testing will be conducted. If the test is 
significant, the null hypothesis will be rejected, and the key secondary 
endpoint OS will be tested at the second IA. . Using O’Brien-Fleming 
boundaries, if the alpha allocated to OS is 0.05, the trial may be stopped 
for overwhelming efficacy if the observed p value is less than 0.027 at the 
second IA assuming there are exactly 120 death events.  The final 
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analysis (FA) will be tested at 2-sided alpha level of 0.0423 
(corresponding to nominal alpha of 0.023). If the alpha allocated to OS is 
0.01, OS will be tested using a similar approach as above. 
Hypothesis for the second key secondary endpoint, complete hematologic 
response rate, will be tested sequentially when OS hypothesis is rejected 
either at second IA or at FA.  The testing level of significance will be the 
same as those used for OS.  For instance if OS is significant at 0.023 level at 
the FA, complete hematologic response rate will also be tested at 2-sided 
alpha level of 0.023 at the FA.
The type I error for all primary endpoints and key secondary endpoints 
using the testing procedure presented in Figure 1 is strongly controlled.   
Those endpoints are grouped into two ordered families 1) hematologic 
response, and 2) organ deterioration and mortality, OS and CR.  The 
closed sequential testing approach will be used for strong type I error 
rate control in the second family. That is, OS will be only tested using the 
same alpha level assigned to 2-year organ deterioration and mortality 
rate if the test on 2-year organ deterioration and mortality rate is 
statistically significant, and then the alpha assigned to OS is allocated 
using O’Brien-Fleming boundaries for OS tests at second IA and FA; 
and CR will be only tested at the same alpha level of OS at second IA or 
FA, if the test on OS is significant at second IA or FA. For testing the two 
families, the fall-back approach (Wiens B.L., 2003) is used to control type 
I error rate.
Sections that also contain this change are:

Section 4.1, Interim Analysis

Section 5.1, Sample Size Justification

Section 5.8.1.1, Primary Efficacy Analysis
Purpose: Add schema to describe the alpha controlled testing procedure.
The primary change occurs in Section 3.2, Statistical Decision Rules:
Added 
Figure:
Figure 1. Statistical Testing Procedure and Alpha Spending Schema
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Purpose:  Further emphasize the type I error control between family 1 and family 2.
The primary change occurs in Section 3.2, Statistical Decision Rules:
Formerly 
read:
Since the testing of  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 2-sided alpha level, the overall type I error rate for all
endpoints, i.e. both primary and all key secondary endpoints, is also 
controlled strongly at 2-sided 0.05 level.
Now 
reads:
Since in the family 2, the testing of key secondary endpoints is gated by the 
significance of the second primary endpoint, and between family 1 and 
family 2, the type I error rate is controlled at 2-sided alpha level by using the 
fall-back approach, the overall type I error rate for all endpoints, i.e. both 
primary and all key secondary endpoints, is also controlled strongly at 2-sided 
0.05 level.
Sections that also contain this change are:

