Clinical trial NCT02046070
Conditions: Multiple Myeloma
Keywords: MLN9708 Newly diagnosed NDMM IXAZOMIB RRMM
Sponsor: Millennium Pharmaceuticals, Inc.
Start date: 2014-03-05; Completion date: 2018-06-29
Enrollment: 148 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a phase 2, multicenter, open-label study in patients with Newly Diagnosed Multiple Myeloma (NDMM) who have not received prior systemic treatment for multiple myeloma (MM) and who are ineligible for high-dose therapy (HDT)-stem cell transplantation (SCT) due to age (ie, ≥ 65 years) or comorbid disease(s) or with Relapsed and/or Refractory Multiple Myeloma (RRMM).

Detailed description:
The investigational drug being tested in this study is called MLN9708 also known as Ixazomib. This study will look at disease response rates and safety in people who take ixazomib in addition to cyclophosphamide and dexamethasone. NDMM participants will be randomly assigned (by chance, like flipping a coin) to one of two treatment groups and RRMM participants will be assigned to a third group:

* NDMM - ixazomib (MLN9708) 4.0 mg + cyclophosphamide 300 mg/m\^2 + dexamethasone 40 mg
* NDMM - ixazomib (MLN9708) 4.0 mg + cyclophosphamide 400 mg/m\^2 + dexamethasone 40 mg
* RRMM - ixazomib (MLN9708) 4.0 mg + cyclophosphamide 300 mg/m\^2 + dexamethasone 40 mg

The study enrolled 148 participants. This multi-centre trial will be conducted in the United States, European Union, and Australia.

Arms: arm 1: Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 15 of a 28-day cycle until progressive disease (PD)/death or unacceptable toxicity \[13 cycles in the Induction Phase continuing in the Maintenance Phase for up to 36 Months\] and cyclophosphamide (CYC) 300 mg/m\^2, tablets, orally, on Days 1, 8 and 15 of a 28-day cycle for 13 cycles or until PD/death or unacceptable toxicity and dexamethasone (DEX) 40 mg, tablets, orally, on Days 1, 8, 15 and 22 (dose reduced to 20 mg for patients \>75 years) of a 28-day cycle for 13 cycles or until PD/death or unacceptable toxicity in participants with NDMM. arm 2: Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 15 of a 28-day cycle until PD/death or unacceptable toxicity \[13 cycles in the Induction Phase continuing in the Maintenance Phase for up to 36 Months\] and cyclophosphamide (CYC) 400 mg/m\^2, tablets, orally, on Days 1, 8 and 15 of a 28-day cycle for 13 cycles or until PD/death or unacceptable toxicity and dexamethasone (DEX) 40 mg, tablets, orally, on Days 1, 8, 15 and 22 (dose reduced to 20 mg for patients \>75 years) of a 28-day cycle for 13 cycles or until PD/death or unacceptable toxicity in participants with NDMM. arm 3: Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 15 of a 28-day cycle and cyclophosphamide 300 mg/m\^2, tablets, orally, on Days 1, 8 and 15 of a 28-day cycle and dexamethasone (DEX) 40 mg, tablets, orally, on Days 1, 8, 15 and 22 (dose reduced to 20 mg for patients \>75 years) of a 28-day cycle until PD/death or unacceptable toxicity in participants with RRMM.
Interventions: intervention 1: Cyclophosphamide intervention 2: Ixazomib intervention 3: Dexamethasone
Intervention descriptions: intervention 1: Cyclophosphamide tablets intervention 2: Ixazomib capsules intervention 3: Dexamethasone tablets

Protocol documents:
Prot_001.pdf: 


•
Title: An Open-Label, Phase 2 Study to Evaluate the Oral Combination of MLN9708 With 
Cyclophosphamide and Dexamethasone In Patients With Newly Diagnosed or Relapsed and/or 
Refractory Multiple Myeloma Requiring Systemic Treatment
NCT Number: NCT02046070
Protocol Approve Date: 6 May 2014
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.


MLN9708
Clinical Study Protocol C16020 Amendment 1, EudraCT Number:  2013-003113-17 
1
CLINICAL STUDY PROTOCOL C16020 AMENDMENT 1
MLN9708
An Open-Label, Phase 2 Study to Evaluate the Oral Combination of MLN9708 With 
Cyclophosphamide and Dexamethasone In Patients With Newly Diagnosed or Relapsed
and/or Refractory Multiple Myeloma Requiring Systemic Treatment
Protocol Number:
C16020
Indication:
Newly Diagnosed or Relapsed and/or Refractory Multiple 
Myeloma
Phase:
2
Sponsor:
Millennium Pharmaceuticals, Inc.
EudraCT Number:
2013-003113-17 
Therapeutic Area:
Oncology
Protocol History
Original
23 July 2013
Amendment 1
6 May 2014
Millennium Pharmaceuticals, Inc.
40 Landsdowne Street
Cambridge, MA  USA  02139
Telephone:  
Approved by:
Note:  If this document was approved electronically, the electronic approval signatures may 
be found at the end of the document.
, MD
, Clinical Research (or 
designee)
Signature
Date DD Month YYYY
, MD
(or designee)
Signature
Date DD Month  YYYY
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.


MLN9708
Clinical Study Protocol C16020 Amendment 1, EudraCT Number:  2013-003113-17 
2
Rationale for Amendment 1
The protocol is being amended to allow for the enrollment of patients with relapsed and/or 
refractory multiple myeloma (RRMM) into the study and the evaluation of oral MLN9708 
when added to a regimen of cyclophosphamide and low-dose dexamethasone (Cd) in this 
patient population.  Consequently, study objectives and endpoints are added and study 
procedures described for this patient population.  The amendment also contains minor 
updates in study procedures to improve protocol clarity and compliance and align the study 
conduct with the sponsor’s current guidelines and practices.  
Purposes for Amendment 1
The purposes of this amendment are to:

Revise the protocol title to reflect the added population of patients with RRMM 

Revise the Study Overview Diagram to include the patient population with RRMM  

Clarify the description of VELCADE/cyclophosphamide/dexamethasone (VCD) as a 
therapeutic option for frontline treatment of patients with multiple myeloma  

Update the details of the clinical experience with MLN9708

Add a brief description of treatment options and prognosis for patients with RRMM  

Provide a rationale for adding patients with RRMM to the study

Revise the description of the study purpose to include patients with RRMM

Add the RRMM population to the discussion of the rationale for the combination 
therapy under evaluation in the study

Add the RRMM population to the discussion of dose intensity schedules for 
cyclophosphamide

Add the primary study objective for patients with RRMM and delineate the primary 
objective for the 2 patient populations

Add the secondary study objectives for patients with RRMM and delineate the 
secondary objectives for the 2 patient populations

Remove the European Organization for Research and Treatment of Cancer (EORTC) 
Multiple Myeloma Module (MY-20) from the assessments to determine changes in 
global health status

Describe the tertiary/exploratory objectives for the 2 patient populations and add an 
additional tertiary objective of health care utilization assessments

Align the primary, secondary, and tertiary study endpoints with the primary, secondary,
and tertiary study objectives

Clarify the study design for patients with newly diagnosed multiple myeloma (NDMM) 
and describe the study design for patients with RRMM

Revise the anticipated number of enrolled patients and investigative sites

Revise the description for anticipated duration of study and timing of the clinical study 
report

Add patients with RRMM to the description of the study population and clarify the 


MLN9708
Clinical Study Protocol C16020 Amendment 1, EudraCT Number:  2013-003113-17 
3
inclusion criteria for the 2 patient populations

Describe the inclusion criteria that pertain to both patient populations (NDMM and 
RRMM)

Add the pregnancy prevention guidelines for cyclophosphamide and dexamethasone

Clarify the exclusion criteria for the 2 patient populations

Revise and update the guidelines for study drug administration

Describe and clarify the MLN9708 administration guidelines for the 2 patient 
populations

Describe and clarify the cyclophosphamide administration guidelines for the 2 patient 
populations

Describe and clarify the dexamethasone administration guidelines for the 2 patient 
populations

Clarify the study enrollment guidelines for the 3 treatment arms

Describe and/or clarify the dose modification guidelines for the 3 treatment arms

Clarify the permitted medications and procedures for patients in the 3 treatment arms

Revise and update the subheading pertaining to infection and add transverse myelitis to 
the discussion of clinical events for MLN9708

Revise the description of capsule sizes and capsule colors for MLN9708 to align with 
the certificate of analysis provided by the manufacturer

Clarify MLN9708 preparation, reconstitution, and dispensation guidelines

Clarify the storage, handling, and accountability requirements for MLN9708

Clarify and/or define treatment assignments for the 3 treatment arms

Clarify timing for performing study procedures

Clarify that assessment of comorbid conditions pertains to patients with NDMM only 
(Arms A and B)

Clarify the guidelines for monitoring of peripheral neuropathy (PN) and PN-related 
events for the 2 patient populations

Revise the definition of enrollment in the study for the 3 treatment arms

Clarify the guidelines for clinical laboratory evaluations

Clarify the procedure for performing the skeletal survey at screening

Clarify that the blood sample for genotyping is optional and not required for study 
enrollment

Revise and clarify disease response assessments for the 3 treatment arms

Add description of health care utilization assessments

Clarify follow-up assessments for progression-free survival and serious adverse event 
(SAE) reporting during follow-up

Describe and/or clarify the statistical considerations to determine sample size for the 
2 patient populations (NDMM and RRMM)

Revise and clarify the randomization or enrollment process for the 3 treatment arms


MLN9708
Clinical Study Protocol C16020 Amendment 1, EudraCT Number:  2013-003113-17 
4

Revise the description of analysis populations

Revise the proposed pooling of the study data and presentation of study results for the 
3 treatment arms

Add text to clearly delineate the primary efficacy endpoint for the 2 patient populations

Revise and update the description of secondary study endpoints

Describe the analysis of health care utilization data

Revise and update the description of safety analysis

Revise the description of assessments pertaining to drug exposure

Revise and update stopping rules for patients in the 3 treatment arms

Update the SAE Reporting contact information to align with the sponsor’s current 
guidelines and practices

Revise and update the reporting guidelines for new malignancies

Add a Schedule of Events for patients enrolled in Arm C (patients with RRMM)

Revise and update footnotes in the Schedule of Events to clarify study procedures

Add health care utilization assessments to the Schedule of Events (NDMM)

Revise table title for the PK sampling schedule to include all 3 treatment arms

Revise and update the timing of predose PK assessments

Correct typographical errors, punctuation, grammar, and formatting
For specific examples of changes in text and where the changes are located, see 
Section 14.8.


MLN9708
Clinical Study Protocol C16020 Amendment 1, EudraCT Number:  2013-003113-17 
5
PROTOCOL SUMMARY
Study Title:  An Open-Label, Phase 2 Study to Evaluate the Oral Combination of MLN9708 With 
Cyclophosphamide and Dexamethasone In Patients With Newly Diagnosed or Relapsed and/or 
Refractory Multiple Myeloma Requiring Systemic Treatment
Number of Patients:  It is anticipated that approximately 148 patients, 70 patients with newly 
diagnosed multiple myeloma (NDMM) and 78 patients with relapsed and/or refractory multiple 
myeloma (RRMM), will be enrolled in the study.  
Study Objectives
Primary:  
For Patients With Newly Diagnosed Multiple Myeloma (NDMM)

To determine the combined response rate of complete response (CR) (including stringent CR
[sCR]) + very good partial response (VGPR) following treatment with oral MLN9708 when 
added to a regimen of cyclophosphamide and low-dose dexamethasone (Cd) during the 
induction phase.
For Patients With Relapsed and/or Refractory Multiple Myeloma (RRMM)

To determine overall response rate (ORR) following treatment with oral MLN9708 when 
added to a regimen of Cd.
Secondary:
For Patients With NDMM

To evaluate the tolerability and toxicity of the combination of oral MLN9708 and Cd

To characterize the pharmacokinetics (PK) in plasma of oral MLN9708 in combination with 
Cd

To determine overall response rate (ORR) (CR + VGPR + PR), CR, VGPR, and PR during 
the induction phase and the ORR (CR + VGPR + PR), CR + VGPR, CR, VGPR, and PR 
throughout the entire treatment period  

To determine time to response for patients who respond during the induction phase

To determine duration of response (DOR) for patients who respond during the induction 
phase

To determine time to progression (TTP)

To evaluate progression-free survival (PFS)

To describe the safety, tolerability, and efficacy of MLN9708 as maintenance therapy in 
patients who continue treatment beyond 13 cycles of induction therapy

To assess change in global health status, as measured by the patient-reported outcome (PRO) 
instruments European Organization for Research and Treatment of Cancer (EORTC) Quality 
of Life Questionnaire (QLQ-C30).
For Patients With RRMM

To evaluate the tolerability and toxicity of the combination of oral MLN9708 and Cd 


MLN9708
Clinical Study Protocol C16020 Amendment 1, EudraCT Number:  2013-003113-17 
6

To characterize the PK in plasma of oral MLN9708 in combination with Cd

To determine CR + VGPR, CR, VGPR, and PR

To determine time to response for patients who respond

To determine DOR for patients who respond with a best response of a CR, VGPR or PR

To determine TTP

To evaluate PFS

To assess change in global health status, as measured by the PRO instruments, EORTC
QLQ-C30.
Exploratory:
For Patients With NDMM and Patients with RRMM:


ccurs, by 
whichever comes first
ession or rib fractures], irradiation of or 
Overview of Study Design:  This is a phase 2 study in patients with NDMM who have not received 
prior systemic treatment for multiple myeloma (MM) and are ineligible for high-dose therapy
(HDT)-stem cell transplantation (SCT) due to age or comorbid disease(s), and in patients with 
RRMM who have received 1 to 3 lines of prior therapy and whose disease is not refractory to 
proteasome inhibitors.  
Patients With NDMM (Arms A and B):  
In patients with NDMM, MLN9708 in combination with Cd will be explored as induction therapy 
for approximately 1 year (13 28-day cycles).  Eligible patients will be randomized 1:1 to either 
Arm A or Arm B.
The safety and efficacy of a weekly planned dose of MLN9708 (4.0 mg) administered orally on 
Days 1, 8, and 15 in combination with cyclophosphamide (300 mg/m2 [Arm A] OR 400 mg/m2
[Arm B] both on Days 1, 8, and 15) and dexamethasone (40 mg on Days 1, 8, 15, and 22; 20 mg for 
patients 75 years of age) of a 28-day cycle will be evaluated.  
The study will begin with a safety lead-in evaluation performed after at least 6 patients from each 
arm have had the opportunity to complete at least 1 cycle of therapy.  Dose-limiting toxicities 
(DLTs) observed in the first 6 patients from each treatment arm will be used to determine the safety 


MLN9708
Clinical Study Protocol C16020 Amendment 1, EudraCT Number:  2013-003113-17 
7
and overall tolerability of the regimen and the feasibility of continued recruitment to the study.  
At the end of the induction phase, patients who have at least stable disease with an acceptable 
toxicity profile will continue treatment in the maintenance therapy phase of the study.  Patients will 
be administered single-agent MLN9708 only (at the dose tolerated at the end of induction) on 
Days 1, 8, and 15 of 28-day cycles as maintenance until disease progression, death or unacceptable 
toxicity.
Patients With RRMM (Arm C)
The safety and efficacy of MLN9708 in combination with Cd will also be explored in patients with 
RRMM.  Eligible patients with relapsed and/or refractory disease will be enrolled in Arm C.  
Enrolled patients will receive a weekly planned dose of MLN9708 4.0 mg on Days 1, 8, and 15 
administered orally in combination with cyclophosphamide 300 mg/m2 on Days 1, 8, and 15 and 
dexamethasone (40 mg on Days 1, 8, 15, and 22; 20 mg for patients 75 years of age) of a 28-day 
cycle.  Patients with an acceptable toxicity profile will continue treatment until they experience 
disease progression, death or unacceptable toxicity.  
A safety lead-in evaluation will be performed after at least 6 patients with RRMM have had the 
opportunity to complete at least 1 cycle of therapy.  DLTs observed in the first 6 patients in this 
treatment arm will be used to determine the safety and overall tolerability of the study regimen and 
the feasibility of continued recruitment of patients to Arm C.  
Study Population:
Patients With NDMM (Arms A and B)  
Adult patients with a confirmed diagnosis of symptomatic MM who have received no prior 
antimyeloma treatment and who are not candidates for HDT-SCT due to age (65 years) or 
comorbidities.  
Patients With RRMM (Arm C)
Adult patients with a confirmed diagnosis of symptomatic MM and relapsed and/or refractory 
disease (RRMM) after 1 to 3 lines of prior therapy and whose disease is not refractory to proteasome 
inhibitors.  
All enrolled patients must have an Eastern Cooperative Oncology Group (ECOG) status of 0 to 2 and 
adequate renal, hepatic, cardiac, and hematological function/status.  Patients with Grade 1 peripheral 
neuropathy (PN) with pain or Grade 2 or higher PN of any cause on clinical examination will be 
excluded.
Duration of Study:  It is anticipated that the total duration of the study will be approximately 
60 months.  This includes approximately 24 months of enrollment and up to 36 months of treatment 
and/or PFS follow-up.  


MLN9708
Clinical Study Protocol C16020 Amendment 1, EudraCT Number:  2013-003113-17 
8
STUDY OVERVIEW DIAGRAM
Screening:  Patients with NDMM
Randomization 1:1
ARM A
(Safety Lead-in 
Evaluation, N = 6)a
Induction
MLN9708
4.0 mg PO
Days 1, 8, and 15
+
Cyclophosphamideb
300 mg/m2 PO
Days 1, 8, and 15
+
Dexamethasone
40 mg POc
Days 1, 8, 15, and 22
Repeat every 28 days for 
13 cycles in the absence of 
PD/death or unacceptable 
toxicity
ARM B
(Safety Lead-in 
Evaluation, N = 6)a
Induction
MLN9708
4.0 mg PO
Days 1, 8, and 15
+
Cyclophosphamide
400 mg/m2 PO
Days 1, 8, and 15
+
Dexamethasone
40 mg POc
Days 1, 8, 15, and 22
Repeat every 28 days for 
13 cycles in the absence of 
PD/death or unacceptable 
toxicity
Maintenance
Single-agent MLN9708 at dose tolerated at the end of 
induction
Days 1, 8, and 15
Repeat every 28 days until PD/death or unacceptable 
toxicity
End of Treatment
Follow-up:  PFS
ARM C
(Safety Lead-in 
Evaluation, N = 6)a
MLN9708
4.0 mg PO
Days 1, 8, and 15
+
Cyclophosphamide
300 mg/m2 PO
Days 1, 8, and 15
+
Dexamethasone
40 mg POc
Days 1, 8, 15, and 22
Repeated every 28 days 
until PD/death or 
unacceptable toxicity. 
Screening:  Patients with 
RRMM
End of Treatment
Follow-up:  PFS
Abbreviations:  NDMM = newly diagnosed multiple myeloma; PD = progressive disease; 
PFS = progression-free survival; PO = orally; RRMM = relapsed and/or refractory multiple myeloma.
a The safety evaluation will be performed after at least 6 patients in each arm have had the opportunity to 
complete Cycle 1 of therapy.
b Intrapatient dose escalation is not planned; however, it may be considered for Arm A depending on the 
safety profile and efficacy observed for Arm B during induction.
c Patients over 75 years of age at the time of enrollment will receive a reduced dexamethasone dose of 20 mg.


MLN9708
Clinical Study Protocol C16020 Amendment 1, EudraCT Number:  2013-003113-17 
9
SCHEDULE OF EVENTS:  ARMS A AND B (NDMM)
SCHEDULE OF EVENTS:  ARMS A and B (NDMM)
Study Procedures
Screeninga
Treatment Period
(28-Day Cycles)
End of Treatmentd
PFS
Follow-upe
INDUCTIONb
CYCLES 1-13
MAINTENANCEb
CYCLE 14 and BEYOND
Day 1c
Day 8
Day 15
Day 22
Day 1
Cycles 14, 15 Only
Days 8, 15, 22
Every 
8 Weeks
Window
-28 to -1
± 1 Week
± 1 Week
Informed Consent
X
Inclusion/Exclusion Criteria 
X
Demographics
X
Complete Medical History and 
Disease Staging
X
Assessment of Comorbid Condition(s)
X
Physical Examf
X
X
Symptom-directed Physical Exam
X
X
Neurologic Assessmentg
X
X
X
X
X
ECOG Performance Status
X
X
X
X
Vital Signs
X
X
X
X
Height (cm)
X
Weight (kg), BSAh
X
Xh
X
X
Serum Pregnancy Testi
X
X
X
12-Lead ECGj
X
Xj
Xj
Hematologyk,l
X
Xk
X
X


MLN9708
Clinical Study Protocol C16020 Amendment 1, EudraCT Number:  2013-003113-17 
10
SCHEDULE OF EVENTS:  ARMS A and B (NDMM)
Study Procedures
Screeninga
Treatment Period
(28-Day Cycles)
End of Treatmentd
PFS
Follow-upe
INDUCTIONb
CYCLES 1-13
MAINTENANCEb
CYCLE 14 and BEYOND
Day 1c
Day 8
Day 15
Day 22
Day 1
Cycles 14, 15 Only
Days 8, 15, 22
Every 
8 Weeks
Window
-28 to -1
± 1 Week
± 1 Week
Cycles 1-3
Xk
X
X
X
Cycles 4-13
Xk
Xk
Clinical Chemistryk
X
Xk
X
Cycles 1-3
Xk
X
X
X
Cycles 4-13
Xk
Urinalysism
X
Xm
QOL Assessmentsn
(EORTC QLQ-C30)
X
X
X
X
X
Health Care Utilization Assessmentn
X
X
X
X
Skeletal Survey
X
Once annually for all patients and at the discretion of the investigatorn
Radiographic Disease Assessment for 
Extramedullary Plasmacytoma
X
Xp
Xp
X
X
2-microglobulin
X
M-protein Measurements (SPEP)q
X
X
X
X
X
M-protein Measurements (UPEP 
[24-hr Urine Collection])q
X
X
X
X
X
Serum Free Light Chain Assayq
X
X
X
X
X
Immunofixation - Serum and Urineq
X
X
X
X
X
Quantification of Igq
X
X
X
X
X


MLN9708
Clinical Study Protocol C16020 Amendment 1, EudraCT Number:  2013-003113-17 
11
SCHEDULE OF EVENTS:  ARMS A and B (NDMM)
Study Procedures
Screeninga
Treatment Period
(28-Day Cycles)
End of Treatmentd
PFS
Follow-upe
INDUCTIONb
CYCLES 1-13
MAINTENANCEb
CYCLE 14 and BEYOND
Day 1c
Day 8
Day 15
Day 22
Day 1
Cycles 14, 15 Only
Days 8, 15, 22
Every 
8 Weeks
Window
-28 to -1
± 1 Week
± 1 Week
Skeletal-related Events
Recorded from the first dose of drug in the study drug regimen until progressive disease
New Primary Malignancy Assessment
Continuous from the start of study drug regimen until death or termination of the study by the sponsor
AE Reportinge
Recorded from the first dose of drug in the study drug regimen through 30 days after last dose of
drug in the study drug regimen
Serious adverse events and serious pretreatment events will be collected from signing of the
informed consent form through 30 days after the last dose of drug in the study drug regimen
Concomitant Medications/Procedures
Recorded from the first dose of drug in the study drug regimen through 30 days after last dose of
drug in the study drug regimen
Abbreviations:  AE = adverse event; BMA = bone marrow aspirate; BSA = body surface area; C1D1 = Cycle 1, Day 1; CR = complete response; 
CT = computed tomography; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EMD = extramedullary disease; 
EORTC = European Organization for Research and Treatment of Cancer; EOT = end of treatment; Ig = immunoglobulin; MM = multiple myeloma; 
MRD = minimal residual disease; MRI = magnetic resonance imaging; OS = overall survival; PD = progressive disease; PET = positron emission 
tomography; PFS = progression-free survival; PN = peripheral neuropathy; PR = partial response; QLQ-C30 = Quality of Life Questionnaire; 
QOL = quality of life; SAE = serious adverse event; SPEP = serum protein electrophoresis; TEAE = treatment-emergent adverse event; UPEP = urine 
protein electrophoresis; VGPR = very good partial response.
Tests and procedures should be performed on schedule, but occasional changes may be allowed (± 3 days) for holidays, vacations, and other administrative 
reasons.  If the study schedule is shifted, both assessments and dosing must be shifted to ensure collection of assessments is completed prior to dosing.  If 
extenuating circumstances prevent a patient from beginning treatment or completing a scheduled procedure or assessment within this time, the patient may 
continue the study only with the permission of the Millennium project clinician or designee.
a Evaluations during the Screening period are to be conducted within 28 days before randomization, unless otherwise noted.  The date of randomization or 
enrollment should be within 7 days of Cycle 1, Day 1 (C1D1).  
b During induction and maintenance, there will be a 3-day window for study visits unless otherwise noted.


MLN9708
Clinical Study Protocol C16020 Amendment 1, EudraCT Number:  2013-003113-17 
12
SCHEDULE OF EVENTS:  ARMS A and B (NDMM)
Study Procedures
Screeninga
Treatment Period
(28-Day Cycles)
End of Treatmentd
PFS
Follow-upe
INDUCTIONb
CYCLES 1-13
MAINTENANCEb
CYCLE 14 and BEYOND
Day 1c
Day 8
Day 15
Day 22
Day 1
Cycles 14, 15 Only
Days 8, 15, 22
Every 
8 Weeks
Window
-28 to -1
± 1 Week
± 1 Week
c Cycle 1, Day 1 is baseline.  All baseline evaluations/procedures are to be conducted at C1D1 before dosing or within 3 days before the first dose of drug 
unless otherwise specified. 
d Patients who do not continue the study drug regimen must complete the end-of-treatment (EOT) visit, which should occur within 30 days (± 1 week) after 
the last dose of study drug or before the start of subsequent antineoplastic therapy.
e
f
The symptom-directed physical exam may be performed at other visits during the treatment cycle at the discretion of the investigator. 
g To assess both MM-related symptoms and TEAEs.  
h Body surface area (BSA) will be calculated at C1D1 and at any subsequent visit that the patient experiences a > 5% change in weight from the weight used 
for the most recent BSA calculation.
i
A serum pregnancy test will be performed for women of childbearing potential during screening, predose on C1D1, and at EOT.  The serum pregnancy test 
may be collected up to 3 days before dosing.  The results must be available and negative before the study drug regimen is administered.  
j
A 12-lead ECG will occur at screening, C1D1, C5D1, C9D1, C13D1, and EOT. 
k Clinical laboratory evaluations will be performed locally and centrally as indicated in Section 7.4.13.  Labs should be collected prior to dosing.  During 
induction, hematology should occur weekly on Days 1, 8, 15, and 22 for Cycles 1 through 3 and on Days 1 and 15 for Cycles 4 through 13.  During 
Maintenance, hematology should occur weekly on Days 1, 8, 15, and 22 for Cycles 14 and 15, and on Day 1 of each cycle thereafter until EOT.  During 
induction, chemistry should occur weekly on Days 1, 8, 15, and 22 for Cycles 1 through 3 and on Day 1 for Cycles 4 through 13.  During Maintenance, 
chemistry should occur on Day 1 of every other cycle starting with Cycle 14 until EOT.  Hematology and chemistry may be collected up to 3 days prior to 
MLN9708 dosing.  Criteria for retreatment are provided in Section 6.3.1.  Hematology is also to be collected upon occurrence of an adverse event (AE) or 
serious adverse event (SAE), suggestive of renal toxicity.  For dosing decisions, local hematology and chemistry laboratory results may be used.  
l
For patients in Arm A, if intrapatient dose escalation of cyclophosphamide occurs, hematology labs will be obtained weekly for the first 3 cycles following 
the escalation.
m A urinalysis is to be done predose on Day 1 of each cycle during induction for all patients.  Urinalysis is also to be done upon occurrence of an AE (or 


MLN9708
Clinical Study Protocol C16020 Amendment 1, EudraCT Number:  2013-003113-17 
13
SCHEDULE OF EVENTS:  ARMS A and B (NDMM)
Study Procedures
Screeninga
Treatment Period
(28-Day Cycles)
End of Treatmentd
PFS
Follow-upe
INDUCTIONb
CYCLES 1-13
MAINTENANCEb
CYCLE 14 and BEYOND
Day 1c
Day 8
Day 15
Day 22
Day 1
Cycles 14, 15 Only
Days 8, 15, 22
Every 
8 Weeks
Window
-28 to -1
± 1 Week
± 1 Week
SAE) suggestive of renal toxicity.
n Patient-reported outcomes assessments and health care utilization assessments should be completed before any other study procedures are performed and 
before the study drug regimen is administered.  
o To be performed at screening (within 8 weeks prior to randomization), once annually, and if at any time the physician believes there are symptoms or signs 
that suggest increased or new bone lesions.  Plain films of symptomatic sites for signs or symptoms of new bone lesions may be obtained instead of a full 
skeletal survey.  At the discretion of the investigator and where regionally permitted, a computed tomography (CT) scan, a positron emission tomography 
computed tomography (PET-CT) scan, or a whole body magnetic resonance imaging (MRI) may be done at screening in place of a skeletal survey, 
provided that the same modality for assessment is used throughout the study.
p For those with documented extramedullary disease, radiographic assessments should be made at screening, at every other cycle during induction and 
maintenance starting at Cycle 2, Day 1, at EOT, and every 8 weeks during progression-free follow-up.  The same imaging modality used at screening 
(CT/PET-CT/MRI) should be used for all follow-up assessments.
q To be performed prior to dosing during induction, every other cycle during maintenance starting with Cycle 14, at EOT, and during PFS follow-up.  Note:  
The collection of these samples is required to be repeated at C1D1 only if the collection during screening was done 14 days before the first dose of the 
study drug regimen.  Serum-only patients will have 24-hour urine collected for UPEP and urine immunofixation at screening, noted complete response 
(CR) or progressive disease (PD), and at EOT. All other patients should have the M component quantification by UPEP and urine immunofixation 
performed prior to dosing in every cycle in induction and every other cycle during maintenance starting with Cycle 14, at EOT, and during PFS follow-up.
r
s
.


MLN9708
Clinical Study Protocol C16020 Amendment 1, EudraCT Number:  2013-003113-17 
14
STUDY DRUG REGIMEN ADMINISTRATION:  ARMS A AND B (NDMM)
INDUCTION
MAINTENANCE
CYCLES 1-13
CYCLE 14 and BEYOND
Study Drug
Route
Day 1
Day 8
Day 15
Day 22
Day 1
Day 8
Day 15
Day 22
MLN9708
PO
X
X
X
X
X
X
Cyclophosphamide
PO
X
X
X
Dexamethasone
PO
X
X
X
X
Abbreviations:  NDMM = newly diagnosed multiple myeloma; PO = per os (by mouth; orally).  


MLN9708
Clinical Study Protocol C16020 Amendment 1, EudraCT Number:  2013-003113-17 
15
SCHEDULE OF EVENTS:  ARM C (RRMM)
SCHEDULE OF EVENTS:  ARM C (RRMM)
Study Procedures
Screeninga
Treatment Periodb
(28-Day Cycles)
End of Treatmentd
PFS
Follow-upe
CYCLE 1 and BEYOND
Day 1c
Day 8
Day 15
Day 22
Every 
8 Weeks
Window
-28 to -1
± 1 Week
± 1 Week
Informed Consent
X
Inclusion/Exclusion Criteria 
X
Demographics
X
Complete Medical History and Disease Staging
X
Physical Examf
X
X
Symptom-directed Physical Exam
X
Neurologic Assessmentg
X
X
X
X
ECOG Performance Status
X
X
X
Vital Signs
X
X
X
Height (cm)
X
Weight (kg), BSAh
X
Xh
X
Serum Pregnancy Testi
X
X
X
12-Lead ECGj
X
Xj
Xj


MLN9708
Clinical Study Protocol C16020 Amendment 1, EudraCT Number:  2013-003113-17 
16
SCHEDULE OF EVENTS:  ARM C (RRMM)
Study Procedures
Screeninga
Treatment Periodb
(28-Day Cycles)
End of Treatmentd
PFS
Follow-upe
CYCLE 1 and BEYOND
Day 1c
Day 8
Day 15
Day 22
Every 
8 Weeks
Window
-28 to -1
± 1 Week
± 1 Week
Hematologyk
X
X
Cycles 1-3
Xk
X
X
X
Cycle 4 and beyond
Xk
Xk
Clinical Chemistryj
X
X
Cycles 1-3
Xk
X
X
X
Cycle 4 and beyond
Xk
Urinalysisl
X
Xl
QOL Assessmentsm
(EORTC QLQ-C30)
X
X
X
X
Health Care Utilization Assessmentm
X
X
X
Skeletal Survey
X
Once annually for all patients and at the discretion of the investigatorn
Radiographic Disease Assessment for Extramedullary 
Plasmacytoma
X
Xo
X
X
2-microglobulin 
X
M-protein Measurements (SPEP)p
X
X
X
X
M-protein Measurements (UPEP [24-hr Urine 
Collection])p
X
X
X
X
Serum Free Light Chain Assayp
X
X
X
X
Immunofixation - Serum and Urinep
X
X
X
X


MLN9708
Clinical Study Protocol C16020 Amendment 1, EudraCT Number:  2013-003113-17 
17
SCHEDULE OF EVENTS:  ARM C (RRMM)
Study Procedures
Screeninga
Treatment Periodb
(28-Day Cycles)
End of Treatmentd
PFS
Follow-upe
CYCLE 1 and BEYOND
Day 1c
Day 8
Day 15
Day 22
Every 
8 Weeks
Window
-28 to -1
± 1 Week
± 1 Week
Quantification of Igp
X
X
X
X
Blood Sample for Genotyping
X
Skeletal-related Events
Recorded from the first dose of drug in the study drug regimen until progressive 
disease
New Primary Malignancy Assessment
Continuous from the start of study drug regimen until death or termination of the study 
by the sponsor
AE Reportinge
Recorded from the first dose of drug in the study drug regimen through 30 days after 
last dose of drug in the study drug regimen
Serious adverse events and serious pretreatment events will be collected from signing 
of the informed consent form through 30 days after the last dose of drug in the study 
drug regimen
Concomitant Medications/Procedures
Recorded from the first dose of drug in the study drug regimen through 30 days after 
last dose of drug in the study drug regimen
Abbreviations:  AE = adverse event; BMA = bone marrow aspirate; BSA = body surface area; C1D1 = Cycle 1, Day 1; CR = complete response; CT = computed 
tomography; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EMD = extramedullary disease; EORTC = European Organization 
for Research and Treatment of Cancer; EOT = end of treatment; Ig = immunoglobulin; MM = multiple myeloma; MRD = minimal residual disease; 
MRI = magnetic resonance imaging; OS = overall survival; PD = progressive disease; PET = positron emission tomography; PFS = progression-free survival; 
PN = peripheral neuropathy; PR = partial response; QLQ-C30 = Quality of Life Questionnaire; QOL = quality of life; SAE = serious adverse event; 
SPEP = serum protein electrophoresis; TEAE = treatment-emergent adverse event; UPEP = urine protein electrophoresis; VGPR = very good partial response.
Tests and procedures should be performed on schedule, but occasional changes may be allowed (± 3 days) for holidays, vacations, and other administrative 
reasons.  If the study schedule is shifted, both assessments and dosing must be shifted to ensure collection of assessments is completed prior to dosing.  If 


MLN9708
Clinical Study Protocol C16020 Amendment 1, EudraCT Number:  2013-003113-17 
18
SCHEDULE OF EVENTS:  ARM C (RRMM)
Study Procedures
Screeninga
Treatment Periodb
(28-Day Cycles)
End of Treatmentd
PFS
Follow-upe
CYCLE 1 and BEYOND
Day 1c
Day 8
Day 15
Day 22
Every 
8 Weeks
Window
-28 to -1
± 1 Week
± 1 Week
extenuating circumstances prevent a patient from beginning treatment or completing a scheduled procedure or assessment within this time, the patient may 
continue the study only with the permission of the Millennium project clinician or designee.
a Evaluations during the Screening period are to be conducted within 28 days before enrollment, unless otherwise noted.  The date of randomization or 
enrollment should be within 7 days of Cycle 1, Day 1 (C1D1).
b During the treatment period, there will be a 3-day window for study visits unless otherwise noted.
c Cycle 1, Day 1 (C1D1) is baseline.  All baseline evaluations/procedures are to be conducted at C1D1 before dosing or within 3 days before the first dose of 
drug unless otherwise specified. 
d Patients who discontinue the study drug regimen must complete the end-of-treatment (EOT) visit, which should occur within 30 days (± 1 week) after the last 
dose of study drug or before the start of subsequent antineoplastic therapy.
e
f
The symptom-directed physical exam may be performed at other visits during the treatment period at the discretion of the investigator. 
g To assess MM-related clinical symptoms and TEAEs.  
h Body surface area (BSA) will be calculated at C1D1 and at any subsequent visit that the patient experiences a > 5% change in weight from the weight used for 
the most recent BSA calculation.  
i
A serum pregnancy test will be performed for women of childbearing potential during screening, predose on C1D1, and at EOT.  The serum pregnancy test 
may be collected up to 3 days before dosing.  The results must be available and negative before the study drug regimen is administered.  
j
A 12-lead ECG will occur at screening and every 4 cycles thereafter during the treatment period, and at EOT. 
k Clinical laboratory evaluations will be performed locally and centrally as indicated in Section 7.4.13.  Labs should be collected prior to dosing.  Hematology 
should occur weekly on Days 1, 8, 15, and 22 for Cycles 1 through 3 and on Days 1 and 15 for Cycle 4 and beyond until EOT.  Chemistry should occur 
weekly on Days 1, 8, 15, and 22 for Cycles 1 through 3 and on Day 1 for Cycle 4 and beyond until EOT.  Hematology and chemistry may be collected up to 


MLN9708
Clinical Study Protocol C16020 Amendment 1, EudraCT Number:  2013-003113-17 
19
SCHEDULE OF EVENTS:  ARM C (RRMM)
Study Procedures
Screeninga
Treatment Periodb
(28-Day Cycles)
End of Treatmentd
PFS
Follow-upe
CYCLE 1 and BEYOND
Day 1c
Day 8
Day 15
Day 22
Every 
8 Weeks
Window
-28 to -1
± 1 Week
± 1 Week
3 days prior to MLN9708 dosing.  Criteria for retreatment are provided in Section 6.3.1.  Hematology is also to be collected upon occurrence of an adverse 
event (AE) or serious adverse event (SAE) suggestive of renal toxicity.  For dosing decisions, local hematology and chemistry laboratory results may be used.  
l
A urinalysis is to be done predose on Day 1 of each cycle during the treatment period for all patients.  Urinalysis is also to be done upon occurrence of an AE 
(or SAE) suggestive of renal toxicity.
m Patient-reported outcomes assessments and health care utilization assessments should be completed before any other study procedures are performed and 
before the study drug regimen is administered.  
n To be performed at screening (within 8 weeks prior to enrollment), once annually, and if at any time the physician believes there are symptoms or signs that 
suggest increased or new bone lesions.  Plain films of symptomatic sites for signs or symptoms of new bone lesions may be obtained instead of a full skeletal 
survey.  At the discretion of the investigator and where regionally permitted, a computed tomography (CT) scan, a positron emission tomography computed 
tomography (PET-CT) scan, or a whole body magnetic resonance imaging (MRI) may be done at screening in place of a skeletal survey, provided that the 
same modality for assessment is used throughout the study.  
o For those with documented extramedullary disease, radiographic assessments should be made at screening, at every other cycle, starting at Cycle 2, Day 1, at 
EOT, and every 8 weeks during progression-free follow-up.  The same imaging modality used at screening (CT/PET-CT/MRI) should be used for all 
follow-up assessments.
p To be performed prior to dosing during the treatment period, at EOT, and during PFS follow-up.  Serum only patients will have 24-hour urine collected for 
UPEP and urine immunofixation at screening, noted CR or PD, and at EOT. All other patients should have the M component quantification by UPEP and 
urine immunofixation performed prior to dosing in every cycle during the treatment period, at EOT, and during PFS follow-up.  
q
d 
 
 
r


MLN9708
Clinical Study Protocol C16020 Amendment 1, EudraCT Number:  2013-003113-17 
20
STUDY DRUG REGIMEN ADMINISTRATION:  ARM C (RRMM)
Treatment Period 
CYCLE 1 and BEYOND 
Study Drug
Route
Day 1
Day 8
Day 15
Day 22
MLN9708
PO
X
X
X
Cyclophosphamide
PO
X
X
X
Dexamethasone
PO
X
X
X
X
Abbreviations:  PO = per os (by mouth; orally); RRMM = relapsed and/or refractory multiple myeloma.  


