Clinical trial NCT04272775
Conditions: Relapsed and/or Refractory Multiple Myeloma
Keywords: Drug Therapy
Sponsor: Takeda
Start date: 2012-06-05; Completion date: 2019-02-15
Enrollment: 14 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The purpose of this study is to evaluate the tolerability, safety, pharmacokinetics (PK) of ixazomib alone or in combination with lenalidomide and dexamethasone (Rd), and antitumor activity of ixazomib in participants with RRMM.

Detailed description:
The drug being tested in this study is called ixazomib. This study will evaluate the tolerability, safety, and PK of ixazomib administered alone or in combination with lenalidomide and dexamethasone in participants with relapsed and/or refractory multiple myeloma.

This study will enroll approximately 24 participants (3 to 6 participants in each dose-escalation cohort). Participants will be assigned to receive treatment in one of the four treatment cohorts:

* Cohort 1: Ixazomib 4.0 mg
* Cohort 2: Ixazomib 4.0 mg + Lenalidomide and Dexamethasone
* Cohort 3: Ixazomib 5.5 mg
* Cohort 4: Ixazomib 5.5 mg + Lenalidomide and Dexamethasone

This multi-center trial will be conducted in Japan. The overall time to participate in this study is approximately 7 years. Participants will make a final visit 29 days after receiving their last dose of drug for a follow-up assessment.

Arms: arm 1: Ixazomib 4.0 milligram (mg), capsules, orally, once, on Days 1, 8, and 15 in 28-day treatment cycle for up to Cycle 87. arm 2: Ixazomib 4.0 mg, capsules, orally, once, on Days 1, 8, and 15 in 28-day treatment cycle along with lenalidomide 25 milligram per day (mg/day), capsules, orally, once, from Days 1 to 21 and dexamethasone 40 mg/day, tablets, orally, once, on Days 1, 8, 15, and 22 in 28-day treatment cycle for up to Cycle 62. arm 3: Ixazomib 5.5 mg, capsules, orally, once, on Days 1, 8, and 15 in 28-day treatment cycle for up to Cycle 87. arm 4: Ixazomib 5.5 mg, capsules, orally, once, on Days 1, 8, and 15 in 28-day treatment cycle along with lenalidomide 25 mg/day, capsules, orally, once, from Days 1 to 21 and dexamethasone 40 mg/day, tablets, orally, once, on Days 1, 8, 15, and 22 in 28-day treatment cycle for up to Cycle 87.
Interventions: intervention 1: Ixazomib intervention 2: Lenalidomide intervention 3: Dexamethasone
Intervention descriptions: intervention 1: Ixazomib capsules. intervention 2: Lenalidomide capsules. intervention 3: Dexamethasone tablets.

Protocol documents:
Prot_000.pdf: 
 
 
Title: A Phase 1 Study of MLN9708 in Japanese Patients with Relapsed and/or 
Refractory Multiple Myeloma 
 
NCT Number: TBD 
Protocol Approve Date: 22-NOV-2016 
 
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 or company confidential information. 
 
This may include, but is not limited to, redaction of the following: 
 
Named persons or organizations associated with the study. 
 
Patient identifiers within the text, tables, or figures or in by-patient data listings. 
 
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. 
 
If needed, certain appendices that contain a large volume of personally identifiable 
information or company confidential information may be removed in their entirety if it 
is considered that they do not add substantially to the interpretation of the data (eg, 
appendix of investigator’s curriculum vitae). 
 


Product: MLN9708
Protocol Number: TB-MC010034
Date: 22 November 2016
Page 1 of 102
CONFIDENTIAL
A Phase 1 Study of MLN9708 in Japanese Patients with 
Relapsed and/or Refractory Multiple Myeloma
MLN9708 (ixazomib citrate)
Protocol Number: TB-MC010034
Clinical Study Sponsor:
Takeda Pharmaceutical Company Limited
1-1, Doshomachi 4-chome, Chuo-ku, Osaka, 540-8645, Japan
Version/Date:
Version 3.3
22 November 2016
Confidentiality Notice
This document contains confidential information of Takeda Pharmaceutical Company Limited.
This document must not be disclosed to anyone other than the study staff and members of the institutional 
review board.  
The information in this document cannot be used for any purpose other than the evaluation or conduct of 
the clinical study without the prior written consent of Takeda Pharmaceutical Company Limited.
If you have questions regarding how this document may be used or shared, or other study-related questions, 
contact the Clinical Study Sponsor.