Section 4.1, Interim Analysis

Section 5.1, Sample Size Justification

Section 5.8.1.1, Primary Efficacy Analysis
Purpose:  Update the sample size, alpha spending, and projected time at interim analysis.
The primary change occurs in Section 4.1, Interim Analysis:
Formerly 
read:
There are two planned formal IAs.  The first IA will be performed when 
approximately 94 patients have been enrolled and have had the opportunity to 
complete 6 cycles of treatment or have discontinued study treatment before 
receiving 6 cycles of treatment. At that time, relevant safety and efficacy data 
from these patients will be queried and cleaned; all analyses at this IA will be 
based on these patients whose data have been cleaned. The study will 
continue only if the test for hematologic response rate is statistically 
significant at 2-sided alpha level of 0.05.  Otherwise, the study will be 
terminated.  This IA is expected to occur approximately 27 months after the 
first patient is enrolled.  During this IA, enrollment to the study will continue. 
If the study continues, the second IA will be performed on 2-year vital organ 
deterioration and mortality rate when approximately 218 patients enrolled 
have had the opportunity to complete 2 years of treatment or have 
discontinued treatment before receiving 2 years of treatment. At that time, 
relevant safety and efficacy data from these patients will be queried and 
cleaned; all analyses at this IA will be based on these patients whose data 
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have been cleaned. This IA is expected to occur approximately 70 months 
after the first patient is enrolled.  
If the test for 2-year vital organ deterioration and mortality rate is significant 
at the second IA, the analyses on OS will be performed and the test 
significance level on OS for the second IA and FA will be determined using 
O’Brien-Fleming boundaries. Assuming there are exactly 120 death events at 
second IA, the trial will be stopped for overwhelming efficacy if the observed 
p value is less than 0.027.  Also at the second IA, the hematologic response 
rate data will be considered as matured and a non-inferential analysis for 
hematologic response rate will be performed.
Now 
reads:
There are two planned formal IAs.  The first IA will be performed when 
approximately 176 patients have been enrolled and have had the opportunity 
to complete 6 cycles of treatment or have discontinued study treatment before 
receiving 6 cycles of treatment.  At that time, relevant safety and efficacy data 
from these patients will be queried and cleaned; all analyses at this IA will be 
based on these patients whose data have been cleaned. This will be the FA 
for hematologic response.  At the first IA, hematologic response will be 
tested using unstratified CMH at a 2-sided alpha level of 0.04.  If the test 
is statistically significant, the study will continue to test organ 
deterioration and mortality rate at a 2-sided alpha of 0.05 at the second 
IA; otherwise organ deterioration and mortality rate will be tested at the 
second IA with a 2-sided alpha of 0.01. This IA is expected to occur 
approximately 54 months after the first patient is enrolled.  During this IA, 
enrollment to the study will continue.                                             
The second IA will be performed when approximately 218 patients enrolled 
have had the opportunity to complete 2 years of treatment or followed up for 
at least 2 years if discontinuing treatment before receiving 2 years of 
treatment.  This IA is expected to occur approximately 98 months from 
the first patient is enrolled.  At that time, relevant safety and efficacy data 
from those patients will be queried and cleaned; all analyses at this IA will be 
based on these patients whose data have been cleaned.
If the test for 2-year vital organ deterioration and mortality rate is significant 
at the second IA, the analyses on OS will be performed and the test 
significance level on OS for the second IA and FA will be determined using 
O’Brien-Fleming boundaries. Assuming there are exactly 120 death events at 
second IA, the trial will be stopped for overwhelming efficacy if the observed 
p value is less than 0.027.  The FA will be tested at 2-sided alpha level of 
0.0423 (corresponding to nominal alpha of 0.023). If the alpha allocated 
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to OS is 0.01, OS will be tested using a similar approach as above using 
O’Brien-Fleming boundaries. 
Sections that also contain this change are:

Section 3.2 Statistical Decision Rules

Section 5.1 Sample Size Justification

Section 5.8.1.1, Primary Efficacy Analysis
Purpose: Update the sample size calculation based on statistical design
The primary change occurs in Section 5.1, Sample Size Justification:
Formerly 
read:
The total sample size was calculated to provide 80% power for the assessment 
of OS.  The study is also adequately powered to test both primary endpoints: 
hematologic response rate and 2-year vital organ deterioration and mortality 
rate. There are two planned IAs and one 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 
26 months, and testing arm median OS of 41.6 months (assuming exponential 
distribution, hazard ratio 0.625).  With 1 IA (second) and 1 FA occurring at 
information time of 0.89 and 1, an average enrollment rate of 3 patient /month 
for the first 5 months, and 5 patient/month thereafter, an additional 28 months 
follow up for all patients after last patient is enrolled, and approximately 10% 
drop out rate, a total of 248 patients will need to be randomized in a 1:1 ratio 
into 2 treatment arms in order to achieve 145 death events.    The O’Brien-
Fleming stopping boundary (Lan-DeMets method) will be used to assign 
alpha level to the second IA and FA.
The parameters used for hematologic response endpoint are a 2-sided test at 
the significance level of α = 0.05, power of 85%, a null hypothesis 
hematologic response rate 45%, and an alternative hypothesis hematologic 
response rate 75%.  Approximately 94 patients are needed for two-sample test 
of the difference of proportions.   Testing for hematologic response 
hypothesis will be performed when approximately 94 patients enrolled have 
had opportunity to either complete 6 cycles of treatment or discontinue 
treatment before receiving 6 cycles of treatment.  This is the first IA for the 
study, also the FA for hematologic response for statistical testing purpose, 
with the opportunity to claim hematologic response rate benefit.  If the test is 
statistically significant in favor of the dexamethasone plus MLN9708 arm, the 
study will continue; otherwise, the study will be terminated. 
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The second IA will be performed when approximately 218 patients enrolled 
have had the opportunity to complete 2 years of treatment or discontinue 
treatment before receiving 2 years of treatment. This will be the FA for 2-year 
vital organ deterioration and mortality rate. With 218 patients, the endpoint of 
2-year vital organ deterioration and mortality rate is powered at 90% at a 2-
sided alpha level of 0.05 with the assumption of 80% deterioration and 
mortality rate in the control arm and 60% rate in the MLN9708 arm. If the 
test for 2-year vital organ deterioration and mortality rate is not significant, 
the study will be terminated; otherwise, OS will be tested. If the test for OS is 
statistically significant, the complete hematologic response rate will be tested 
at the same alpha level as that for OS and the study may be stopped for 
evidence of efficacy; if the test for OS is not statistically significant, the study 
will continue to the FA.
Now 
reads:
The total sample size was calculated to provide 80% power for the assessment 
of OS with the allocated alpha 0.05.  The study is also adequately powered 
to test both primary endpoints: hematologic response rate and 2-year vital 
organ deterioration and mortality rate. There are two planned IAs and one 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 
26 months, and testing arm median OS of 41.6 months (assuming exponential 
distribution, hazard ratio 0.625).  With 1 IA (second) and 1 FA occurring at 
information time of 0.89 and 1, an average enrollment rate of 3 patient /month 
for the first 5 months, and 3-5 patient/month thereafter, an additional 28 
months follow up for all patients after last patient is enrolled, and 
approximately 10% drop out rate, a total of 248 patients will need to be 
randomized in a 1:1 ratio into 2 treatment arms in order to achieve 145 death 
events.    The O’Brien-Fleming stopping boundary (Lan-DeMets method) will 
be used to assign alpha level to the second IA and FA.
The parameters used for hematologic response endpoint are a 2-sided test at 
the significance level of α = 0.04, power of 90%, a null hypothesis 
hematologic response rate 40%, and an alternative hypothesis hematologic 
response rate 65%.  Approximately 176 patients are needed for two-sample 
test of the difference of proportions.   Testing for hematologic response 
hypothesis will be performed when approximately 176 patients enrolled have 
had opportunity to either complete 6 cycles of treatment or discontinue 
treatment before receiving 6 cycles of treatment.  This is the first IA for the 
study, also the FA for hematologic response for statistical testing purpose, 
with the opportunity to claim hematologic response rate benefit.  If the test is 
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statistically significant in favor of the dexamethasone plus MLN9708 arm, 
the second IA for organ deterioration and mortality will be tested at 2-
sided α = 0.05 based on fallback approach, otherwise it’ll be tested at 2-
sided α = 0.01.
The second IA will be performed when approximately 218 patients enrolled 
have had the opportunity to complete 2 years of treatment or discontinue 
treatment before receiving 2 years of treatment. This will be the FA for 2-year 
vital organ deterioration and mortality rate. With 218 patients, the endpoint of 
2-year vital organ deterioration and mortality rate is powered at 90% at a 2-
sided alpha level of 0.05 with the assumption of 80% deterioration and 
mortality rate in the control arm and 60% rate in the MLN9708 arm. If first 
IA result is not significant, power of 2-year vital organ deterioration and 
mortality rate will be 74% at a 2-sided alpha level of 0.01. If the test for 2-
year vital organ deterioration and mortality rate is not significant, there will 
not be any formal testing; otherwise, OS will be tested. If the test for OS is 
statistically significant, the complete hematologic response rate will be tested 
at the same alpha level as that for OS and the study may be stopped for 
evidence of efficacy; if the test for OS is not statistically significant, the study 
will continue to the FA. 
Sections that also contain this change are:

Section 3.2, Statistical Decision Rules

Section 4.1, Interim Analysis

Section 5.8.1.1, Primary Efficacy Analysis
Purpose:  Update the decision rules as 2-year vital organ deterioration and mortality rate 
is the second primary endpoint and OS is the first key secondary endpoint.
The primary change occurs in Section 5.8.1.1, Primary Efficacy Analysis:
Formerly 
read:
The unstratified CMH test will be used to compare hematologic response rate 
between the 2 treatment arms when 94 ITT patients have had the opportunity 
to receive 6 cycles of treatment, or discontinued treatment prior to 6 cycles.  
If the hematologic response rate is higher in the dexamethasone plus 
MLN9708 arm (arm A), and the 2-sided CMH test p value is < 0.05, null 
hypothesis will be rejected.  Therefore statistical significance will be claimed 
for dexamethasone plus MLN9708.
…
The unstratified CMH test will be used to make comparisons between the 2 
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treatment arms at the second IA when approximately 218 patients enrolled 
have had the opportunity to complete 2 years of treatment or have 
discontinued treatment before receiving 2 years of treatment.  If the 2-year 
organ deterioration and mortality rate is lower in the dexamethasone plus 
MLN9708 arm (arm A), and the 2-sided CMH test p value is < 0.05, null 
hypothesis will be rejected.  Therefore statistical significance will be claimed 
for dexamethasone plus MLN9708.
Now 
reads:
The unstratified CMH test will be used to compare hematologic response rate 
between the 2 treatment arms when 176 ITT patients have had the opportunity 
to receive 6 cycles of treatment, or discontinued treatment prior to 6 cycles.  
If the hematologic response rate is higher in the dexamethasone plus 
MLN9708 arm (arm A), and the 2-sided CMH test p value is ≤ 0.04, null 
hypothesis will be rejected.  Therefore statistical significance will be claimed 
for dexamethasone plus MLN9708.
...
The unstratified CMH test will be used to make comparisons between the 2 
treatment arms when approximately 218 patients enrolled have had the 
opportunity to complete 2 years of treatment or have discontinued treatment 
before receiving 2 years of treatment.  If the 2-yaer organ deterioration and 
mortality rate is lower in the dexamethasone plus MLN9708 arm (arm A), 
and the 2-sided CMH test p value is ≤ 0.05 when hematologic response 
endpoint is significant or ≤ 0.01 when hematologic response endpoint is 
not significant, null hypothesis will be rejected.  Therefore statistical 
significance will be claimed for dexamethasone plus MLN9708.
Sections that also contain this change are:

Section 3.2, Statistical Decision Rules

Section 4.1,Interim Analysis

Section 5.1,Sample Size Justification
Purpose:  Reduce redundant information.
The primary change occurs in Section 2.3, Safety Population:
Deleted 
text:
The safety population is defined as all patients who receive at least 1 dose of 
any treatment drug.  Patients will be analyzed according to the treatment 
actually received.  That is, those patients who are randomized to Arm B but 
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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.
Purpose:  Update CR criteria based on C16011 Protocol amendment 4.
The primary change occurs in Section 8.1 Appendix 1
Deleted 
text:
Complete Response (CR):
Negative serum & urine immunofixation, normal kappa:lambda FLC ratio, 
<5% plasma cells in bone marrow without clonal dominance
Section 5.6.3, Baseline Disease Status, also contain this change.
Purpose:  Update CR criteria based on C16011 Protocol amendment 4.
The primary change occurs in 5.6.3 Baseline Disease Status:
Deleted 
text:
Baseline disease status will be summarized by the treatment arms in the ITT 
population, including time since initial diagnosis (months), type and number 
of organ involvement, type and quantity of involved free light chain, dFLC, 
serum κ/λ ratio, serum and urine m-protein quantity, serum and urine 
immunofixation results, % plasma cell in bone marrow core biopsy and/or 
aspirate, skeletal survey results, cardiac biomarker stage, Eastern Cooperative 
Oncology Group (ECOG) performance status, ß2-microglobulin, serum 
creatinine, serum creatinine clearance, total urine creatinine, urine creatinine 
clearance, serum albumin, alkaline phosphatase, ALT, AST, serum cardiac 
markers (NT-proBNP, BNP, troponin T), NYHA classification, and other
parameters as appropriate.  Separate by-patient listings will also be presented.
Section 8.1, Appendix 1, also contain this change.
Purpose:  Correct typographical errors, punctuation, grammar, and formatting
These changes are not listed individually.
8.4   
Rationale for Amendment 1 
The main purpose of this amendment is to incorporate the statistically-relevant changes in 
Protocol C16011, amendment 1, dated 01 June 2012.  
Purposes for amendment 1 are to:

Change the second primary endpoint from overall survival (OS) to 2-year vital organ 
(that is, heart or kidney) deterioration and mortality rate

Include OS as a key secondary endpoint
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
Remove liver from the list of vital organs with amyloid involvement required at 
study entry 

Revise definitions of relapsed and refractory disease to clarify 60-day period

Replace reference to Medical Resource Utilization (MRU) with Health Utilization 
(HU) to reflect the Sponsor’s updated terminology

Replace reference to Independent Review Committee with Adjudication Committee 
to accurately reflect how hematologic and organ response and vital organ 
deterioration will be assessed

Add hypothesis for 2-year vital organ deterioration and mortality rate; remove 
hypothesis for organ response and stabilization rate 

Update the decision rules as 2-year vital organ deterioration and mortality rate is the 
second primary endpoint and OS as the first key secondary endpoint 

Provide distribution of strong control of type I error control for key secondary 
endpoints and critical value calculation for complete hematologic response rate once 
OS is statistically significant at the final analysis

Update sample size calculation on OS due to different information fraction between 
second interim analysis and final analysis, and different assumption on enrollment 
rate 

Provide sample size calculation on 2-year vital organ deterioration and mortality 
rate; Add one non-inferential analysis for hematologic response rate at the second 
interim analysis

Clarify the definition of missing data and statistical methods to deal with missing 
data in primary analysis  

Provide the formula to calculate creatinine clearance 

Provide the formula to calculate months since diagnosis  

Add the populations for analysis at interim analyses

Provide primary efficacy analysis for 2-year vital organ deterioration and mortality 
rate 

Add 2 additional sensitivity analyses for primary endpoints 

Update sensitivity analyses for key secondary efficacy analysis 

Add time to vital organ deterioration or death, vital organ response rate, organ 
response rate, and organ PFS as additional regular secondary efficacy endpoints and 
analysis 

Add Appendix 2 for the proof of strong control of Type I error rate for both 
secondary endpoints  

Correct typographical errors, punctuation, grammar, and formatting
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ELECTRONIC SIGNATURES 
 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C16011 Statistical Analysis Plan Amend 2 2015-07-14
Clinical Approval
15-Jul-2015 17:37
Biostatistics Approval
15-Jul-2015 17:46
Statistical Approval
15-Jul-2015 17:51
Clinical Science Approval
15-Jul-2015 19:30
Biostatistics Approval
15-Jul-2015 20:41
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