MLN9708
Clinical Study Protocol C16020 Amendment 1, EudraCT Number:  2013-003113-17 
21
Pharmacokinetic Sampling Schedule for All Patients in Safety Lead-In (Arms A, B, 
C)
PK Sampling Time Point
Drug Administration
Cycle 1
Cycle 2
D1
D2
D3
D5
D8
D15 D16 D17 D19 D22
D1
Predosea
X
15 min postdose (3 min)
X
30 min postdose (5 min)
X
1 h postdose (15 min)
X
1.5 h postdose (15 min)
X
2 h postdose (15 min)
X
4 h postdose (45 min)
X
8 h postdose (1 h)
X
24 h postdose (1 h)
X
48 h postdose (2 h)
X
96 h postdose (4 h)
X
168 h postdose (4 h) 
(prior to Day 8 dose)
X
Predosea
X
15 min postdose (3 min)
X
30 min postdose (5 min)
X
1 h postdose (15 min)
X
1.5 h postdose (15 min)
X
2 h postdose (15 min)
X
4 h postdose (45 min)
X
8 h postdose (1 h)
X
24 h postdose (1 h)
X
48 h postdose (2 h)
X
96 h postdose (4 h)
X
168 h postdose (4 h)
X
Predosea
X
Abbreviations:  D = day; PK = pharmacokinetic(s).
a Predose PK assessments should occur within 2 hours before dosing.


MLN9708
Clinical Study Protocol C16020 Amendment 1, EudraCT Number:  2013-003113-17 
22
Pharmacokinetic Sampling for All Patients (Arms A, B, and C) (Excluding Safety 
Lead-in Patients)
PK Sampling Time Point
Cycle 1
Cycles 2-3
D1
D8
D15
D22
D1
D8
D15
D22
Predosea
X
X
X
X
X
1 h postdose (15 min)
X
Collect at any time during clinic visit
X
X
Abbreviations:  D = day; PK = pharmacokinetics.
a Predose PK assessments should occur within 2 hours before dosing.


MLN9708
Clinical Study Protocol C16020 Amendment 1, EudraCT Number:  2013-003113-17 
23
TABLE OF CONTENTS
LIST OF TABLES..................................................................................................................26
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS ............................................27
1. BACKGROUND AND STUDY RATIONALE ................................................................31
1.1 Scientific Background ..................................................................................................31
1.1.1 Disease Under Treatment.......................................................................................31
1.1.2 MLN9708...............................................................................................................32
1.2 Nonclinical Experience.................................................................................................33
1.3 Clinical Experience.......................................................................................................33
1.3.1 Pharmacokinetics and Drug Metabolism...............................................................35
1.4 Study Rationale.............................................................................................................36
1.4.1 Feasibility of Combination of MLN9708, Cyclophosphamide, and 
Dexamethasone Therapy ................................................................................38
1.4.2 Rationale for the Combination of MLN9708, Cyclophosphamide, and 
Dexamethasone Dose and Dosing Schedule...................................................39
1.5 Rationale for Biomarker Measurements.......................................................................41
1.6 Rationale for Pharmacokinetic Measurements.............................................................42
1.7 Potential Risks and Benefits.........................................................................................43
2. STUDY OBJECTIVES ......................................................................................................44
2.1 Primary Objectives .......................................................................................................44
2.2 Secondary Objectives ...................................................................................................44
2.3 Exploratory Objectives.................................................................................................46
3. STUDY ENDPOINTS........................................................................................................46
3.1 Primary Endpoint..........................................................................................................46
3.2 Secondary Endpoints ....................................................................................................47
3.3 Exploratory Endpoints..................................................................................................48
4. STUDY DESIGN ...............................................................................................................49
4.1 Overview of Study Design ...........................................................................................49
4.2 Number of Patients .......................................................................................................51
4.3 Duration of Study .........................................................................................................51
5. STUDY POPULATION.....................................................................................................51
5.1 Inclusion Criteria ..........................................................................................................51
5.2 Exclusion Criteria.........................................................................................................54
6. STUDY DRUG...................................................................................................................56
6.1 Study Drug Administration ..........................................................................................56
6.1.1 MLN9708 Administration .....................................................................................56
6.1.2 Cyclophosphamide Administration .......................................................................57
6.1.3 Dexamethasone Administration.............................................................................59
6.2 Safety Lead-in...............................................................................................................59
6.2.1 Safety Lead-in Evaluable Patients.........................................................................60
6.2.2 Rules for Continuous Study Enrollment................................................................60
6.3 Dose Modification Guidelines......................................................................................62
6.3.1 Criteria for Toxicity Recovery Before Beginning the Next Cycle and 
Midcycle of Treatment ...................................................................................62


MLN9708
Clinical Study Protocol C16020 Amendment 1, EudraCT Number:  2013-003113-17 
24
6.3.2 Criteria for Selection and Timing of Dose Modification (Delays, Reductions, 
and Discontinuations).....................................................................................63
6.3.3 Permitted Dose Level Reductions..........................................................................64
6.3.4 Dose Adjustments for Hematologic Toxicity:  MLN9708 and 
Cyclophosphamide .........................................................................................64
6.3.5 Dose Adjustments for Nonhematologic Toxicity:  MLN9708 and 
Cyclophosphamide .........................................................................................66
6.3.6 Dexamethasone-Related Treatment Modification.................................................68
6.4 Excluded Concomitant Medications and Procedures ...................................................69
6.5 Permitted Concomitant Medications and Procedures...................................................70
6.6 Precautions and Restrictions.........................................................................................71
6.7 Management of Clinical Events ...................................................................................72
6.8 Blinding and Unblinding ..............................................................................................75
6.9 Description of Investigational Agents ..........................................................................75
6.9.1 MLN9708 Preparation, Reconstitution, and Dispensation....................................75
6.9.2 MLN9708 Packaging and Labeling.......................................................................75
6.9.3 MLN9708 Storage, Handling, and Accountability................................................76
6.9.4 Dexamethasone - Noninvestigational Medicinal Agent........................................77
6.9.5 Cyclophosphamide - Noninvestigational Medicinal Agent...................................77
6.10 Other Protocol-Specified Materials............................................................................77
7. STUDY CONDUCT...........................................................................................................77
7.1 Study Personnel and Organizations..............................................................................77
7.2 Arrangements for Recruitment of Patients ...................................................................78
7.3 Treatment Group Assignments.....................................................................................78
7.4 Study Procedures ..........................................................................................................78
7.4.1 Informed Consent ..................................................................................................78
7.4.2 Patient Demographics............................................................................................78
7.4.3 Medical History .....................................................................................................79
7.4.4 Assessment of Comorbid Condition(s) – Arms A and B.......................................79
7.4.5 Physical Examination ............................................................................................79
7.4.6 Eastern Cooperative Oncology Group Performance Status...................................79
7.4.7 Vital Signs, Body Weight, Height, and Body Surface Area..................................79
7.4.8 Pregnancy Test.......................................................................................................79
7.4.9 Electrocardiogram..................................................................................................80
7.4.10 Concomitant Medications and Procedures ..........................................................80
7.4.11 Adverse Events ....................................................................................................80
7.4.12 Enrollment ...........................................................................................................80
7.4.13 Clinical Laboratory Evaluations..........................................................................81
7.4.14 Quality of Life Assessment (European Organization for Research and 
Treatment of Cancer)......................................................................................82
7.4.15 Skeletal Survey ....................................................................................................82
7.4.16 Skeletal-Related Events.......................................................................................82
7.4.17 Bone Marrow Aspiration .....................................................................................83
7.4.18 Blood Sample for Genotyping.............................................................................83
7.4.19 Quantification of M-Protein.................................................................................84
7.4.20 Quantification of Immunoglobulins.....................................................................84


MLN9708
Clinical Study Protocol C16020 Amendment 1, EudraCT Number:  2013-003113-17 
25
7.4.21 Serum Free Light Chain Assay............................................................................84
7.4.22 Immunofixation of Serum and Urine...................................................................84
7.4.23 Radiographic Disease Assessments.....................................................................84
7.4.24 Disease Response Assessment.............................................................................84
7.4.25 Health Care Utilization Assessments...................................................................85
7.4.26 Follow-up Assessments (Progression-Free Survival)..........................................85
7.5 Completion of Treatment..............................................................................................86
7.6 Completion of Study.....................................................................................................86
7.7 Discontinuation of Treatment With Study Drug, and Patient Replacement.................86
7.8 Withdrawal of Patients From Study .............................................................................87
7.9 Study Compliance.........................................................................................................87
8. STATISTICAL AND QUANTITATIVE ANALYSES.....................................................88
8.1 Statistical Methods .......................................................................................................88
8.1.1 Determination of Sample Size...............................................................................88
8.1.2 Randomization and Stratification ..........................................................................88
8.1.3 Populations for Analysis........................................................................................88
8.1.4 Procedures for Handling Missing, Unused, and Spurious Data ............................89
8.1.5 Demographic and Baseline Characteristics ...........................................................89
8.1.6 Efficacy Analysis...................................................................................................89
8.1.7 Analyses of Patient-Reported Outcomes...............................................................91
8.1.8 Analysis of Health Care Utilization Data ..............................................................91
8.1.9 Pharmacokinetics/Biomarkers ...............................................................................91
8.1.10 Safety Analysis ....................................................................................................92
8.1.11 Interim Analysis...................................................................................................95
9. ADVERSE EVENTS..........................................................................................................96
9.1 Definitions ....................................................................................................................96
9.1.1 Pretreatment Event Definition ...............................................................................96
9.1.2 Adverse Event Definition ......................................................................................96
9.1.3 Serious Adverse Event Definition .........................................................................96
9.1.4 Procedures for Recording and Reporting Adverse Events and Serious 
Adverse Events ...............................................................................................97
9.1.5 Monitoring of Adverse Events and Period of Observation....................................99
9.1.6 Procedures for Reporting Drug Exposure During Pregnancy and Birth Events..100
10. ADMINISTRATIVE REQUIREMENTS ......................................................................100
10.1 Good Clinical Practice..............................................................................................100
10.2 Data Quality Assurance............................................................................................100
10.3 Electronic Case Report Form Completion................................................................101
10.4 Study Monitoring......................................................................................................101
10.5 Ethical Considerations..............................................................................................102
10.6 Patient Information and Informed Consent ..............................................................102
10.7 Patient Confidentiality..............................................................................................102
10.8 Investigator Compliance...........................................................................................102
10.9 On-site Audits...........................................................................................................103
10.10 Investigator and Site Responsibility for Drug Accountability ...............................103
10.11 Product Complaints ................................................................................................103
10.12 Closure of the Study ...............................................................................................104


MLN9708
Clinical Study Protocol C16020 Amendment 1, EudraCT Number:  2013-003113-17 
26
10.13 Record Retention ....................................................................................................104
11. USE OF INFORMATION..............................................................................................105
12. INVESTIGATOR AGREEMENT .................................................................................106
13. REFERENCES ...............................................................................................................107
14. APPENDICES ................................................................................................................111
14.1 Multiple Myeloma Diagnostic Criteria.....................................................................111
14.2 Cockcroft Gault Equation.........................................................................................111
14.3 Eastern Cooperative Oncology Group (ECOG) Scale for Performance Status........112
14.4 Steroid Equivalent Doses..........................................................................................112
14.5 International Staging System Criteria and Durie Salmon Criteria ...........................113
14.6 European Organization for Research and Treatment of Cancer (EORTC) 
Quality of Life Questionnaire (QLQ-C30) (version 3).......................................114
14.7 International Myeloma Working Group (IMWG) Response Criteria ......................116
14.8 Amendment 1 Detailed Summary of Changes .........................................................117
LIST OF TABLES
Table 6-1   
Criteria for Hematological and Nonhematological Recovery ........................63
Table 6-2   
Permitted Dose Level Reductions for MLN9708, Cyclophosphamide, and 
Dexamethasone...............................................................................................64
Table 6-3   
Dose Adjustments for Thrombocytopenia......................................................65
Table 6-4   
Dose Adjustments for Neutropenia ................................................................66
Table 6-5   
Dose Adjustments for Nonhematologic Toxicities Attributed to MLN9708 .67
Table 6-6   
Dose Adjustments for Nonhematologic Toxicities Attributed to 
Cyclophosphamide .........................................................................................68
Table 6-7   
Dexamethasone–Related Treatment Modification (Delays, Reductions, and 
Discontinuations) Guidelines Due to Adverse Events....................................68
Table 6-8   
MLN9708 Capsules........................................................................................75
Table 7-1   
Response Assessment .....................................................................................85


MLN9708
Clinical Study Protocol C16020 Amendment 1, EudraCT Number:  2013-003113-17 
27
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS
Abbreviation
Term
5-HT3
5-hydroxytryptamine 3 serotonin receptor
AE
adverse event
AL
light-chain
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ASCO
American Society of Clinical Oncology
ASCT
autologous stem cell transplant 
AST
aspartate aminotransferase
AUC
area under the plasma concentration versus time curve
BCRP
breast cancer resistance protein
BMA
bone marrow aspirate
BSA
body surface area
BUN
blood urea nitrogen
C1D1
Cycle 1, Day 1
CBC
complete blood count
Cd
cyclophosphamide and low-dose dexamethasone
CCd
combination with cyclophosphamide/dexamethasone
CI
confidence interval
CL
clearance, IV dosing
Cmax
single-dose maximum (peak) concentration  
CO2
carbon dioxide
CR
complete response
CrCL
creatinine clearance
CSR
clinical study report
CT
computed tomography
CyBorD
cyclophosphamide, bortezomib and dexamethasone 
CYP
cytochrome P450
DDI
drug-drug interaction
DLT
dose-limiting toxicity
DNA
deoxyribonucleic acid
DOR
duration of response   
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EMD
extramedullary disease
EORTC 
European Organization for Research and Treatment of Cancer 


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Abbreviation
Term
EOT
End of Treatment (visit)
FISH
fluorescence in situ hybridization
GCP
Good Clinical Practice
G-CSF
granulocyte colony stimulating factor
GI
gastrointestinal
GM-CSF
granulocyte macrophage-colony stimulating factor
HDT
high-dose therapy
HIV
human immunodeficiency virus
HR
hazard ratio
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IMWG
International Myeloma Working Group
IR
immunophenotype
IRB
institutional review board
ISS
International Staging System
ITT
intent-to-treat
IV
intravenous; intravenously
IWRS
interactive web response system
K-M
Kaplan-Meier
LDH
lactate dehydrogenase
MDS
myelodysplastic syndrome
MedDRA
Medical Dictionary for Regulatory Activities
Millennium
Millennium Pharmaceuticals, Inc., and its affiliates
MM
multiple myeloma
MP
melphalan/prednisone
MPR
MP/lenalidomide
MPR-R
MP/lenalidomide followed by lenalidomide continuous therapy
MPT
melphalan/prednisone/thalidomide
MRD
minimal residual disease
MRP2
multidrug resistance associated protein
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NDMM
newly diagnosed multiple myeloma 
NSAIDs
nonsteroidal anti-inflammatory drugs 
OR
overall response


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Abbreviation
Term
ORR
overall response rate
OS
overall survival 
PD
progressive disease (disease progression)
PET
positron emission tomography
PFS
progression-free survival 
Pgp
P-glycoprotein
PI
(United States) Package Insert
PK
pharmacokinetic(s)
PN
peripheral neuropathy
PO
per os; by mouth (orally)
POEMS
polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and 
skin changes
PR
partial response 
PRES
posterior reversible encephalopathy syndrome
PRO
patient-reported outcome
QLQ-C30
Quality of Life Questionnaire
QOL
quality of life
QTc
rate-corrected QT interval (millisec) of electrocardiograph
RevDex
Revlimid (lenalidomide)/dexamethasone 
RP2D
recommended phase 2 dose
RRAL
relapsed and/or refractory systemic light chain amyloidosis
RRMM
relapsed and/or refractory multiple myeloma 
RVd
Revlimid/VELCADE/dexamethasone 
SAE
serious adverse event
sCR
stringent complete response
SCT
stem cell transplantation
SMA
Safety Management Attachment
SmPC
Summary of Product Characteristics
SPEP
serum protein electrophoresis
SRE
skeletal-related events
t1/2
terminal disposition half-life
TEAE
treatment-emergent adverse event
ThalDex
thalidomide/dexamethasone 
Tmax
single-dose first time of occurrence of maximum (peak) concentration
TTP
time to progression 
ULN
upper limit of the normal range
UPEP
urine protein electrophoresis
UPS
ubiquitin-proteasome system
US
United States
VCD
VELCADE/cyclophosphamide/dexamethasone
VDD
VELCADE, doxorubicin and dexamethasone 


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Abbreviation
Term
VelDex
VELCADE/dexamethasone 
VGPR
very good partial response
VMP
VELCADE/melphalan/prednisone 
WHO
World Health Organization


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1.   
BACKGROUND AND STUDY RATIONALE
1.1   
Scientific Background
1.1.1   
Disease Under Treatment
Multiple myeloma (MM) is a B-cell tumor characterized by the accumulation of plasma 
cells in the bone marrow (and other organs) and can result in bone marrow failure, bone 
destruction, hypercalcemia, and renal failure.  It constitutes approximately 1% of all 
reported neoplasms and approximately 13% of hematologic cancers worldwide.(1)  In the 
Americas, Canada, and Western European countries, approximately 5 to 7 new cases of MM 
are diagnosed per 100,000 people each year.(1, 2, 3)  Although less common in Asian 
countries, incidences of MM have increased almost 4-fold in the past 25 years and are 
characterized by younger onset age, more invasive disease, and a less favorable prognosis.(4, 
5)
MM is sensitive to many cytotoxic drugs, including alkylating agents and anthracyclines, 
and to corticosteroids for both initial treatment and relapsed disease.  Over the past decade, 
the treatment of newly diagnosed multiple myeloma (NDMM) has evolved due to 
availability of the proteasome inhibitor VELCADE® (bortezomib), and the 
immunomodulatory agents thalidomide and lenalidomide (Revlimid). These, along with the 
use of high-dose therapy and autologous stem cell transplant (ASCT) in selected patients, 
have led to improved survival in myeloma.(6, 7, 8)  Therapeutic regimens for NDMM 
recommended by the National Comprehensive Cancer Network (NCCN) include 
VELCADE/dexamethasone (VelDex), thalidomide/dexamethasone (ThalDex), Revlimid
(lenalidomide)/dexamethasone (RevDex), VELCADE/cyclophosphamide/dexamethasone 
(VCD), Revlimid/VELCADE/dexamethasone (RVd); VELCADE/melphalan/prednisone 
(VMP), melphalan/prednisone/thalidomide (MPT), and VELCADE, doxorubicin and 
dexamethasone (VDD). Among these regimens, VMP and MPT are used for 
transplant-ineligible patients only, while others are used for both transplant-eligible and 
transplant-ineligible patient populations. VCD is one of several preferred therapeutic 
options available as frontline therapy for transplant-eligible patients.
Although these new treatments have significantly changed the outcome for patients with 
NDMM, this malignant disease remains incurable and requires long-term treatment. In the 
elderly patient population strategies to optimize the initial induction therapy with the 
development of new agents and new combination therapies and the role of maintenance 
treatment continue to be evaluated, with the goal to identify the most effective approach 


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while maximizing the quality of life (QOL). For patients with relapsed and/or refractory 
multiple myeloma (RRMM) who experience disease progression after their initial therapy,
response to subsequent treatments varies with a decreased likelihood of response and a 
tendency towards a shorter duration of response (DOR). Ultimately, RRMM becomes
refractory to approved therapies, and patients have no alternative treatment options.
MLN9708, a small molecule 20S proteasome inhibitor has been developed by Millennium 
Pharmaceuticals, Inc. (Millennium) in an effort to expand the therapeutic armamentarium 
against MM.
1.1.2   
MLN9708
Protein homeostasis that occurs through regulation of protein production and destruction is 
one of the critical biological processes that play a role in cell survival, growth, and 
signaling.  The ubiquitin-proteasome system (UPS) is the major regulatory system through 
which protein homeostasis occurs and represents the primary mechanism by which cells 
degrade proteins, including those involved in growth control, cell cycle regulation, and 
apoptosis.  The 26S proteasome is comprised of a catalytic proteolytic core (20S) and 
2 regulatory subunits (19S).  Inhibition of the 20S core with first generation VELCADE (a 
potent, reversible, and specific inhibitor of the proteasome), results in the inhibition of 
protein degradation and the disruption of several distinct cell regulatory mechanisms, further 
resulting in inhibition of cell growth and survival pathways, dysregulation of the cell cycle, 
and induction of apoptosis. Inhibition of the 20S proteasome pathway has been proven 
useful in the treatment of MM and mantle cell lymphoma.
As an example and for patients with NDMM who are not eligible for ASCT, adding VMP 
not only improved response rates, but also prolonged overall survival.(9) Final results of the 
international, multicenter, phase 3 VISTA trial confirmed that after 5 years of follow-up, 
VMP was associated with a persistent, significant overall survival (OS) benefit versus 
melphalan/prednisone (MP) with a median 13.3 month increase (43.1 vs 56.4 months, 
hazard ratio [HR] 0.695, p = 0.0004). The OS benefit with VMP was seen across 
prespecified patient subgroups (age ≥75 years, stage III myeloma, creatinine clearance 
< 60 mL/min) and maintained, despite substantial use of novel agent-based salvage 
therapies.(10) In an effort to improve tolerability and to lower the discontinuation rate due to 
treatment-related side effects, reported as 33% with VMP, a once-weekly dosing regimen of 
VELCADE instead of the typical twice-weekly schedule (as used in the VISTA trial) was 
tested in combination with MP.  Reduced toxicity, specifically reduced Grades 3 to 4 


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peripheral neuropathy (PN) was observed and similar efficacy demonstrated.(11, 12) Weekly 
administration of VELCADE is now being commonly used in clinical practice.  Recently, 
results of a pivotal study have also shown similar efficacy with reduced incidence of PN 
with subcutaneous VELCADE leading to its approval as new route of administration.(12)
MLN9708 is a next-generation oral proteasome inhibitor that is in clinical development for 
the treatment of both hematologic and nonhematologic malignancies and represents the first 
orally bioavailable proteasome inhibitor to enter clinical development. MLN9708 was 
developed to build upon the attributes of VELCADE and to address its limitations with a 
more convenient dosing schedule. When hydrolyzed from its citrate ester form (MLN9708) 
to its boronic acid form (MLN2238), like VELCADE, MLN2238 is active against the β5 
subunit of the 20S proteasome. MLN2238 produces reversible inhibition and, in contrast to 
VELCADE, rapidly dissociates from the β5 subunit. It is expected that the different binding 
kinetics and pharmacologic profile compared with VELCADE will translate into similar 
efficacy and potentially better safety profiles; therefore, MLN9708 is being tested as a 
therapeutic treatment for nonhematologic and hematologic malignancies.
1.2   
Nonclinical Experience
Detailed information regarding the nonclinical pharmacology and toxicology of MLN9708
may be found in the Investigator’s Brochure (IB).
1.3   
Clinical Experience
MLN9708 has been evaluated as an oral single agent in phase 1 studies that have included 
patients with advanced solid tumors, lymphoma, relapsed and/or refractory MM (RRMM), 
and relapsed or refractory light-chain (AL) amyloidosis and demonstrated early signs of 
activity.  Ongoing studies continue to investigate both single-agent MLN9708 and 
MLN9708 in combination with standard treatments.  Based on encouraging preliminary data 
observed in patients with MM requiring systemic treatment, two phase 3 trials in NDMM 
(C16014) and RRMM (C16010) patient populations are currently evaluating MLN9708 in 
combination with RevDex versus placebo/RevDex. Both trials are combining MLN9708 at 
a weekly dose of 4.0 mg on Days 1, 8, and 15 in a 28-day cycle to a standard dose of 
lenalidomide with a weekly dexamethasone dose of 40 mg. In addition, ongoing clinical 
pharmacology studies include evaluation of drug-drug interactions with ketoconazole and 
rifampin, effect of food, and oral bioavailability. Studies evaluating the safety and
pharmacokinetic (PK) of MLN9708 alone (in Japanese patients) and in combination with 


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lenalidomide and dexamethasone in Asian adult patients (including Japanese patients) with a 
diagnosis of NDMM are ongoing.
As of 27 March 2013, preliminary clinical data are available for a total of 653 patients 
across 13 studies.  The emerging safety profile indicates that MLN9708 is generally well
tolerated.  The adverse events (AEs) are consistent with the known effects of proteasome 
inhibition and are similar to what has been previously reported with VELCADE though the 
severity of some, for example peripheral neuropathy, is less.  While some of these potential 
toxicities may be severe, they can be managed by clinical monitoring and standard medical 
intervention, or, as needed, dose modification or discontinuation.  
Fatigue was the most common AE reported among 384 patients treated in the oral (PO)
studies (47%).  Other common AEs reported in the pooled intravenous (IV) and PO safety 
populations include nausea, thrombocytopenia, diarrhea, and vomiting.  Rash is also a 
commonly reported treatment-emergent event; however, there is some variety in its 
characterization and causality resulting in different preferred terms to describe it.  A 
high-level term outline of rash events includes rashes, eruptions and exanthems NEC; 
pruritus NEC; erythemas; papulosquamous conditions; and exfoliative conditions.  The dose 
escalation phases of most trials reported in the IB have now completed enrollment, and 
gastrointestinal (GI) symptoms were the common dose-limiting toxicities (DLTs) when the 
use of prophylactic antiemetics was not permitted per protocol.  In the expansion cohorts or 
phase 2 cohorts (as per each study), the incidence and severity of GI symptoms was
mitigated by the use of the lower maximum tolerated dose(MTD)/recommended phase 2 
dose (RP2D) (as per each study) and standard clinical usage of antiemetics and/or 
antidiarrheal medications as deemed appropriate.  Prophylactic use of antiemetics has not 
been required as with other agents but (as outlined in Section 6.7) has been used according 
to standard practice and are effective.
In the expansion cohorts or phase 2 cohorts (as per each study), the incidence and severity of 
GI symptoms will be mitigated by the use of the lower MTD/RP2D (as per each study) and 
standard clinical usage of antiemetics and/or antidiarrheal medications as deemed 
appropriate.
The most frequent (at least 20% of patients) treatment-emergent adverse events (TEAEs)
reported with the PO formulation pooled from single-agent studies (n = 201) irrespective of 
causality to MLN9708, were nausea (
of patients), fatigue (
), diarrhea (
), 
vomiting (
), thrombocytopenia (
), decreased appetite (
), fever and anemia 


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(
each).  The most frequent (at least 20% of patients) TEAEs reported with the PO 
formulation pooled from combination trials (irrespective of the combination) (n = 173), 
irrespective of causality to MLN9708, were diarrhea (
), fatigue (
), nausea
), 
peripheral edema (
), constipation 
), insomnia (
), thrombocytopenia (
), 
anemia and vomiting (
% each), neutropenia (
), back pain (
, pyrexia (
), 
peripheral edema (
), and fever, cough, hypokalemia, neutropenia, and upper respiratory 
tract infection 
each).  Overall, rash of all grades is reported in approximately 50% of 
patients and is more common when MLN9708 is given in combination with lenalidomide 
where rash is an overlapping toxicity.  
Additional detailed information regarding the clinical experience of MLN9708 may be 
found in the IB, including information on the IV formulation.
1.3.1   
Pharmacokinetics and Drug Metabolism
Clinical IV and PO PK data show that MLN9708 (measured as the biologically active
boronic acid form of MLN9708 [MLN2238]) has multiexponential disposition with a rapid
initial phase that is largely over by 4 hours. Oral MLN9708 is rapidly absorbed with a
median single-dose first time of occurrence of maximum (peak) concentration (Tmax) of
approximately 0.5 to 2.0 hours and a terminal disposition half-life (t1/2) after multiple dosing
of approximately 5 to 7 days.(13)  Results of a population PK analysis (n = 137) show that
there is no relationship between body surface area (BSA) or body weight and clearance
(CL). Also, based on stochastic simulations for fixed dose, exposures are independent of the
individual patient’s BSA.(14)  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 current MLN9708 IB and Safety 
Management Attachment (SMA) 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 (< 5% of dose). In vitro studies indicate that
MLN9708 is metabolized by multiple cytochrome P450s (CYPs) and non-CYP
enzymes/proteins. The rank order of relative biotransformation activity of the 5 major
human CYP isozymes was 3A4 (34.2%) > 1A2 (30.7%) > 2D6 (14.7%) > 2C9 (12.1%) 
> 2C19 (< 1%).  MLN9708 is not an inhibitor of CYPs 1A2, 2C9, 2C19, 2D6, or 3A4 nor a
time-dependent inhibitor of CYP3A4/5. The potential for MLN9708 treatment to produce
drug-drug interactions (DDIs) via CYP inhibition is inferred to be low. However, there may 
be a potential for DDIs with a concomitant strong CYP3A4 or CYP1A2 inhibitor or inducer 


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because of the potential for first-pass metabolism when MLN9708 is administered via the 
PO route and because of the moderate contribution of CYP3A4- and CYP1A2-mediated 
metabolism of MLN9708 in human liver microsomes. MLN2238 may be a weak substrate 
of P-glycoprotein (Pgp), breast cancer resistance protein (BCRP), and multidrug resistance 
associated protein (MRP2) efflux pump transporters. MLN2238 is not an inhibitor of Pgp, 
BCRP, and MRP2.  The potential for DDIs with substrates or inhibitors of Pgp, BCRP, and 
MRP2 is, therefore, inferred to be low.  Clinical Study C16009 (Arm 1) with ketoconazole, a 
strong CYP3A4 inhibitor, showed a 2-fold increase in area under the plasma concentration 
versus time curve (AUC) in the presence of ketoconazole.  This resulted in the continued 
exclusion of strong CYP3A4 inhibitors in ongoing/planned clinical studies.
Further details on these studies are provided in the IB.  
1.4   
Study Rationale
Induction
Over the last decade, progress in treatment paradigms for MM comes through a series of 
investigations examining the efficacy of proteasome inhibitors and immunomodulatory 
drugs used in various combinations and sequences. After confirmation of significant 
activity in the relapsed setting, these new drugs were examined in combination with 
dexamethasone in the frontline setting and consistently demonstrated higher and deeper 
response rate and improved progression-free survival (PFS). This has been followed by 
3-drug combination regimens that either combined the drugs or added the new drug to an 
alkylating based backbone (MP or cyclophosphamide and low-dose dexamethasone [Cd]).  
VELCADE, in combination with an alkylating agent has shown to be a highly effective 
initial therapy. As discussed in Section 1.1.2, results of VELCADE plus MP in patients with 
NDMM not eligible for transplantation have demonstrated improved response rate and 
prolonged overall survival.(9)  Although VMP is standard of care in patients with NDMM, 
the use of melphalan as a backbone is declining in recent years due to the impact on the stem 
cells and the known risk of secondary leukemia and myelodysplastic syndrome (MDS) with 
the use of melphalan. Increased interest emerges for Cd as a combination partner because of 
less myelosuppression and a more favorable long-term toxicity profile (lower incidence of 
secondary leukemia) compared to melphalan, and it also demonstrated good efficacy. 
Over the last few years, encouraging results from phase 2 trials exploring the combination of 
VELCADE, with Cd have shown to induce a high rate of deep responses when administered 


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as induction before ASCT. Reeder et al. have reported high overall response (OR), very 
good partial response (VGPR), and complete response (CR) rates of 90%, 60%, and 41%,
respectively in frontline transplant-eligible patients treated with a cyclophosphamide, 
bortezomib (VELCADE), and dexamethasone (CyBorD) regimen.(15) Similar results were 
reported in the Evolution trial on the VCD-mod arm.(16) Common adverse reactions 
included in both trials were hematological toxicities, PN, GI disturbances, and fatigue, all 
considered clinically manageable. These encouraging preliminary safety and efficacy 
results prompted the evaluation of the fully oral combination of MLN9708 with Cd as 
induction therapy in a transplant-ineligible patient population with NDMM. 
Maintenance
The goal of treatment in elderly patients is to achieve CR, ultimately resulting in improved 
survival. Complete response achievement, however, is not the only objective of treatment,
as it is possible to further improve the depth of response and the outcome by prolonged 
therapy or maintenance after a CR is achieved.(12, 17)  Mateos reported an upgrade in 
responses in elderly patients with untreated MM with a VELCADE-based maintenance 
therapy after induction with either VMP or MPT and a benefit in terms of PFS. 
Maintenance therapy greatly increased the number of CRs.(9, 12)  Positive results for a 
maintenance setting were also reported with lenalidomide. Palumbo demonstrated that 
adding lenalidomide to MP with lenalidomide as maintenance significantly improved PFS in 
the same patient population: median PFS was significantly longer with MP/lenalidomide 
followed by lenalidomide continuous therapy (MPR-R) (31 months) than with
MP/lenalidomide (MPR) (14 months; HR, 0.49; p < 0.001) or MP (13 months; HR, 0.40; 
p < 0.001).(17)
Relapsed and/or Refractory Disease
Although multiple therapies are available for patients with RRMM, the frequent relapses 
that characterize this disease highlight a need for new therapies for patients in whom prior 
treatments have failed.(18) VCD has been shown to be an effective treatment in patients with 
RRMM and has a favorable toxicity profile. VCD is recognized by the NCCN as salvage 
therapy for patients with RRMM with an ORR of 75% to 83%.(19, 20)  
The early development program of MLN9708 in patients with RRMM investigated 2 dose
schedules commonly used with the first-in-class proteasome inhibitor, VELCADE. In the
open-label, dose-escalation, phase 1 studies, C16003 and C16004, MLN9708 was 
administered on a twice-weekly (Days 1, 4, 8, and 11 of a 21-day cycle) schedule and on a 


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weekly schedule (Days 1, 8, and 15 of a 28-day cycle), respectively. In both studies, 
patients had MM that had relapsed following at least 2 lines of therapy that included 
bortezomib, thalidomide (or lenalidomide), and corticosteroids. In both studies, the MTD 
cohorts were expanded.  Patients enrolled in these expansion cohorts had relapsed or
refractory disease (refractory was defined as disease progression while on therapy or within 
60 days after the last dose of therapy), and included patients who had been previously 
treated with a proteasome inhibitor such as VELCADE or carfilzomib and considered to be 
sensitive to a proteasome inhibitor or patients who were proteasome inhibitor naive. 
Preliminary data suggest that MLN9708 has antitumor activity in heavily pretreated patients 
with MM, with an ORR of 27% for the MTD expansion cohort in Study C16004. In both 
studies, durable responses and disease control have been observed with a generally 
acceptable toxicity profile.
The inclusion of an RRMM treatment arm in this study is proposed on the basis of results of 
VELCADE in patients with previously treated MM and the emerging activity seen with 
MLN9708 in patients with previously treated and untreated MM.  
The purpose of Study C16020 is to determine the safety, tolerability, and efficacy of oral 
MLN9708 when added to a Cd backbone in patients with NDMM and RRMM.  For patients 
with NDMM, extending the duration of the response through prolonged use of single-agent 
MLN9708 as maintenance therapy following induction will also be evaluated. Patients with 
NDMM who are stable or responding at the end of induction therapy will continue to receive 
MLN9708 as maintenance treatment. 
1.4.1   
Feasibility of Combination of MLN9708, Cyclophosphamide, and 
Dexamethasone Therapy
Treatment with oral Cd is generally well tolerated.  The primary side effect of 
cyclophosphamide is bone marrow suppression, particularly neutropenia and GI 
disturbances such as nausea, vomiting, and diarrhea. Treatment with dexamethasone can 
induce steroid side effects, such as hyperglycemia, fluid retention, increased appetite, or 
behavioral changes in susceptible patients.  Adverse events reported in MLN9708 clinical 
trials are generally consistent with the known effects of proteasome inhibition and are 
generally similar to what has been previously reported with VELCADE, though the severity 
of some may vary, for example GI toxicity is more, while PN is less with MLN9708.  The 
most common and significant AEs reported include GI disorders, thrombocytopenia, and 
rash.