Product: MLN9708
Protocol Number: TB-MC010034
Date: 22 November 2016
Page 2 of 102
CONFIDENTIAL
Document History
Version 1: 12 January 2012
Version 2: 7 February 2012
Version 2.1:  7 March 2012
Version 2.2:  11 September 2012
Version 3: 4 December 2013
Version 3.1:  4 December 2014
Version 3.2:  18 November 2015


Product: MLN9708
Protocol Number: TB-MC010034
Date: 22 November 2016
Page 3 of 102
CONFIDENTIAL
PROTOCOL SUMMARY
Study Title: A Phase 1 Study of MLN9708 in Japanese Patients With Relapsed and/or 
Refractory Multiple Myeloma
Study Phase: 1
Indication: Patients with relapsed and/or refractory multiple myeloma
Study Objectives: 
Primary: 
• To evaluate the tolerability, safety, and pharmacokinetics of MLN9708 alone or in 
combination with lenalidomide and dexamethasone (Rd) in patients with relapsed and/or
refractory multiple myeloma.
Secondary: 
• To evaluate the antitumor activity of MLN9708 in patients with relapsed and/or 
refractory multiple myeloma.
Overview of Study Design:  
This study consists of the following 4 cohorts.
• Cohort 1: MLN9708 4.0 mg
• Cohort 2: MLN9708 4.0 mg + Rd
• Cohort 3: MLN9708 5.5 mg
• Cohort 4: MLN9708 5.5 mg + Rd
Three subjects will be enrolled sequentially from cohort 1 (MLN9708 4.0 mg alone). If dose-
limiting toxicity (DLT) occurs in one subject during DLT-assessment period, 3 additional 
subjects will be enrolled in the same applicable cohort to evaluate the tolerability in a total of 6
subjects. If DLT occurs in 2 of the 3 subjects, the given dosage is considered intolerable. If 
DLT occurs in 2 of the 6 subjects, the sponsor will determine the tolerability to the given dosage
after discussing with the Efficacy and Safety Evaluation Committee (ESEC).
The sponsor will evaluate the tolerability of MLN9708 dosage on the basis of the safety data 
including DLT incidences during the DLT-assessment period.  The sponsor will decide whether 
the next cohort will be studied and the dose of the next cohort in consultation with the ESEC, if 
necessary. If the current cohort is considered tolerable, the next cohort will be in the order of 
cohorts 2 (MLN9708 4.0 mg plus Rd), 3 (MLN9708 5.5 mg alone), and 4 (MLN9708 5.5 mg 
plus Rd).  Even if a dosage is considered tolerable and transition to the next cohort is 
considered feasible, the next cohort may not be studied based on the results of the overseas 
clinical studies and the current study.  
The additional written informed consent for extended treatment will be obtained before the first 
dose of MLN9708 in Cycle 2 from the subjects who meet the criteria in “6.4 Criteria for 
Beginning the Next Cycle of Treatment“ and have no safety concern. Subjects who do not give
the consent will undergo end of study (EOS) visit on 29 days after the last dose of MLN9708 in 
Cycle 1. The subjects giving the consent can continue the study treatment up to 12 cycles 
unless they meet the criteria in “8.1 Removal of Subjects” including evidence of progressive 
disease (PD) and intolerable toxicity. Subjects may remain on treatment after the 12 cycles if 
the investigator considers it beneficial for the subjects.
All subjects should undergo end of study visit on 29 days after the last dose of MLN9708.
The overall study design is described in “Study Design and Treatment Schema”.