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When VELCADE was added to cyclophosphamide/dexamethasone (CyBorD and VCD 
regimen) the combination was shown to be tolerable, although neuropathy was common.
All AEs reported were expected from each drug administered as a single agent and 
considered manageable with either appropriate clinical support or dose reduction.  The 
discontinuation rate due to AE was ≤12%.  For CyBorD, the most commonly reported AEs 
Grade 3 or higher were cytopenia and hyperglycemia.  The major reason for dose reduction 
of cyclophosphamide included thrombocytopenia and neutropenia, which appeared in early 
cycles, whereas neuropathy was the major cause for dose reduction of VELCADE in later 
cycles.  A similar safety profile was observed with VCD.  Based on the available safety data 
on the combination of VELCADE/cyclophosphamide/dexamethasone, the expected 
overlapping toxicities such as hematological toxicities when MLN9708 is combined with 
cyclophosphamide are anticipated to be similar as with CyBorD or VCD regimen and 
manageable.  Standard clinical usage of antiemetic and/or antidiarrheal agents to control 
potential increased GI toxicities seen with MLN9708 compared with VELCADE may be 
necessary though not expected to be dose limiting in the dose and schedule being tested.  
Given the similar safety and tolerability profile of MLN9708 compared with VELCADE,
adding MLN9708 to a Cd backbone is anticipated to be feasible from a safety perspective in 
both the NDMM and RRMM settings.
1.4.2   
Rationale for the Combination of MLN9708, Cyclophosphamide, and 
Dexamethasone Dose and Dosing Schedule
MLN9708
Oral MLN9708 administered weekly on Days 1, 8, and 15 of a 28-day cycle is supported by 
nonclinical data and clinical trial results in which MLN9708 has been given either as a 
single agent or in combination with a standard dose of RevDex (C16005) or MP (C16006).  
A weekly dose of MLN9708 at 4.0 mg was consistently declared as MTD or RP2D across 
the MLN9708 program (single agent or in combination) and is currently the RP3D tested in 
the ongoing registration trials (C16010, C16011, and C16014) in patients with either MM or 
AL amyloidosis.  Most relevant to the dosing schedule selected is the previously mentioned 
Study C16006, an ongoing, open-label, multi-arm, dose-escalation, phase 1/2 study in which 
MLN9708 is tested in combination with MP in elderly patients with NDMM, ineligible for 
transplant. After an induction therapy of the combination for 1 year, single-agent MLN9708 
is administered as maintenance therapy. In Arm B of the phase 1 portion of the study, 
patients were enrolled in each of the following cohorts:  Cohort 1 (MLN9708 3.0 mg), 
Cohort 2 (MLN9708 4.0 mg) and Cohort 3 (MLN9708 5.5 mg) given weekly on Days 1, 8,
and 15 on a 28-day cycle, in combination with melphalan (6 mg/m2) and prednisone 


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(60 mg/m2). MLN9708 4.0 mg was determined to be the MTD and the RP2D, with no DLT 
reported in that cohort, while DLTs reported in 2 of 5 patients in the 5.5-mg cohort included 
Grade 4 esophageal ulcer and Grade 3 thrombocytopenia, with Grade 3 hematemesis; 
Grade 3 nausea, vomiting, and diarrhea; and Grade 3 ileus and neurogenic bladder.  
Preliminary results in the ongoing MTD cohort suggest an overall safe and well tolerated 
induction regimen with comparable efficacy as to historical controls.  Selection of the same 
weekly RP2D dose of MLN9708 at 4.0 mg on Days 1, 8, and 15 of a 28-day cycle has been 
shown to be safe and tolerable when added to MP was logically considered for the Cd
combination.  
Cyclophosphamide
The dose-intensity schedules for cyclophosphamide tested in the myeloma setting are 
numerous and there is no dosing regimen that can be considered standard in either the 
frontline or relapsed and/or refractory disease setting.  Recent studies evaluating the 
combination of Cd with VELCADE in a transplant-eligible patient population (CyBorD and 
VCD-mod) combined standard twice-weekly VELCADE dosing to weekly 
cyclophosphamide administration of either 300 mg/m2 or 500 mg/m2 continuously or with a 
1-week break. As mentioned previously, both dosing regimens were tolerable with 
manageable toxicities.  More recently, preliminary results exploring carfilzomib, another
proteasome inhibitor in combination with cyclophosphamide/dexamethasone (CCd) in a 
NDMM elderly patient population were presented at the European Hematology Association
Congress 2013.(21) A weekly cyclophosphamide dose of 300 mg/m2 on Days 1, 8, and 15 
and a dexamethasone dose of 40 mg weekly in a 28-day cycle was used.  This combination 
was shown to have a good efficacy and safety profile: discontinuation rate for AEs of 11%. 
No differences in response rate and safety between patients younger and older than 75 years 
were observed.  On the basis of available data on weekly cyclophosphamide tested in 
combination with a proteasome inhibitor in both transplant-eligible and transplant-ineligible 
patients with NDMM, weekly cyclophosphamide at a dose of 300 mg/m2 on Days 1, 8, and 
15 on a 28-day cycle was a safe and tolerable dose to consider and was selected for Arm A
and the population with relapsed and/or refractory disease to be enrolled in Arm C.  Because 
cyclophosphamide was also successfully tested at a dose of 500 mg/m2 weekly in patients
with NDMM considered for transplantation, and because depth of response matters, a 
weekly dose of cyclophosphamide of 400 mg/m2 will be explored in Arm B to determine 
whether an increased dose of the backbone agent may translate into better efficacy while 
providing an acceptable safety/tolerability profile.


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Although various dose schedules have been used for cyclophosphamide in combination with 
VELCADE in the relapsed and/or refractory disease setting, including the 500 mg weekly 
dose(19) or 50 mg daily dose,(20) a weekly dose of 300 mg/m2 on Days 1, 8, and 15 of a 
28-day cycle is expected to be tolerable in combination with a proteasome inhibitor, based 
on the toxicity profile observed in patients with NDMM.  An alternative dose schedule may 
be considered for Arm C if the planned dosage is not tolerated.  
Dexamethasone
Dexamethasone enhances the activity of MLN9708 and of cyclophosphamide, and is used at 
the proposed study dose and schedule (40 mg on Days 1, 8, 15, and 22) in other MLN9708 
clinical studies (C16010, C16011, and C16014).  An open-label, randomized, controlled,
Eastern Cooperative Oncology Group (ECOG) clinical trial using this dose and schedule 
reported better short-term OS and lower toxicity than the high-dose dexamethasone schedule 
(40 mg on Days 1-4, 9-12, and 17-20) when added to lenalidomide.(22)
1.5   
Rationale for Biomarker Measurements
Minimal Residual Disease Assessment
Residual disease, present yet undetected by conventional techniques following therapy, 
leads to disease relapse and mortality.  Complete response remains the optimal objective in 
front-line treatment of myeloma to improve survival. The definition of CR has evolved in 
recent years from normalization of serum protein electrophoresis and bone marrow 
morphology with negative immunofixation, to normal serum free light-chain ratio test 
(stringent CR; sCR), and more recently to normal immunophenotype (IR).(23)  Emerging 
data assessing the presence of minimal residual disease (MRD) using flow cytometric 
techniques to immunophenotype bone marrow aspirate material obtained during CR 
assessment in combination with k/λ ratio are starting to demonstrate the potential value of 
being able to assess the presence of MRD.
Immunophenotyping defines a tumor’s surface marker profile via flow cytometry and is 
highly sensitive to the presence of tumor cells in marrow specimens. Patients with tumor 
cells below the detection threshold (1 in ~10,000 plasma cells) are considered to be MRD 
negative.(23)  Although the long-term utility of this approach is still in its early days in MM, 
several studies have indicated that MRD-negative patients experienced longer PFS and OS 
than flow cytometric-positive patients.(24) Recently, Paiva and colleagues have investigated 
the impact of IR versus CR and sCR in 260 newly diagnosed elderly (65 years) patients 


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with MM treated with novel agents in the PETHEMA/GEM 05 trial. In this trial, IR showed 
significant increased 3-year rates of PFS and (time to progression [TTP] compared with 
those in sCR or CR (90% vs 69% and 60%, and 96% vs 71% and 68% [p 0.001])
respectively. On a multivariate COX regression analysis for PFS, only IR status was an 
independent prognostic factor (relative risk, 4.1; 95% CI, 1.4-12.0; p 0.01).(24)
Blood Sample Genotyping
variants in proteasome subunits
as important contributors to 
VELCADE clinical activity. A blood sample will be collected at screening to test if specific 
growth, survival, and/or drug resistance of a given patient’s myeloma. Additional 
associations with either the efficacy or safety of MLN9708 may be examined if there is a 
1.6   
Rationale for Pharmacokinetic Measurements


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1.7   
Potential Risks and Benefits


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Further information can be found in Section 1.4.1 and Section 1.4.2 and in the MLN9708 IB
and SMA.
2.   
STUDY OBJECTIVES
2.1   
Primary Objectives
The primary objective for patients with newly diagnosed multiple myeloma (NDMM) is:

To determine the combined response rate of CR (including stringent CR [sCR]) + 
VGPR following treatment with oral MLN9708 when added to a regimen of 
cyclophosphamide and low-dose dexamethasone (Cd) during the induction phase
The primary objective for patients with relapsed and/or refractory multiple myeloma 
(RRMM) is:

To determine overall response rate (ORR; CR + VGPR +partial response [PR]), 
following treatment with oral MLN9708 when added to a regimen of Cd  
2.2   
Secondary Objectives
For patients with NDMM, the secondary objectives are:

To evaluate the tolerability and toxicity of the combination of oral MLN9708 with
Cd

To characterize the PK in plasma of oral MLN9708 in combination with Cd

To determine overall response rate (ORR; CR + VGPR + PR), CR, VGPR, and PR
during the induction phase and the ORR (CR + VGPR + PR), CR + VGPR, CR, 
VGPR, and PR throughout the entire treatment period  


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
To determine time to response for patients who respond during the induction phase

To determine duration of response (DOR) for patients who respond during the 
induction phase

To determine TTP

To evaluate PFS

To describe the safety, tolerability, and efficacy of MLN9708 as maintenance 
therapy in patients who continue treatment beyond 13 cycles of induction therapy

To assess change in global health status, as measured by the patient-reported 
outcome (PRO) instruments European Organization for Research and Treatment of 
Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30)
For patients with RRMM, the secondary objectives are:

To evaluate the tolerability and toxicity of the combination of oral MLN9708 with
Cd

To characterize the PK in plasma of oral MLN9708 in combination with Cd

To determine CR + VGPR, CR, VGPR, and PR

To determine time to response for patients who respond 

To determine DOR

To determine TTP

To evaluate PFS

To assess change in global health status, as measured by the patient-reported 
outcome (PRO) instruments European Organization for Research and Treatment of 
Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30)


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2.3   
Exploratory Objectives
For patients with NDMM and patients with RRMM, the exploratory objectives are:

3.   
STUDY ENDPOINTS
3.1   
Primary Endpoint
For patients with NDMM, the primary endpoints are:

Combined response rate of CR (including sCR) + VGPR during the induction phase 
in patients treated with MLN9708 when added to a regimen of Cd.
For patients with RRMM, the primary endpoint is:

ORR (CR + VGPR +PR) in patients treated with MLN9708 when added to a 
regimen of Cd.  


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3.2   
Secondary Endpoints
For patients with NDMM, the secondary endpoints are:

All AEs, Grade 3 or higher AEs, AEs resulting in discontinuation, AEs resulting in 
dose reduction, serious adverse events (SAEs), and assessments of clinical laboratory 
values

PK parameters including, but not limited to single-dose maximum (peak) 
concentration  (Cmax), Tmax, and AUC

ORR (CR + VGPR + PR), CR, VGPR, PR, stable disease (SD), progressive disease 
(PD) during the induction phase; ORR, CR + VGPR, CR, VGPR, PR, SD and PD
and throughout the entire study

Time to response, defined as the time interval from the date of enrollment to the date 
of first documented response during the induction phase

DOR, defined for responders as the time interval from the date of first response to 
the date of disease progression

TTP, defined as the time interval from the date of enrollment to the date of first 
documented disease progression

PFS, defined as the time interval from the date of enrollment to the date of first 
documented disease progression or death

AEs, SAEs, AEs resulting in discontinuation, AEs resulting in dose reduction in 
patients remaining on treatment after 13 cycles, ORR, CR, VGPR, and PR of 
single-agent MLN9708 as maintenance therapy in patients remaining on treatment 
after 13 cycles

Comparison of change in global health status between baseline and each postbaseline 
assessment, as measured by the global health scale, functioning, and symptoms of 
the EORTC QLQ-C30.


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For patients with RRMM, the secondary endpoints are:

All AEs, Grade 3 or higher AEs, AEs resulting in discontinuation, AEs resulting in 
dose reduction, serious adverse events (SAEs), and assessments of clinical laboratory 
values

PK parameters including but not limited to single-dose maximum (peak) 
concentration (Cmax), Tmax, and AUC

CR + VGPR, CR, VGPR, PR, SD, PD 

Time to response

DOR

TTP

PFS

Comparison of change in global health status between baseline and each postbaseline 
assessment, as measured by the global health scale, functioning, and symptoms of 
the EORTC QLQ-C30.
3.3   
Exploratory Endpoints
For patients with NDMM and patients with RRMM, the exploratory endpoints are:
Estimate of the frequency of detection of MRD within bone marrow aspirate samples 
via flow cytometry in patients assessed at suspected CR and its impact on PFS
The potential relationship between response or resistance to MLN9708 treatment and 


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
. 
4.   
STUDY DESIGN 
4.1   
Overview of Study Design
This is a phase 2, multicenter, open-label study in patients with NDMM who have not 
received prior systemic treatment for MM and who are ineligible for high-dose therapy 
(HDT)-SCT due to age (ie, ≥65 years) or comorbid disease(s) and in patients with RRMM 
who have received 1 to 3 lines of prior therapy and whose disease is not refractory to 
proteasome inhibitors.  It is expected that approximately 148 patients will be enrolled in this 
study. 
Patients With NDMM (Arms A and B)
Patients with NDMM will be randomized 1:1 to either Arm A or Arm B. Each 28-day
treatment cycle consists of oral MLN9708 (4.0 mg on Days 1, 8, and 15) administered in 
combination with cyclophosphamide (300 mg/m2 [Arm A] OR 400 mg/m2 [Arm B] both on 
Days 1, 8, and 15) and dexamethasone (40 mg on Days 1, 8, 15, and 22). Patients over 
75 years of age will receive a reduced dose of dexamethasone 20 mg on the same weekly 
schedule.  Patients may receive MLN9708 in combination with Cd for an induction phase of 
approximately 1 year (13 28-day cycles) and if at least stable disease has been reached
with an acceptable toxicity profile, patients will be administered, as maintenance, 
single-agent MLN9708 (at the dose tolerated at the end of induction) on Days 1, 8, and 15 in 
28-day treatment cycles until disease progression, death, or unacceptable toxicity.
Patients With RRMM (Arm C)
Patients with RRMM will receive MLN9708 4.0 mg weekly on Days 1, 8, and 15, in 
combination with cyclophosphamide 300 mg/m2 on Days 1, 8, and 15, and dexamethasone 
40 mg on Days 1, 8, 15, and 22 of a 28-day cycle (all orally administered).  Patients over 
75 years of age will receive the reduced dose of dexamethasone 20 mg on the same weekly 


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schedule.  Patients with an acceptable toxicity profile will continue treatment until disease 
progression, death, or unacceptable toxicity.  
All Patients (Arms A, B, and C)
For all 3 treatment arms (Arms A, B, and C), a safety lead-in evaluation will be performed 
after at least 6 patients in each treatment arm have had the opportunity to complete at least 
1 cycle of therapy.  Dose-limiting toxicities (DLTs) observed in the first 6 patients from 
each treatment arm will be used to determine the safety and overall tolerability of the 
regimen and the feasibility of continued recruitment to the study.  
No formal interim analysis is planned; however, both safety and efficacy will be continually 
monitored (see Section 8.1.11) throughout study conduct.  
Response will be assessed according to the International Myeloma Working Group (IMWG)
criteria.  For patients with NDMM (Arms A and B), these assessments will be performed at 
every cycle during the induction phase and at every other cycle during the maintenance
phase.  For patients with RRMM (Arm C), response will be assessed at every cycle during 
the treatment period.  Radiographic disease assessments are to be performed for patients 
with documented extramedullary disease.  Patients discontinuing study drug before disease 
progression (ie, for withdrawal of consent or unacceptable toxicity) will be followed for PFS 
until disease progression or death. 
Eastern Cooperative Oncology Group performance score and AEs will be assessed, and 
laboratory values, urine analysis, vital signs, and electrocardiograms (ECGs) will be 
obtained to evaluate the safety and tolerability of the combination therapy. Toxicity will be 
evaluated according to National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE) version 4.03, effective 14 June 2010.(31)
Serial blood samples for determination of the plasma concentration of MLN9708 and tumor 
specific markers, will be obtained at prespecified time points as described in Schedule of
Events.
The study drug regimen will be discontinued for a patient in any of the 3 treatment arms 
who experiences disease progression or unacceptable study drug-related toxicities. This 
includes MLN9708 in combination with Cd during the induction period for patients with 
NDMM (Arms A and B) or the treatment period for patients with RRMM (Arm C).  
MLN9708 will also be discontinued for patients with NDMM (Arms A and B) who 


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experience disease progression during the maintenance phase.  Patients may discontinue 
therapy at any time.  Patients will attend the end of treatment (EOT) visit 30 days (± 7 days) 
after receiving their last dose of study drug regimen.  
4.2   
Number of Patients
It is anticipated that approximately 148 patients, 70 patients with NDMM and 78 patients 
with RRMM, will be enrolled in this study from approximately 30 study centers globally.
4.3   
Duration of Study
It is anticipated that the total duration of the study will be approximately 60 months.  This 
includes 24 months of enrollment and up to 36 months of treatment and/or PFS follow-up.  
The analyses for the clinical study report (CSR) will be conducted after all enrolled patients 
have had the opportunity to complete 13 cycles of the study drug regimen.  
5.   
STUDY POPULATION
Two patient populations will be enrolled in this study:

Adult patients with a confirmed diagnosis of symptomatic MM who have received 
no prior antimyeloma treatment (NDMM) and are not candidates for HDT-SCT due 
to age (65 years) or comorbidities; and 

Adult patients with a confirmed diagnosis of symptomatic MM and relapsed and/or 
refractory disease (RRMM) after 1 to 3 lines of prior therapy and whose disease is 
not refractory to proteasome inhibitors
5.1   
Inclusion Criteria
Each patient with NDMM must meet all of the following inclusion criteria to be enrolled in 
the study:
1. Adult male or female patients 18 years of age or older with a confirmed diagnosis of 
symptomatic MM according to standard criteria (see Section 14.1 and Section 14.5).


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2. Patients for whom cyclophosphamide and dexamethasone treatment is appropriate 
and who are considered not eligible for HDT-SCT for 1 or more of the following 
reasons:

The patient is 65 years of age or older.

The patient is less than 65 years of age but has significant comorbid condition(s) 
that are, in the opinion of the investigator, likely to have a negative impact on 
tolerability of HDT-SCT.
Each patient with RRMM must meet all of the following inclusion criteria to be enrolled in 
the study:
3. Adult male or female patients 18 years or older with a confirmed diagnosis of 
symptomatic MM either currently or at the time of initial diagnosis, according to 
standard criteria (see Section 14.1 and Section 14.5), and relapsed and/or refractory 
disease after 1 to 3 lines of prior therapy.  A patient is considered to have refractory 
disease if disease progression occurred during the treatment period or within 60 days 
of receiving the last dose of a given therapy.  A line of therapy is defined as 1 or 
more cycles of a single-agent or combination therapy or a sequence of planned 
treatments such as induction therapy followed by autologous stem cell 
transplantation (ASCT) and then maintenance therapy.
4. No evidence of graft-versus-host disease for patients who have undergone prior 
allogeneic stem cell transplantation.  
In addition, all patients (NDMM and RRMM) must meet all of the remaining criteria:  
5. Patients must have measurable disease defined by at least 1 of the following 
3 measurements:

Serum M-protein ≥1 g/dL (≥10 g/L).

Urine M-protein ≥200 mg/24 hours.

Serum free light chain assay:  involved free light chain level ≥10 mg/dL 
(≥100 mg/L), provided that the serum free light chain ratio is abnormal.
6. Patients must meet all of the following clinical laboratory criteria:


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
Absolute neutrophil count (ANC) ≥1000/mm3 and platelet count ≥75,000/mm3.  
Platelet transfusions to help patients meet eligibility criteria are not allowed 
within 3 days prior to administration of the study drug.

Total bilirubin ≤1.5 the upper limit of the normal range (ULN).

Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 
≤3 ULN.

Calculated creatinine clearance (CrCL) ≥30 mL/min (see Section 14.2).
7. Eastern Cooperative Oncology Group performance status of 0, 1, or 2 (see 
Section 14.3).
8. Female patients who:

Are postmenopausal for at least 1 year before the screening visit, or

Are surgically sterile, or

If they are of childbearing potential, agree to practice 2 effective methods of 
contraception, at the same time, from the time of signing the informed consent 
through 90 days after the last dose of study drug, or

Agree to practice true abstinence over the period previously described, when this 
is in line with the preferred and usual lifestyle of the subject. (Periodic 
abstinence (eg, calendar, ovulation, symptothermal, postovulation methods] and 
withdrawal are not acceptable methods of contraception.), and 

Adhere to any treatment-specific pregnancy prevention guidelines for 
cyclophosphamide(32, 33) and dexamethasone(34, 35, 36)
Male patients, even if surgically sterilized (ie, status postvasectomy), who:

Agree to practice effective barrier contraception during the entire study treatment 
period and through 90 days after the last dose of study drug, or

Agree to practice true abstinence over the period previously described, when this 
is in line with the preferred and usual lifestyle of the subject. (Periodic 
abstinence [eg, calendar, ovulation, symptothermal, postovulation methods for 


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the female partner] and withdrawal are not acceptable methods of 
contraception.), and 

Adhere to any treatment-specific pregnancy prevention guidelines for 
cyclophosphamide(32, 33) and dexamethasone(34, 35, 36)
9. Voluntary written consent must be given before performance of any study-related 
procedure not part of standard medical care, with the understanding that consent may 
be withdrawn by the patient at any time without prejudice to future medical care.
10. Suitable venous access for the study-required blood sampling.
11. Patient is willing and able to adhere to the study visit schedule and other protocol 
requirements.
5.2   
Exclusion Criteria
Patients meeting any of the following exclusion criteria are not to be enrolled in the study:
1. Prior treatment for multiple myeloma with either standard of care treatment or 
investigational regimen (for patients with NDMM only).
NOTE:  Prior treatment with corticosteroids (maximum dose of corticosteroids 
should not exceed the equivalent of 160 mg of dexamethasone over 14 days [see 
Section 14.4 for a list of steroid equivalent doses]).  Localized radiation is permitted 
as long as it is below a therapeutic level and administered at least 14 days prior to the 
first dose of study treatment.
2. Diagnosis of smoldering MM, Waldenström’s macroglobulinemia, POEMS 
(polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin 
changes) syndrome, plasma cell leukemia, primary amyloidosis, myelodysplastic 
syndrome, or myeloproliferative syndrome. 
3. Central nervous system involvement.
4. Diagnosed or treated for another malignancy within 2 years before the first dose 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.


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5. Peripheral neuropathy Grade 1 with pain or Grade 2 or higher peripheral neuropathy 
of any cause on clinical examination during the Screening period.
6. Known GI disease or GI procedure that could interfere with the oral absorption or 
tolerance of study drug, including difficulty swallowing.
7. Infection requiring IV antibiotic therapy or other serious infection within 14 days 
before the first dose of study drug. 
8. Ongoing or active infection, known human immunodeficiency virus (HIV) positive, 
active hepatitis B or C infection 
9. Systemic treatment with strong inhibitors of CYP1A2 (fluvoxamine, enoxacin, 
ciprofloxacin), strong inhibitors of CYP3A (clarithromycin, telithromycin, 
itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole) or strong 
CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, 
phenobarbital), or use of Ginkgo biloba or St. John’s wort within 14 days before the 
first dose of study treatment.
10. Known allergy to any of the study medications, their analogues, or excipients in the 
various formulations.
11. Major surgery within 14 days before the first dose of study drug.  (Note:  
kyphoplasty or vertebroplasty is not considered major surgery.)
12. Female patients who are lactating and breastfeeding or have a positive serum 
pregnancy test during the Screening period. 
13. Any serious medical or psychiatric illness that could, in the investigator’s opinion, 
potentially interfere with the completion of treatment according to this protocol.
14. 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.
15. Treatment with any investigational products for reasons other than MM within 
30 days before the first dose of study drug.


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6.   
STUDY DRUG
6.1   
Study Drug Administration
All protocol-specific criteria for administration of study drug must be met and documented 
prior to drug administration.  The study drug regimen 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 study drug should 
be modified as needed to accommodate patient tolerance to treatment; this may include 
symptomatic treatment, dose interruptions, and adjustments of dose.
All doses must be taken as outlined in the Schedule of Events. Dosing should be performed 
on schedule, but occasional changes in patient scheduling are allowable (± 3 days) for 
holidays and vacations, except during Cycle 1 for all patients enrolled in the safety lead-in 
cohort.  After the safety lead-in is completed within a treatment arm, an occasional change 
in the dosing schedule (± 1 week) may be allowable for other administrative reasons after 
consultation with the Millennium project clinician (or designee).  Eligible patients may take 
MLN9708 in combination with Cd at home as directed.  Refer to the Study Manual for 
additional instructions regarding study drug administration.
6.1.1   
MLN9708 Administration
Patients With NDMM (Arms A and B)
During induction, oral MLN9708 will be given weekly at a dose of 4.0 mg on Days 1, 8, and 
15 of a 28-day cycle.  
At the end of 13 cycles of treatment, the maintenance phase will start.  If the patient is still 
on study (has achieved at least stable disease with an acceptable toxicity profile), MLN9708 
will be continued as a single agent, weekly on Days 1, 8, and 15 of a 28-day cycle at the 
same dose being given at the end of induction therapy.  Under certain circumstances the 
maintenance dose may be increased up to but not exceeding the starting dose of the 
induction phase if the investigator and Millennium project clinician (or designee) both agree 
that it would be beneficial for the patient.  


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Patients With RRMM (Arm C)
For patients with RRMM, oral MLN9708 will be given weekly on Days 1, 8, and 15 of 
28-day cycle at the planned dose of 4.0 mg until disease progression or unacceptable toxicity 
occurs.  
All Patients (Arms A, B, and C)
For all 3 treatment arms, 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.  
Patients should be instructed to swallow MLN9708 capsules whole with water and not to
chew, break, or open the capsules.  Each dose of MLN9708 will be taken orally with 
approximately 8 ounces (ie, 240 mL) total of water consumed.
Missed doses on Days 1 and 8 can be taken as soon as the patient remembers as long as the 
next scheduled dose is 72 hours or more away.  The missed dose on Day 15 can be taken 
only up to 72 hours after the planned dose (no later than on Day 18).  A double dose should 
not be taken to make up for a missed dose.  Patients who vomit a dose after ingestion will 
not receive an additional dose, but should resume dosing at the time of the next scheduled 
dose.
Patients should be monitored for toxicity as necessary, and doses of MLN9708 should be 
modified as needed to accommodate patient tolerance to treatment; this may include 
symptomatic treatment, dose interruptions, and/or adjustments of MLN9708 dose.  
Following agreement between the investigator and the sponsor, and after completing 
3 cycles of treatment, eligible patients may take MLN9708 at home as directed; however, all 
patients will be required to report to the clinic for Day 1 of each cycle for scheduled 
assessments (see the Schedule of Events).
6.1.2   
Cyclophosphamide Administration
Patients With NDMM (Arms A and B)
During induction, cyclophosphamide will be given weekly as a single, oral dose of 
300 mg/m2 (Arm A) OR 400 mg/m2 (Arm B) and rounded to the nearest 50 mg, on Days 1, 
8, and 15 of a 28-day cycle.  
At the end of 13 cycles of treatment, the maintenance phase will start.  If the patient is still 
on study, cyclophosphamide will be discontinued.


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Intrapatient Dose Escalation of Cyclophosphamide for Arm A
Intrapatient dose escalation is not planned; however, if during the continuous monitoring of 
the study data, clear evidence of antitumor activity is observed in Arm B (cyclophosphamide 
400 mg/m2) with an overall acceptable safety/tolerability profile, patients in Arm A 
(cyclophosphamide 300 mg/m2) who have tolerated treatment with cyclophosphamide well 
at the initially assigned dose may be allowed to increase their dose of cyclophosphamide to 
400 mg/m2 in subsequent cycles of treatment following sponsor and investigator review of 
the available observed data.  Patients in whom an increase in the dose of cyclophosphamide 
is being considered must have completed at least 2 cycles of treatment at their initially 
assigned dose.  Hematology laboratory samples will be obtained weekly for the next
3 cycles once the dose has been increased.
Patients With RRMM (Arm C)
For patients with RRMM, cyclophosphamide will be given weekly on Days 1, 8, and 15 of a 
28-day cycle as a single, oral dose of 300 mg/m2 and rounded to the nearest 50 mg.  An 
alternative dose schedule of cyclophosphamide may be explored for Arm C if the planned 
dose is not tolerated.
All Patients (Arms A, B, and C)
For all 3 treatment arms, it is recommended that cyclophosphamide be taken in the morning 
and at approximately the same time each dosing day. Cyclophosphamide should be taken 
with solid food or milk.  Patients should be instructed to drink plenty of fluids and to urinate 
frequently during treatment with cyclophosphamide.  Patients should be instructed to 
swallow cyclophosphamide capsules whole with water and not to chew, break, or open the 
capsules.
Missed doses can be taken within 48 hours from the planned dose.  If more than 48 hours
have elapsed, the missed dose should be skipped and the next dose taken according to the 
regular dosing schedule.  A double dose should not be taken to make up for a missed dose.  
If the patient vomits after taking a dose, the patient should not repeat the dose but should 
resume dosing at the time of the next scheduled dose.
Body surface area will be calculated using a standard formula on Cycle 1, Day 1 and on 
Day 1 of subsequent cycles.  If the patient experiences a > 5% change in body weight from 
the weight used for the most recent BSA calculation, the BSA should be recalculated to 
determine the dose of cyclophosphamide.  


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6.1.3   
Dexamethasone Administration
Patients With NDMM (Arms A and B)
During induction, dexamethasone will be given as a weekly oral dose of 40 mg on Days 1, 
8, 15, and 22 of a 28-day cycle.  Patients older than 75 years of age at the time of 
randomization will receive a reduced dose of dexamethasone 20 mg on the same weekly 
schedule.
At the end of 13 cycles of treatment, maintenance phase will start.  If the patient is still on 
study, dexamethasone will be discontinued.
Patients With RRMM (Arm C)
For patients with RRMM, dexamethasone will be given as a weekly oral dose of 40 mg on 
Days 1, 8, 15, and 22 of a 28-day cycle.  Patients older than 75 years of age at the time of 
enrollment will receive the reduced dose of dexamethasone 20 mg on the same weekly 
schedule.  
All Patients (Arms A, B, and C)
For all 3 treatment arms, it is recommended that dexamethasone be taken in the morning and 
at approximately the same time each dosing day.  Dexamethasone should be taken with solid 
food or milk.  
Missed doses can be taken within 48 hours from the planned dose.  If more than 48 hours 
have elapsed, the missed dose should be skipped, and the next dose taken according to the 
regular dosing schedule.  A double dose should not be taken to make up for a missed dose.  
If the patient vomits after taking a dose, the patient should not repeat the dose but should 
resume dosing at the time of the next scheduled dose.
6.2   
Safety Lead-in
A safety evaluation will be performed after at least 6 safety lead-in evaluable patients have 
had the opportunity to complete at least 1 cycle of treatment in each of the 3 treatment arms
(Arms A, B, and C).  Toxicities observed in the first 6 safety lead-in evaluable patients from 
each of the 3 treatment arms will be used to determine the safety and overall tolerability of 
the regimen in the 2 patient populations (patients with NDMM assigned to Arm A or Arm B 
and patients with RRMM enrolled in Arm C) and the feasibility of continued recruitment to 
the study.  


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6.2.1   
Safety Lead-in Evaluable Patients
Patients who do not receive all doses of MLN9708 or cyclophosphamide during Cycle 1 per 
the Schedule of Events for reasons other than an AE will be replaced for safety evaluation.  
Patients who receive all doses of MLN9708 and cyclophosphamide but, for unforeseen 
circumstances, recovery of toxicity is not available and safety in Cycle 1 cannot be fully 
evaluated, may be replaced.  Toxicity leading to dose modification in Cycle 2 and beyond 
will be considered when determining continuous enrollment in the treatment arm.
6.2.2   
Rules for Continuous Study Enrollment
For each of the 3 treatment arms, a tolerable dose will require first-cycle DLTs 
(Section 6.2.1) in no more than 1 of 6 safety lead-in evaluable patients in that treatment arm.
For patients with NDMM, when 2 of 6 safety lead-in patients experience DLTs
(Section 6.2.1) in 1 treatment arm and no more than 1 of 6 DLT-evaluable patients 
experience DLTs in the other arms, depending on the overall safety profile and the type of 
AEs/DLTs observed in the treatment arms, the decision will be made to either stop 
enrollment in that treatment arm or expand that treatment arm with 6 additional patients.  A 
tolerable dose will then require first-cycle DLTs in no more than 3 of 12 safety lead-in 
evaluable patients in the expanding treatment arm to proceed with enrollment.
Enrollment in any of the 3 treatment arms (NDMM and RRMM) will be held until the 6th 
patient has had the opportunity to complete Cycle 1, if a DLT occurs in 1 of the first 
5 patients enrolled in that arm.  Accrual to a treatment arm will also be stopped if any of the 
first 5 patients experience AEs, which may not qualify as DLTs per protocol-defined
criteria, but the project clinician believes that it is in the interest of patient safety to hold 
enrollment until all 6 patients complete Cycle 1.  If the first 5 patients complete Cycle 1 
without any DLTs being observed, enrollment may continue in that treatment arm and will 
not need to be held until the 6th patient completes Cycle 1, provided that the regimen is 
being tolerated and no safety concerns are identified.  Enrollment in each treatment arm will
occur independently, so that accrual of patients to any of the 3 treatment arms can proceed 
even if enrollment is being held in another treatment arm. In addition, patients previously 
enrolled in the treatment arm in which accrual is being held will have the opportunity to 
continue to receive the study drug regimen as long as it is being well tolerated and no safety 
concerns are identified in those patients.  Randomization is required only when patients are 
being enrolled in Arms A and B concurrently.  


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After the safety lead-in evaluation, if 1 of the treatment arms for patients with NDMM is 
stopped, enrollment in the other arm will continue.  If the decision is made to stop both 
treatment arms (Arms A and B), enrollment in the entire study, including accrual of patients 
to treatment Arm C may be stopped or alternative dosing levels for all 3 treatment arms may 
be evaluated following discussion between the sponsor and the investigators.  If after the 
safety lead-in evaluation, accrual to Arm C is stopped, enrollment in the other 2 treatment 
arms may continue and alternate dose schedules may be explored for Arm C, following 
discussion between the sponsor and investigators.  
Expansion of a safety lead-in cohort is permissible if such measures are needed for patient 
safety or for a better understanding of the dose-related toxicity, exposure, or 
pharmacodynamics of the combination. 
6.2.2.1   
Evaluation of Toxicity:  DLT Criteria
Toxicity will be evaluated according to the NCI CTCAE version 4.03.(31)  These criteria are 
provided in the Study Manual.  The following AEs that are considered by the investigator to 
be even possibly related to the MLN9708 in combination with Cd will be considered as 
DLTs (Cycle 1 only):
1. Grade 3 neutropenia with fever and/or infection, where fever is defined as a 
temperature > 38.3C.
2. Grade 4 neutropenia (ANC < 500/mm3) lasting at least 7 consecutive days.
3. Grade 3 thrombocytopenia with clinically significant bleeding, defined as a blood 
loss of > 100 cc or the requirement for a red blood cell transfusion.
4. Grade 4 thrombocytopenia (platelets < 25,000/mm3) lasting at least 7 consecutive 
days or associated with bleeding.
5. A platelet count < 10,000/mm3.
6. Grade 3 or higher nausea and/or emesis despite the use of optimal antiemetic 
prophylaxis.  Optimal antiemetic prophylaxis is defined as an antiemetic regimen
that employs a 5-hydroxytryptamine 3 serotonin receptor (5-HT3) antagonist given in 
standard doses and according to standard schedules.
7. Grade 3 or higher diarrhea that occurs despite maximal supportive therapy.


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8. Any other Grade 3 or higher nonhematologic toxicity with the following exceptions:

Grade 3 arthralgia/myalgia.

Brief (< 1 week) Grade 3 fatigue.
9. A delay of more than 2 weeks in the subsequent cycle of treatment because of a lack 
of adequate recovery of combination study drug-related hematological or
nonhematologic toxicities.
10. Other combination study drug-related nonhematologic toxicities Grade 2 or higher 
that, in the opinion of the investigator, require dose reduction on either MLN9708 or 
cyclophosphamide or discontinuation of the study drug regimen during Cycle 1.
6.3   
Dose Modification Guidelines
Patients will be evaluated weekly for the first 3 cycles and regularly thereafter while on 
treatment for possible toxicities that may have occurred after the previous dose(s).  
Toxicities are to be assessed according to the NCI CTCAE version 4.03.(31)  Each AE should 
be attributed to a specific drug, if possible, so that the dose modifications can be made 
accordingly.  Reduction of 1 agent and not the other is appropriate if toxicity is related 
primarily to 1 of the 3 agents.  Before beginning the next cycle of treatment, refer to the 
guidelines in Section 6.3.1.  Further clarification can be obtained in consultation with the 
Millennium project clinician (or designee).  If multiple toxicities are noted, the dose 
adjustments and/or delays should be made according to the most severe toxicity guidelines.  
The same dose modification guidelines will apply during the maintenance phase for patients 
with NDMM (Arms A and B) who are receiving MLN9708, unless otherwise noted.
6.3.1   
Criteria for Toxicity Recovery Before Beginning the Next Cycle and 
Midcycle of Treatment
If a patient fails to meet the criteria outlined in Table 6-1 for the beginning of the next cycle 
of treatment, initiation of the next cycle should be delayed for 1 week.  At the end of that 
time, the patient should be re-evaluated to determine whether the criteria for retreatment 
have been met.  If the start of the next cycle requires a delay of more than 2 weeks because 
of incomplete recovery from treatment-related toxicity, see Section 6.3.3 for recommended 
dose reductions.  The maximum delay before treatment should be discontinued will be 
3 weeks, unless there is evidence for clinical benefit upon agreement by the investigator and 
Millennium project clinician (or designee).


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Table 6-1   
Criteria for Hematological and Nonhematological Recovery
To Start a New Cycle (Day 1)
To Redose Within a Cycle (Days 8 and 15)
ANC
ANC must be ≥1,000/mm3
ANC must be ≥750/mm3
Platelet
Platelet count must be 
≥75,000/mm3
Platelet count must be ≥50,000/mm3
Nonhematological
All other nonhematologic toxicities
(except for alopecia) must have 
resolved to ≤Grade 1 or to the 
patient’s baseline condition
Neuropathy must be ≤Grade 1 (with no pain)
Other nonhematologic toxicities should be 
< Grade 3.  Refer to Table 6-5.
Abbreviation:  ANC = absolute neutrophil count.
6.3.2   
Criteria for Selection and Timing of Dose Modification (Delays, Reductions, 
and Discontinuations)
During the induction phase for patients with NDMM and during treatment for patients with 
RRMM, the decision regarding which study drug requires dose reduction will be dependent 
upon the toxicity, its onset, and time course.  Alternative dose modifications may be 
recommended after discussion with the investigator and Millennium project clinician (or 
designee) to maximize exposure of study treatment while protecting patient safety given that 
there may be overlapping dose-limiting toxicities (eg, thrombocytopenia, neutropenia, 
nausea/vomiting, diarrhea).  
If any drug dose was held during the previous cycle and was restarted with a 1-level dose 
reduction without requiring an interruption for the remainder of the cycle, then that reduced 
dose will be initiated on Day 1 of the following cycle.  If any drug dose was held for the 
remainder of the previous cycle or if the new cycle is held due to known hematologic 
toxicity newly encountered on the scheduled Day 1, then the new cycle will be started with a 
1-level dose reduction.  The maximum delay before treatment should be discontinued will 
be 3 weeks, unless there is evidence for clinical benefit upon agreement by the investigator 
and Millennium project clinician (or designee).  
For patients with NDMM, the dose adjustments for MLN9708 during the maintenance 
period follow the same criteria as during the induction phase; however, dose reduction 
should be favored over the use of granulocyte colony stimulating factor (G-CSF).  In the 
very specific case where a patient experiences toxicities despite 2 dose reductions of 
MLN9708, an alternative dose schedule (ie, dosing on Days 1 and 15 on a 28-day cycle) 
may be recommended after discussion between the investigator and Millennium project 


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clinician (or designee) to maximize exposure to study treatment while protecting patient 
safety.
During Study Conduct
In the event of nondrug-related severe renal impairment (CrCL < 30 mL/min) or moderate 
or severe hepatic impairment (total bilirubin > 1.5 ULN and AST/ALT > 3 ULN) 
occurring at any time during study conduct, dose may be modified upon discussion between 
sponsor and investigator.
6.3.3   
Permitted Dose Level Reductions
Throughout the study, no more than 2 dose reductions are permitted for each drug unless 
there is evidence for clinical benefit upon agreement by the investigator and Millennium 
project clinician (or designee).  Table 6-2 outlines the permitted dose reductions for 
MLN9708, cyclophosphamide, and dexamethasone for the 3 treatment arms.
Table 6-2   
Permitted Dose Level Reductions for MLN9708, Cyclophosphamide, 
and Dexamethasone
Starting Dose
Dose Level Reduction
-1
-2
-3
MLN9708
4.0 mg
3.0 mg
2.3 mg
Discontinued
Cyclophosphamide
Arm A and Arm C
Arm B
300 mg/m2
400 mg/m2
200 mg/m2
300 mg/m2
100 mg/m2
200 mg/m2
Discontinued
Discontinued
Dexamethasone
< 75 years
≥75 years
40 mg
20 mg
20 mg
8 mg
8 mg
Discontinued
Discontinued
Discontinued
6.3.4   
Dose Adjustments for Hematologic Toxicity:  MLN9708 and 
Cyclophosphamide
Dose adjustments to MLN9708 and cyclophosphamide for thrombocytopenia are presented 
in Table 6-3.


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Table 6-3   
Dose Adjustments for Thrombocytopenia 
Platelet Count
NCI CTCAE Grade
Action on Drug During Cycle
Further Considerations
Platelets < 50,000-25,000/mm3 
without clinically significant 
bleeding

Hold study drug regimen. Check CBC 
weekly at minimum. Resume treatment 
at current dose level. See Table 6-1.
The maximum delay 
before treatment should 
be discontinued is 
3 weeks.
Grade 3
(< 50,000-25,000/mm3) with 
clinically significant bleeding 
OR
Grade 4
(< 25,000/mm3)
OR
Delay of > 2 weeks in the start 
of a subsequent cycle due to lack 
of platelet recovery (count 
< 75,000/mm3) as defined in 
Section 6.3.1

Hold study drug regimen. Check CBC 
weekly at minimum.

Dose adjustment at subsequent cycles
per Table 6-2:
First occurrence:
Decrease MLN9708 by 1 dose 
level 
Second occurrence:
Decrease cyclophosphamide by 
1 dose level 
Third occurrence:
Decrease MLN9708 by 1 dose 
level 
Fourth occurrence:
Decrease cyclophosphamide by 
1 dose level 
Abbreviations:  CBC = complete blood count; NCI CTCAE = National Cancer Institute Common 
Terminology Criteria for Adverse Events.
Dose adjustments to MLN9708 and cyclophosphamide for neutropenia are presented in 
Table 6-4.


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Table 6-4   
Dose Adjustments for Neutropenia 
Neutrophil Count
NCI CTCAE Grade
Action on Drug During Cycle
Further Considerations
ANC < 750 - 500/mm3 
without fever

Hold treatment regimen. Check CBC weekly 
at minimum. See Table 6-1.

Resume treatment regimen at current dose 
level. See Table 6-2.

Introduction of G-CSF prophylaxis per 
ASCO guidelines may be considered.a
The maximum delay before 
treatment should be 
discontinued is 3 weeks.
Grade 3 with fever
(ANC < 1,000 -
500/mm3 and 
temperature > 38.3C)
OR
Grade 4
(ANC < 500/mm3)
OR
Delay of > 2 weeks in 
the start of a 
subsequent cycle due 
to lack of neutrophil 
recovery (ANC 
< 1,000) as defined in 
Section 6.3.1

Hold treatment regimen. Check CBC weekly 
at minimum.

Introduction of G-CSF prophylaxis as per 
ASCO guidelines may be considered at any 
time as sole and unique adjustment if 
neutropenia is the only toxicity for which an 
adjustment is required (G-CSF is not allowed
at Cycle 1 for safety lead-in patients).a

If G-CSF is not an option or no longer an 
option, dose adjustment must follow 
subsequent sequences per Table 6-2:
First occurrence: 
Decrease cyclophosphamide by 1 dose 
level 
Second occurrence:
Decrease MLN9708 by 1 dose level 
Third occurrence:
Decrease cyclophosphamide by 1 dose 
level 
Fourth occurrence:
Decrease MLN9708 by 1 dose level 
Abbreviations:  ANC = absolute neutrophil count; ASCO = American Society of Clinical Oncology; 
CBC = complete blood count; G-CSF = granulocyte colony stimulating factor.
a Only short-acting G-CSF may be used (ie, pegylated G-CSF and longer-acting G-CSF are prohibited).
6.3.5   
Dose Adjustments for Nonhematologic Toxicity:  MLN9708 and 
Cyclophosphamide
Dose adjustments for nonhematologic toxicities attributed to MLN9708 are presented in 
Table 6-5.


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Table 6-5   
Dose Adjustments for Nonhematologic Toxicities Attributed to 
MLN9708
Toxicity
Criteria
Action on Drug During 
Cycle
Further Considerations
Peripheral 
Neuropathy
Grade 1 peripheral 
neuropathy 
No action
Grade 1 signs and
symptoms:  
asymptomatic, without 
pain or loss of function, 
clinical or diagnostic 
observations only(31)
Grade 1 peripheral 
neuropathy with pain or 
Grade 2 peripheral 
neuropathy
Hold MLN9708 until 
resolution to Grade ≤1 
without pain or baseline
Grade 2 signs and
symptoms:  moderate 
symptoms, limiting 
instrumental activities of 
daily living (ADL)(31)
Grade 2 peripheral 
neuropathy with pain or 
Grade 3 peripheral 
neuropathy

Hold MLN9708 until 
resolution to Grade ≤1 
without pain or 
baseline 

Reduce MLN9708 to 
next lower dose upon 
recovery per Table 6-2
Grade 3 signs and
symptoms:  severe 
symptoms, limiting self 
care ADL, assistive 
device indicated(31)
Grade 4 peripheral 
neuropathy
Discontinue MLN9708
Grade 2 Rash
Symptomatic recommendations per Section 6.7. The investigator and Millennium 
project clinician (or designee) may discuss considerations for dose modifications and 
symptom management.
All Other 
Grade ≥3 
Nonhematologic 
Toxicities
Hold MLN9708 until resolution to Grade < 1 or baseline.
Reduce MLN9708 by 1 dose level as outlined in Table 6-2.
The maximum delay before treatment should be discontinued is 3 weeks.
Note: A dose level reduction will be made either based on within-cycle criteria or for 
a subsequent cycle criteria, but not for both for a same cycle.
Grade 4 
Nonhematologic 
Toxicities (except 
alopecia)
Consider permanently discontinuing MLN9708, unless there is evidence for clinical 
benefit upon agreement by the investigator and Millennium project clinician (or 
designee).
Dose adjustments for nonhematologic toxicities attributed to cyclophosphamide are 
presented in Table 6-6.  
The investigator and Millennium project clinician (or designee) may discuss considerations 
for dose modifications (see package insert/Summary of Product Characteristics [SmPC]).


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Table 6-6   
Dose Adjustments for Nonhematologic Toxicities Attributed to 
Cyclophosphamide
Toxicity
Criteria
Action on Drug During 
Cyclea
Further 
Considerations
Any 
Nonhematologic 
Toxicity
Grade 3
OR
Delay of > 2 weeks in the start 
of a subsequent cycle due to 
lack of nonhematologic 
toxicities recovery > Grade 1 or 
not to the patient as defined in 
Section 6.3.1

Hold cyclophosphamide 
until resolution to 
Grade < 1or baseline

Reduce 
cyclophosphamide by 
1 dose level per Table 6-2
The maximum delay 
before treatment 
should be 
discontinued is 
3 weeks.
Grade 4

Discontinue 
cyclophosphamide 
according to the early 
stopping rule (see 
Section 8.1.11)
a Alternative dose reductions may be discussed between the investigator and the sponsor.
6.3.6   
Dexamethasone-Related Treatment Modification
Treatment modifications due to dexamethasone-related AEs are outlined in Table 6-7.(34)
The investigator and Millennium project clinician (or designee) may discuss considerations 
for dose modifications (see US package insert/SmPC).  Alternative dose modifications may 
be recommended after discussion with the investigator and Millennium project 
clinician/designee in order to maximize exposure of study treatment while protecting patient 
safety.
Table 6-7   
Dexamethasone–Related Treatment Modification (Delays, Reductions,
and Discontinuations) Guidelines Due to Adverse Events
Adverse Event (Severity)
Action on Dexamethasonea
Gastrointestinal
Dyspepsia, gastric, or duodenal ulcer, 
gastritis Grade 1-2 (requiring medical 
management)
Treat with histamine-2 blockers, sucralfate, 
or omeprazole.  If symptoms persist 
despite these measures, decrease 
dexamethasone by 1 dose level.
Grade ≥3 (requiring hospitalization or 
surgery)
Hold dexamethasone until symptoms 
adequately controlled.  Restart and 
decrease 1 dose level of current dose along 
with concurrent therapy with histamine-2 
blockers, sucralfate, or omeprazole.  If 
symptoms persist despite these measures, 
discontinue dexamethasone and do not 
resume.


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Table 6-7   
Dexamethasone–Related Treatment Modification (Delays, Reductions,
and Discontinuations) Guidelines Due to Adverse Events
Adverse Event (Severity)
Action on Dexamethasonea
Acute pancreatitis
Discontinue dexamethasone and do not 
resume.
Cardiovascular
Edema Grade 2 (limiting function and 
unresponsive to therapy or anasarca)
Diuretics as needed and decrease 
dexamethasone by 1 dose level.  If edema 
persists despite these measures, decrease
dose another level.  Discontinue 
dexamethasone and do not resume if 
symptoms persist despite second reduction.
Neurological
Confusion or mood alteration Grade 2 
Hold dexamethasone until symptoms 
resolve.  Restart with 1 dose level 
reduction.  If symptoms persist despite 
these measures, discontinue 
dexamethasone and do not resume.
Musculoskeletal
Muscle weakness Grade 2 (interfering 
with function and/or interfering with 
activities of daily living)
Decrease dexamethasone dose by 1 dose 
level.  If weakness persists despite these 
measures, decrease dose by 1 dose level.  
Discontinue dexamethasone and do not 
resume if symptoms persist.  
Metabolic
Hyperglycemia Grade ≥3 
Treatment with insulin or oral 
hypoglycemics as needed. If uncontrolled 
despite these measures, decrease dose by 
1 dose level until levels are satisfactory.
a Alternative dose reductions may be discussed between the investigator and the sponsor.
6.4   
Excluded Concomitant Medications and Procedures
The following medications and procedures are prohibited during the study.
Systemic treatment with any of the following metabolizing enzyme inhibitors is not 
permitted in this study. (A DDI with a strong inhibitor would increase the MLN2238 
exposure and could lead to a higher probability of an AE.):

Strong inhibitors of CYP1A2:  fluvoxamine, enoxacin, ciprofloxacin

Strong inhibitors of CYP3A:  clarithromycin, telithromycin, itraconazole, 
voriconazole, ketoconazole, nefazodone, and posaconazole
Systemic treatment with any of the following metabolizing enzyme inducers should be 
avoided, unless there is no appropriate alternative medication for the patient’s use 
(Rationale:  Unlike with inhibitors, if there were to be a DDI with an inducer, MLN2238 
exposure would be less; therefore, there would be a reduced chance of an AE.  However, 


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there may be less chance for an antitumor effect, but that is not an absolute reason to be 
taken off MLN9708):

Strong CYP3A inducers:  rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, 
and phenobarbital

Excluded foods and dietary supplements include St. John’s wort and Ginkgo biloba
The following procedures are prohibited during the study.

Any antineoplastic treatment with activity against MM, other than study drugs

Radiation therapy (note that, in general, the requirement for local radiation therapy 
indicates disease progression)

Platelet transfusions to help patients meet eligibility criteria are not allowed within 
3 days prior to study drug dosing for any dosing day
6.5   
Permitted Concomitant Medications and Procedures
The following medications and procedures are permitted during the study:

Myeloid growth factors (eg, G-CSF, granulocyte macrophage-colony stimulating 
factor [GM-CSF]) are not allowed during Cycle 1 for the safety lead-in patients, but 
may be considered according to standard clinical practice in Cycle 2 and beyond 
during the induction phase for patients in Arms A and B, and in Cycle 2 and beyond 
during the treatment period for patients in Arm C.  Prophylactic antibiotics are not 
allowed during Cycle 1 for the safety lead-in patients, but may be considered 
according to standard clinical practice in Cycle 2 and beyond during the induction 
phase for patients in Arms A and B, and during the treatment period for patients in 
Arm C.  No prophylactic antibiotics should be administered during the maintenance
phase for patients in Arms A and B.

Erythropoietin.

Patients should be transfused with red blood cells and platelets as clinically indicated
(except as noted previously regarding eligibility).

Antiviral therapy such as acyclovir is allowed.


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
Concomitant treatment with bisphosphonates will be permitted.

Supportive measures consistent with optimal patient care may be given throughout 
the study.
6.6   
Precautions and Restrictions 

Fluid deficit should be corrected before initiation of treatment and during treatment.

Nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided with impaired 
renal function given reported NSAID-induced renal failure in patients with decreased 
renal function.
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: 

Postmenopausal for at least 1 year before the screening visit, or

Surgically sterile, or

If they are of childbearing potential, agree to practice 2 effective methods of 
contraception from the time of signing of the informed consent form through 90 days
after the last dose of study drug, or

Agree to practice true abstinence over the period previously described, when this is 
in line with the preferred and usual lifestyle of the subject.  (Periodic abstinence [eg, 
calendar, ovulation, symptothermal, postovulation methods] and withdrawal are not 
acceptable methods of contraception.), and 

Adhere to any treatment-specific pregnancy prevention guidelines for 
cyclophosphamide(32, 33) and dexamethasone(34, 35, 36)
Male patients, even if surgically sterilized (ie, status postvasectomy) must agree to 1 of the 
following:


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
Practice effective barrier contraception during the entire study treatment period and 
through 90 days after the last dose of study drug, or

Agree to practice true abstinence for the period described previously, when this is in 
line with the preferred and usual lifestyle of the subject.  (Periodic abstinence [eg, 
calendar, ovulation, symptothermal, postovulation methods for the female partner]
and withdrawal are not acceptable methods of contraception.), and 

Adhere to any treatment-specific pregnancy prevention guidelines for 
cyclophosphamide(32, 33) and dexamethasone(34, 35, 36)
6.7   
Management of Clinical Events 
Please refer to the appropriate US Package Insert or SmPC for information relating to AEs 
attributed to cyclophosphamide 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.  
Erythematous Rash With or Without Pruritus
As with VELCADE, 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 predominantly on the trunk or extremities.  Rash has been most commonly 
characterized as maculopapular or macular.  To date, when it does occur, rash is most 
commonly reported within the first 3 cycles of therapy.  The rash is often transient, 
self-limiting, and is typically Grade 1or Grade 2.
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 IV antihistamines or corticosteroids.  
Administration of MLN9708 (and/or other causative agent if given in combination) should 


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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, 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.
Nausea and/or Vomiting
Standard antiemetics including 5-HT3 serotonin receptor antagonists are recommended for 
emesis if it occurs once treatment is initiated; prophylactic anti-emetics may also be 
considered at the physician’s discretion.  Dexamethasone should not be administered as an 
anti-emetic.  Fluid deficit should be corrected before initiation of study drug and during 
treatment.
Diarrhea
Prophylactic antidiarrheals will not be used in this protocol; however, diarrhea should be 
managed according to clinical practice, including the administration of antidiarrheals once 
infectious causes are excluded.  Fluid intake should be maintained to avoid dehydration.  
Fluid deficit should be corrected before initiation of treatment and during treatment.  
Hypotension
Symptomatic hypotension and orthostatic hypotension 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 hypotension or hypertension) should be managed 
according to standard clinical practice, including considerations for dose adjustments of 
their concomitant medications during the course of the trial.  Fluid deficit should be 
corrected before initiation of study drug and as needed during treatment to avoid 
dehydration.


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Thrombocytopenia
Blood counts should be monitored regularly as outlined in the protocol with additional 
testing obtained according to standard clinical practice.  Thrombocytopenia may be severe 
but has been manageable with platelet transfusions according to standard clinical practice.  
MLN9708 administration should be modified per dose modification recommendations in the 
protocol when thrombocytopenia occurs (see Section 6.3.4).  Therapy can be reinitiated at a 
reduced level upon recovery of platelet counts.  A rare risk is thrombotic thrombocytopenic 
purpura, a rare blood disorder where blood clots form in small blood vessels throughout the 
body characterized by thrombocytopenia, petechiae, fever, or possibly more serious signs 
and symptoms.  Thrombotic thrombocytopenic purpura should be managed symptomatically 
according to standard medical practice.
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 6.3.4).  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 GI toxicities and dehydration.  Fluid deficit 
should be corrected before initiation of study drug and as needed during treatment to avoid 
dehydration (see Section 6.6).
Posterior Reversible Encephalopathy Syndrome
One case of posterior reversible encephalopathy syndrome (PRES), which ultimately 
resolved, has been reported with MLN9708.  This condition is characterized by headache, 
seizures, and visual loss, and abrupt increase in blood pressure.  Diagnosis may be 
confirmed by a radiologic procedure.  If the syndrome is diagnosed or suspected, 
symptom-directed treatment should be maintained until the condition is reversed by control 
of hypertension or other instigating factors.  


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Transverse Myelitis
Transverse myelitis has been reported in a patient who was receiving MLN9708.  It is not 
known whether MLN9708 causes transverse myelitis.  However, because it was reported in 
a patient who was receiving MLN9708, the possibility that MLN9708 may have contributed
to transverse myelitis cannot be excluded.  Transverse myelitis should be managed 
according to standard medical practice.
6.8   
Blinding and Unblinding
This is an open-label study; no blinding methods will be employed.
6.9   
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 6-8:  
Table 6-8   
MLN9708 Capsules
Dose Strength
Capsule Size
Capsule Color
4.0 mg
Size 3
Ivory
3.0 mg
Size 4
Light gray
2.3 mg
Size 4
Flesh
For additional details, please see the MLN9708 IB and Pharmacy Manual.
6.9.1   
MLN9708 Preparation, Reconstitution, and Dispensation
For blistered material, the capsules are packaged in cold-form foil-foil blisters in a 
child-resistant carton.  
6.9.2   
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. 


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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. 
6.9.3   
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 to 46°F, 2°C to 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.
After completing 3 cycles of treatment, patients may be allowed to self administer this 
medication at home.  Patients are to be instructed on proper storage, accountability, and 
administration of MLN9708, including that MLN9708 is to be taken as intact capsules.
MLN9708 capsules dispensed to the patient for take-home dosing should remain in the 
blister packaging and carton and refrigerated as noted previously until the point of use.  
Comprehensive instructions should be provided to the patient to ensure compliance with 
dosing procedures.  Patients should be instructed to store the medication refrigerated (36°F
to 46°F, 2°C to 8°C).  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 to the clinic.  Any extreme in temperature should be reported as an 
excursion and should be dealt with on a case-by-case basis. 
Because MLN9708 is an anticancer drug, as with other potentially toxic compounds, caution 
should be exercised when handling the study drug.  Patients should be instructed not to 
chew, break, or open capsules.  In case of contact with broken capsules, raising dust should 
be avoided during the clean-up operation.  The product may be harmful by inhalation, 
ingestion, or skin absorption.  Gloves and protective clothing should be worn during clean-
up and during return of broken capsules and powder to minimize skin contact.  The area 
should be ventilated and the site washed with soap and water after material pick up is 
complete.  The material should be disposed of as hazardous medical waste in compliance 
with federal, state, and local regulations.  
In case of contact with the powder (eg, from a broken capsule), skin should be washed 
immediately with soap and copious amounts of water for at least 15 minutes.  In case of 


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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.
Please refer to the Pharmacy Manual for additional instructions.
6.9.4   
Dexamethasone - Noninvestigational Medicinal Agent
Dexamethasone is a marketed 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. 
6.9.5   
Cyclophosphamide - Noninvestigational Medicinal Agent
Cyclophosphamide is a marketed 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, 
appropriate labeling, and compliance with local and regional regulations.  Additional details 
are provided in the package insert/SmPC.
6.10   
Other Protocol-Specified Materials  
No other drugs or ancillary material are supplied for use in this study.
7.   
STUDY CONDUCT
This trial will be conducted in compliance with the protocol, good clinical practice (GCP),
applicable regulatory requirements, and International Conference on Harmonisation (ICH) 
guidelines.
7.1   
Study Personnel and Organizations
The contact information for the Millennium project clinician (or designee) for this study, the 
central laboratory, any additional clinical laboratories or vendors may be found in the Study 
Manual.  A full list of investigators is available in the sponsor’s investigator database.


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7.2   
Arrangements for Recruitment of Patients
Recruitment and enrollment strategies for this study may include recruitment from the 
investigator’s local practice or referrals from other physicians.  If advertisements become 
part of the recruitment strategy, they will be reviewed by the institutional review board 
(IRB)/independent ethics committee (IEC).  It is not envisioned that prisoners (or other 
populations that might be subject to coercion or exploitation) will be enrolled into this study.
7.3   
Treatment Group Assignments 
After written informed consent has been obtained, patients with NDMM will be randomized 
1:1 to either Arm A or Arm B. Patients with RRMM will be assigned to Arm C.  A
centralized interactive web response system (IWRS) will be used for randomization and 
enrollment of all patients.  If a patient with NDMM discontinues from the study, the 
randomization code for that patient will not be reused.  No patient will be allowed to re-enter 
the study after discontinuing from the study.
7.4   
Study Procedures
Patients will be evaluated at scheduled visits over 4 study periods: Screening, Treatment, 
EOT, and Follow-Up (PFS).  Tests and procedures should be performed on schedule, but 
occasional changes may be allowed (± 3 days) for holidays, vacations, and other 
administrative reasons.  If the study schedule is shifted, both assessments and dosing must 
be shifted to ensure collection of assessments is completed prior to dosing.  If extenuating 
circumstances prevent a patient from beginning treatment or completing a scheduled 
procedure or assessment within this time, the patient may continue the study only with the 
permission of the Millennium project clinician or designee.
Refer to the Schedule of Events for timing of assessments.  Additional details are provided 
as necessary in the sections that follow.
7.4.1   
Informed Consent
Each patient must provide written informed consent before any study-required procedures 
are conducted, unless those procedures are performed as part of the patient’s standard care.  
7.4.2   
Patient Demographics
The date of birth, race, ethnicity, and sex of the patient are to be recorded during screening.


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7.4.3   
Medical History
During the Screening period, a complete medical history will be compiled for each patient, 
including diagnosis (see Section 14.1) and International Staging System (ISS) staging (see 
Section 14.5) of MM.  The history should include a review of all current medications and 
the patient’s current smoking status.
7.4.4   
Assessment of Comorbid Condition(s) – Arms A and B
During the Screening period, an assessment of comorbid condition(s) is to be conducted for 
patients with NDMM only.   
7.4.5   
Physical Examination
A physical examination will be completed per standard of care at the time specified in the
Schedule of Events.  A symptom-directed physical examination will also be conducted at the 
time points specified in the Schedule of Events.  A neurologic examination is to be 
conducted to assess both MM-related clinical findings and TEAEs; note timing in the 
Schedule of Events.  
7.4.6   
Eastern Cooperative Oncology Group Performance Status
Performance status will be assessed using the ECOG performance scale (see Section 14.3) at 
the time points specified in the Schedule of Events.
7.4.7   
Vital Signs, Body Weight, Height, and Body Surface Area
Measurement of vital signs, including temperature, blood pressure, heart rate, respiratory 
rate, and weight will be obtained at the time points specified in the Schedule of Events.  
Height will be measured at the screening visit only.
For purposes of cyclophosphamide dosing, BSA will be calculated using a standard formula 
on Cycle 1, Day 1 and at subsequent visits if the patient experiences a > 5% change in body 
weight from the weight used for the most recent BSA calculation.  The application of 
institutional standards to allow for dosing according to the current weight is acceptable.
7.4.8   
Pregnancy Test
A serum pregnancy test will be performed for women of childbearing potential at screening,
within 3 days prior to dosing, and at EOT. The results from these tests must be available 
and negative before the first dose of the study drug regimen is administered.


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The Cycle 1, Day 1 pregnancy test may be collected up to 3 days before dosing.  The results
must be available and negative before the first dose. If the Cycle 1, Day 1 serum pregnancy
results are not be available before dosing, a urine pregnancy test may be performed.
Pregnancy tests may also be repeated during the study at the request of IEC/IRBs or if 
required by local regulations.
7.4.9   
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 obtained include PR interval, QRS interval, QT interval, 
QTc interval, and waveforms.
7.4.10   
Concomitant Medications and Procedures
See Section 6.4 for a list of prohibited concomitant medications and therapies and 
Section 6.5 for a list of allowed concomitant medications and therapies.  
7.4.11   
Adverse Events
Monitoring of AEs, serious and nonserious, will be conducted throughout the study as 
specified in the Schedule of Events.  Refer to Section 9 for details regarding definitions, 
documentation, and reporting of pretreatment events, AEs, and SAEs.  
Note that in this study, PN will be captured in the same manner as all other adverse events 
during the induction and maintenance phases for patients in Arms A and B and during the 
treatment period for patients in Arm C, with the exception that downgrading of PN events 
must be reported until 1) resolution, 2) the start of a second-line alternative antineoplastic 
treatment, or 3) 6 months after treatment discontinuation, whichever occurs first. If the 
patient exhibits PN at EOT, then PN will be followed during the PFS follow-up period (see 
Section 8.1.10.1 and Section 9.1.5).
7.4.12   
Enrollment
A patient is considered to be enrolled in the study when the patient is assigned to 1 of the 
3 treatment arms in the study.
Procedures for completion of the enrollment information are described in the Study Manual.


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7.4.13   
Clinical Laboratory Evaluations
Clinical laboratory evaluations will be performed by a central laboratory.  For dosing 
decisions, local hematology and chemistry laboratory results may be used; however, samples 
must still be sent to the central laboratory for evaluation.  Blood samples for analysis of the 
following clinical chemistry and hematological parameters will be obtained as specified in 
the Schedule of Events. 
Local laboratory evaluations may be done more frequently at the investigator’s discretion, ie 
for acute management of TEAEs.  Handling and shipment of central clinical laboratory 
samples are outlined in the Study Manual.
Clinical Chemistry, Hematology, and Urinalysis
Blood and urine samples for analysis of the following clinical chemistry and hematological 
parameters will be obtained as specified in the Schedule of Events.  
Hematology

Hemoglobin

Hematocrit

Platelet (count)
Leukocytes with differential
Neutrophils (absolute neutrophil count [ANC])
Serum Chemistry

Blood urea nitrogen 
(BUN)

Creatinine

Bilirubin (total)

Urate

Lactate 
dehydrogenase 
(LDH)

Phosphate
Albumin
Alkaline phosphatase 
(ALP)
Aspartate 
aminotransferase (AST)
Alanine 
aminotransferase (ALT)
Glucose 
Sodium
Potassium
Calcium
Chloride
Carbon dioxide (CO2)
Magnesium
β2-microglobulin (β2) 
analysis (Screening 
only)
Urinalysis

Turbidity and Color

pH

Specific gravity

Protein
Ketones
Bilirubin
Occult Blood
Nitrite
Urobilinogen
Glucose
Leukocytes
Microscopic assessment


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7.4.14   
Quality of Life Assessment (European Organization for Research and 
Treatment of Cancer)  
The QOL assessments (EORTC QLQ-C30; see Section 14.6) will be completed by the 
patient as specified in the Schedule of Events.  The EORTC QLQ-30 incorporates 
5 functional scales (physical functioning, role functioning, emotional functioning, cognitive 
functioning, and social functioning), 1 global health status scale, 3 symptom scales (fatigue, 
nausea and vomiting, and pain), and 6 single items (dyspnea, insomnia, appetite loss, 
constipation, diarrhea, and financial difficulties).  The time recall period for this instrument 
is 1 week (the week immediately preceding the assessment).  
These are reliable and valid measures of health-related QOL in patients with cancer and 
takes about 15 minutes to complete.  The instruments consist of a total of 50 items and have 
been validated and used in many countries.  
These QOL assessments must be completed before other assessments are performed or any 
drug in the study drug regimen is administered.
7.4.15   
Skeletal Survey
7.4.16   
Skeletal-Related Events


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7.4.17   
Bone Marrow Aspiration
Local Laboratory Evaluations
Disease Assessment
A bone marrow aspirate (BMA) will be obtained at screening for disease assessment and at 
any time a bone marrow aspirate sample is obtained to assess CR or to investigate suspected 
PD.  This evaluation will be performed locally.  A standard BMA drawn prior to consent is 
acceptable provided this is collected within 42 days of the first dose.
Determination of the /λ ratio by immunohistochemistry or immunofluorescence should be 
performed to assess for sCR when a CR has been documented.  A bone marrow biopsy can 
additionally be performed per local standards for disease assessments.
Cytogenetics
If a sufficient sample is available, cytogenetic evaluation should be performed at screening 
using fluorescence in situ hybridization (FISH) and/or conventional cytogenetics 
(karyotype).  Examples of cytogenetic markers that may be evaluated are deletion 17p, 
t(4:14), t(14:16), t(14:20), del 13/13q and del 1q20.  All cytogenetic evaluations will be 
performed locally according to local standards.
Central Laboratory Evaluations
Minimal Residual Disease (MRD)
7.4.18   
Blood Sample for Genotyping


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7.4.19   
Quantification of M-Protein
A blood sample and urine sample will be obtained at screening and at the time points 
specified in the Schedule of Events.  
7.4.20   
Quantification of Immunoglobulins
A blood sample for quantification of immunoglobulins (IgM, IgG, IgA, IgD, and IgE) will 
be obtained at screening and at times outlined in the Schedule of Events.  
7.4.21   
Serum Free Light Chain Assay
A blood sample for serum free light chain assay will be obtained at screening and at the
times outlined in the Schedule of Events.
7.4.22   
Immunofixation of Serum and Urine
Serum and urine samples will be obtained for serum and urine immunofixation tests at
screening and at the times outlined in the Schedule of Events.
7.4.23   
Radiographic Disease Assessments
For patients with documented extramedullary disease, other assessments and scans, such as 
a CT, PET-CT, or MRI scan, may be required to better delineate the sites and measurements 
of extramedullary disease.  Follow-up scans should use the same imaging modality used at 
screening and at the time points specified in the Schedule of Events, until disease 
progression. 
All follow-up scans should use the same imaging modality used at screening.
Radiographs will be analyzed locally and reports maintained with the patient record for 
review during monitoring visits.
7.4.24   
Disease Response Assessment
Patients will be assessed for disease response according to the IMWG criteria (see 
Section 14.7).(23)  
Response assessments should be performed at the times outlined in the Schedule of Events.  
Response categories are as follows:


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Table 7-1   
Response Assessment
Complete response
CR
Subcategory:  stringent complete response
sCR
Very good partial response
VGPR
Partial response
PR
Stable disease
SD
Progressive disease
PD
CR should be confirmed with follow-up assessments of serum protein electrophoresis 
(SPEP), urine protein electrophoresis (UPEP), immunofixation of blood and urine, and 
serum free light chains as outlined in Section 14.7.  One bone marrow assessment has to 
occur to document CR; no second bone marrow confirmation is needed.
Please note that to determine a response of sCR, bone marrow, immunohistochemistry or
immunofluorescence for /ratio, and serum free light chain assay should be performed for 
all patients suspected to be in CR to meet this requirement of this response category.
At any point during treatment, patients for whom disease progression is suspected will have 
response assessments repeated to confirm the assessment (local laboratory assessment is 
permitted).  
7.4.25   
Health Care Utilization Assessments
Health care utilization data will also be collected for all patients as specified in the Schedule
of Events.  Examples of data to be collected are the number, duration, and type of medical 
care encounters, such as inpatient admissions, outpatient visits, the accompanying reason for 
the visit (eg, medication, procedure, an AE), and homecare.  In addition, the number is also 
captured of missed work days or other activities for the patient and patient’s caregiver.
7.4.26   
Follow-up Assessments (Progression-Free Survival) 
Patients who stop treatment for any reason other than PD will continue to have 
progression-free follow-up visits.  See the Schedule of Events for appropriate assessments.
The PFS follow-up visits should occur every 8 weeks from EOT until the occurrence of 
progressive disease or death, or the patient withdraws consent for further follow-up.  
If the patient exhibits PN at end of treatment, then PN will be followed during the PFS 
follow-up period in clinic every 4 weeks.  See the Schedule of Events for further details.


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NOTE:  Related SAEs must be reported to the Millennium Department of 
Pharmacovigilance & Risk Management or designee.  This includes deaths that the 
investigator considers related to study drug that occur during the posttreatment follow up.  In 
addition, new primary malignancies that occur during the follow-up periods, irrespective of 
causality to study regimen, must be reported to the Millennium Department of 
Pharmacovigilance & Risk Management or designee through death or termination of the 
study by the sponsor.  
Refer to Section 9 for details regarding definitions, documentation, and reporting of SAEs.
7.5   
Completion of Treatment
Patients will be considered to have completed the treatment if they meet any of the 
following criteria:
Have received at least 13 cycles of treatment
Progressive disease/death after the completion of Cycle 1
7.6   
Completion of Study
Patients will be considered to have completed the study if they are followed until 
documented progressive disease/death or until the sponsor terminates the study.
7.7   
Discontinuation of Treatment With Study Drug, and Patient Replacement
For patients who did not complete treatment as defined in Section 7.5, treatment with study 
drug must be discontinued for pregnancy.  Treatment may be discontinued permanently if 
any of the following criteria are met:

Adverse event (including SAE)

Protocol violation

Progressive disease 

Study terminated by sponsor

Withdrawal by subject

Lost to follow-up


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
Other
Once study drug has been discontinued, all study procedures outlined for the End of 
Treatment visit will be completed as specified in the Schedule of Events.  The primary 
reason for study drug discontinuation will be recorded on the electronic case report form 
(eCRF).
Note that some patients may discontinue study drug for reasons other than PD before
completing the full treatment course; these will remain in the study for posttreatment 
assessments as outlined in the Schedule of Events until disease progression occurs.
7.8   
Withdrawal of Patients From Study
A patient may be withdrawn from the study for any of the following reasons:

Lost to follow-up

Study terminated by sponsor

Withdrawal by subject

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.
7.9   
Study Compliance
Study drug will be administered or dispensed only to eligible patients under the supervision 
of the investigator or identified subinvestigator(s).  The appropriate study personnel will 
maintain records of study drug receipt and dispensing.  The clinical team and the clinical 
research associate will review treatment compliance during investigational visits and at the 
completion of the study.


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8.   
STATISTICAL AND QUANTITATIVE ANALYSES
8.1   
Statistical Methods
8.1.1   
Determination of Sample Size
The total sample size for the study will be approximately 148 patients.  Approximately 
70 patients with NDMM will be randomized 1:1 to Arm A or Arm B and approximately 
78 patients with RRMM will be enrolled in Arm C.  
For patients with NDMM (Arms A and B), the sample size is calculated by using 1 group 
Chi-square test for each arm separately based on the CR + VGPR rate following a 
MLN9708 combined treatment regimen. With 31 response-evaluable patients per treatment 
arm, there will be 80% power to test a null hypothesis CR + VGPR rate of 27% and an 
alternative hypothesis CR + VGPR rate of 45% at 1-sided significant level of α = 0.10.  
Therefore, assuming 10% of patients are not response evaluable, approximately 35 patients 
each (70 total) will be enrolled in these 2 treatment arms.
For patients with RRMM (Arm C), the sample size is calculated by using 1 group 
Chi-square test for each arm separately based on the ORR rate following a MLN9708 
combined treatment regimen.  With 71 response-evaluable patients in Arm C, there will be 
80% power to test a null hypothesis ORR rate of 60% and an alternative hypothesis ORR 
rate of 72% at 1-sided significant level of α = 0.10.  Therefore, assuming 10% of patients are 
not response evaluable, approximately 78 patients will be enrolled in Arm C in this study.
8.1.2   
Randomization and Stratification
This study will use a central (ie, not center-specific) randomization ratio of 1:1 to assign 
patients to Arm A or Arm B.  Randomization is not required if accrual to either Arm A or 
Arm B is stopped.  No randomization will be used for patients in Arm C but an IWRS will 
be used for enrollment.  
8.1.3   
Populations for Analysis  
The populations used for analysis will include the following:

Safety Population: Patients who receive at least 1 dose of any study drug. The 
safety population will be used for safety analyses.  It will also be used for the 
analyses of TTP, PFS, QOL, and health care utlization data.


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
DLT-Evaluable Population:  Patients in the safety lead-in cohort who receive all 
doses of MLN9708 and at least 80% of the cyclophosphamide dose during Cycle 1 
per the Schedule of Events, or experience a DLT in Cycle 1.  Patients must take all 
doses in Cycle 1 as outlined in the Schedule of Events if patients do not experience 
DLTs.  None of the doses can be delayed during Cycle 1 due to patient scheduling.

Response-Evaluable Population:  The response-evaluable population is defined as 
patients who receive at least 2 of the 3 MLN9708 doses during Cycle 1, have 
measurable disease at baseline, and at least 1 postbaseline response assessment. The 
response-evaluable population will be used for the analyses of response rates, time to 
response, and DOR.

Pharmacokinetic Analysis Population:  All patients who have sufficient dosing 
data and MLN9708 concentration-time data to permit calculation of MLN9708 PK 
parameters.
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.  
For QOL in EORTC QLQ-C30, if a multi-item subscale has a missing item, then the average 
of the remaining items will be used as the Scale score, as long as at least half the items in 
that Scale are present.  Example:  for fatigue, if Item 12 is missing, the average score of 
Items 10 and 18 will be used.
Data that are potentially spurious or erroneous will be examined according to standard data 
management operating procedures.
8.1.5   
Demographic and Baseline Characteristics
Demographic and baseline characteristics will be summarized for each treatment arm and by 
the total of Arm A + Arm B, including gender, age, race, weight, height, BSA, primary 
diagnosis, and other parameters as appropriate.  No inferential statistics will be carried out.
8.1.6   
Efficacy Analysis
The IMWG response criteria will be used in this study (see Section 14.7). 