Product: MLN9708
Protocol Number: TB-MC010034
Date: 22 November 2016
Page 4 of 102
CONFIDENTIAL
Primary and Secondary Endpoints:  
Primary:  
• DLT, adverse events, body weight, vital sign, 12-lead ECGs, and laboratory tests
• Plasma MLN2238 (active boronic acid form of MLN9708) concentration
Secondary:  
• Number of subjects with complete response (CR), very good partial response (VGPR), or 
partial response (PR)
Number of Subjects: 12 to 24 (3 to 6 subjects in each cohort)
Number of Study Center(s): 5 centers
Summary of Subject Eligibility Criteria:  
Inclusion Criteria:
Patients must give written consent to the participation and meet ALL of the following inclusion 
criteria to be eligible for the study.
Disease related  
1)
Japanese patients with multiple myeloma according to diagnostic criteria shown in 
Appendix E
2)
Previously treated with 2 or more regimens including all the following drugs:
• bortezomib
• thalidomide or lenalidomide
• corticosteroids
3)
Patients who have relapsed following the previous therapy or failed to continue the
treatment due to their intolerability to the last treatment regimen for multiple myeloma
4)
Measurable disease defined by at least one 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 FLC level ≥ 10 mg/dL (≥100 mg/L), 
provided that the serum FLC ratio is abnormal.
5)
Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
Demographic 
6)
Patients 20 years or older at giving their informed consent
7)
Patients must be able to stay in the hospital for Cycle 1 treatment
Laboratory values
Patients must meet the following laboratory criteria at screening.  Patients must not receive
granulocyte colony stimulating factor (G-CSF) or blood transfusion within 7 days before the 
test of neutrophil and platelet counts:
8)
Absolute neutrophil count (ANC): ≥1,000/mm3
9)
Platelet count: ≥  75,000/mm3


Product: MLN9708
Protocol Number: TB-MC010034
Date: 22 November 2016
Page 5 of 102
CONFIDENTIAL
10) Total bilirubin: ≤1.5 × the upper limit of normal range (ULN)
11) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST): ≤3 × ULN
12) Creatinine clearance: calculated by using Cockcroft-Gault formula (Appendix F)
MLN9708 monotherapy cohort: ≥ 30 mL/min
MLN9708 with Rd cohort: ≥ 60 mL/min
General 
13) Patients recovered (Grade 1) from the toxicities of the prior treatments. 
ANC ≥1,000/mm3.
14) Life expectancy of at least 3 months, in the judgment of the investigator
15) Patients conforming to proper management guidelines of lenalidomide (MLN9708 
with Rd cohort only)
Exclusion Criteria:
Patients meeting ANY of the following exclusion criteria cannot be enrolled in the study.
Disease related  
1)
Patients with plasmacytoma only
2)
Patients with plasma cell leukemia
3)
Patients with central nervous system invasion
Medications  
4)
Radiotherapy within 14 days before enrollment.
5)
Other anti-tumor drug administration within 21 days before enrollment.
6)
Other investigational products administration within 21 days before enrollment (60 
days from the last dose for carfilzomib). 
7)
Antibody treatment within 42 days before enrollment.
8)
Systemic treatment with potent CYP1A2 inhibitors (fluvoxamine, enoxacin), potent 
CYP3A inhibitors (clarithromycin, telithromycin, itraconazole, voriconazole, 
ketoconazole), or potent CYP3A inducers (rifampin, rifabutin, carbamazepine, 
phenytoin, phenobarbital), or use of foods containing Ginkgo biloba extract, St. John’s 
Wort, or grapefruit within 14 days before enrollment.
9)
Treatment with corticosteroids greater than 10 mg of prednisolone per day. Inhaled 
and topical steroids are permitted.
Other medical conditions
10) Peripheral neuropathy ≥ Grade 2.
11) Diarrhea ≥ Grade 2.
12) Major surgery requiring general anesthesia within 14 days before enrollment.
13) Infection requiring systemic antibiotic treatment or other serious infections within 14 
days before enrollment.
14) Evidence of concurrent uncontrolled cardiovascular conditions including hypertension, 
cardiac arrhythmias, New York Heart Association (NYHA) Class III or worse
congestive heart failure, angina, myocardial infarction, or cerebral infarction within 6
months before enrollment.