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8.1.6.1   
Primary Efficacy 
For patients with NDMM (Arms A and B), the primary endpoint is the CR + VGPR rate 
during the induction phase.  For patients with RRMM (Arm C), the primary endpoint is 
ORR.  
The primary efficacy analysis will be based on the response-evaluable population (patients 
enrolled in the safety lead-in portion are included).  Estimates of the CR + VGPR rates for 
Arms A and B, and ORR for Arm C will be presented with 2-sided 95% exact binomial 
confidence intervals (CIs).  
8.1.6.2   
Secondary Efficacy
The secondary efficacy endpoints include ORR (Arms A and B only), CR + VGPR (Arm C 
only), CR, VGPR, PR, time to response, DOR, TTP, PFS, and the change from baseline in 
QOL. 
Time to response is defined as the time from the date of enrollment to the date of the first 
documentation of a confirmed response in a patient who responded during the induction 
phase.
DOR is defined as the time from the date of first documentation of a confirmed response to 
the date of first documented PD.
TTP is defined as the time from the date of enrollment to the date of first documentation of 
PD.
PFS is defined as the time from the date of enrollment to the date of first documented PD or 
death.
Time to event data will be summarized by 25th, 50th (median), and 75th percentiles with 
associated 2-sided 95% CIs and percentage of censored observations.
The response rates, time to response, and DOR will be analyzed for the response-evaluable 
population.  Time to response may also be measured in the population of patients with a 
confirmed response.  Time to progression and PFS will be analyzed based on the safety
population.  The response rates will be analyzed similarly to the primary endpoint.  Time to 
response, DOR, TTP, and PFS will be analyzed using standard survival analysis techniques 
based on Kaplan-Meier estimates.  If appropriate, the association between responses and 
time to event parameters, such as the difference of PFS among patients with or without sCR, 


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might be examined.  The efficacy results will be summarized for each treatment arm and for 
the total of Arms A and B.  
8.1.6.3   
Exploratory Efficacy Endpoints and Analysis
Minimal Residual Disease Analysis
8.1.7   
Analyses of Patient-Reported Outcomes
Analyses of patient-reported outcomes will be performed using the safety population and 
summarized for each treatment arm and by the total of Arm A + Arm B.
QOL will be assessed using the EORTC QLQ-C30.  QOL assessments will be analyzed 
using the safety population to determine if response to therapy is accompanied by 
measurable improvement in QOL.  Descriptive statistics will be presented for change from 
baseline in QOL assessment over time.  Analyses will be performed on summary scores as 
well as individual items.
8.1.8   
Analysis of Health Care Utilization Data
Analyses of health care utilization data will be performed using safety population and 
summarized for each treatment arm and by the total of Arm A + Arm B 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 caregiver.  
8.1.9   
Pharmacokinetics/Biomarkers
Pharmacokinetic Analysis


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Safety Lead-in Cohort
Individual and mean plasma concentration data will be plotted over time.  A summary table 
will be presented for the plasma concentration data.
Pharmacokinetic parameters will be estimated using noncompartmental analysis methods.  
The plasma PK parameters calculated for individual plasma MLN2238 concentration-time 
data will include, but are not limited to:  Cmax, Tmax, and AUC.
Pharmacokinetic parameters will be summarized using descriptive statistics.
All Patients
Pharmacokinetic data collected for all patients including patients in the safety lead-in cohort 
of the study will be used to perform population PK analysis using a nonlinear mixed effects 
modeling approach and will assess the effect of various demographic covariates on PK 
including data from other studies of MLN9708, if possible.
Biomarkers
8.1.10   
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 and summarized for each treatment arm and by the total of 
Arm A + Arm B.  
Treatment-emergent AEs that occur after administration of the first dose of study drug 
through 30 days after the last dose of study drug will be tabulated.  
Adverse events will be tabulated according to the Medical Dictionary for Regulatory 
Activities (MedDRA) and will include the following categories: 

Treatment-emergent AEs


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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 all patients)

Serious adverse events
A listing of treatment-emergent AEs resulting in study drug discontinuation will be 
provided.
For the safety lead-in phase, the incidence of DLTs will be listed.  
Development of new or worsening of existing SREs (eg, new fractures [excluding vertebral 
compression or rib fractures], irradiation of or surgery on bone, or spinal cord compression) 
from baseline through the development of PD will be summarized and presented.
Descriptive statistics for the actual values of clinical laboratory parameters (and/or change 
from baseline in clinical laboratory parameters) will be presented for all scheduled 
measurements over time.  Mean laboratory values over time will be plotted for key 
laboratory parameters.
Descriptive statistics for the actual values (and/or the changes from baseline) of vital signs 
and weight over time 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 postbaseline value. Graphical displays of key safety 
parameters, such as scatter plots of baseline versus worst postbaseline values, may be used 
to understand the MLN9708 safety profile.
All concomitant medications collected from screening through the study period will be 
classified to preferred terms according to the World Health Organization (WHO) drug 
dictionary.
Additional safety analyses may be performed to most clearly enumerate rates of toxicities 
and to further define the safety profile of MLN9708.


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8.1.10.1   
Peripheral Neuropathy Events
Peripheral neuropathy event is defined as the treatment-emergent adverse event in the 
high-level term of peripheral neuropathies NEC according to MedDRA. 
8.1.10.2   Drug Exposure of MLN9708, Cyclophosphamide, and Dexamethasone
Treatment duration, number of treatment cycles, number of doses, the total doses received 
and dose intensity of MLN9708, cyclophosphamide, and dexamethasone will be
summarized for each treatment arm and for the total of Arm A + Arm B.  


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8.1.11   
Interim Analysis 
Safety Lead-in Evaluation
A safety lead-in evaluation will be performed after at least 6 safety lead-in evaluable 
patients in each treatment arm have had the opportunity to complete 1 cycle of therapy. No 
formal statistical analyses are planned for this safety lead-in evaluation.
Continuous Monitoring and Early Stopping Rule
No formal interim analysis is planned.  However, both safety and efficacy will be 
continuously monitored on the basis of prespecified stopping rules.  Grade 4 or higher 
nonhematological toxicities will be monitored for each arm starting from the first 
12 enrolled patients and then every 6 additional enrolled patients based on a Bayesian 
monitoring strategy.(37)  If the stopping bounds of ≥4/12, ≥6/18, ≥7/24, and ≥8/30 for 
Arms A and B (patients with NDMM), or the stopping bounds of ≥4/12, ≥6/18,≥7/24, 
≥8/30, ≥9/36, ≥11/42, ≥12/48, ≥13/54, ≥14/60, ≥15/66, and ≥16/72 for Arm C (patients 
with RRMM) have been achieved, accrual to the study will be suspended to allow for 
investigation.  If the stopping rule is met, there is at least 80% probability that the true 
toxicity rate will be greater than 18%.  After consideration by the study team, a decision will 
be made as to whether accrual can be resumed.  
The efficacy will be monitored by the Bayesian Predictive Probability method(38) starting 
from the first 12 response-evaluable patients after 6 cycles of treatment and then every 
6 additional response-evaluable patients for Arms A and B or every 12 additional 
response-evaluable patients for Arm C.  If the futility stopping bounds (CR + VGPR) of 
2/12, 4/18, 7/24, and 10/30 for Arms A and B, or the stopping bounds (ORR) of 
≤3/12, ≤10/24, ≤18/36, ≤26/48, and ≤36/60 for Arm C have been met, further 
investigation will be made by the study team to assess if accrual to any of the 3 treatment
arms may be terminated due to futility.  These futility stopping rules are established to allow 
no larger than 0.15 overall type I error rate (one-sided) and still maintain power of 
approximately 80%.


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9.   
ADVERSE EVENTS
9.1   
Definitions
9.1.1   
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.
9.1.2   
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.  
9.1.3   
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 laboratory abnormality, will be 
determined using the NCI CTCAE version 4.03, effective 14 June 2010.(31)  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/mm3 is considered Grade 3 (severe) but may not be considered serious.  Seriousness 
(not intensity) serves as a guide for defining regulatory reporting obligations.
9.1.4   
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 9.1.5 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 9.1) 
must be reported (see Section 9.1.5 for the period of observation) by the investigator to the 
Millennium Department of Pharmacovigilance & Risk Management 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.  Serious adverse event report information must be consistent with 
the data provided on the eCRF.
SAE Reporting Contact Information
Cognizant
US and Canada
Toll-Free Fax #: 
E-mail: 
All other countries (Rest of World)
Fax #: 
0
E-mail: 
Planned hospital admissions or surgical procedures for an illness or disease that existed
before the patient was enrolled in the trial are not to be considered AEs unless the condition 
deteriorated in an unexpected manner during the trial (eg, surgery was performed earlier or 
later than planned).
For both serious and nonserious AEs, the investigator must determine both the intensity of 
the event and the relationship of the event to study drug administration.  For serious 
pretreatment events, the investigator must determine both the intensity of the event and the 
relationship of the event to study procedures.
Intensity for each AE, including any laboratory abnormality, will be determined using the 
NCI CTCAE version 4.03, effective 14 June 2010.(31)  The criteria are provided in the Study 
Manual.
Relationship to study drug administration will be determined by the investigator responding 
yes or no to this question:  Is there a reasonable possibility that the AE is associated with the 
study drug?


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9.1.5   
Monitoring of Adverse Events and Period of Observation  
AEs, both nonserious and serious, will be monitored throughout the study as follows:    

AEs will be reported from the first dose of study drug through 30 days after 
administration of the last dose of study drug and recorded in the eCRFs.  
Note that in this study, PN will be captured in the same manner as all other adverse 
events during the induction and maintenance phase for patients in Arms A and B and 
the treatment period for patients in Arm C, with the exception that downgrading of 
PN events must be reported until resolution.  If the patient exhibits PN at end of 
treatment, then PN will be followed during the PFS follow-up period until 1) 
resolution of PN, 2) the start of an alternative antineoplastic treatment, or 3) 
6 months after treatment discontinuation, whichever occurs first.  Once a patient has 
entered PFS follow-up, assessment of PN will be done in clinic every 4 weeks for up 
to 6 months.  

Serious pretreatment events will be reported to the Millennium Department of 
Pharmacovigilance & Risk Management or designee from the time of the signing of 
the informed consent form (ICF) up to first dose of study drug, but will not be 
recorded in the eCRF.

Related and unrelated SAEs will be reported to the Millennium Department of 
Pharmacovigilance & Risk Management 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.  After this period, only related SAEs must be reported to the 
Millennium Department of Pharmacovigilance & Risk Management or designee.  
Serious adverse events should be monitored until they are resolved or are clearly 
determined to be due to a patient’s stable or chronic condition or intercurrent 
illness(es). In addition, new primary malignancies that occur during the follow-up 
periods must be reported, irrespective of causality to the study drug, from the first 
dose of study drug through death, until termination of the study by the sponsor, or for 
a minimum of 3 years after the last dose of the investigational product, whichever 
comes first.


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9.1.6   
Procedures for Reporting Drug Exposure During Pregnancy and Birth 
Events
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of 
age or disease state) of a female patient occurring while the patient is on study drug or 
within 90 days of the patient’s last dose of study drug, are considered immediately 
reportable events.  Study drug is to be discontinued immediately.  The sponsor must also be 
contacted immediately by faxing a completed Pregnancy Form to the Millennium 
Department of Pharmacovigilance & Risk Management or designee. The pregnancy must 
be followed for the final pregnancy outcome.  The pregnancy, suspected pregnancy, or 
positive pregnancy test must be reported to Millennium Department of Pharmacovigilance & 
Risk Management or designee immediately by facsimile, or other appropriate method, using 
the Pregnancy Initial Report Form, or approved equivalent form. The female patient should 
be referred to an obstetrician-gynecologist, preferably one experienced in reproductive 
toxicity for further evaluation and counseling.  The pregnancy must be followed for the final 
pregnancy outcome. 
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 & Risk 
Management or designee.  Every effort should be made to follow the pregnancy for the final 
pregnancy outcome.
10.   
ADMINISTRATIVE REQUIREMENTS
10.1   
Good Clinical Practice
The study will be conducted in accordance with the ICH-GCP and the appropriate regulatory 
requirement(s).  The investigator will be thoroughly familiar with the appropriate use of the 
study drug as described in the protocol and the IB.
10.2   
Data Quality Assurance
The investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each study 
patient.  Study data will be entered into an eCRF by site personnel using a secure, validated, 
web-based electronic data capture (EDC) application.  Millennium will have access to all 
data upon entry in the EDC application.  


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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.
10.3   
Electronic Case Report Form Completion 
Millennium or designee will provide the study sites with secure access to and training on the 
EDC application, sufficient to permit site personnel to enter or correct information in the 
eCRFs for the patients for whom they are responsible.
Electronic case report forms will be completed for each study patient.  It is the investigator’s
responsibility to ensure the accuracy, completeness, clarity, and timeliness of the data 
reported in the patient’s eCRF.
The investigator, or designated representative, should complete the eCRF as soon as 
possible after information is collected.
The investigator must provide through the EDC application formal approval of all the 
information in the eCRFs and changes to the eCRFs to endorse the final submitted data for 
the patients for which he or she is responsible.  The audit trail entry will show the user’s 
identification information and the date and time of the correction.
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.
10.4   
Study Monitoring
Monitoring and auditing procedures developed or approved by Millennium will be followed 
to comply with GCP guidelines.
All information recorded on the eCRFs for this study must be consistent with the patient’s 
source documentation.  During the course of the study, the study monitor will make study 
site visits to review protocol compliance, verify eCRFs against source documentation, assess 
drug accountability, and ensure that the study is being conducted according to pertinent 
regulatory requirements.  The review of medical records will be performed in a manner that 
ensures that patient confidentiality is maintained.  


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10.5   
Ethical Considerations
The study will be conducted in accordance with applicable regulatory requirement(s) and 
will adhere to GCP standards.  The IRB/IEC will review all appropriate study 
documentation to safeguard the rights, safety, and well-being of the patients.  The study will 
be conducted only at sites where IRB/IEC approval has been obtained.  The protocol, IB, 
ICF, advertisements (if applicable), written information given to the patients (including 
diary cards), safety updates, annual progress reports, and any revisions to these documents 
will be provided to the IRB/IEC by the investigator or the sponsor, as allowed by local 
regulations.
10.6   
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.
10.7   
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.
10.8  
Investigator Compliance
The investigator will conduct the trial in compliance with the protocol provided by 
Millennium and given approval/favorable opinion by the IRB/IEC and the appropriate 
regulatory authority(ies).  Modifications to the protocol are not to be made without 
agreement of both the investigator and Millennium.  Changes to the protocol will require 
written IRB/IEC approval/favorable opinion before implementation, except when the 
modification is needed to eliminate an immediate hazard or hazards to patients.  Millennium, 
or a designee, will submit all protocol modifications to the appropriate regulatory 
authority(ies) in accordance with the governing regulations.
When immediate deviation from the protocol is required to eliminate an immediate hazard 
or hazards to patients, the investigator will contact Millennium, or a designee, if 


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circumstances permit, to discuss the planned course of action.  Any departures from the 
protocol must be documented.
10.9   
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.
10.10   Investigator and Site Responsibility for Drug Accountability
Accountability for the study drug at the trial site is the responsibility of the investigator.  
Drug accountability records indicating the drug’s delivery date to the site, inventory at the 
site, use by each patient, and amount returned to Millennium, or a designee (or disposal of 
the drug, if approved by Millennium) will be maintained by the clinical site.  Millennium or 
its designee will review drug accountability at the site on an ongoing basis.
All material containing study drug will be treated and disposed of in accordance with 
governing regulations.
10.11   Product Complaints
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 
 
 (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.
For Product Complaints,
call 
 
 at
 (
)
(US and International)
Product complaints in and of themselves are not AEs.  If a product complaint results in an 
SAE, an SAE form should be completed and sent to Cognizant (refer to Section 9.1.4).


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10.12   Closure of the Study
Within 90 days of the end of the study, the sponsor will notify the competent authorities and 
the IECs in all member states where the study is being carried out that the study has ended.
Within 1 year of the end of the study, a summary of the clinical trial results will be 
submitted to the competent authorities and IECs in all member states involved in the study.
Study participation by individual sites or the entire study may be prematurely terminated if, 
in the opinion of the investigator or Millennium, there is sufficient reasonable cause.  
Written notification documenting the reason for study termination will be provided to the 
investigator or Millennium by the terminating party.
Circumstances that may warrant termination include, but are not limited to:

Determination of unexpected, significant, or unacceptable risk to patients

Failure to enter patients at an acceptable rate

Insufficient adherence to protocol requirements

Insufficient, incomplete, and/or unevaluable data

Determination of efficacy based on interim analysis

Plans to modify, suspend or discontinue the development of the study drug
Should the study be closed prematurely, the site will no longer be able to access the EDC 
application, will not have a right to use the EDC application, and will cease using the 
password or access materials once their participation in the study has concluded.  In the 
event that any access devices for the EDC application have been provided, these will be 
returned to Millennium once the site’s participation in the study has concluded.
Within 15 days of premature closure, Millennium must notify the competent authorities and 
IECs of any member state where the study is being conducted, providing the reasons for 
study closure. 
10.13   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 


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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.  
11.   
USE OF INFORMATION
All information regarding MLN9708 supplied by Millennium to the investigator is 
privileged and 
 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.
The Millennium project clinician (or designee) will be the lead and corresponding author on 
abstracts and publications of the data generated from this study; the overall principal 
investigator or lead enroller will be the last author. Subsequently, individual investigators 
may publish results from their study center in compliance with their agreements with 
Millennium. Millennium reserves the right to determine which authors are named on 
abstracts and publications and also reserves the right to determine the order in which named 
authors appear.


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12.   
INVESTIGATOR AGREEMENT
I have read Protocol C16020 Amendment 1:  An Open-Label, Phase 2 Study to Evaluate the
Oral Combination of MLN9708 With Cyclophosphamide and Dexamethasone In Patients 
With Newly Diagnosed or Relapsed and/or Refractory Multiple Myeloma Requiring 
Systemic Treatment
I agree to conduct the study as detailed herein and in compliance with International 
Conference on Harmonisation Guidelines for Good Clinical Practice and applicable 
regulatory requirements and to inform all who assist me in the conduct of this study of their 
responsibilities and obligations.
Principal investigator printed name
Principal investigator signature
Date
Investigational site or name of institution and 
location (printed)


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13.   
REFERENCES
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Harousseau JL, Dreyling M, Group EGW. Multiple myeloma: ESMO clinical 
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4.
Huang SY, Yao M, Tang JL, Lee WC, Tsay W, Cheng AL, et al. Epidemiology of 
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Qiu L, Wang Y, Qi P, Zou D, Zhao Y, Qi J. Clinical Epidemiological Study on 
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Kumar SK, Rajkumar SV, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK, et al. 
Improved survival in multiple myeloma and the impact of novel therapies. Blood 
2008;111(5):2516-20.
7.
Brenner H, Gondos A, Pulte D. Recent major improvement in long-term survival of 
younger patients with multiple myeloma. Blood 2008;111(5):2521-6.
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Libby E, Ebaid A, Quintana D, Wiggins C. Declining myeloma mortality rates in the 
United States following introduction of novel therapies In: International Myeloma 
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9.
San Miguel J, Schlag R, Khuageva N, Dimopoulos M, Shpilberg O, Kropff M, et al. 
Continued Overall Survival Benefit After 5 Years' Follow-up with Bortezomib-
Melphalan-Prednisone (VMP) Versus Melphalan-Prednisone (MP) in Patients with 
Previously Untreated Multiple Myeloma, and No Increased Risk of Second Primary 
Malignancies: Final Results of the Phase 3 VISTA Trial. Blood (ASH Annual 
Meeting Abstracts) 2011;118(21):abstr 476.
10.
San Miguel J, Schlag R, Khuageva N, Dimopoulos M, Shpilberg O, Kropff M, et al. 
Persistent overall survival benefit and no increased risk of second malignancies with 
bortezomib-melphalan-prednisone versus melphalan-prednisone in patients with 
previously untreated multiple myeloma. J Clin Oncol 2013;31(4):448-55.


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11.
Palumbo A, Cavallo F, Hardan I, Ciccone G, Larocca A, Cavalli M, et al. A Phase III 
Study to Compare Melphalan, Prednisone, Lenalidomide (MPR) Versus Melphalan 
200 Mg/m2 and Autologous Transplantation (MEL200) In Newly Diagnosed 
Multiple Myeloma Patients. Blood (ASH Annual Meeting Abstracts) 
2010;116:Abstract 3573.
12.
Mateos MV, Oriol A, Martinez-Lopez J, Gutierrez N, Teruel AI, de Paz R, et al. 
Bortezomib, melphalan, and prednisone versus bortezomib, thalidomide, and 
prednisone as induction therapy followed by maintenance treatment with bortezomib 
and thalidomide versus bortezomib and prednisone in elderly patients with untreated 
multiple myeloma: a randomised trial. Lancet Oncology 2010;11(10):934-41.
13.
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.
14.
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.
15.
Reeder CB, Reece DE, Kukreti V, Chen C, Trudel S, Hentz J, et al. 
Cyclophosphamide, bortezomib and dexamethasone induction for newly diagnosed 
multiple myeloma: high response rates in a phase II clinical trial. Leukemia 
2009;23(7):1337-41.
16.
Kumar SK, Flinn I, Noga SJ, Hari P, Rifkin R, Callander N, et al. Bortezomib, 
dexamethasone, cyclophosphamide and lenalidomide combination for newly 
diagnosed multiple myeloma: phase 1 results from the multicenter EVOLUTION 
study. Leukemia 2010;24(7):1350-6.
17.
Palumbo A, Hajek R, Delforge M, Kropff M, Petrucci MT, Catalano J, et al. 
Continuous lenalidomide treatment for newly diagnosed multiple myeloma. New 
England Journal of Medicine 2012;366(19):1759-69.
18.
National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice 
Guidelines in Oncology (NCCN Guidelines):  Multiple Myeloma. Version 1.2014.  
2013.
19.
Davies FE, Wu P, Jenner M, Srikanth M, Saso R, Morgan GJ. The combination of 
cyclophosphamide, velcade and dexamethasone induces high response rates with 
comparable toxicity to velcade alone and velcade plus dexamethasone. 
Haematologica 2007;92(8):1149-50.


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20.
Kropff M, Bisping G, Schuck E, Liebisch P, Lang N, Hentrich M, et al. Bortezomib 
in combination with intermediate-dose dexamethasone and continuous low-dose oral 
cyclophosphamide for relapsed multiple myeloma. British Journal of Haematology 
2007;138(3):330-7.
21.
Bringhen S, Federica C, Petrucci M, Gay F, Federico V, Conticello C, et al. 
Carfilzomib, Cyclophosphamide And Dexamethasone (CCd) For Newly Diagnosed 
Multiple Myeloma (MM) Patients: Initial Results Of A Multicenter, Open Label 
Phase II Study. In: 19th Congress of European Hematology Association (EHA) 
2013; Milan, Italy; p. abstr S578.
22.
Rajkumar S, Jacobus S, Callander N, Fonseca R, Vesole D, Williams M, et al. 
Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose 
dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-
label randomised controlled trial. Lancet Oncology 2010;11(1):29-37.
23.
Rajkumar SV, Harousseau JL, Durie B, Anderson KC, Dimopoulos M, Kyle R, et al. 
Consensus recommendations for the uniform reporting of clinical trials: report of the 
International Myeloma Workshop Consensus Panel 1. Blood 2011;117(18):4691-5.
24.
Paiva B, Martinez-Lopez J, Vidriales MB, Mateos MV, Montalban MA, Fernandez-
Redondo E, et al. Comparison of immunofixation, serum free light chain, and 
immunophenotyping for response evaluation and prognostication in multiple 
myeloma. Journal of Clinical Oncology 2011;29(12):1627-33.
25.
Coiffier B, Li W, Henitz ED, Karkera JD, Favis R, Gaffney D, et al. Prespecified 
Candidate Biomarkers Identify Follicular Lymphoma Patients Who Achieved
Longer Progression-Free Survival with Bortezomib-Rituximab Versus Rituximab. 
Clinical Cancer Research 2013;19(9):2551-2561.
26.
Du J, Huo J, Shi J, Yuan Z, Zhang C, Fu W, et al. Polymorphisms of nuclear factor-
{kappa}B family genes are associated with development of multiple myeloma and 
treatment outcome in patients receiving bortezomib-based regimens. Haematologica 
2011;96(5):729-37.
27.
de Jonge ME, Huitema AD, Rodenhuis S, Beijnen JH. Clinical pharmacokinetics of 
cyclophosphamide. Clinical Pharmacokinetics 2005;44(11):1135-64.
28.
Ren S, Yang JS, Kalhorn TF, Slattery JT. Oxidation of cyclophosphamide to 4-
hydroxycyclophosphamide and deschloroethylcyclophosphamide in human liver 
microsomes. Cancer Research 1997;57(19):4229-35.
29.
Roy P, Yu LJ, Crespi CL, Waxman DJ. Development of a substrate-activity based 
approach to identify the major human liver P-450 catalysts of cyclophosphamide and 
ifosfamide activation based on cDNA-expressed activities and liver microsomal P-
450 profiles. Drug Metab Dispos 1999;27(6):655-66.


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30.
San Miguel J, Hájek R, Špiˇcka I, Chen C, Gutierrez M, Schusterbauer C, et al. Oral 
MLN9708, an investigational proteasome inhibitor, in combination with melphalan 
and prednisone in patients with previously untreated multiple myeloma: a phase 1 
study. In: 17th Congress of the European Hematology Association (EHA); 2012; 
Amsterdam, The Netherlands.
31.
U.S. Department of Health and Human Services, National Institutes of Health 
National Cancer Institute. Common Terminology Criteria for Adverse Events 
(CTCAE). Version 4.03. 14 June 2010.
32.
CYTOXAN® (cyclophosphamide) [package insert]. Princeton, NJ: Bristol-Myers 
Squibb Company; 2005.
33.
Cyclophosphamide 50 tablets [Summary of Product Characteristics]. Kent, United 
Kingdom: Pharmacia Limited; 2012. Report No.: CP 6_2.
34.
Dexamethasone 8 mg GALEN® tablets [Summary of Product Characteristics]. Kiel, 
Germany: GALENpharma GmbH; 2009.
35.
Dexamethasone 4 mg GALEN® tablets [Summary of Product Characteristics]. Kiel, 
Germany: GALENpharma GmbH; 2009.
36.
Dexamethasone Tablets USP; Dexamethasone Oral Solution; Dexamethasone 
IntensolTM Oral Solution (Concentrate) [package insert]. Columbus, OH: Roxane 
Laboratories, Inc.; 2007.
37.
Thall PF, Sung HG. Some extensions and applications of a Bayesian strategy for 
monitoring multiple outcomes in clinical trials. Statistics in Medicine 
1998;17(14):1563-80.
38.
Lee JJ, Liu DD. A predictive probability design for phase II cancer clinical trials. 
Clin Trials 2008;5(2):93-106.
39.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. 
Nephron 1976;16(1):31-41.
40.
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.
41.
Knoben J, Anderson P. Handbook of Clinical Drug Data, 6th ed.: Drug Intelligence 
Pub, Inc.; 1988.
42.
Greipp PR, San Miguel J, Durie BG, Crowley JJ, Barlogie B, Blade J, et al. 
International staging system for multiple myeloma. Journal of Clinical Oncology 
2005;23(15):3412-20.
43.
Durie BG, Salmon SE. A clinical staging system for multiple myeloma. Correlation 
of measured myeloma cell mass with presenting clinical features, response to 
treatment, and survival. Cancer 1975;36(3):842-54.


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14.   
APPENDICES
14.1   
Multiple Myeloma Diagnostic Criteria
IMWG Criteria for the Diagnosis of Myeloma
Diagnosis
Diagnostic Criteria: All Three Required
Symptomatic multiple myelomaa

Monoclonal plasma cells in the bone marrow 10% 
and/or presence of a biopsy-proven plasmacytoma

Monoclonal protein present in the serum and/or urineb

Myeloma-related organ dysfunction (1)
[C] Calcium elevation in the blood (serum calcium 
> 10.5 mg/l or upper limit of normal)
[R] Renal insufficiency (serum creatinine > 2 mg per 
100 mL)
[A] Anemia (hemoglobin < 10 g per 100 mL or 2 g 
<normal)
[B] Lytic bone lesions or osteoporosisd
Source:  International Myeloma Foundation, myeloma.org. Accessed 16 January 2012.
a These criteria identify Stage IB and Stages II and III A/B myeloma by Durie/Salmon stage. Stage IA 
becomes smoldering or indolent myeloma.
b If no monoclonal protein is detected (non-secretory disease), then 30% monoclonal bone marrow 
plasma cells and/or a biopsy-proven plasmacytoma required.
c A variety of other types of end-organ dysfunctions can occasionally occur and lead to a need for therapy. 
Such dysfunction is sufficient to support classification as myeloma if proven to be myeloma related.
d If a solitary (biopsy-proven) plasmacytoma or osteoporosis alone (without fractures) is the sole defining 
criteria, then 30% plasma cells are required in the bone marrow.
14.2   
Cockcroft Gault Equation
For males:  
Creatinine Clearance = (140-age[years]) weight [kg]  OR   (140–age[years]) weight [kg]
72 (serum creatinine [mg/dL])      0.81 (serum creatinine [mol/L])
For females:  
Creatinine Clearance =
    0.85 (140-age [years]) weight [kg] OR 0.85 (140-age [years]) weight [kg]
    72 (serum creatinine [mg/dL])
0.81 (serum creatinine [mol/L])
Source:  Cockcroft DW, Gault MH.  Prediction of creatinine clearance from serum creatinine.  Nephron 
1976;16(1):31-41.(39)


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14.3   
Eastern Cooperative Oncology Group (ECOG) Scale for Performance Status
Grade
Description
0
Normal activity.  Fully active, able to carry on all predisease performance without restriction
1
Symptoms but ambulatory.  Restricted in physically strenuous activity, but ambulatory and 
able to carry out work of a light or sedentary nature (eg, light housework, office work)
2
In bed < 50% of the time.  Ambulatory and capable of all self-care, but unable to carry out 
any work activities.  Up and about more than 50% of waking hours.
3
In bed > 50% of the time.  Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours.
4
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  Totally confined to 
bed or chair
5
Dead
Source:  Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET et al. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5 (6):649-55.(40)
14.4   
Steroid Equivalent Doses
Approximately equivalent doses:
Steroid
Glucocorticoid
Anti-inflammatory
(mg)
Mineralicorticoid
(mg)
Half-life
(hours)
Cortisone
100
100
812
Hydrocortisone
80
80
812
Prednisone
20
100
1236
Prednisolone
20
100
1236
Methylprednisolone
16
no effect
1236
Dexamethasone
2
no effect
3672
Source:  Knoben JE, Anderson PO.  Handbook of Clinical Drug Data, 6th ed.  Drug Intelligence Pub, Inc.  
1988.(41)


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14.5   
International Staging System Criteria and Durie Salmon Criteria
The International Staging System (ISS) or Durie-Salmon criteria may be used for staging, 
according to local standard practice.
International Staging System
Stage
Criteria
Stage I
Serum 2-microglobulin < 3.5 mg/L
Serum albumin 3.5 g/dL
Stage II
Neither Stage I or Stage IIIa
Stage III
Serum 2-microglobulin 5.5 mg/L 
Source:  Greipp PR, San Miguel J, Durie BG, Crowley JJ, Barlogie B, Blade J, et al.  International staging 
system for multiple myeloma.  Journal of Clinical Oncology 2005;23(15):3412-20.(42)
Abbreviations:  ISS = International Staging System.
a There are 2 categories for Stage II:  serum 2-microglobulin < 3.5 mg/L but serum albumin < 3.5 g/dL; 
or serum 2-microglobulin 3.5 to < 5.5 mg/L irrespective of the serum albumin level.
Durie-Salmon Criteria
Stage
Criteria
I
All the following:

Hemoglobin value > 10 g/dL 

Serum calcium value normal or 12 mg/dL 

Bone X-ray, normal bone structure (scale 0), or solitary bone plasmacytoma only 

Low M component production rate
o
IgG value < 5 g/dL; IgA value < 3 g/dL 
o
Bence Jones protein < 4 g/24 h
II
Neither stage I nor stage III
III
1 or more of the following:

Hemoglobin value < 8.5 g/dL 

Serum calcium value > 12 mg/dL 

Advanced lytic bone lesions (scale 3) 

High M component production rate
o
IgG value > 7 g/dL; IgA value >5 g/dL
o
Bence Jones protein >12 g/24 h
Source:  Durie BG, Salmon SE.  A clinical staging system for multiple myeloma.  Correlation of measured 
myeloma cell mass with presenting clinical features, response to treatment, and survival.  Cancer 
1975;36(3):842-54.(43)
Abbreviations:  IgA = immunoglobulin A; IgG = immunoglobulin G.
Durie-Salmon subclassifications (either A or B):
A:  Relatively normal renal function (serum creatinine value < 2.0 mg/dL).
B:  Abnormal renal function (serum creatinine value 2.0 mg/dL).


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14.6   
European Organization for Research and Treatment of Cancer (EORTC)
Quality of Life Questionnaire (QLQ-C30) (version 3)


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14.7   
International Myeloma Working Group (IMWG) Response Criteria
Table 1. IMWG uniform response criteria by response subcategory for multiple myeloma
CR*
Stringent complete 
respon se (sCR)†
VGPR*
PR
SD
PD†
Negative
CR as defined, plus
Serum and urine
Š 50% reduction of serum
Not meeting criteria for CR,
Increase of 25% fr om l owest
immunofixation of
M-component
M-protein and reduction
VGPR, PR, or PD
response value in any of the
serum and urine,
detectable by
in 24- hour urinar y
following:
and
immunofixation
M-protein byŠ 90% or
but not on
to < 200 mg/24 hours
electrophoresis,
or
Disappear ance of any
Normal FLC ratio and
Š 90% reduction in
If the ser um and urine
Serum M-component (absolute
soft tissue
serum M-
M-protein are not
increase must be
plasmacytomas,
component plus
measur able, a decrease
Š 0.5 g/dL), and/or
and
urine
Š 50% in the difference
M-component
between involved and
< 100 mg/24 h
uninvol ved FLC levels is
required in place of the
M-protein criteria
< 5% PCs in bone 
marrow
Absence of cl onal PCs by 
immunohistochemistr y 
or 2- to 4-color flow 
cytometr y
If serum and urine M-
protein ar e not 
measur able, and serum 
free light assayis also 
not measurable, Š 50% 
reduction in bone 
marrow PCs is required 
in place of M-protein, 
provided baseline 
percentage was Š 30%
In addition to the above 
criteria, if present at 
baseline, Š 50% 
reduction in the size of 
soft tissue 
plasmacytomas is also 
required
Urine M-component (absolute 
increase must
be Š 200 mg/24 h), and/or
Onlyin pati ents without 
measur able serum and urine 
M-protein levels: the 
differ ence between involved 
and uninvolved FLC levels 
(absolute increase must be
> 10 mg/dL)
Onlyin pati ents without 
measur able serum and urine 
M protein levels and without 
measur able disease byFLC 
levels, bone marrow PC 
percentage (absolute 
percentage must be Š 10%)
Definite development of new 
bone lesi ons or soft tissue 
plasmacytomas or definite 
increase in the size of 
existing bone lesions or soft 
tissue plasmacytomas 
Development of
hypercalcemia
(corrected ser um calcium 
> 11.5 mg/dL) that can
be attributed solely to the
PC proliferative disor der
Adapted from Durie et al7 and Kyle et al13 with permission. All response categories (CR, sCR, VGPR, PR, and PD) require 2 consecutive assessments made at any time 
before the institution of any new therapy; CR, sCR, VGPR, PR, and SD categories also require no known evidence of progressive or new bone lesions if r adiographic studies 
wer e performed. VGPR and CR categories require serum and urine studies r egardless of whether disease at baseline was measurable on serum, urine, both, or neither. 
Radiographic studies are not required to satisfythese response requirements. Bone marrow assessments need not be confir med. F or PD, serum M-component increases of 
mor e than or equal to 1 g/dL ar e sufficient to define rel apse if starting M-component is Š 5 g/dL.
PCs indicate plasma cells.
*Clarifications to IMWG criteria for coding CR and VGPR in patients in whom the only measurable disease is by serum F LC levels: CR in such patients indicates a nor mal  
FLC ratio of 0.26 to 1.65 in addition to CR criteria listed above. VGPR in such patients requires a > 90% decrease in the difference between involved and uninvolved FLC  
levels.
†Clarifications to IMWG criteria for coding PD: Bone marrow criteria for PD are to be used onl y in patients without measurabledisease by M pr otein and by F LC levels; 
“25% incr ease” refers to M protein, FLC, and bone marrowresults, and does not refer to bone l esions, soft tissue plasmacytomas, or hypercalcemi a and the “lowest response 
value” does not need to be a confirmed value.


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14.8   Amendment 1 Detailed Summary of Changes
THE PRIMARY SECTIONS OF THE PROTOCOL AFFECTED BY THE CHANGES IN 
AMENDMENT 1 ARE INDICATED.  THE CORRESPONDING TEXT HAS BEEN 
REVISED THROUGHOUT THE PROTOCOL.
Purpose:  Revise the protocol title to reflect the added population of patients with RRMM  
The primary change occurs on Title Page:
Formerly 
read:
An Open-Label, Phase 2 Study to Evaluate the Oral Combination of 
MLN9708 With Cyclophosphamide and Dexamethasone In Patients With 
Newly Diagnosed Multiple Myeloma Requiring Systemic Treatment.
Now reads:
An Open-Label, Phase 2 Study to Evaluate the Oral Combination of 
MLN9708 With Cyclophosphamide and Dexamethasone In Patients With 
Newly Diagnosed or Relapsed and/or Refractory Multiple Myeloma 
Requiring Systemic Treatment.
Sections that also contain this change are:

Protocol Summary

Section 12, INVESTIGATOR AGREEMENT
Purpose:  Revise the Study Overview Diagram to include the patient population with 
RRMM
The change occurs in Study Overview Diagram:
Summary 
of change:
A schematic was added of study overview for patients s with RRMM
Purpose:  Clarify the description of VELCADE/cyclophosphamide/dexamethasone (VCD) 
as a therapeutic option for frontline treatment of patients with multiple myeloma
The change occurs in Section 1.1.1, Disease Under Treatment:
Deleted 
text:  
VCD has become a standard of care and is one of several preferred 
therapeutic options available as frontline therapy for transplant-eligible 
patients.