Product: MLN9708
Protocol Number: TB-MC010034
Date: 22 November 2016
Page 6 of 102
CONFIDENTIAL
15) Corrected QT interval (QTc) > 470 milliseconds on a 12-lead ECG obtained during the 
screening period.
16) Tested positive for human immunodeficiency virus (HIV) antibody, hepatitis B virus
surface antigen (HBs antigen), or hepatitis C virus (HCV) antibody during the 
screening period.
17) Hypersensitivity to MLN9708 (including excipients), boron, or boron-containing 
drugs.
18) Hypersensitivity to lenalidomide, or dexamethasone, or excipients contained in the 
formulation of each drug (MLN9708 with Rd cohort only). 
19) Known gastrointestinal diseases (difficulty swallowing, inflamed gastroenteritis, and 
Crohn disease), or gastrointestinal procedure (endoscopic procedure is permitted), that 
could interfere with the oral absorption or tolerance of the study treatment.
20) Uncontrolled diabetes mellitus.
21) A history of interstitial lung disease or lung fibrosis, or a current complication of 
interstitial lung disease or lung fibrosis diagnosed by diagnostic chest imaging.
22) Prior or current complications of deep vein thrombosis or pulmonary embolism 
(MLN9708 with Rd cohort only).
23) 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 complete resection.
General
24) Patients who do not consent to use adequate contraceptive precautions (e.g. condoms 
and oral contraceptives) during the following term: 
• For women with childbearing potential*, from when giving their consent through 3
months after the last dose of MLN9708, dexamethasone, or lenalidomide 
• For men having their partners with childbearing potential, from giving their consent 
through 4 months after last dose of MLN9708, dexamethasone, or lenalidomide
* Women with child-bearing potential are those who are premenopausal (menopause is defined as the 
time when there has been no menstrual periods for at least 1 year), or who have not had a bilateral tube 
ligation, bilateral oophorectomy, or hysterectomy. The menstruation is possibly interrupted by 
chemotherapy not defined as menopause.)
25) Pregnant (e.g. positive for pregnancy test) or lactating. Lactation is prohibited from the 
first dose through 6 months after the last dose of MLN9708, dexamethasone, and 
lenalidomide. 
26) Use of an investigational medical device within 28 days before enrollment.
27) Any inabilities that could potentially interfere with the consent or completion of 
treatment according to this protocol. 
28) Having difficulties in participation to this study by the investigator’s judgment
Investigational Product Dosage and Administration:  
One capsule of MLN9708 will be orally administered once weekly for 3 weeks (Days 1, 8, and 
15, and skip Day 22) in a 28-day cycle for up to 12 cycles.
• Cohort 1: 4.0 mg of MLN9708


Product: MLN9708
Protocol Number: TB-MC010034
Date: 22 November 2016
Page 7 of 102
CONFIDENTIAL
• Cohort 2: 4.0 mg of MLN9708 plus Rd
• Cohort 3: 5.5 mg of MLN9708
• Cohort 4: 5.5 mg of MLN9708 plus Rd
One capsule contains 4.0 or 5.5 mg of active boronic acid form of MLN9708 (MLN2238)
Statistical Considerations:  
Demographic data and all endpoints data will be analyzed. Summary statistics (number of 
subjects, mean, median, standard deviation, maximum, and minimum) will be calculated for the 
continuous data. Frequency and percentage will be calculated for the categorical data.
The incidence and percentage of treatment-emergent adverse events will be summarized by 
system organ class (SOC) and preferred term (PT) of the ICH Medical Dictionary for 
Regulatory Activities (MedDRA) and by grade. In addition, the following adverse events will 
be summarized with the same method.
•
Serious adverse events
•
Adverse events leading to permanent discontinuation of study treatment
•
Treatment-related adverse events
•
Treatment-related serious adverse events
•
Treatment-related adverse events leading to permanent discontinuation of study treatment
DLT will be summarized in DLT analysis set.
Sponsor:  Takeda Pharmaceutical Company Limited


Product: MLN9708
Protocol Number: TB-MC010034
Date: 22 November 2016
Page 8 of 102
CONFIDENTIAL
Study Design and Treatment Schema
Screening Period
Subject Enrollment
Treatment Period
Cohort 1: MLN9708 4.0 mg
Study Day
MLN9708
Cycle 1*
Day 1
Day 8
Day 15
Day 22
X
X
X
-
* Repeat the same administration schedule for Cycle 2 and after
Cohort 2: MLN9708 4.0 mg + Rd
Study Day
MLN9708
Cycle 1*
Day 1
Day 8
Day 15
Day 22
X
X
X
-
Lenalidomide
Day 1 - 21
Dexamethasone
X
X
X
X
Cohort 3: MLN9708 5.5 mg
Study Day
MLN9708
Cycle 1*
Day 1
Day 8
Day 15
Day 22
X
X
X
-
Cohort 4: MLN9708 5.5 mg + Rd
Study Day
MLN9708
Cycle 1*
Day 1
Day 8
Day 15
Day 22
X
X
X
-
Lenalidomide
Day 1 - 21
Dexamethasone
X
X
X
X
Tolerable 
Move up to next 
cohort
Tolerable 
Move up to next 
cohort
Tolerable 
Move up to next 
cohort
The sponsor will decide whether the next cohort will be studied and the dose of 
the next cohort in consultation with Efficacy and Safety Evaluation committee, 
if necessary, after 28 days (until observation of Day 29 of treatment period) 
have past since the first dose.
End of Study Visit (29 days after the last dose)