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Purpose:  Update the details of the clinical experience with MLN9708
The change occurs in Section 1.3, Clinical Experience:
Formerly 
read:
The adverse events (AEs) are consistent with the class-based effects of 
proteasome inhibition and are similar to what has been previously reported 
with VELCADE though the severity of some, for example peripheral 
neuropathy, is less.
Now reads:  The adverse events (AEs) are consistent with the known effects of 
proteasome inhibition and are similar to what has been previously reported 
with VELCADE though the severity of some, for example peripheral 
neuropathy, is less.
Section 1.4.1, Feasibility of Combination of MLN9708, Cyclophosphamide, and 
Dexamethasone Therapy also contains this change.  
Purpose:  Add a brief description of treatment options and prognosis for patients with 
RRMM
The change occurs in Section 1.1.1, Disease Under Treatment:
Added text:
For patients with relapsed and/or refractory multiple myeloma (RRMM)
who experience disease progression after their initial therapy, response to 
subsequent treatments varies with a decreased likelihood of response and 
a tendency towards a shorter duration of response (DOR).  Ultimately,
RRMM becomes refractory to approved therapies, and patients have no
alternative treatment options.
Purpose:  Provide a rationale for adding patients with RRMM to the study
The change occurs in Section 1.4, Study Rationale:
Added text:
Relapsed and/or Refractory Disease
Although multiple therapies are available for patients with RRMM, the
frequent relapses that characterize this disease highlight a need for new
therapies for patients in whom prior treatments have failed.(18)  VCD has
been shown to be an effective treatment in patients with RRMM and has
a favorable toxicity profile.  VCD is recognized by the NCCN as salvage
therapy for patients with RRMM with an ORR of 75% to 83%.(19, 20)
The early development program of MLN9708 in patients with RRMM
investigated 2 dose schedules commonly used with the first-in-class
proteasome inhibitor, VELCADE.  In the open-label, dose-escalation,
phase 1 studies, C16003 and C16004, MLN9708 was administered on a
twice-weekly (Days 1, 4, 8, and 11 of a 21-day cycle) schedule and on a
weekly schedule (Days 1, 8, and 15 of a 28-day cycle), respectively.  In


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both studies, patients had MM that had relapsed following at least 2 lines
of therapy that included bortezomib, thalidomide (or lenalidomide), and
corticosteroids.  In both studies, the MTD cohorts were expanded.  
Patients enrolled in these expansion cohorts had relapsed or refractory
disease (refractory was defined as disease progression while on therapy
or within 60 days after the last dose of therapy), and included patients
who had been previously treated with a proteasome inhibitor such as
VELCADE or carfilzomib and considered to be sensitive to a proteasome
inhibitor or patients who were proteasome inhibitor naive.  Preliminary
data suggest that MLN9708 has antitumor activity in heavily pretreated
patients with MM, with an ORR of 27% for the MTD expansion cohort
in Study C16004.  In both studies, durable responses and disease control
have been observed with a generally acceptable toxicity profile.
The inclusion of an RRMM treatment arm in this study is proposed on
the basis of results of VELCADE in patients with previously treated MM
and the emerging activity seen with MLN9708 in patients with previously 
treated and untreated MM.
Purpose:  Revise the description of the study purpose to include patients with RRMM
The change occurs in Section 1.4, Study Rationale:
Formerly 
read:
The purpose of Study C16020 is to determine the safety, tolerability, and 
efficacy when MLN9708 is added to a Cd backbone.  Extending the duration 
of the response through prolonged use of single-agent MLN9708 as 
maintenance therapy following induction will also be evaluated.  Patients 
with stable or responding disease at the end of induction therapy will continue 
on maintenance treatment.  
Now reads:
The purpose of Study C16020 is to determine the safety, tolerability, and 
efficacy of oral MLN9708 when added to a Cd backbone in patients with
NDMM and RRMM.  For patients with NDMM, extending the duration of 
the response through prolonged use of single-agent MLN9708 as maintenance 
therapy following induction will also be evaluated.  Patients with NDMM
who are stable or responding at the end of induction therapy will continue to
receive MLN9708 as maintenance treatment.
Purpose:  Add the RRMM population to the discussion of the rationale for the combination 
therapy under evaluation in the study
The change occurs in Section 1.4.1, Feasibility of Combination of MLN9708, 
Cyclophosphamide, and Dexamethasone Therapy:  
Formerly 
read:
Given the similar safety and tolerability profile of MLN9708 compared to
VELCADE, adding MLN9708 to a Cd backbone is anticipated to be feasible 
from a safety perspective.  


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Now reads: 
Given the similar safety and tolerability profile of MLN9708 compared with
VELCADE, adding MLN9708 to a Cd backbone is anticipated to be feasible 
from a safety perspective in both the NDMM and RRMM settings.
Purpose:  Add the RRMM population to the discussion of dose intensity schedules for 
cyclophosphamide
The change occurs in Section 1.4.2, Rationale for the Combination of MLN9708, 
Cyclophosphamide, and Dexamethasone Dose and Dosing Schedule:
Formerly 
read:
The dose-intensity schedules for cyclophosphamide tested in the myeloma 
setting are numerous and there is no dosing regimen that can be considered 
standard.  
…
On the basis of available data on weekly cyclophosphamide tested in 
combination with a proteasome inhibitor in both transplant-eligible and 
transplant-noneligible NDMM patients, weekly cyclophosphamide at a dose 
of 300 mg/m2 on Days 1, 8, and 15 on a 28-day cycle was a safe and tolerable 
dose to consider and was selected for Arm A.  
Now reads:
The dose-intensity schedules for cyclophosphamide tested in the myeloma 
setting are numerous and there is no dosing regimen that can be considered 
standard in either the frontline or relapsed and/or refractory disease
setting.  
… On the basis of available data on weekly cyclophosphamide tested in 
combination with a proteasome inhibitor in both transplant-eligible and 
transplant-ineligible patients with NDMM, weekly cyclophosphamide at a 
dose of 300 mg/m2 on Days 1, 8, and 15 on a 28-day cycle was a safe and 
tolerable dose to consider and was selected for Arm A and the population
with relapsed and/or refractory disease to be enrolled in Arm C.  
…
Although various dose schedules have been used for cyclophosphamide in
combination with VELCADE in the relapsed and/or refractory setting,
including the 500 mg weekly dose(19) or 50 mg daily dose,(20) a weekly dose 
of 300 mg/m2 on Days 1, 8, and 15 of a 28-day cycle is expected to be
tolerable in combination with a proteasome inhibitor, based on the
toxicity profile observed in patients with NDMM.  An alternative dose
schedule may be considered for Arm C if the planned dosage is not
tolerated.


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Purpose:  Add the primary study objective for patients with RRMM and delineate the 
primary objective for the 2 patient populations
The primary change occurs in Section 2.1, Primary Objectives:
Formerly 
read:
The primary objective is:

To determine the combined response rate of CR (including stringent CR 
[sCR]) + VGPR following treatment of oral MLN9708 when added to a 
standard regimen of cyclophosphamide, and low-dose dexamethasone 
(Cd) during the induction phase
Now reads:
The primary objective for patients with newly diagnosed multiple 
myeloma (NDMM) is:

To determine the combined response rate of CR (including stringent CR 
[sCR]) + VGPR following treatment with oral MLN9708 when added to 
a regimen of cyclophosphamide and low-dose dexamethasone (Cd) 
during the induction phase
The primary objective for patients with relapsed and/or refractory 
multiple myeloma (RRMM) is:

To determine overall response rate (ORR; CR + VGPR + partial 
response[PR]) following treatment with oral MLN9708 when added
to a regimen of Cd
The Protocol Summary also contains this change.
Purpose:  Add the secondary study objectives for patients with RRMM and delineate the 
secondary objectives for the 2 patient populations
The primary change occurs in Section 2.2, Secondary Objectives:
Formerly 
read:
The secondary objectives include:

To evaluate the tolerability and toxicity of the combination of oral 
MLN9708 with Cd in patients with NDMM

To characterize the PK in plasma of oral MLN9708 in combination with 
Cd in patients with NDMM
Now reads:
For patients with NDMM, the secondary objectives are:

To evaluate the tolerability and toxicity of the combination of oral 
MLN9708 with Cd

To characterize the PK in plasma of oral MLN9708 in combination with 
Cd
…
For patients with RRMM, the secondary objectives are:


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
To evaluate the tolerability and toxicity of the combination of oral 
MLN9708 with Cd

To characterize the PK in plasma of oral MLN9708 in combination 
with Cd

To determine CR + VGPR, CR, VGPR, and PR 

To determine time to response for patients who respond

To determine DOR

To determine TTP

To evaluate PFS

To assess change in global health status, as measured by the 
patient-reported outcome (PRO) instruments European 
Organization for Research and Treatment of Cancer (EORTC) 
Quality of Life Questionnaire (QLQ-C30)
The Protocol Summary also contains this change.
Purpose:  Remove the EORTC Multiple Myeloma Module (MY-20) from the assessments 
to determine changes in global health status
The primary change occurs in Section 2.2, Secondary Objectives:
Deleted 
text:
To assess change in global health status, as measured by the patient-reported 
outcome (PRO) instruments European Organization for Research and 
Treatment of Cancer (EORTC) Quality-of-Life Questionnaire (QLQ-C30) 
and Multiple Myeloma Module (MY-20)
Sections that also contain this change are:

Protocol Summary

Schedule of Events

Section 3.2, Secondary Endpoints

Section 7.4.14, Quality of Life Assessment (European Organization for Research and 
Treatment of Cancer)

Section 8.1.7, Analyses of Patient-Reported Outcomes

Deleted Section 14.7


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Purpose:  Describe the tertiary/exploratory objectives for the 2 patient populations and add 
an additional tertiary objective of health care utilization assessments
The primary change occurs in Section 2.3, Exploratory Objectives:
Formerly 
read:
The exploratory objectives include:
Now reads:
For patients with NDMM and patients with RRMM, the exploratory 
objectives are:
bute to population PK and
exposure/response analysis
The Protocol Summary also contains this change.
Purpose:  Align the primary, secondary, and tertiary study endpoints with the primary, 
secondary, and tertiary study objectives
The change occurs in Section 3.1, Primary Endpoint:  
Formerly 
read:
The primary endpoints include:

Combined response rate of CR (including sCR) + VGPR in patients 
treated with MLN9708 when added to a standard care regimen of Cd 
during the induction phase
3.2   Secondary Endpoints
The secondary endpoints include:
…

ORR (CR + VGPR + PR), CR, VGPR, and PR during the induction 
phase and throughout the entire study
…
3.3   Exploratory Endpoints
The exploratory endpoints include:

Now reads:
For patients with NDMM, the primary endpoints are:

Combined response rate of CR (including sCR) + VGPR during the 
induction phase in patients treated with MLN9708 when added to a 
regimen of Cd


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For patients with RRMM, the primary endpoint is:

ORR (CR + VGPR +PR) in patients treated with MLN9708 when
added to a regimen of Cd
3.2   Secondary Endpoints
For patients with NDMM, the secondary endpoints are:
…

ORR (CR + VGPR + PR), CR, VGPR, PR, stable disease (SD), 
progressive disease (PD) during the induction phase; ORR, CR +
VGPR, CR, VGPR, PR, SD and PD and throughout the entire study
…
For patients with RRMM, the secondary endpoints are:

All AEs, Grade 3 or higher AEs, AEs resulting in discontinuation,
AEs resulting in dose reduction, serious adverse events (SAEs), 
and assessments of clinical laboratory values

PK parameters including but not limited to single-dose maximum
(peak) concentration (Cmax), Tmax, and AUC 

CR + VGPR, CR, VGPR, PR, SD, PD

Time to response

DOR

TTP

PFS

Comparison of change in global health status between baseline
and each postbaseline assessment, as measured by the global
health scale, functioning, and symptoms of the EORTC QLQ-C30
3.3   Exploratory Endpoints
For patients with NDMM and patients with RRMM, the exploratory 
endpoints are:

…

Purpose:  Clarify the study design for patients with NDMM and describe the study design 
for patients with RRMM
The primary change occurs in Section 4.1, Overview of Study Design:  
Formerly 
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read:  
who have not received prior systemic treatment for MM and who are 
ineligible for high-dose therapy (HDT)-SCT due to age (ie, ≥65 years) or 
comorbid disease(s).  It is expected that approximately 70 patients will be 
enrolled in this study.  
Once enrolled, patients will be randomized 1:1 to either Arm A or Arm B.  
Each 28-day treatment cycle is composed of oral MLN9708 (4.0 mg on 
Days 1, 8, and 15) administered in combination with cyclophosphamide 
(300 mg/m2 [Arm A] OR 400 mg/m2 [Arm B] both on Days 1, 8, and 15) and 
dexamethasone (40 mg on Days 1, 8, 15, and 22).  Patients over 75 years old 
will receive a reduced dose of dexamethasone (20 mg).  Patients may receive 
MLN9708 in combination with Cd for an induction phase of approximately 1 
year (13 × 28-day cycles) and if at least stable disease (SD) has been reached 
with an acceptable toxicity profile, patients will be administered, as 
maintenance, single-agent MLN9708 (at the dose tolerated at the end of 
induction) on Days 1, 8, and 15 in 28-day treatment cycles until PD/death or 
unacceptable toxicity.
A safety lead-in evaluation will be performed after at least 6 patients in each 
treatment arm have had the opportunity to complete at least 1 cycle of 
therapy.  Toxicities observed in the first 6 patients from each arm will be used 
to determine the safety of the regimen and the feasibility to proceed to 
continue enrollment to the study.
No formal interim analysis is planned; however, both safety and efficacy will 
be continuously monitored (see Section 8.1.10) throughout study conduct.  
Response will be assessed according to the International Myeloma Working 
Group (IMWG) criteria for all patients every cycle during the induction phase 
and every other cycle during maintenance.  Radiographic disease assessments 
are to be performed for patients with documented extramedullary disease.  
Patients discontinuing study drug prior to PD (ie, for withdrawal of consent, 
unacceptable toxicity, or initiation of alternative antineoplastic therapy) will 
be followed for PFS until PD/death.
…
MLN9708 in combination with Cd will be discontinued early if a patient 
experiences PD or unacceptable study drug related toxicities.  Patients may 
discontinue therapy at any time.  Patients will attend the end of treatment 
(EOT) visit 30 days after receiving their last dose of study drug regimen.  
Now reads: 
This is a phase 2, multicenter, open-label study in patients with NDMM who 
have not received prior systemic treatment for MM and who are ineligible for 
high-dose therapy (HDT)-SCT due to age (ie, ≥65 years) or comorbid 
disease(s) and in patients with RRMM who have received 1 to 3 lines of 
prior therapy and whose disease is not refractory to proteasome 
inhibitors.  It is expected that approximately 148 patients will be enrolled in 
this study.  


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Patients With NDMM:  Treatment Arms A and B
Patients with NDMM will be randomized 1:1 to either Arm A or Arm B.  
Each 28-day treatment cycle consists of oral MLN9708 (4.0 mg on Days 1, 8, 
and 15) administered in combination with cyclophosphamide (300 mg/m2
[Arm A] OR 400 mg/m2 [Arm B] both on Days 1, 8, and 15) and 
dexamethasone (40 mg on Days 1, 8, 15, and 22).  Patients over 75 years of
age will receive a reduced dose of dexamethasone 20 mg on the same
weekly schedule.  Patients may receive MLN9708 in combination with Cd 
for an induction phase of approximately 1 year (13 28-day cycles) and if at 
least stable disease has been reached with an acceptable toxicity profile, 
patients will be administered, as maintenance, single-agent MLN9708 (at the 
dose tolerated at the end of induction) on Days 1, 8, and 15 in 28-day 
treatment cycles until disease progression, death, or unacceptable toxicity.
Patients With RRMM:  Treatment Arm C
Patients with RRMM will receive MLN9708 4.0 mg weekly on Days 1, 8,
and 15, in combination with cyclophosphamide 300 mg/m2 on Days 1, 8,
and 15, and dexamethasone 40 mg on Days 1, 8, 15, and 22 of a 28-day
cycle (all orally administered).  Patients over 75 years of age will receive
the reduced dose of dexamethasone 20 mg on the same weekly schedule.  
Patients with an acceptable toxicity profile will continue treatment until
disease progression, death, or unacceptable toxicity.
All Patients:  Treatment Arms A, B, and C
For all 3 treatment arms, a safety lead-in evaluation will be performed after 
at least 6 patients in each treatment arm have had the opportunity to complete 
at least 1 cycle of therapy.  Dose-limiting toxicities (DLTs) observed in the 
first 6 patients from each treatment arm will be used to determine the safety 
and overall tolerability of the regimen and the feasibility of continued
recruitment to the study.  
No formal interim analysis is planned; however, both safety and efficacy will 
be continually monitored (see Section 8.1.11) throughout study conduct.  
Response will be assessed according to the International Myeloma Working 
Group (IMWG) criteria.  For patients with NDMM (Arms A and B), these 
assessments will be performed at every cycle during the induction phase 
and at every other cycle during the maintenance phase.  For patients with 
RRMM (Arm C), response will be assessed at every cycle during the
treatment period.  Radiographic disease assessments are to be performed for 
patients with documented extramedullary disease.  Patients discontinuing 
study drug before disease progression (ie, for withdrawal of consent or
unacceptable toxicity) will be followed for PFS until disease progression or
death.
…
The study drug regimen will be discontinued for a patient in any of the 


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3 treatment arms who experiences disease progression or unacceptable 
study drug related toxicities.  This includes MLN9708 in combination with
Cd during the induction period for patients with NDMM (Arms A and B)
or the treatment period for patients with RRMM (Arm C).  MLN9708
will also be discontinued for patients with NDMM (Arms A and B) who
experience disease progression during the maintenance phase.  Patients 
may discontinue therapy at any time.  Patients will attend the end of treatment 
(EOT) visit 30 days (± 7 days) after receiving their last dose of study drug 
regimen.  
The Protocol Summary also contains these changes.  
Purpose:  Revise the anticipated number of enrolled patients and investigative sites
The primary change occurs in Section 4.2, Number of Patients:  
Formerly 
read:  
Approximately 70 patients will be enrolled in this study from approximately 
20 study centers globally.  
Now 
reads:
It is anticipated that approximately 148 patients, 70 patients with NDMM
and 78 patients with RRMM, will be enrolled in this study from 
approximately 30 study centers globally.
Sections that also contain this change are:

Protocol Summary

Section 8.1.1, Determination of Sample Size  
Purpose:  Revise the description for anticipated duration of study and timing of the clinical 
study report
The change occurs in Section 4.3, Duration of Study:  
Formerly 
read:  
This includes 24 months of enrollment, 12 months of induction therapy, and 
24 months of maintenance and/or PFS follow-up after the last patient 
completes induction therapy or until 75% of patients have progressed, 
whichever occurs first.
The analyses for the clinical study report (CSR) will be conducted after all 
patients enrolled in the study have had the opportunity to complete induction 
therapy.  
Now reads:  This includes 24 months of enrollment and up to 36 months of treatment
and/or PFS follow-up.  
The analyses for the clinical study report (CSR) will be conducted after all 
enrolled patients have had the opportunity to complete 13 cycles of the study 
drug regimen.


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The Protocol Summary also contains this change.  
Purpose: Add patients with RRMM to the description of study population and clarify the 
inclusion criteria for the 2 patient populations
The change occurs in Section 5, STUDY POPULATION:
Formerly 
read:  
Adult patients age 18 or older with a confirmed diagnosis of symptomatic 
MM who have received no prior antimyeloma treatment and who are 
ineligible for HDT-SCT due to age (65 years) or comorbidities will be 
enrolled in this study.
Now reads:  Two patient populations will be enrolled in this study:

Adult patients with a confirmed diagnosis of symptomatic MM who 
have received no prior antimyeloma treatment (NDMM) and are not 
candidates for HDT-SCT due to age (65 years) or comorbidities; and

Adult patients with a confirmed diagnosis of symptomatic MM and 
relapsed and/or refractory disease (RRMM) after 1 to 3 lines of 
prior therapy and whose disease is not refractory to proteasome 
inhibitors
Section 5.1, Inclusion Criteria, also contains this change.  
Purpose:  Describe the inclusion criteria that pertain to both patient populations (NDMM 
and RRMM)
The change occurs in Section 5.1, Inclusion Criteria:  
Formerly 
read:  
Patients must meet the following clinical laboratory criteria:

Absolute neutrophil count (ANC) ≥1000/mm3 and platelet count 
≥75,000/mm3.  Platelet transfusions to help patients meet eligibility 
criteria are not allowed within 3 days prior to study drug dosing.
Now reads:
In addition, all patients (NDMM and RRMM) must meet all of the
remaining criteria:  
…
Patients must meet all of the following clinical laboratory criteria:

Absolute neutrophil count (ANC) ≥1000/mm3 and platelet count 
≥75,000/mm3.  Platelet transfusions to help patients meet eligibility 
criteria are not allowed within 3 days prior to administration of the
study drug.


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Purpose:  Add the pregnancy prevention guidelines for cyclophosphamide and 
dexamethasone
The primary change occurs in Section 5.1, Inclusion Criteria:  
Added text:

Agree to practice true abstinence over the period previously described, 
when this is in line with the preferred and usual lifestyle of the subject.  
(Periodic abstinence (eg, calendar, ovulation, symptothermal, 
postovulation methods] and withdrawal are not acceptable methods of 
contraception.), and

Adhere to any treatment-specific pregnancy prevention guidelines
for cyclophosphamide(32, 33) and dexamethasone(34, 35, 36)
Section 6.6, Precautions and Restrictions also contains this change.  
Purpose:  Clarify the exclusion criteria for the 2 patient populations
The change occurs in Section 5.2, Exclusion Criteria:  
Formerly 
read:  
Patients meeting any of the following exclusion criteria are not to be 
randomized to treatment:
1. Prior treatment for multiple myeloma with either standard of care treatment 
or investigational regimen.
…
5.  Peripheral neuropathy Grade 1 with pain or ≥Grade 2 of any cause on 
clinical examination during the Screening period.
Now reads:
Patients meeting any of the following exclusion criteria are not to be enrolled
in the study:
1. Prior treatment for multiple myeloma with either standard of care treatment 
or investigational regimen (for patients with NDMM only).
…
5.  Peripheral neuropathy Grade 1 with pain or Grade 2 or higher peripheral
neuropathy of any cause on clinical examination during the Screening 
period.


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Purpose:  Revise and update the guidelines for study drug administration
The change occurs in Section 6.1, Study Drug Administration:
Added text:  Dosing should be performed on schedule, but occasional changes in
patient scheduling are allowable (± 3 days) for holidays and vacations,
except during Cycle 1 for all patients enrolled in the safety lead-in
cohort.  After the safety lead-in is completed within a treatment arm, an
occasional change in the dosing schedule (± 1 week) may be allowable for
other administrative reasons after consultation with the Millennium
project clinician (or designee).  
Purpose:  Describe and clarify the MLN9708 administration guidelines for the 2 patient 
populations
The primary change occurs in Section 6.1.1, MLN9708 Administration:  
Formerly 
read:
During induction, oral MLN9708 will be given weekly at a dose of 4.0 mg on 
Days 1, 8, and 15 of a 28-day cycle.  
At the end of 13 cycles of treatment, maintenance phase will start.  If the 
patient is still on study (has achieved at least SD with an acceptable toxicity 
profile), MLN9708 will be continued as a single agent, weekly (Days 1, 8, and 
15) in a 28-day cycle at the same dose tolerated at the end of induction 
therapy.  Under certain circumstances the maintenance dose may be increased 
up to but not exceeding the starting dose of the induction phase if the 
investigator and Millennium project clinician (or designee) both agree that it 
would be beneficial for the patient.  
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.  Patients should be instructed to swallow MLN9708 capsules whole with 
water and not to chew, break, or open the capsules.  Each dose of MLN9708 
will be taken orally with approximately 8 ounces (ie, 240 mL) total of water 
consumed.
Missed doses can be taken as soon as the patient remembers as long as the next 
scheduled dose is 72 hours or more away.  
Now 
reads:
Patients With NDMM (Arms A and B):  
During induction, oral MLN9708 will be given weekly at a dose of 4.0 mg on 
Days 1, 8, and 15 of a 28-day cycle.  
At the end of 13 cycles of treatment, the maintenance phase will start.  If the 
patient is still on study (has achieved at least stable disease with an acceptable 
toxicity profile), MLN9708 will be continued as a single agent, weekly on
Days 1, 8, and 15 of a 28-day cycle at the same dose being given at the end of 
induction therapy.  Under certain circumstances the maintenance dose may be 
increased up to but not exceeding the starting dose of the induction phase if the 


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investigator and Millennium project clinician (or designee) both agree that it 
would be beneficial for the patient.  
Patients With RRMM (Arm C):
For patients with RRMM, oral MLN9708 will be given weekly on Days 1,
8, and 15 of 28-day cycle at the dose of 4.0 mg until disease progression or
unacceptable toxicity occurs.  
All Patients (Arms A, B, and C)
For all 3 treatment arms, 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.  Patients should be instructed to swallow MLN9708 
capsules whole with water and not to chew, break, or open the capsules.  Each 
dose of MLN9708 will be taken orally with approximately 8 ounces (ie, 
240 mL) total of water consumed.
Missed doses on Days 1 and 8 can be taken as soon as the patient remembers 
as long as the next scheduled dose is 72 hours or more away.  The missed
dose on Day 15 can be taken only up to 72 hours after the planned dose
(no later than on Day 18).  
The Protocol Summary also contains this change.  
Purpose:  Describe and clarify the cyclophosphamide administration guidelines for the 
2 patient populations
The change occurs in Section 6.1.2, Cyclophosphamide Administration:
Formerly 
read:
During induction, cyclophosphamide will be given weekly as a single, oral 
dose of 300 mg/m2 (Arm A) OR 400 mg/m2 (Arm B) and rounded to the 
nearest 50 mg, on Days 1, 8, and 15 of a 28-day cycle.  
At the end of 13 cycles of treatment, the maintenance phase will start.  If the 
patient is still on study, cyclophosphamide will be discontinued.
It is recommended that cyclophosphamide be taken in the morning and at 
approximately the same time each dosing day.  Cyclophosphamide should be 
taken at least 1 hour after MLN9708 with food or milk.  Patients should be 
instructed to drink plenty of fluids and to urinate frequently during treatment 
with cyclophosphamide.  Patients should be instructed to swallow 
cyclophosphamide capsules whole with water and not to chew, break, or 
open the capsules.
Missed doses can be taken within 48 hours from the last dose.  If more than 
48 hours has elapsed, the missed dose should be skipped and the next dose 
taken according to the regular dosing schedule.  A double dose should not be 
taken to make up for a missed dose.  If the patient vomits after taking a dose, 
the patient should not repeat the dose but should resume dosing at the time of 
the next scheduled dose.


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BSA will be calculated using a standard formula on Cycle 1, Day 1 and on 
Day 1 of subsequent cycles if the patient experiences a > 5% change in body 
weight from the weight used for the most recent BSA calculation.
Intrapatient Dose Escalation of Cyclophosphamide
Intrapatient dose escalation is not planned; however, if during, the 
continuous monitoring of the study, clear evidence of antitumor activity is 
observed in Arm B (cyclophosphamide 400 mg/m2) with an overall 
acceptable safety/tolerability profile, patients in Arm A (cyclophosphamide 
300 mg/m2) who have tolerated treatment with cyclophosphamide well at the 
initially assigned dose may be allowed to increase their dose of 
cyclophosphamide to 400 mg/m2 in subsequent cycles of treatment following 
sponsor and investigator review of the available observed data.  Patients in 
whom an increase in the dose of cyclophosphamide is being considered must 
have completed at least 2 cycles of treatment at their initially assigned dose.  
Hematology laboratory samples will be drawn weekly for the following 
3 cycles once escalation has occurred.    
Now reads:
Patients with NDMM (Arms A and B)
During induction, cyclophosphamide will be given weekly as a single, oral 
dose of 300 mg/m2 (Arm A) OR 400 mg/m2 (Arm B) and rounded to the 
nearest 50 mg, on Days 1, 8, and 15 of a 28-day cycle.  
At the end of 13 cycles of treatment, the maintenance phase will start.  If the 
patient is still on study, cyclophosphamide will be discontinued.
Intrapatient Dose Escalation of Cyclophosphamide for Arm A
Intrapatient dose escalation is not planned; however, if during the 
continuous monitoring of the study data, clear evidence of antitumor
activity is observed in Arm B (cyclophosphamide 400 mg/m2) with an 
overall acceptable safety/tolerability profile, patients in Arm A
(cyclophosphamide 300 mg/m2) who have tolerated treatment with 
cyclophosphamide well at the initially assigned dose may be allowed to
increase their dose of cyclophosphamide to 400 mg/m2 in subsequent 
cycles of treatment following sponsor and investigator review of the 
available observed data.  Patients in whom an increase in the dose of
cyclophosphamide is being considered must have completed at least 
2 cycles of treatment at their initially assigned dose.  Hematology 
laboratory samples will be obtained weekly for the next 3 cycles once the 
dose has been increased.
Patients with RRMM (Arm C)
For patients with RRMM, cyclophosphamide will be given weekly on 
Days 1, 8, and 15 of a 28-day cycle as a single, oral dose of 300 mg/m2
and rounded to the nearest 50 mg.  An alternative dose schedule of 
cyclophosphamide may be explored for Arm C if the planned dose is not 
tolerated.


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All Patients:  Treatment Arms A, B, and C
For all 3 treatment arms, it is recommended that cyclophosphamide be 
taken in the morning and at approximately the same time each dosing day.  
Cyclophosphamide should be taken with solid food or milk.  Patients should 
be instructed to drink plenty of fluids and to urinate frequently during 
treatment with cyclophosphamide.  Patients should be instructed to swallow 
cyclophosphamide capsules whole with water and not to chew, break, or 
open the capsules.
Missed doses can be taken within 48 hours from the planned dose.  If more 
than 48 hours have elapsed, the missed dose should be skipped and the next 
dose taken according to the regular dosing schedule.  A double dose should 
not be taken to make up for a missed dose.  If the patient vomits after taking 
a dose, the patient should not repeat the dose but should resume dosing at the 
time of the next scheduled dose.
Body surface area will be calculated using a standard formula on Cycle 1, 
Day 1 and on Day 1 of subsequent cycles.  If the patient experiences a > 5% 
change in body weight from the weight used for the most recent BSA 
calculation, the BSA should be recalculated to determine the dose of
cyclophosphamide.  
Purpose:  Describe and clarify the dexamethasone administration guidelines for the 
2 patient populations
The change occurs in Section 6.1.3, Dexamethasone Administration:  
Formerly 
read:  
During induction, dexamethasone will be given as a weekly oral dose of 
40 mg on Days 1, 8, 15, and 22 of a 28-day cycle.  Patients over 75 years old
will receive a reduced dose of dexamethasone (20 mg, same schedule).
At the end of 13 cycles of treatment, maintenance phase will start.  If the 
patient is still on study, dexamethasone will be discontinued.
It is recommended that dexamethasone be taken in the morning and at 
approximately the same time each dosing day.  Dexamethasone should be 
taken at least 1 hour after MLN9708 with food or milk.  
Missed doses can be taken within 48 hours from the last dose.  If more than 
48 hours has elapsed, the missed dose should be skipped, and the next dose 
taken according to the regular dosing schedule.  A double dose should not be 
taken to make up for a missed dose.  If the patient vomits after taking a dose, 
the patient should not repeat the dose but should resume dosing at the time of 
the next scheduled dose.
Now reads:  
Patients With NDMM (Arms A and B)
During induction, dexamethasone will be given as a weekly oral dose of 
40 mg on Days 1, 8, 15, and 22 of a 28-day cycle.  Patients older than
75 years of age at the time of randomization will receive a reduced dose of 


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dexamethasone 20 mg on the same weekly schedule.
At the end of 13 cycles of treatment, maintenance phase will start.  If the 
patient is still on study, dexamethasone will be discontinued.
Patients With RRMM (Arm C)
For patients with RRMM, dexamethasone will be given as a weekly oral 
dose of 40 mg on Days 1, 8, 15, and 22 of a 28-day cycle.  Patients older 
than 75 years of age at the time of enrollment will receive the reduced 
dose of dexamethasone 20 mg on the same weekly schedule.  
All Patients (Arms A, B, and C)
For all 3 treatment arms, it is recommended that dexamethasone be taken 
in the morning and at approximately the same time each dosing day.  
Dexamethasone should be taken with solid food or milk.  
Missed doses can be taken within 48 hours from the planned dose.  If more 
than 48 hours have elapsed, the missed dose should be skipped, and the next 
dose taken according to the regular dosing schedule.  A double dose should 
not be taken to make up for a missed dose.  If the patient vomits after taking 
a dose, the patient should not repeat the dose but should resume dosing at the 
time of the next scheduled dose.
Purpose:  Clarify the study enrollment guidelines for the 3 treatment arms
The change occurs in Section 6.2, Safety Lead-in:  
Formerly 
read:
6.2   Safety Lead-in
A safety evaluation will be performed after at least 6 safety lead-in evaluable 
patients have had the opportunity to complete at least 1 cycle of treatment in 
each arm.  Toxicities observed in the first 6 safety lead-in evaluable patients 
from each arm will be used to determine the safety and overall tolerability of 
the regimen and the feasibility of continued recruitment to the study.
…
6.2.2   Rules for Continuous Study Enrollment
A tolerable dose will require first-cycle DLTs (Section 6.3.1) in no more 
than 1 of 6 safety lead-in evaluable patients enrolled at a specific dose level.
When 2 of 6 safety lead-in patients experience DLTs (Section 6.3.1) in 
1 treatment arm and no more than 1 of 6 DLT-evaluable patients experience 
DLTs in the other arm, depending on the overall safety profile and the type 
of AEs/DLTs observed in both treatment arms, the decision will be made to 
either stop enrollment in that treatment arm or expand that treatment arm 
with 6 additional patients.  A tolerable dose will then require first-cycle 
DLTs in no more than 3 of 12 safety lead-in evaluable patients in the 
expanding treatment arm to proceed with enrollment.
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evaluable patient has been enrolled, (or the 12th lead-in patient in the case of 
expansion) and has had the opportunity to complete Cycle 1.  After the 
safety lead-in evaluation, if a treatment arm is stopped, enrollment in the 
other arm will continue.
If the decision is made to stop both treatment arms, enrollment in the entire 
study will either stop or alternative dosing levels may be evaluated following 
discussion between the sponsor and the investigators.  
Now reads:
6.2   Safety Lead-in
A safety evaluation will be performed after at least 6 safety lead-in evaluable 
patients have had the opportunity to complete at least 1 cycle of treatment in 
each of the 3 treatment arms (Arms A, B, and C).  Toxicities observed in 
the first 6 safety lead-in evaluable patients from each of the 3 treatment
arms will be used to determine the safety and overall tolerability of the 
regimen in the 2 patient populations (patients with NDMM assigned to 
Arm A or Arm B and patients with RRMM enrolled in Arm C) and the 
feasibility of continued recruitment to the study.
…
6.2.2   Rules for Continuous Study Enrollment
For each of the 3 treatment arms, a tolerable dose will require first-cycle 
DLTs (Section 6.2.1) in no more than 1 of 6 safety lead-in evaluable patients 
in that treatment arm.
For patients with NDMM, when 2 of 6 safety lead-in patients experience 
DLTs (Section 6.2.1) in 1 treatment arm and no more than 1 of 6 DLT-
evaluable patients experience DLTs in the other arms, depending on the 
overall safety profile and the type of AEs/DLTs observed in the treatment 
arms, the decision will be made to either stop enrollment in that treatment 
arm or expand that treatment arm with 6 additional patients.  A tolerable 
dose will then require first-cycle DLTs in no more than 3 of 12 safety lead-in 
evaluable patients in the expanding treatment arm to proceed with 
enrollment.
Enrollment in any of the 3 treatment arms (NDMM and RRMM) will be 
held until the 6th patient has had the opportunity to complete Cycle 1, if 
a DLT occurs in 1 of the first 5 patients enrolled in that arm.  Accrual to 
a treatment arm will also be stopped if any of the first 5 patients 
experience AEs, which may not qualify as DLTs per protocol-defined 
criteria, but the project clinician believes that it is in the interest of 
patient safety to hold enrollment until all 6 patients complete Cycle 1.  If 
the first 5 patients complete Cycle 1 without any DLTs being observed, 
enrollment may continue in that treatment arm and will not need to be 
held until the 6th patient completes Cycle 1, provided that the regimen is 
being tolerated and no safety concerns are identified.  Enrollment in 
each treatment arm will occur independently, so that accrual of patients 
to any of the 3 treatment arms can proceed even if enrollment is being 


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held in another treatment arm.  In addition, patients previously enrolled 
in the treatment arm in which accrual is being held will have the 
opportunity to continue to receive the study drug regimen as long as it is 
being well tolerated and no safety concerns are identified in those 
patients.  Randomization is required only when patients are being 
enrolled in Arms A and B concurrently.  
After the safety lead-in evaluation, if 1 of the treatment arms for 
patients with NDMM is stopped, enrollment in the other arm will 
continue.  If the decision is made to stop both treatment arms (Arms A and
B), enrollment in the entire study, including accrual of patients to
treatment Arm C may be stopped or alternative dosing levels for all 
3 treatment arms may be evaluated following discussion between the 
sponsor and the investigators.  If after the safety lead-in evaluation, 
accrual to Arm C is stopped, enrollment in the other 2 treatment arms
may continue and alternate dose schedules may be explored for Arm C,
following discussion between the sponsor and investigators.  
Purpose:  Describe and/or clarify the dose modification guidelines for the 3 treatment arms.  
The change occurs in Section 6.3, Dose Modification Guidelines:
Formerly 
read:  
The same dose modification guidelines will apply to maintenance cycles
unless otherwise noted.
Now reads:  
The same dose modification guidelines will apply during the maintenance 
phase for patients with NDMM (Arms A and B) who are receiving
MLN9708, unless otherwise noted
Sections that also contain this change are:

Section 6.3.2, Criteria for Selection and Timing of Dose Modification (Delays, 
Reductions, and Discontinuations)

Section 6.3.3, Permitted Dose Level Reductions

Section 6.3.4, Dose Adjustments for Hematologic Toxicity:  MLN9708 and 
Cyclophosphamide, Table 6-4, Dose Adjustments for Neutropenia
Purpose:  Clarify the permitted medications and procedures for patients in the 3 treatment 
arms
The change occurs in Section 6.5, Permitted Concomitant Medications and Procedures: 
Formerly 
read:  
Myeloid growth factors (eg, G-CSF, granulocyte macrophage-colony
stimulating factor [GM-CSF]) are not allowed during Cycle 1 for the safety 
lead-in patients in Arm A and Arm B, but may be considered according to 
standard clinical practice in Cycle 2 and beyond during the induction phase.  
Prophylactic antibiotics are not allowed during Cycle 1 for the safety lead-in 
patients in Arm A and Arm B, but may be considered according to standard 


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clinical practice in Cycle 2 and beyond during the induction phase.  No 
prophylactic antibiotics should be administered during maintenance.
Now reads:  
Myeloid growth factors (eg, G-CSF, granulocyte macrophage-colony 
stimulating factor [GM-CSF]) are not allowed during Cycle 1 for the safety 
lead-in patients, but may be considered according to standard clinical 
practice in Cycle 2 and beyond during the induction phase for patients in
Arms A and B, and in Cycle 2 and beyond during the treatment period 
for patients in Arm C.  Prophylactic antibiotics are not allowed during 
Cycle 1 for the safety lead-in patients, but may be considered according to 
standard clinical practice in Cycle 2 and beyond during the induction phase 
for patients in Arms A and B, and during the treatment period for 
patients in Arm C.  No prophylactic antibiotics should be administered 
during maintenance for patients in Arms A and B.  
Purpose:  Revise and update the subheading pertaining to infection and add transverse 
myelitis to the discussion of clinical events for MLN9708
The change occurs in Section 6.7, Management of Clinical Events
Added text:  
Prophylaxis Against Risk of Reactivation of Herpes Infection
Transverse Myelitis
Transverse myelitis has been reported in a patient who was receiving
MLN9708.  It is not known whether MLN9708 causes transverse
myelitis.  However, because it was reported in a patient who was
receiving MLN9708, the possibility that MLN9708 may have
contributed to transverse myelitis cannot be excluded.  Transverse
myelitis should be managed according to standard medical practice.
Purpose:  Revise the description of capsule sizes and capsule colors for MLN9708 to align 
with the certificate of analysis provided by the manufacturer
The change occurs in Section 6.9, Description of Investigational Agents, Table 6-8, 
MLN9708 Capsules:
Formerly 
read:
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
Now reads:
Dose Strength
Capsule Size
Capsule Color
4.0 mg
Size 3
Ivory 
3.0 mg
Size 4
Light gray
2.3 mg
Size 4
Flesh


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Purpose:  Clarify MLN9708 preparation, reconstitution, and dispensation guidelines
The change occurs in Section 6.9.1, MLN9708 Preparation, Reconstitution, and 
Dispensation:  
Deleted text:  MLN9708 is an anticancer drug and, as with other potentially toxic 
compounds, caution should be exercised when handling MLN9708 capsules.  
Purpose:  Clarify the storage, handling, and accountability requirements for MLN9708
The change occurs in Section 6.9.3, MLN9708 Storage, Handling, and Accountability:  
Formerly 
read:
MLN9708 capsules dispensed to the patient for take-home dosing should 
remain in the blister packaging and carton and refrigerated as noted 
previously until the point of use.  Comprehensive instructions should be 
provided to the patient to ensure compliance with dosing procedures.  
Patients who are receiving take-home medication should be given only 
1 cycle of medication at a time.  Patients should be instructed to store the 
medication refrigerated (36°F to 46°F, 2°C to 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.  
Now reads:
MLN9708 capsules dispensed to the patient for take-home dosing should 
remain in the blister packaging and carton and refrigerated as noted 
previously until the point of use.  Comprehensive instructions should be 
provided to the patient to ensure compliance with dosing procedures.  
Patients should be instructed to store the medication refrigerated (36°F to 
46°F, 2°C to 8°C).  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 to the clinic.  Any extreme 
in temperature should be reported as an excursion and should be dealt with 
on a case-by-case basis.
Because MLN9708 is an anticancer drug, as with other potentially toxic 
compounds, caution should be exercised when handling the study drug.  


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Purpose:  Clarify and/or define treatment assignments for the 3 treatment arms
The change occurs in Section 7.3, Treatment Group Assignments:
Formerly 
read:
After written informed consent has been obtained, patients will be 
randomized in a 1:1 ratio to either Arm A or Arm B. A centralized
randomization using interactive voice response system (IVRS) will be used.  
If a patient discontinues from the study, that randomization code will not be 
reused, and the patient will not be allowed to re-enter the study.
Now reads:
After written informed consent has been obtained, patients with NDMM will 
be randomized 1:1 to either Arm A or Arm B.  Patients with RRMM will
be assigned to Arm C.  A centralized interactive web response system
(IWRS) will be used for randomization and enrollment of all patients.  If 
a patient with NDMM discontinues from the study, the randomization code 
for that patient will not be reused.  No patient will not be allowed to 
re-enter the study after discontinuing from the study.  
Purpose:  Clarify timing for performing study procedures
The change occurs in Section 7.4, Study Procedures:
Formerly 
read:  
Tests and procedures should be performed on schedule, but occasional 
changes may be allowed (± 2 days) for holidays, vacations, and other 
administrative reasons.
Now reads:  
Tests and procedures should be performed on schedule, but occasional 
changes may be allowed (± 3 days) for holidays, vacations, and other 
administrative reasons.
The Schedule of Events also contains this change.  
Purpose:  Clarify that assessment of comorbid conditions pertains to patients with NDMM 
only (Arms A and B)
The change occurs in Section 7.4.4, Assessment of Comorbid Condition(s) – Arms A and B:
Added text:  
Assessment of Comorbid Condition(s) – Arms A and B
During the Screening period, an assessment of comorbid condition(s) is to be 
conducted for patients with NDMM only.


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Purpose:  Clarify the guidelines for monitoring of peripheral neuropathy (PN) and 
PN-related events for the 2 patient populations
The primary change occurs in Section 7.4.11, Adverse Events:  
Formerly 
read:  
Note that in this study, PN will be captured in the same manner as all other 
adverse events during the induction and maintenance periods, with the 
exception that downgrading of PN events must be reported until 1) 
resolution, 2) the start of a second-line alternative antineoplastic treatment, 
or 3) 6 months after treatment discontinuation, whichever occurs first.
Now reads:  
Note that in this study, PN will be captured in the same manner as all other 
adverse events during the induction and maintenance phases for patients in 
Arms A and B and the treatment period for patients in Arm C, with the 
exception that downgrading of PN events must be reported until 1) 
resolution, 2) the start of a second-line alternative antineoplastic treatment, 
or 3) 6 months after treatment discontinuation, whichever occurs first.
Section 9.1.5, Monitoring of Adverse Events and Period of Observation, also contains this 
change.  
Purpose:  Revise the definition of enrollment in the study for the 3 treatment arms
The change occurs in Section 7.4.12, Enrollment:
Formerly 
read:  
A patient is considered to be enrolled in the study when the patient has been 
randomized to study treatment.  
Now reads:  
A patient is considered to be enrolled in the study when the patient is
assigned to 1 of the 3 treatment arms in the study.
Purpose:  Clarify the guidelines for clinical laboratory evaluations
The change occurs in Section 7.4.13, Clinical Laboratory Evaluations:  
Formerly 
read:  
Clinical laboratory evaluations will be performed by a central laboratory.  
For patients eligible for take home dosing, labs may be collected locally with 
the exception of Day 1 of each cycle.  For dosing decisions, local 
hematology and chemistry laboratory results may be used.  
Now reads:  
Clinical laboratory evaluations will be performed by a central laboratory.  
For dosing decisions, local hematology and chemistry laboratory results may 
be used; however, samples must still be sent to the central laboratory for 
evaluation.  


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Purpose:  Clarify the procedure for performing the skeletal survey at screening
The change occurs in Section 7.4.15, Skeletal Survey:  
Formerly 
read:  
A complete skeletal survey, using roentgenography, will be performed at 
screening (within 8 weeks prior to randomization), once annually, and if at 
any time the physician believes there are symptoms or signs that suggest 
increased or new bone lesions.  
Now reads:  
A complete skeletal survey, using conventional X-ray, will be performed at 
screening (within 8 weeks prior to enrollment), once annually, and if at any 
time the physician believes there are symptoms or signs that suggest 
increased or new bone lesions.
Purpose:  Clarify that the blood sample for genotyping is optional and not required for 
study enrollment
The change occurs in Section 7.4.18, Blood Sample for Genotyping:
Added text:  
This blood sample is optional and is not required for enrollment in the 
study.
Purpose:  Revise and clarify disease response assessments for the 3 treatment arms
The change occurs in Section 7.4.24, Disease Response Assessment:  
Formerly 
read:  
Response assessments should occur at the times outlined in the Schedule of
Events.  
…
At any point during treatment (induction or maintenance), patients suspected 
of having PD will have response assessments repeated to confirm disease 
progression (ie, 2 sets of response assessments at least 1 week apart; local 
laboratory assessment is permitted).  
Now reads:  
Response assessments should be performed at the times outlined in the 
Schedule of Events.
…
At any point during treatment, patients for whom disease progression is
suspected will have response assessments repeated to confirm the
assessment (local laboratory assessment is permitted).  


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Purpose:  Add description of health care utilization assessments
The change occurs in Section 7.4.25, Health Care Utilization Assessments:
Added text:
Health care utilization data will also be collected for all patients as
specified in the Schedule of Events.  Examples of data to be collected are
the number, duration, and type of medical care encounters, such as
inpatient admissions, outpatient visits, the accompanying reason for the
visit (eg, medication, procedure, an AE), and homecare.  In addition, the
number is also captured of missed work days or other activities for the
patient and patient’s caregiver.
Purpose:  Clarify follow-up assessments for progression-free survival and SAE reporting 
during follow-up
The change occurs in Section 7.4.26, Follow-up Assessments (Progression-Free Survival):  
Formerly 
read:  
The PFS follow-up visits should occur every 8 weeks from EOT until the 
occurrence of PD/death, the patient withdraws consent for further follow-up, 
or the initiation of alternative antineoplastic therapy.  All subsequent 
antineoplastic therapies will be recorded, regardless if they are initiated 
before or after PD.
…
In addition, new primary malignancies that occur during the follow-up 
periods, irrespective of causality to study regimen, must be reported to the 
Millennium Department of Pharmacovigilance or designee.
Now reads:  
The PFS follow-up visits should occur every 8 weeks from EOT until the 
occurrence of progressive disease or death, or the patient withdraws 
consent for further follow-up.
…
In addition, new primary malignancies that occur during the follow-up 
periods, irrespective of causality to study regimen, must be reported to the 
Millennium Department of Pharmacovigilance & Risk Management or 
designee through death or termination of the study by the sponsor.


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Purpose:  Describe and/or clarify the statistical considerations to determine sample size for 
the 2 patient populations (NDMM and RRMM)
The change occurs in Section 8.1.1, Determination of Sample Size:
Formerly 
read:  
The sample size in is calculated using 1 group Chi-square test for each arm 
separately based on the CR + VGPR rate following a MLN9708 combined 
treatment regimen.  With 31 response-evaluable patients, there will be 80% 
power to test a null hypothesis CR + VGPR rate of 27% and an alternative 
hypothesis CR + VGPR rate of 45% at 1-sided significant level of α = 0.10.  
Therefore, assuming 10% of patients are not response evaluable, 
approximately 35 patients per arm (70 total) will be enrolled in this study.
Now reads:  The total sample size for the study will be approximately 148 patients.  
Approximately 70 patients with NDMM will be randomized 1:1 to
Arm A or Arm B and approximately 78 patients with RRMM will be 
enrolled in Arm C.  
For patients with NDMM (Arms A and B), the sample size is calculated by
using 1 group Chi-square test for each arm separately based on the 
CR + VGPR rate following a MLN9708 combined treatment regimen.  With 
31 response-evaluable patients per treatment arm, there will be 80% power 
to test a null hypothesis CR + VGPR rate of 27% and an alternative 
hypothesis CR + VGPR rate of 45% at 1-sided significant level of α = 0.10.  
Therefore, assuming 10% of patients are not response evaluable, 
approximately 35 patients each (70 total) will be enrolled in these
2 treatment arms.
For patients with RRMM (Arm C), the sample size is calculated by using
1 group Chi-square test for each arm separately based on the ORR rate
following a MLN9708 combined treatment regimen.  With
71 response-evaluable patients in Arm C, there will be 80% power to test
a null hypothesis ORR rate of 60% and an alternative hypothesis ORR
rate of 72% at 1-sided significant level of α = 0.10.  Therefore, assuming
10% of patients are not response evaluable, approximately 78 patients
will be enrolled in Arm C in this study.


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Purpose:  Revise and clarify the randomization or enrollment process for the 3 treatment 
arms
The change occurs in Section 8.1.2, Randomization and Stratification:  
Formerly 
read:  
This study will use a central (ie, not center-specific) randomization ratio of 
1:1 to Arm A or Arm B.
Now reads:
This study will use a central (ie, not center-specific) randomization ratio of 
1:1 to assign patients to Arm A or Arm B.  Randomization is not required if 
accrual to either Arm A or Arm B is stopped.  No randomization will be 
used for patients in Arm C but an IWRS will be used for enrollment.
Purpose:  Revise the description of analysis populations
The change occurs in Section 8.1.3, Populations for Analysis:  
Formerly 
read:  

Safety Population:  Patients who receive at least 1 dose of any study 
drug.  The safety population will be used for safety analyses.  The safety 
population will be used for the analyses of TTP and PFS.

DLT-Evaluable Population:  Patients in the safety lead-in cohort who 
receive all doses of MLN9708 and cyclophosphamide during Cycle 1 
per the Schedule of Events, or experience a DLT in Cycle 1.  
Now reads:

Safety Population:  Patients who receive at least 1 dose of any study 
drug.  The safety population will be used for safety analyses.  It will 
also be used for the analyses of TTP, PFS, QOL, and health care 
utilization data.

DLT-Evaluable Population:  Patients in the safety lead-in cohort who 
receive all doses of MLN9708 and at least 80% of the
cyclophosphamide dose during Cycle 1 per the Schedule of Events, or 
experience a DLT in Cycle 1.  
Purpose:  Revise the proposed pooling of the study data and presentation of study results 
for the 3 treatment arms
The primary change occurs in Section 8.1.5, Demographic and Baseline Characteristics:  
Formerly 
read:  
Demographic and baseline characteristics will be summarized by treatment 
arm and by total, including gender, age, race, weight, height, BSA, primary 
diagnosis, and other parameters as appropriate.  
Now reads:  Demographic and baseline characteristics will be summarized for each 
treatment arm and by the total of Arms A and B, including gender, age, race, 
weight, height, BSA, primary diagnosis, and other parameters as appropriate.


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Sections that also contain this change are:

Section 8.1.6.2, Secondary Efficacy

Section 8.1.7, Analyses of Patient-Reported Outcomes

Section 8.1.8, Analysis of Health Care Utilization Data

Section 8.1.10, Safety Analysis

Section 8.1.10.1, Peripheral Neuropathy Events

Section 8.1.10.2, Drug Exposure of MLN9708, Cyclophosphamide, and 
Dexamethasone.
Purpose:  Add text to clearly delineate the primary efficacy endpoint for the 2 patient 
populations
The change occurs in Section 8.1.6.1, Primary Efficacy:  
Added 
text:  
For patients with NDMM (Arms A and B), the primary endpoint is the 
CR + VGPR rate during the induction phase.  For patients with RRMM
(Arm C), the primary endpoint is ORR.  
The primary efficacy analysis will be based on the response-evaluable 
population (patients enrolled in the safety lead-in portion are included).  
Estimates of the CR + VGPR rates for Arms A and B, and ORR for Arm C
will be presented with 2-sided 95% exact binomial confidence intervals (CIs).  
Purpose:  Revise and update the description of secondary study endpoints
The change occurs in Section 8.1.6.2, Secondary Efficacy:  
Formerly 
read:
The secondary efficacy parameters include the ORR (CR + VGPR + PR), CR, 
VGPR, PR, time to response, DOR, TTP, PFS, and the change from baseline 
in QOL.  
Now 
reads:
The secondary efficacy endpoints include ORR (Arms A and B only), 
CR + VGPR (Arm C only), CR, VGPR, PR, time to response, DOR, TTP, 
PFS, and the change from baseline in QOL.
Purpose:  Describe the analysis of health care utilization data
The change occurs in Section 8.1.8, Analysis of Health Care Utilization Data:  
Added 
text:  
Analyses of health care utilization data will be performed using the safety
population and summarized for each treatment arm and by the total of 
Arm A + Arm B 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 caregiver.  


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Purpose:  Revise and update the description of safety analysis
The primary change occurs in Section 8.1.10, Safety Analysis:
Formerly 
read:
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.  
Now 
reads:
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 and summarized for each
treatment arm and by the total of Arm A + Arm B.
Purpose:  Revise the description of assessments pertaining to drug exposure
The change occurs in Section 8.1.10.2, Drug Exposure of MLN9708, Cyclophosphamide, 
and Dexamethasone:  
Formerly 
read:
The total doses received, number of treatment cycles, number of doses, and 
dose intensity of MLN9708, cyclophosphamide, and dexamethasone will be 
presented and summarized.  
Now 
reads:
Treatment duration, number of treatment cycles, number of doses, the total
doses received and dose intensity of MLN9708, cyclophosphamide, and 
dexamethasone will be summarized for each treatment arm and for the total
of Arms A and B.
Purpose:  Revise and update stopping rules for patients in the 3 treatment arms
The change occurs in Section 8.1.11, Interim Analysis:
Formerly 
read:
No formal interim analysis is planned.  However, both safety and efficacy will 
be continuously monitored.  Grade 4 or greater nonhematological toxicities 
will be monitored for each arm starting from the first 12 enrolled patients and 
then every 6 additional enrolled patients based on a Bayesian monitoring 
strategy.(37)  If the stopping bounds of ≥4/12, ≥6/18, ≥7/24, and ≥8/30 have 
been achieved, accrual to the study will be suspended to allow for 
investigation.  After consideration by the study team, a decision will be made 
as to whether accrual can be resumed.  If the stopping rule is met, there is at 
least 80% probability that the true toxicity rate will be greater than 18%.
Similarly, the efficacy will be monitored for each arm starting from the first 
12 response evaluable patients after 6 cycles of treatment and then every 
6 additional response evaluable patients by the Bayesian Predictive Probability 
method.  
If the futility stopping bounds (CR + VGPR) of ≤2/12, ≤4/18, ≤7/24, and 


MLN9708
Clinical Study Protocol C16020 Amendment 1, EudraCT Number:  2013-003113-17 
147
≤10/30 have been met, further investigation will be made by the study team to 
assess if either arm may be terminated due to futility.
Now 
reads:
No formal interim analysis is planned.  However, both safety and efficacy will 
be continuously monitored on the basis of prespecified stopping rules.  
Grade 4 or higher nonhematological toxicities will be monitored for each arm 
starting from the first 12 enrolled patients and then every 6 additional enrolled 
patients based on a Bayesian monitoring strategy.(37)  If the stopping bounds of 
≥4/12, ≥6/18, ≥7/24, and ≥8/30 for Arms A and B (patients with NDMM), 
or the stopping bounds of ≥4/12, ≥6/18,≥7/24, ≥8/30, ≥9/36, ≥11/42, 
≥12/48, ≥13/54, ≥14/60, ≥15/66, and ≥16/72 for Arm C (patients with 
RRMM) have been achieved, accrual to the study will be suspended to allow 
for investigation.  If the stopping rule is met, there is at least 80% probability 
that the true toxicity rate will be greater than 18%.  After consideration by 
the study team, a decision will be made as to whether accrual can be 
resumed.  
The efficacy will be monitored by the Bayesian Predictive Probability method 
starting from the first 12 response-evaluable patients after 6 cycles of 
treatment and then every 6 additional response evaluable patients for 
Arms A and B or every 12 additional response-evaluable patients for 
Arm C.  If the futility stopping bounds (CR + VGPR) of ≤2/12, ≤4/18, 
≤7/24, and ≤10/30 for Arms A and B, or the stopping bounds (ORR) of 
≤3/12, ≤10/24, ≤18/36, ≤26/48, and ≤36/60 for Arm C have been met, 
further investigation will be made by the study team to assess if accrual to
any of the 3 treatment arms may be terminated due to futility.  These futility 
stopping rules are established to allow no larger than 0.15 overall type I
error rate (one-sided) and still maintain power of approximately 80%.
Purpose:  Update the SAE Reporting contact information to align with the sponsor’s 
current guidelines and practices
The primary change occurs in Section 9.1.4, Procedures for Recording and Reporting 
Adverse Events and Serious Adverse Events:
Formerly 
read:
SAE Reporting Contact Information
(North & South America):
24-hour helpline:  
Fax:  
 (all other countries):
24-hour helpline:  
Fax:  


MLN9708
Clinical Study Protocol C16020 Amendment 1, EudraCT Number:  2013-003113-17 
148
Now 
reads:  
SAE Reporting Contact Information
Cognizant
US and Canada:
Toll-Free Fax #: 
E-mail:  
All other countries (Rest of World):
Fax #: 
E-mail:  
Section 10.11, Product Complaints, also contains this change.
Purpose:  Revise and update reporting requirements for new malignancies
The change occurs in Section 9.1.5, Monitoring of Adverse Events and Period of 
Observation:
Formerly 
read:
In addition, all cases of new primary malignancy will be immediately reported 
to the Millennium Department of Pharmacovigilance & Risk Management or 
designee, in compliance with regional governing regulations.  
Now 
reads:  
In addition, new primary malignancies that occur during the follow-up
periods must be reported, irrespective of causality to the study drug, from
the first dose of study drug through death, until termination of the study
by the sponsor, or for a minimum of 3 years after the last dose of the
investigational product, whichever comes first.
Purpose:  Add a Schedule of Events for patients enrolled in Arm C (patients with RRMM)
The change occurs in the Schedule of Events:  Arm C (RRMM)
Summary 
of change:
Two tables were added:  Schedule of Events:  Arm C (RRMM) and Study 
Drug Regimen Administration:  Arm C (RRMM).  
Purpose:  Revise and update footnotes in the Schedule of Events to clarify study procedures
The change occurs in the Schedule of Events:  Arms A and B (NDMM)
Formerly 
read:  
Tests and procedures should be performed on schedule, but occasional changes 
may be allowed (± 2 days) for holidays, vacations, and other administrative 
reasons.  
…
a  Evaluations during the Screening period are to be conducted within 28 days 
before randomization, unless otherwise noted.  


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149
b  During induction and maintenance, there will be a 2-day window for study 
visits unless otherwise noted.  
…
g  Body surface area (BSA) will be recalculated during induction for dosing 
purposes if a subject experiences a > 5% change in weight from the weight 
used in the most recent BSA calculation.
…
o  To be performed prior to dosing during induction, every other cycle during 
maintenance starting with Cycle 14, at EOT, and during PFS follow-up.
Now 
reads:  
Tests and procedures should be performed on schedule, but occasional changes 
may be allowed (± 3 days) for holidays, vacations, and other administrative 
reasons.  
…
a  Evaluations during the Screening period are to be conducted within 28 days 
before randomization, unless otherwise noted.  The date of randomization or 
enrollment should be within 7 days of Cycle 1, Day 1 (C1D1).
b  During induction and maintenance, there will be a 3-day window for study 
visits unless otherwise noted.
…
g  To assess MM-related symptoms and TEAEs.  
h  Body surface area (BSA) will be calculated at C1D1 and at any
subsequent visit that the patient experiences a > 5% change in weight from 
the weight used for the most recent BSA calculation.
…
n  Patient-reported outcomes assessments and health care utilization
assessments should be completed before any other study procedures are
performed and before the study drug regimen is administered.
…
q  To be performed prior to dosing during induction, every other cycle during 
maintenance starting with Cycle 14, at EOT, and during PFS follow-up.  Note:  
The collection of these samples is required to be repeated at C1D1 only if 
the collection during screening was done 14 days before the first dose of 
the study drug regimen.  Serum-only patients will have 24-hour urine 
collected for UPEP and urine immunofixation at screening, noted 
complete response (CR) or progressive disease (PD), and at EOT.  All 
other patients should have the M-component quantification by UPEP and 
urine immunofixation performed prior to dosing in every cycle in 
induction and every other cycle during the maintenance phase starting 
with Cycle 14, at EOT, and during PFS follow-up.


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150
Purpose:  Add health care utilization assessments to the Schedule of Events (NDMM)
The change occurs in Schedule of Events:  Arms A and B (NDMM)
Summary 
of change:  
A row for Health Care Utilization Assessment was added to the Schedule of 
Events.  
Purpose:  Revise table title for the PK sampling schedule to include all 3 treatment arms
The change occurs in the Schedule of Events, Pharmacokinetic Sampling Schedule for All 
Patients in Safety Lead-In:  
Added 
text:
Pharmacokinetic Sampling Schedule for All Patients in Safety Lead-In
(Arms A, B, C)
Purpose:  Revise and update the timing of predose PK assessments
The change occurs in Pharmacokinetic Sampling Schedule for All Patients in Safety Lead-
In (Arms A, B, C), footnote a:  
Formerly 
read:
a  Predose PK assessments should occur within 1 hour of dosing.
Now reads:
a  Predose PK assessments should occur within 2 hours before dosing
Purpose:  Correct typographical errors, punctuation, grammar, and formatting
These changes are not listed individually.


 
 
 
 
 
 
 
 
ELECTRONIC SIGNATURES 
 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
An Open-Label, Phase 2 Study to Evaluate the Oral Combination of MLN9708 With
Cyclophosphamide and Dexamethasone In Patients With Newly Diagnosed or Relapsed
and/or Refractory Multiple Myeloma Requiring Systemic Treatment.
Clinical VP Approval
 18:46
Clinical Approval
 19:11

SAP_000.pdf: 


• Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: An Open-Label, Phase 2 Study to Evaluate the Oral Combination of MLN9708 with 
Cyclophosphamlde and Dexamethasone in.Patients with Newly Diagnosed Multiple Myeloma 
or Relapsed antVor Refractory Muµiple Myeloma Requiring Systemic Treatment 
NCT Number: NCT02046070
SAP Approve Date: 22Aug 2016
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable (PPD) information 
or company confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.


MLN9708 
Statistieal Analysis Plan Study C16020 
STATISTICAL ANALYSIS PLAN 
An Open-Label, Phase 2 Study to Evaluate the Oral Combination of MLN9708 with 
C,clophosphamlde and Dexamethasone in.Patients with Newly Diagnosed Multiple 
Myeloma or Relapsed antVor Refractory Muµiple Myeloma Requiring Systemic 
Treatment 
SAP Version: 
Final 
Date 
Date 
Date 
Confidential 
Protocol#: C16020 Amendment 1 
Date of Statistical Analysis Plan: 
22Aug2016 
Approval Signatures 
1 






MLN9708
Statistical Analysis Plan Study C16020
2
TABLE OF CONTENTS
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.........................................4
1. INTRODUCTION............................................................................................................8
1.1 Study Design..............................................................................................................8
1.2 Study Objectives ........................................................................................................9
1.2.1 Primary Objectives ..............................................................................................9
1.2.2 Secondary Objectives...........................................................................................9
1.2.3 Exploratory Objectives ......................................................................................11
2. POPULATIONS FOR ANALYSIS................................................................................11
2.1 Safety Population .....................................................................................................11
2.2 DLT-Evaluable Population.......................................................................................12
2.3 Response-Evaluable Population................................................................................12
2.4 Pharmacokinetic Analysis Population.......................................................................12
3. HYPOTHESES AND DECISION RULES.....................................................................12
4. INTERIM ANALYSIS...................................................................................................13
4.1 Safety Lead-in Evaluation ........................................................................................13
4.2 Continuous Monitoring and Early Stopping Rule......................................................13
5. STATISTICAL METHODOLOGY ...............................................................................14
5.1 Sample Size Justification..........................................................................................14
5.2 Randomization and Stratification..............................................................................15
5.3 Unblinding ...............................................................................................................15
5.4 Data Handling ..........................................................................................................15
5.4.1 Methods for Handling Missing Data...................................................................15
5.4.2 Definition of Baseline Values ............................................................................19
5.4.3 Windowing of Visits..........................................................................................19
5.4.4 Justification of Pooling ......................................................................................19
5.4.5 Withdrawals, Dropouts, Lost to Follow-up.........................................................19
5.4.6 General Conventions for Determining Duration .................................................19
5.5 Patient Disposition ...................................................................................................20
5.6 Demographics and Baseline Characteristics..............................................................20
5.6.1 Demographics....................................................................................................20
5.6.2 Disease Specific History ....................................................................................20
5.6.3 Baseline Disease Characteristics ........................................................................21
5.6.4 Extent of Disease and Bone Marrow Cytogenetic Results at Baseline ................21
5.6.5 General Medical History....................................................................................22
5.7 Treatments and Medications .....................................................................................22
5.7.1 Concomitant Medications and Procedures..........................................................22
5.7.2 Study Treatments...............................................................................................22
5.8 Efficacy Analyses.....................................................................................................24
5.8.1 Primary Efficacy Endpoints ...............................................................................24
5.8.2 Secondary Efficacy Endpoints ...........................................................................24
5.8.3 Exploratory Efficacy Endpoints Analysis...........................................................25
5.9 Analysis of Health Care Utilization Data ..................................................................28
5.10 Pharmacokinetic, Pharmacodynamic.......................................................................28


MLN9708
Statistical Analysis Plan Study C16020
3
5.10.1 Pharmacokinetic Analyses ...............................................................................28
5.10.2 Pharmacodynamic Analyses.............................................................................30
5.11 Safety Analyses ......................................................................................................30
5.11.1 Adverse Events................................................................................................30
5.11.2 Laboratory Data...............................................................................................34
5.11.3 Vital Signs .......................................................................................................35
5.11.4 Electrocardiograms ..........................................................................................35
5.11.5 Eastern Cooperative Oncology Group Performance Status ...............................36
5.11.6 Other Safety Assessments ................................................................................36
6. CHANGES TO PLANNED ANALYSES FROM PROTOCOL .....................................36
7. PROGRAMMING CONSIDERATIONS .......................................................................36
7.1 Statistical Software...................................................................................................36
7.2 Rules and Definitions ...............................................................................................36
8. REFERENCES...............................................................................................................36


MLN9708
Statistical Analysis Plan Study C16020
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
5-HT3
5-hydroxytryptamine 3 serotonin receptor
AE
adverse event
ALL
acute lymphoblastic leukemia
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AML
acute myelogenous leukemia
ANC
absolute neutrophil count
API
active pharmaceutical ingredient
aPTT
activated partial thromboplastin time
Ara-C
Cytarabine
ASCO
American Society of Clinical Oncology
ASCT
autologous stem cell transplant 
AST
aspartate aminotransferase
AUC
area under the plasma concentration versus time curve
BCRP
breast cancer resistance protein
hCG
beta-human chorionic gonadotropin
BID
bis in die; twice a day
BM
bone marrow
BSA
body surface area
BUN
blood urea nitrogen
BZD
Benzodiazepines
CBC
complete blood count
CFR
Code of Federal Regulations
Cmax
single-dose maximum (peak) concentration  
CNS
central nervous system
CO2
carbon dioxide
CR
complete response   
CRM
continual reassessment method
CRP
C-reactive protein
CSF-1R
colony-stimulating factor 1 receptor
CT
computed tomography
CV
coefficient of variation or cardiovascular choose one
CYP
cytochrome P450
DLT
dose-limiting toxicity
DME
drug metabolizing enzymes
DNA
deoxyribonucleic acid
DOR
duration of response   
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group


MLN9708
Statistical Analysis Plan Study C16020
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
eCRF
electronic case report form
EDC
electronic data capture
ELISA
enzyme-linked immunosorbent assay
EORTC QLQ-C30
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire 
EOS
End of Study (visit)
EOT
End of Treatment (visit)
EU
European Union
FDA
United States Food and Drug Administration
GCP
Good Clinical Practice
G-CSF
granulocyte colony stimulating factor
GGT
gamma glutamyl transferase
GI
Gastrointestinal
GLP
Good Laboratory Practices
GM-CSF
granulocyte macrophage-colony stimulating factor
GMP
Good Manufacturing Practice
Hb
Hemoglobin
Hct
Hematocrit
HDPE
high-density polyethylene
HDT
high-dose therapy
hERG
human ether-à-go-go related gene
HIV
human immunodeficiency virus
HNSTD
highest nonseverely toxic dose
IB
Investigator’s Brochure
IC50
concentration producing 50% inhibition
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IMiD
immunomodulating drugs
inc
Including
IR
Immunophenotype
IRB
institutional review board
ITT
intent-to-treat
IV
intravenous; intravenously
IVRS
interactive voice response system
Ki
inhibition constant
KPS
Karnofsky Performance Status
LDH
lactate dehydrogenase
LFT
liver function test(s)
Ixazomib
Generic name of MLN9708


MLN9708
Statistical Analysis Plan Study C16020
6
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
Millennium
Millennium Pharmaceuticals, Inc., and its affiliates
MM
multiple myeloma
MRD
minimal residual disease
MRI
magnetic resonance imaging
MRU
medical resource utilization
MTD
maximum tolerated dose
MUGA
multiple gated acquisition (scan)
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 
NPO
nothing by mouth
nCR
nearly complete response
NYHA
New York Heart Association
ORR
overall response rate
OS
overall survival 
PBMC
peripheral blood mononuclear cell
PCR
polymerase chain reaction
PD
progressive disease (disease progression)
PFS
progression-free survival 
Pgp
P-glycoprotein
PK
pharmacokinetic(s)
PN
peripheral neuropathy
PO
per os; by mouth (orally)
POEMS
polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and 
skin changes
PR
partial response
PRO
patient-reported outcome
PSA
prostate-specific antigen
QD
quaque die; each day; once daily
QID
quater in die; 4 times a day
QOD
quaque altera die; every other day
QOL
quality of life
QTc
rate-corrected QT interval (millisec) of electrocardiograph
RBC
red blood cell
RECIST
Response Evaluation Criteria in Solid Tumors
RRAL
relapsed and/or refractory systemic light chain amyloidosis
RRMM
refractory multiple myeloma 
SAE
serious adverse event
SC
Subcutaneous


MLN9708
Statistical Analysis Plan Study C16020
7
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
sCR
stringent complete response
SCT
stem cell transplant 
SD
stable disease
SmPC
Summary of Product Characteristics
t1/2
terminal disposition half-life
TGI
tumor growth inhibition
Tmax
first time of occurrence of maximum (peak) concentration
TTP
time-to-progression 
UK
United Kingdom
ULN
upper limit of the normal range
US
United States
VGPR
very good partial response
VMP
VELCADE to melphalan and prednisone 
WBC
white blood cell
WHO
World Health Organization


MLN9708
Statistical Analysis Plan Study C16020
8
1.
INTRODUCTION
In general, the purpose of the statistical analysis plan (SAP) is to provide a framework that 
addresses the protocol objectives in a statistically rigorous fashion, with minimized bias or 
analytical deficiencies.  Specifically, this plan has the following purpose:
To prospectively (a priori) outline the types of analyses and data presentations that will 
address the study objectives outlined in the protocol, and to explain in detail how the data 
will be handled and analyzed, adhering to commonly accepted standards and practices of 
biostatistical analysis in the pharmaceutical industry.
1.1   
Study Design
This is an open-label, phase 2 study designed to evaluate the safety and efficacy of the 
combination of Ixazomib with cyclophosphamide (C) and dexamethasone (d) in patients 
with NDMM who have not received prior systemic treatment for multiple myeloma (MM) 
and are ineligible for high-dose therapy (HDT)-stem cell transplantation (SCT) due to age or 
comorbid disease(s), and in patients with RRMM who have received 1 to 3 lines of prior 
therapy and whose disease is not refractory to proteasome inhibitors.
Patients with NDMM will receive Ixazomib in combination with Cd for an induction phase 
up to approximately 1 year (13 28-day cycles) and, if at least stable disease has been 
reached with an acceptable toxicity profile after induction, patients will be administered, as 
maintenance, single-agent Ixazomib (at the dose tolerated at the end of induction) in 28-day 
treatment cycles until progressive disease (PD), death or unacceptable toxicity. Patients will 
be randomized 1:1 to either Arm A or Arm B, which have different doses of 
cyclophosphamide during induction period. During induction phase, each 28-day treatment 
cycle consists of oral Ixazomib(4.0 mg on Days 1, 8, and 15) administered in combination 
with cyclophosphamide (300 mg/m2 [Arm A] OR 400 mg/m2 [Arm B] both on Days 1, 8, 
and 15) and dexamethasone (40 mg on Days 1, 8, 15, and 22) all administered orally.
Patients over 75 years of age will receive a reduced dose of dexamethasone 20 mg on the 
same weekly schedule. During maintenance phase, each 28-day treatment cycle consists of
single agent oral Ixazomib(4.0 mg on Days 1, 8, and 15).
Patients with RRMM (Arm C) will receive Ixazomib 4.0 mg weekly on Days 1, 8, and 15, in 
combination with cyclophosphamide 300 mg/m2 on Days 1, 8, and 15, and dexamethasone 
40 mg on Days 1, 8, 15, and 22 of a 28-day cycle (all orally administered).  Patients over 


MLN9708
Statistical Analysis Plan Study C16020
9
75 years of age will receive a reduced dose of dexamethasone 20 mg on the same weekly 
schedule. Patients with RRMM will be enrolled to Arm C and treated until disease 
progression, death or unacceptable toxicity. No maintenance phase is planned for Arm C. 
For all three treatment arms, a safety lead-in evaluation will be performed after at least 
6 patients in each treatment arm have had the opportunity to complete at least 1 cycle of 
therapy.  DLTs observed in the first 6 patients in this treatment arm will be used to 
determine the safety and overall tolerability of the study regimen and the feasibility of 
continued recruitment of patients to the study.  
Patients will attend an End-of-Treatment (EOT) visit approximately 30 days after receiving 
their last dose of study drug. Patients who stop treatment for any reason other than PD will 
continue to have PFS follow-up visits. The PFS follow-up visits should occur every 8 weeks 
from EOT until the occurrence of PD or death, the patient withdraws consent for further 
follow-up, whichever comes first. 
The study will be conducted to fully characterize the safety, tolerability, efficacy, quality of 
life (QOL), and the pharmacokinetics (PK) of Ixazomib. 
1.2   
Study Objectives
1.2.1  Primary Objectives
The primary objective for patients with newly diagnosed multiple myeloma (NDMM) is:

To determine the combined response rate of complete response (CR) (including
stringent CR [sCR]) + very good partial response (VGPR) following treatment of
oral Ixazomib when added to a standard regimen of cyclophosphamide and low-dose
dexamethasone (Cd) during the induction phase.
The primary objective for patients with relapsed and/or refractory multiple myeloma 
(RRMM) is:

To determine overall response rate (ORR; CR + VGPR +partial response [PR]),
following treatment with oral Ixazomib when added to a regimen of Cd.
1.2.2 Secondary Objectives
For patients with NDMM, the secondary objectives are:


MLN9708
Statistical Analysis Plan Study C16020
10

To evaluate the tolerability and toxicity of the combination of oral Ixazomib with Cd

To characterize the PK in plasma of oral Ixazomib in combination with Cd

To determine overall response rate (ORR; CR + VGPR + PR), CR, VGPR, and PR
during the induction phase and the ORR (CR + VGPR + PR), CR + VGPR, CR,
VGPR, and PR throughout the entire treatment period

To determine time to response for patients who respond during the induction phase

To determine duration of response (DOR) for patients who respond during the
induction phase

To determine time to progression(TTP)

To evaluate PFS

To describe the safety, tolerability, and efficacy of Ixazomib as maintenance therapy
in patients who continue treatment beyond 13 cycles of induction therapy

To assess change in global health status, as measured by the patient-reported
outcome (PRO) instrument: European Organization for Research and Treatment of
Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30).
For patients with RRMM, the secondary objectives are:

To evaluate the tolerability and toxicity of the combination of oral Ixazomib with Cd

To characterize the PK in plasma of oral Ixazomib in combination with Cd

To determine CR + VGPR, CR, VGPR, and PR

To determine time to response for patients who respond

To determine DOR

To determine TTP

To evaluate PFS


MLN9708
Statistical Analysis Plan Study C16020
11

To assess change in global health status, as measured by the patient-reported
outcome (PRO) instrument: European Organization for Research and Treatment of
Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30).
1.2.3  Exploratory Objectives
The exploratory objectives are:
2.
POPULATIONS FOR ANALYSIS
2.1   
Safety Population
The safety population is defined as all patients who receive at least 1 dose of any study drug.  
Patients will be analyzed according to the treatment arm actually received. The safety 
population will be used for safety related analyses such as AE, concomitant medication, 
laboratory tests, and vital signs. In addition, it will also be used for the analyses of TTP, PFS 
and QOL data.


MLN9708
Statistical Analysis Plan Study C16020
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2.2       DLT-Evaluable Population
The DLT-Evaluable population is defined as patients in the safety lead-in cohort who 
receive all doses of Ixazomib and at least 80% of cyclophosphamide during Cycle 1 or 
experience a DLT in Cycle 1. Patients must take all doses in Cycle 1 as outlined in the 
Schedule of Events if patients do not experience DLTs. The DLT-Evaluable population will 
be used to evaluate the toxicity and determine a tolerable dose and dose modification 
following Cycle I of safety lead-in.
2.3      Response-Evaluable Population
The response evaluable population is defined as patients who receive at least 2 of the 3 
Ixazomib doses during Cycle 1, have measureable disease at baseline, and at least 1 post-
baseline response assessment. The response-evaluable population will be used for the 
analyses of response rates (RR), time to response (TTR), and duration of response (DOR). 
Measurable disease is defined by the documentation of at least 1 of the following 3 
measurements:

Serum M-protein 1 g/dL (10 g/L).

Urine M-protein 200 mg/24 hours.

Serum free light chain (FLC) assay:  involved free light chain level 10 mg/dL
(100 mg/L) provided the serum free light chain ratio is abnormal.
2.4     Pharmacokinetic Analysis Population
The Pharmacokinetic analysis population is defined as all patients who are enrolled in the 
safety lead-in cohort and have sufficient dosing data and Ixazomib concentration-time data 
to permit calculation of Ixazomib pharmacokinetic parameters.
3.
HYPOTHESES AND DECISION RULES
For patients with NDMM, the null hypothesis is that the combined CR+VGPR rate is not 
different in the treatment arms of Ixazomib in combination with cyclophosphamide and low-
dose dexamethasone from the specified response rate based on historical control, i.e.,
H0: CR+VGPR rate = 27%
The alternative hypothesis is that Clinical response rate in the treatment arm is different 
from that of historical control, i.e.,


MLN9708
Statistical Analysis Plan Study C16020
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HA: CR+VGPR rate > 27%
For patients with RRMM, the null hypothesis is that the overall response rate (ORR: CR + 
VGPR + partial response [PR]) is not different in the treatment arm of Ixazomib in 
combination with cyclophosphamide and low-dose dexamethasone from the specified 
response rate based on historical control, i.e.,
H0: CR+VGPR+PR rate = 60%
The alternative hypothesis is that Clinical response rate in the treatment arm is different 
from that of historical control, i.e.,
HA: CR+VGPR+PR rate > 60%
The one group chi-square test will be used to test the hypothesis at a type I error rate of 0.10 
(one - sided). 
4.
INTERIM ANALYSIS
4.1   
Safety Lead-in Evaluation
A safety lead-in evaluation will be performed after at least 6 safety lead-in evaluable 
patients in each treatment arm have had the opportunity to complete 1 cycle of therapy. No 
formal statistical analysis is planned for the safety lead-in evaluation.
4.2   
Continuous Monitoring and Early Stopping Rule
There is no formal interim analysis planned. Continuous data monitoring regarding safety 
and efficacy will be conducted based on the Bayesian monitoring strategy. Two proportions 
will be calculated for each arm: PF, the proportion of patients who are considered an 
effectiveness success, and PS, the proportion of patients who experienced one or more 
Grade 4 or higher non-hematological toxicities. PF will be evaluated on the first 12 response-
evaluable patients and then every 6 additional response-evaluable patients; PS will be 
evaluated on the first 12 enrolled patients and then every 6 enrolled patients. 
If the stopping bounds of Ps≥4/12, Ps≥6/18, Ps≥7/24, and Ps≥8/30 for Arms A and B 
(patients with NDMM), or the stopping bounds of Ps≥4/12, Ps ≥6/18, Ps≥7/24, Ps≥8/30, 
Ps≥9/36, Ps≥11/42, Ps≥12/48, Ps≥13/54, Ps≥14/60, Ps≥15/66, and Ps≥16/72 for Arm C 
(patients with RRMM) have been achieved, accrual to the study will be suspended to allow 
for investigation.  If the stopping rule is met, there is at least 80% probability that the true 


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toxicity rate will be greater than 18%.  After consideration by the study team, a decision will 
be made as to whether accrual can be resumed.
If the futility stopping bounds (CR + VGPR) of PF 2/12, PF 4/18, PF 7/24, and PF
10/30 for Arms A and B, or the futility stopping bounds (ORR) of PF ≤5/12, PF ≤12/24,
PF ≤20/36, PF ≤29/48, and PF ≤37/60 for Arm C have been met, further investigation will
be made by the study team to assess if accrual to any of the 3 treatment arms may be
terminated due to futility.  These futility stopping rules are established to allow no larger
than 10% overall type I error rate (one-sided) and still maintain power of approximately
80%.
5.
STATISTICAL METHODOLOGY
In general, summary tabulations will be presented to display the number of observations, 
mean, standard deviation, median, minimum, and maximum for continuous variables, and
the number and percentage (of nonmissing) per category for categorical data, unless 
specified otherwise. Patients will be analyzed at the dose level to which they were originally 
assigned, unless specified otherwise, including those who receive subsequent treatment at a 
lower dose level or a higher dose level. Tables will be summarized by treatment arms.
At the time of clinical study report(CSR) lock, all relevant data will be queried and cleaned; 
a database snapshot will be taken and used for the CSR. Additional treatment data will be 
entered into the database through study termination. Analyses may be updated based on 
additional information. An addendum to the CSR may be written if warranted based on these 
analyses.
5.1  
Sample Size Justification
This is a 3-arm open-label, multicenter, phase 2 study designed to evaluate the efficacy and 
safety of the oral combination of Ixazomib with cyclophophamide and dexamethasone in 
patients with NDMM (Arm A or Arm B) or patients with RRMM (Arm C). 
For patients with NDMM(Arm A or Arm B), the sample size is calculated by using one
group chi-square test for each arm separately based on the CR + VGPR rate following 
Ixazomib combined treatment regimen. With 31 response-evaluable patients per treatment 
arm (Arm A or Arm B), there will be 80% power to test a null hypothesis CR + VGPR rate 
of 27% and an alternative hypothesis CR + VGPR rate of 45% at 1-sided significant level of 
α = 0.10.  Assuming 10% patients are not response evaluable, approximately 35 patients 
each (70 total) will be enrolled in these 2 treatment arms (Arm A and Arm B).


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For patients with RRMM (Arm C), the sample size is calculated by using one group 
chi-square test based on the ORR rate following a Ixazomib combined treatment regimen.  
With 71 response-evaluable patients in Arm C, there will be 80% power to test a null 
hypothesis ORR rate of 60% and an alternative hypothesis ORR rate of 72% at 1-sided 
significant level of α = 0.10.  Assuming 10% patients are not response evaluable, 
approximately 78 patients will be enrolled in Arm C.
Overall, approximately 148 patients will be enrolled in this study. 
5.2   
Randomization and Stratification 
For patients with NDMM (Arm A or Arm B), a central (not center specific) randomization 
scheme will be used. Eligible patients will be randomized to Arm A or Arm B at a ratio of 
1:1.  A randomization number will be assigned to each patient.  The randomization 
assignment will be implemented by an interactive web response system (IWRS).  
Randomization is not required if accrual to either Arm A or Arm B is stopped, and therefore 
the enrollment can remain open for the other arm. 
For patients with RRMM (Arm C), randomization will not be used but an IWRS will be 
implemented for enrollment.  
5.3   
Unblinding
This is an open-label study.  No unblinding methodology is required.
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. No imputation of missing data will be performed 
unless specified.  
5.4.1.1     Missing Data in Patient Reported Outcomes (PROs)
For PRO data, missing data imputation will be based on published instrument specific 
methods.
For QOL in EORTC QLQ-C30, if a multi-item subscale has a missing item, then the average 
of the remaining items will be used as the Scale score, as long as at least half the items in 


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that Scale are present.  Example:  for fatigue, if Item 12 is missing, the average score of 
Items 10 and 18 will be used.
5.4.1.2   Missing/Partial Dates in Screening Visit
The following rules apply to dates recorded during the screening visits. 
1. If only the day-component is missing, the first day of the month will be used if the 
year and the month are the same as those for the first dose of study drug.  Otherwise, 
the 15th will be used. 
2. If only the year is present, and it is the same as the year of the first dose of study 
drug, the 15th of January will be used unless it is later than the first dose, in which 
case the date of the first of January will be used. 
3. If only a year is present, and it is not the same as the year of the first dose of study 
drug, the 15th of June will be used, unless other data indicate that the date is earlier.  
5.4.1.3   Missing/Partial Dates in Adverse Events/Concomitant Therapies/Subsequent 
Therapies
5.4.1.3.1   Missing/Partial Dates in Adverse Events
Adverse events with stop dates that are completely or partially missing will be imputed as 
follows:
1
If the stop date has month and year but day is missing, the last day of the month will 
be imputed
2
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 imputed date is later than the date of death, the date of death will be used as 
the imputed date instead. If the stop date of an adverse event is completely missing, then this 
event will be regarded as ongoing and will be included in the summary table.
Adverse events with start dates that are completely or partially missing will be imputed as 
follows:
1. If the start date has month and year but day is missing


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a.
If the onset month and year are same as that of first dose date, the first dose 
date will be used instead. If the onset month and year are different from that 
of the first dose date, then the first day of the month will be used.
b. After imputation, the imputed dates will be compared against the stop date. If 
this imputed date is later than the stop date (possibly imputed), then the stop 
date will be used instead
2. If the start date has year, but day and month are missing
a.
If the onset year is same as that of first dose date, then the first dose date will 
be used instead
b. If onset year is different than that of the first dose date, the 1st of January of 
the year will be imputed.
c.
After the imputation, the imputed dates will be compared against the dose 
stop date. If this imputed date is later than the stop date (possibly imputed), 
then the stop date will be used instead.
If the start date of an adverse event is completely missing, then it is imputed with the first 
dose date.
5.4.1.3.2   Missing/Partial Dates in Concomitant Therapies
Concomitant therapies with start dates that are completely or partially missing will be 
analyzed as follows:
1. 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 are: 
a.
On or after the month and year of the date of the first dose of study drug
and 
b. On or before the month and year of the date of the last dose of study drug 
plus 30 days.
2. If the start date has year, but day and month are missing, the therapy will be included 
in the summary table if the year is:


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a.
On or after the year of the date of the first dose of study drug
and
b. On or before the year of the date of the last dose of study drug plus 30 days.
If the start date of concomitant therapies is completely missing and the stop date of 
concomitant therapies is prior to the date of the first dose of study drug, then this therapy 
will not be included. 
If the start date of concomitant therapies is completely missing and the stop date of 
concomitant therapies is on or after the date of the first dose of study drug, then the therapy 
will be included in the summary table.
If the start date and stop date of concomitant therapies are completely missing, then the 
therapy will be included in the summary table.
5.4.1.3.3   Missing/Partial Dates in Subsequent Therapies
Subsequent therapies with start dates that are completely or partially missing will be 
analyzed as follows:
1.
When month and year are present and the day is missing,
a.
If the onset month and year are the same as the month and year of last dose of
study drug, the day of last dose + 1 will be imputed.
b. If the onset month and year are not the same as the month and year of last dose of
study drug, the first day of the month is imputed.
2. When only a year is present,
a.
If the onset year is the same as the year of last dose of study drug, the date of last
dose + 1 will be imputed.
b. If the onset year is not the same as the year of last dose of study drug, the first
day of the year is imputed.
      If no components of the onset date are present the date of last dose + 1 will be imputed.


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5.4.2   
Definition of Baseline Values
In general, the baseline value is defined as the value collected at the time closest to, but 
prior to, the first dose of study drug on Day 1 of Cycle 1.  For example, this applies to most 
of safety chemistry and hematology labs.
However, for certain efficacy related labs (serum and urine M-protein, free light chain, 
response biomarkers etc), baseline is defined as the worst value (usually highest but could be 
lowest in some cases for certain biomarkers) from central labs (both scheduled and 
unscheduled) prior to first dosing. If all central labs are missing, then the worst value 
obtained from local lab (both scheduled and unscheduled) will be used.  Please note that 
decisions regarding eligibility (such as response evaluable) may be made using either local
or central laboratory.
5.4.3   
Windowing of Visits
All data will be categorized based on the scheduled visit at which they were 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, Lost 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 5.8.2.
5.4.6   
General Conventions for Determining Duration
The duration of an event is calculated as: date of end of the event – date of start of the event 
+1. It shall be used for deriving the duration form a reference time point, e.g., days on 
treatment = date of last dose- date – date of first dose +1 and for time to event analyses such 
as survival or time to tumor progression. Table, listing, figure (TLF) shells will specify if 
there are exceptions.


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5.5   
Patient Disposition
The 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 treatment 
regimen, primary reason for discontinuation from the treatment regimen, patients ongoing in 
follow-up, patients off study during follow-up and primary reason off study during follow-
up. Percentages will be presented for each arm and the total of Arm A + Arm B. Patient 
disposition will be summarized and listed. The number and percentage of patients 
discontinued from the treatment regimen, primary reason for discontinuation from the 
treatment regimen will also be summarized for induction phase and maintenance phase 
separately for Arm A, Arm B and the total of Arm A + Arm B.
5.6   
Demographics and Baseline Characteristics
5.6.1   
Demographics
Demographic data will be summarized by each treatment arm and by the total of Arm A + 
Arm B.  Baseline demographic data to be evaluated include gender, age, race, ethnicity, 
height, weight, body surface area (BSA), and other parameters as appropriate. No inferential 
statistics will be carried out.
Age will be calculated from date of birth and date of informed consent. 
The formulation for BSA (Mosteller, 1987) is:
BSA = sqrt(height(cm) x weight (kg) / 3600).
5.6.2   
Disease Specific History
Disease specific history will be summarized to include type of myeloma at diagnosis, Durie-
Salmon stage at diagnosis, International Stage System (ISS) at diagnosis, evidence of lytic 
bone disease and extramedullary disease, and the prior therapies for patients with RRMM 
(number of patients with prior therapy, lines of prior therapies,  best hematological response 
to prior therapy, type of prior therapy in the format of therapy contained, number of patients 
who received VELCADE as the last line of prior therapy, number of patients refractory to 
any line of prior therapy). Disease specific history will be summarized and listed by each 
treatment arm and by the total of Arm A + Arm B. The months from prior diagnosis to the 
first dose of ixazomibis calculated by 


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first dose date - date of diagnosis 
365.25/12
5.6.3   
Baseline Disease Characteristics
Baseline disease characteristics will be summarized by each treatment arm and the total of 
Arm A + Arm B including serum M-protein, urine M-protein, serum free light chain, serum 
free light chain ratio,
2
-microglobin and its category (i.e., < 2.5, 2.5-5.5, > 5.5 mg/L), 
serum creatinine and its category, (<=2, >2 mg/dL), calculated creatinine clearance and its 
category (<30, 30-<60, 60-<90, >=90 mL/min), serum albumin by category (i.e., <3.5,
>=3.5 g/dL), corrected calcium, hemoglobin, platelet count, neutrophil count, LDH and 
Eastern Cooperative Oncology Group (ECOG) performance status. 
Creatinine clearance will be calculated using the Cockcroft-Gault formulas as follows:
For male patients: 
For female patients:
Integer values will be used. 
For patients with heavy chain, the patient’s type of myeloma is determined by the 
combination of heavy chain type (IgG, IgA, IgM, IgD, and other) and light chain type 
(Kappa, Lambda, and biclonal). In descriptive summaries, the disease will be categorized by 
the heavy chain type first, then within each of these categories, patients will be further 
classified according to their light chain type. For patients with light chain only, patients will 
be classified according to their light chain type.
5.6.4   
Extent of Disease and Bone Marrow Cytogenetic Results at Baseline 
The extent of disease at baseline will be summarized including number of patients with a 
bone marrow aspirate, bone marrow aspirate results (% plasma cells, % megakaryocytes 
[mg/dL])
creatinine
(serum
72
weight[kg]
Age[yrs])
(140
clearance
creatinine




[mg/dL])
creatinine
(serum
72
weight[kg]
Age[yrs])
(140
85
.0
clearance
creatinine







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present), number of patients with a bone marrow biopsy, bone marrow biopsy results (% 
plasma cells, % cellularity, type of cellularity, % Kappa/Lambda ratio performed), skeletal 
survey results (normal, abnormal not clinically significant, abnormal clinically significant, 
and not done) and imaging including magnetic resonance imaging (MRI) / computed 
tomography (CT) results (normal, abnormal not clinically significant, abnormal clinically 
significant, and not done), number and percentage of lytic bone lesions present,  number of 
extramedullary plasmacytoma present, and type of extramedullary plasmacytoma. 
Bone marrow cytogenetic results at baseline from the conventional/karyotype and 
molecular/FISH cytogenetic analyses methods will be displayed. The results will be 
categorized as “Normal”, “Abnormal” and “Indeterminate”. The percentage of each 
category will be summarized.  Abnormal types of interest, including but not limited to, del 
13, del 17, t(4;14), t(11;14), t(14;16), -13q, -17p, hyperdiploidy, hypodiploidy and high risk 
cytogenetics group (del 17, -17p, t(4,14) or t(14,16)), will also be tabulated. 
By-patient listings for these baseline characteristics will also be presented.
5.6.5   
General Medical History 
General medical history data will be presented in a by-patient listing. 
5.7   
Treatments and Medications
5.7.1   
Concomitant Medications and Procedures
Concomitant medications will be coded by generic term using the World Health 
Organization (WHO) Drug Dictionary.  The number and percentage of patients taking 
concomitant medications will be tabulated by WHO drug generic term from the first dose of 
study treatment through 30 days after the last dose of study medication. Concomitant 
procedures will not be coded.
Concomitant medications and procedures will be presented in by-patient listings.
5.7.2   
Study Treatments
Eligible patients will take Ixazomib in combination with Cd. Patients with NDMM will be 
randomized to either to Arm A or Arm B. Patients with RRMM will be enrolled in Arm C.
During induction, patients with NDMM will be randomized to receive a combination of oral 
Ixazomib at a dose of 4.0 mg and a dose of cyclophosphamide at 300 mg/m2 (Arm A) or 400 


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mg/m2 (Arm B) on days 1, 8 and 15 of a 28-day cycle and dose of 40 mg of dexamethasone 
on Days 1, 8, 15, and 22 of a 28-day cycle; patients with RRMM will receive a combination 
of oral Ixazomib at a dose of 4.0 mg and a dose of cyclophosphamide at 300 mg/m2 on days 
1, 8 and 15 of a 28-day cycle and a dose of 40 mg of dexamethasone on Days 1, 8, 15, and 
22 of a 28-day cycle. Patients over 75 years of age will receive a reduced dose of 
dexamethasone 20 mg on the same weekly schedule. 
At the end of the induction phase, a maintenance phase starts for patients with NDMM
(Arms A and B only) who have at least stable disease. Patients will receive single-agent 
Ixazomib (at the dose tolerated at the end of induction phase) on Days 1, 8, 15 of 28-day 
cycles until progression/death or unacceptable toxicity.  
5.7.2.1   Extent of Exposure
A patient will be considered as treated in a cycle as long as this patient received any amount 
of study drug in that cycle. A treatment cycle is defined as a cycle in which the patient 
received any amount of study drug. A treatment cycle for a specific drug is defined as a 
cycle in which the patient received any amount of that drug.
Relative dose intensity (%) is defined as 100 × (total amount of dose taken (mg)) / (sum of 
the planned dose over all treatment cycles).
The exposure to each study drug will be summarized including the number of cycles, total 
amount of dose taken (in mg), total number of doses taken, number and percentages of 
patients by treatment cycles, and relative dose intensity. An aggregate summary of numbers 
and percentages of patients who had 1-6, 7-13, 14-20, 21-26, >26 treatment cycles will also 
be presented in the same table. 
Exposure of Ixazomib will be presented by overall treatment period, induction period (Arms 
A and B only), and maintenance period (Arms A and B only). The summary of each study 
drug exposure will be presented by each treatment arm and the total of (Arm A + Arm B) in 
a similar format. 
Dosing data will also be presented in a by-patient listing.
5.7.2.2   Treatment Modifications
The actions for each study drug (dose reduction, held, missed, increased, delayed, 
discontinued permanently, etc) will be summarized for all patients, over all treatment 


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periods, and by each cycle for Cycle 1 though Cycle 13, aggregated for Cycles 1-6, 7-13 
(for all drugs) and then for the remainder of cycles.
5.8   
Efficacy Analyses
Response will be assessed according to the International Myeloma Working Group (IMWG) 
criteria for all patients at every cycle during the treatment period and subsequently every 8 
weeks during the PFS follow-up period until disease progression or the patient is off the 
study. Other efficacy parameters including, but not limited to time to, time to response 
(TTR) and duration of response (DOR) will be presented in listings and summarized if 
appropriate. Summary of best M-Protein Response to treatment will also be presented.
Subgroup analysis by age, ISS stage, creatinine clearance, ASCT, lines of prior therapy 
(RRMM), etc may also be explored for some efficacy endpoints.
5.8.1   
Primary Efficacy Endpoints
For patients with NDMM, the primary endpoint is the combined response rate of CR + 
VGPR during the induction phase. For patients with RRMM, the primary endpoint is ORR. 
The primary efficacy analysis will be based on the response-evaluable population. Estimates 
of CR + VGPR and ORR will be calculated with 2-sided 95% exact binomial confidence 
intervals.
5.8.2   
Secondary Efficacy Endpoints
For patients with NDMM, secondary efficacy endpoints include ORR (CR + VGPR + PR), 
CR, VGPR, PR rate during the induction phase, and ORR (CR + VGPR + PR), combined 
response rate (CR + VGPR), VGPR, CR, PR throughout the entire treatment period; TTR,
DOR for patients who respond during the induction phase, TTP, PFS throughout the entire 
treatment period.  
For patients with RRMM, secondary efficacy endpoints include combined response rate (CR 
+ VGPR), VGPR, CR, PR, TTR, DOR, TTP, PFS.
Time to response (TTR) is defined as the time from the date of first dose of study treatment 
to the date of the first documentation of a confirmed PR or better response up to the 
initiation of alternative therapy in a patient who responded.
DOR is defined as the time from the date of first documentation of a confirmed PR or better 
to the date of first documented PD up to the initiation of alternative therapy. Responders 


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without documentation of PD will be censored at the date of the last response assessment
that is SD or better prior to the date of the initiation of alternative therapy. DOR will be 
categorized as CR+VGPR+PR, CR+VGPR, and CR.
TTP is defined as the time from the date of first dose of study treatment to the date of first 
documentation of PD. Patients without documentation of PD will be censored at the date of 
the last response assessment that is SD or better prior to the date of initiation of  alternative 
therapy. Patients with no response assessment will be censored at the date of first dose.
PFS is defined as the time from the date of first dose of study treatment to the date of first 
documented PD or death. Patients without documentation of PD or death will be censored at 
the date of the last response assessment that is SD or better prior to the date of initiation of 
alternative therapy. Patients with no response assessment will be censored at the date of first 
dose.
Time-to-event data will be summarized by 25th, 50th (median), and 75th percentiles with 
associated 2-sided 95% confidence intervals, as well as percent of censored observations.
The response rates, time to response, and DOR will be analyzed based on Response-
Evaluable populations. TTP and PFS will be analyzed based on the safety population. The 
response rates will be analyzed similarly to the primary endpoint. DOR, TTP and PFS will 
be analyzed using standard survival analysis techniques based on Kaplan-Meier estimates.
The efficacy results will be summarized for each treatment arm and for the total of Arm A 
and Arm B.
5.8.3     Exploratory Efficacy Endpoints Analysis
5.8.3.1   
Minimal Residual Disease Analysis 


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5.8.3.2   
Patient Reported Outcome Analysis (PRO)
Quality of Life will be assessed using the EORTC QLQ-C30 and analyses will be performed 
using the safety population for each treatment arm and the total of Arm A + Arm B.
Descriptive statistics will be presented for the change from baseline in QOL assessment over 
time. For patients with NDMM who enter maintenance therapy after 13 cycles of induction 
treatment, descriptive statistics will be presented for the change from baseline and change 
from Cycle 13 in QOL assessment over time. Analyses will be performed on summary 
scores as well as subscale scores.
The scale/subscale scores of EORTC QLQ-C30 are defined as shown in Table 5-1. Primary 
subscales for analysis (with associated items in parenthesis) include Pain (items 9, 19), 
Fatigue (items 10, 12, 18), Physical functioning (items 1-5), and Global health status/QOL 
(items 29-30).  Secondary subscales for analysis include Nausea/Vomiting (items 14-15), 
Dyspnea (item 8), Insomnia (item 11), Appetite loss (item 13), Constipation (item 16), 
Diarrhea (item 17), Financial difficulties (item 28), Role functioning (items 6-7), Cognitive 
functioning (items 20, 25), Emotional functioning (items 21-24), and Social functioning 
(items 26-27).  QOL data will be reported for the responders (confirmed best response of 
CR+VGPR+PR) and non-responders to assess the QOL differences associated with disease 
response. In addition, PRO responder analyses by tumor responder groups will be 
performed, where PRO responders are defined as patients who improved by 10 points or 
more on the EORTC QLQ-C30 global health scale at any time post-baseline, and tumor 
responders are defined as CR+VGPR+PR, CR+VGPR, and CR respectively.
Published scoring manual and guidelines will be used to determine EORTC QLQ-C30 scale 
scores and handle missing data.  Further investigation of missing patterns, imputation and 
subsequent sensitivity analyses may be conducted.


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Table 5-1   
Definition of Subscale Scores of EORTC QLQ-C30
Scale/Subscale
Individual Items
Physical functioning
1-5
Role functioning
6-7
Emotional functioning
21-24
Cognitive functioning
20, 25
Social functioning
26-27
Quality of life
29-30
Fatigue
10, 12, 18
Nausea and vomiting
14-15
Pain
9, 19
Dyspnea
8
Insomnia
11
Appetite loss 
13
Constipation 
16
Diarrhea
17
Financial difficulties 
28
5.8.3.3   
Efficacy Assessment as Maintenance Therapy 
For patients with NDMM who enter maintenance therapy after 13 cycles of induction 
treatment, the efficacy of Ixazomib as maintenance therapy will be evaluated.  The duration 
of maintenance therapy will be further explored.  Additional efficacy endpoints include shift 
table for response categories, landmark analysis of PFS, and other efficacy endpoints if 
appropriate in the maintenance therapy portion of the study. For the efficacy endpoints 
above, the staring time point will be the first date of maintenance therapy.
5.8.3.4
Biomarker Analysis 


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5.9   
Analysis of Health Care Utilization Data
Analyses of health care utilization data will be performed using the safety population and 
summarized for each treatment arm and by the total of Arm A + Arm B. In general, 
descriptive statistics of medical encounters (length of stay, inpatient, outpatient, and reason), 
and number of missing days from work or other activities by patient and caregiver will be 
presented.  
5.10   Pharmacokinetic, Pharmacodynamic
5.10.1   Pharmacokinetic Analyses
The PK analysis population will be used for the description of the PK profile and for the 
calculation of PK parameters.
Safety Lead-in Cohort
PK evaluation will be based on concentrations of Ixazomib in specimens collected at pre-
specified times prior to and following drug administration. Actual specimen collection times 
will be used for the calculation of PK parameters. In the event that actual collection times 
are either unreliable or missing, scheduled collection times will be used. For ease of 
presentation, scheduled collection times will be used to present results in tables and figures.  
Both scheduled and actual collection times will be presented in listings.
Concentrations of Ixazomib that are below the limit of quantification (BLQ) will be treated 
as zero. Concentration data that are considered anomalous may be excluded from the 
concentration summaries and plots and will not be used in the calculation of PK parameters. 
Evidence or explanations will be provided to justify the exclusion of data.
When summarizing concentrations or PK parameters, a minimum of 2 values are required to 
show the mean and geometric mean, and at least 3 values are required to show the standard 
deviation and coefficient of variation (CV). 
Individual patient plasma concentration data will be listed.  Concentrations will be 
summarized (N, mean, standard deviation, CV, geometric mean, median, minimum, and 
maximum) according to Arm (A, B, or C) and dosing cycle and day.  
A semi-logarithmic plot of the mean plasma concentration-time curves of 
ixazomibfollowing Cycle 1, Day 1 dosing (pre-dose to 168 hours) and Cycle 1, Day 15 
dosing (pre-dose to 336 hours) will be provided, respectively. Linear and semi-logarithmic 


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plots of the aggregate individual plasma concentration-time curves (“spaghetti” plots) of 
ixazomibfollowing Cycle 1, Day 1 dosing (pre-dose to 168 hours) and Cycle 1, Day 15 
dosing (pre-dose to 336 hours), grouped according to Arm will be provided, respectively. In 
linear plots, a value of zero will be substituted for any BLQ values. In semi-logarithmic 
plots, BLQ values will be treated as missing.
Pharmacokinetic parameters will be calculated using non-compartmental analysis methods.  
The following PK parameters will be computed, as data permits, from concentration-time 
data: 
Parameter
Definition
Units
Cmax
Observed maximum concentration
ng/mL
Tmax
First time Cmax is observed
hr
AUCtau
Area under the concentration-time curve from time 0 to the end of the 
dosing interval, estimated using the linear-log  trapezoidal method
hr*ng/mL
λz
Terminal disposition phase rate constant
1/hr
t1/2
Terminal disposition phase half-life
hr
Rac
Accumulation ratio
unitless
Different PK parameters will be calculated following dosing on Day 1and Day 15. 
The PK parameters to be estimated for each day of dosing are as follows:
PK Parameter
Dosing Day
1
15
Cmax
X
X
Tmax
X
X
AUCtau  (tau = 168 hr)
X
X
λz
X
t1/2
X
Rac
X
Individual patient parameter data will be listed. PK parameters will be summarized (N, 
arithmetic mean, standard deviation, CV, geometric mean, median, minimum, and 
maximum) according to Arm and dosing cycle and day.


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All Patients
Concentration-time data from patients not in the safety lead-in cohort will be listed only. 
Pharmacokinetic data collected for all patients including patients in the safety lead-in cohort 
of the study may be used to perform population PK analysis using a nonlinear mixed effects 
modeling approach to assess the effect of various demographic covariates on PK including 
data from other studies of Ixazomib, if possible.
5.10.2   Pharmacodynamic Analyses 
Not applicable
5.11   Safety Analyses
Safety analysis will be performed using the safety population by each treatment arm or the 
total of Arm A + Arm B. Summary tabulations will be presented to display the frequency of
incidence, intensity, type of AEs, ECGs, vital sign measurements, and clinical laboratory 
results.  
For the lead in patients, the incidence of DLT will be listed. 
5.11.1   Adverse Events
5.11.1.1   Adverse Events
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). AEs will be reported from the first dose of study drug through 30 days after 
administration of the last dose of study drug. All AEs will be presented in a by-patient 
listing. AEs will be tabulated according to the MedDRA by system organ class, high level 
terms and preferred terms. Treatment-emergent is defined as any AE that occurs after 
administration of the first dose of any study treatment through 30 days after the last dose of 
any study treatment.
Summary tabulations will include the following categories:

Treatment-emergent AEs

Drug-related treatment-emergent AEs


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
Grade 3 or higher treatment-emergent AEs (also grade 3 only and 4 only will be
reported seperately)

Grade 3 or higher drug-related treatment-emergent AEs (also grade 3 only and 4 only
will be reported separately)

The most commonly reported treatment-emergent AEs (i.e., those events reported by
> 10% of all patients)

Serious adverse events

Treatment-emergent AEs resulting in study drug reduction

Treatment-emergent AEs resulting in any study drug discontinuation
For patients with NDMM who enter maintenance therapy after 13 cycles of induction 
treatment, AEs will be tabulated according to the MedDRA by system organ class, high 
level terms and preferred terms for induction phase and maintenance phase. Summary 
tabulations will include the following categories: 

Treatment-emergent AEs

Grade 3 or higher treatment-emergent AEs

Serious adverse events

Treatment-emergent AEs resulting in study drug reduction

Treatment-emergent AEs resulting in any study drug discontinuation
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 AE(1). Patients with the 
same AE more than once will have the maximum intensity of that event counted once within 
each body system, once within each high level term, and once within each preferred term. 


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Most commonly reported (at least 10% of all patients) treatment-emergent AEs will be 
presented by preferred term only. Patients with the same AE more than once will have that 
event counted only once within each preferred term.
An overall summary AE table will include numbers and percentages of patients who had any 
AE, drug-related AE, grade 3 or higher AE, grade 3 or higher drug-related AE, serious AE 
(SAE), drug-related SAE, AE resulting in any drug discontinuation, AE resulting in any
dose reduction, AE resulting in any dose modification (defined as delay, reduction or 
discontinuation), and on-study deaths. On-study death is defined as the death that occurs 
between the first dose of study drug and up to 30 days after the last dose.
Additionally, by-patient listings of the AE of special interest will be presented including 
rash, peripheral neuropathies, thrombocytopenia, and gastrointestinal disorders, if 
appropriate.
5.11.1.2   Peripheral Neuropathy Events


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5.11.1.3   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 SAEs will be summarized similarly.
In addition, a by-patient listing of the SAEs will be presented (the listing will contain all 
SAEs regardless of treatment-emergent AE status).
5.11.1.4   Deaths
A by-patient listing of the on-study deaths will be presented.  On-study death is defined as 
the death that occurs between the first dose of study drug up to 30 days after the last dose of 
study drug.
5.11.1.5   Adverse Events Resulting in Discontinuation of Study Drug
The number and percentage of patients experiencing at least one adverse event resulting in 
discontinuation of any study drug will be summarized by MedDRA system organ class, high 
level term, and preferred term.
A by-patient listing of treatment-emergent AEs resulting in discontinuation of any study 
drug will be presented.  All AEs resulting in discontinuation of any study drug occurring on-
study will be displayed.
5.11.1.6   Adverse Events Resulting in Dose Reduction
The number and percentage of patients experiencing at least one adverse event resulting in 
any dose reduction will be summarized by MedDRA system organ class, high level term, 
and preferred term.
A by-patient listing of AEs resulting in dose reduction of any study drug will be presented.  
All AEs resulting in dose reduction of any study drug occurring on-study will be displayed.


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5.11.1.7   Dose Limiting Toxicities (DLTs)
A by-patient listing of DLTs that occur during Cycle 1 of treatment will be presented only 
for patients participating in the safety lead-in.
5.11.2   Laboratory Data
For the purposes of summarization in both the tables and listings, all laboratory values will 
be converted to standardized units.  If a lab value is reported using a non-numeric qualifier 
(e.g., less than (<) a certain value, or greater than (>) a certain value), the given numeric 
value will be used in the summary statistics, ignoring the non-numeric qualifier. However, 
for the bone marrow plasma cell percentage, the convention of (x-1)% (mainly for < 5% for 
CR) will be used.
Laboratory test results from the central laboratory will be used when they are available.  
Laboratory test results from local laboratories will be used only when no central laboratory 
test results exist at the same sample collection time point, unless specified otherwise.
Laboratory test results will be summarized according to the scheduled sample collection 
time point.  Change from baseline will also be presented. The parameters to be analyzed 
include, but are not limited to:

Hematology:  hemoglobin, hematocrit, platelet count, leukocytes with
differential,and neutrophils (absolute neutrophil count [ANC])

Clinical chemistry:  blood urea nitrogen, creatinine, total bilirubin, urate, lactate
dehydrogenase (LDH), gamma glutamyl transferase (GGT), phosphate, albumin,
alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine
aminotransferase (ALT), glucose, calcium, sodium, potassium, chloride, carbon
dioxide (CO2), and magnesium.
Shift tables the change in CTCAE grade will be constructed for hematology and chemistry 
laboratory parameters which have corresponding CTCAE grades to tabulate changes in NCI 
CTCAE (version 4.03)(1) from baseline to worst post baseline on study CTCAE grade.  All 
the data from both scheduled and unscheduled time points are to be included in the shift 
table. However, at each time point, the central lab value is used preferentially. Only when 
the central lab value is not available will the local lab value be used
Worst changes from baseline for creatinine clearance will be tabulated and categorized by ≤ 
30 mL/min and > 30 mL/min, and ≤ 60 mL/min and > 60 mL/min.


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The mean and median estimates over time may be graphed for a selected list of lab
parameters. These include but not limited to: LDH, creatinine, albumin, calcium, sodium, 
and phosphate from serum chemistry and WBC, absolute neutrophil count, hemoglobin, 
platelet count from hematology. 
For patients with NDMM who enter maintenance therapy after 13 cycles of induction 
treatment, selected hematological parameters such as ANC, ALC, platelets, hemoglobin may 
be analyzed by induction phase and maintenance phase separately.
The box plots of creatinine, M-protein values, change of M-protein from baseline over time 
will be graphed as well.  For mean/median figures over time and box plots over time, only the 
data from scheduled time points are included. At the same scheduled time point, if the central 
lab value is available, then it is used. Only if the central lab value is not available will the 
local lab value be used.
If appropriate, line graphs of individual tests over time will be used to show changes in 
laboratory measures over time for each individual patient. For figures showing the individual-
patient lab values over time, all scheduled and unscheduled time points are included. At the 
same time point, if the central lab value is available, it is used; if not, the local lab value is 
used.
By-patient listings to be presented include hematology, clinical chemistry and urinalysis.
5.11.3   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 
and the total of Arm A + Arm B. Change from baseline will also be presented. A by-patient 
listing will also be presented.
5.11.4   Electrocardiograms
ECGs, including abnormalities, will be listed in a by-patient listing.
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)


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where RR = 60 / heart rate (bpm)
5.11.5   Eastern Cooperative Oncology Group Performance Status
Eastern Cooperative Oncology Group performance status over time will be summarized.  
Shifts from baseline to postbaseline over time will be summarized by treatment arm and the 
total of Arm A + Arm B.  
5.11.6   Other Safety Assessments
Pregnancy testing results will be presented in a by-patient listing.
Additional safety analyses may be determined at any time to enumerate rates of toxicities 
and to further define the safety profile of the study drugs. 
6.   
CHANGES TO PLANNED ANALYSES FROM PROTOCOL
There are no changes to the planned analyses from that described in the protocol.
Reference materials for this statistical plan include Clinical Study Protocol C16020 
Amendment 1 (May 2014). 
7.   
PROGRAMMING CONSIDERATIONS
7.1   
Statistical Software 
SAS version 9.2 (or higher) will be used for all analyses.  
7.2   
Rules and Definitions
Patient populations are defined in Section 2.
Baseline values are defined in Section 5.4.2.
8.   
REFERENCES
1. Durie BG, Harousseau JL, Miguel JS, Blade J, Barlogie B, Anderson K, et al. 
International uniform response criteria for multiple myeloma. Leukemia 2006; 20(9): 
1467-73.
2. Mosteller RD: Simplified Calculation of Body Surface Area. N Engl J Med 1987 Oct 
22;317(17):1098 (letter).
3. U.S. Department of Health and Human Services, National Institutes of Health 
National Cancer Institute. Common Terminology Criteria for Adverse Events 
(CTCAE). Version 4.03. 14 June 2010.


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4. Lee JJ, Liu DD. A predictive probability design for phase II cancer clinical trials.
Clin Trials 2008;5(2):93-106.
5. Thall PF, Sung HG: Some extensions and applications of a Bayesian strategy for
monitoring multiple outcomes in clinical trials. Statistics in Medicine 1998; 17(14):
1563-80.