Product: MLN9708
Protocol Number: TB-MC010034
Date: 22 November 2016
Page 9 of 102
CONFIDENTIAL
Study Glossary
Abbreviation
Definition/Explanation
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
AUC
area under the concentration versus time curve
BCRP
breast cancer resistance protein
CLb
blood clearance
CLp
plasma clearance
Cmax
maximum plasma concentration
CR
complete response
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome P450
DLT
dose-limiting toxicity
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EOS
end of study
ESEC
the Efficacy and Safety Evaluation Committee
FLC
free light chain
GCP
Good Clinical Practice
G-CSF
granulocyte colony stimulating factor
GLP
Good Laboratory Practice
HbA1c
hemoglobin A1c
HBV
hepatitis B virus
HCV
hepatitis C virus
hERG
human ether à-go-go-related gene
HIV
human immunodeficiency virus
IC50
half-maximal inhibitory concentration
ICH
International Conference on Harmonisation
IRB
institutional review board
IV
intravenous(ly)
J-GCP
Ministerial Ordinance Concerning the Standards for the Conduct of 
Clinical Trials of Medicinal Products including the relevant notifications
LDH
lactate dehydrogenase
1/3


Product: MLN9708
Protocol Number: TB-MC010034
Date: 22 November 2016
Page 10 of 102
CONFIDENTIAL
Abbreviation
Definition/Explanation
MedDRA
Medical Dictionary for Regulatory Activities
MHLW
Ministry of Health, Labour and Welfare
MPI
Millennium Pharmaceuticals, Inc
MRI
magnetic resonance imaging
MRP2
multidrug resistance protein 2
MTD
maximum tolerated dose
NCCN
National Comprehensive Cancer Network
NYHA
New York Heart Association
PD
progressive disease
P-gp
para-glycoprotein
PO
by mouth, orally
PR
partial response
PT
preferred term
QTc
corrected QT interval
RBC
red blood cell
Rd 
lenalidomide and dexamethasone 
RevMate®
the lenalidomide proper management procedures
sCR
stringent complete response
SD
stable disease
SCID
severe combined immunodeficient
SOC
system organ class
SpO2
transcutaneous oxygen saturation
t1/2
elimination half-life
Tmax
time to first maximum plasma concentration
ULN
upper limit of normal range
VGPR
very good partial response
VRd
bortezomib, lenalidomide and low-dose dexamethasone
Vss
volume of distribution at steady-state
Vss,b
blood volume of distribution at steady-state
Vss,p
plasma volume of distribution at steady-state
2/3


Product: MLN9708
Protocol Number: TB-MC010034
Date: 22 November 2016
Page 11 of 102
CONFIDENTIAL
Term
Definition/Explanation
For overall study
Study Initiation
The start of the study for the first subject
End of Study
The end of the study for the last subject
For each subject
Study Initiation
The start of screening
End of study
The date of the last safety follow-up visit, or withdrawal of consent, or 
death
Start of Screening
The date a subject signs the informed consent
Study Day 1
The first day of the study-specific treatment
Enrollment
The date on Enrollment Confirmation Form
Screening failure
Subjects not enrolled into the study after signing of the informed consent
Baseline values
Values obtained on Study Day 1 prior to the first study-specified treatment.  
When no variables/evaluations are scheduled on Study Day 1, the values 
obtained during screening period immediately before Study Day 1 are used 
as baseline values.
MLN2238
Active boronic acid form of MLN9708
3/3


Product: MLN9708
Protocol Number: TB-MC010034
Date: 22 November 2016
Page 12 of 102
CONFIDENTIAL
Table of Contents
Page
PROTOCOL SUMMARY ········································································3
Study Design and Treatment Schema ····························································8
Study Glossary······················································································9
1.
BACKGROUND AND RATIONALE ··················································· 16
1.1
Multiple myeloma·································································· 16
1.2
MLN9708 ··········································································· 17
1.3
Nonclinical Studies································································· 17
1.3.1
Pharmacology··························································· 18
1.3.2
Pharmacokinetics ······················································· 18
1.3.3
Safety Pharmacology··················································· 20
1.3.4
Toxicology Study······················································· 21
1.4
Clinical Experience ································································ 21
1.4.1
Clinical Studies in Relapsed or Refractory Multiple 
Myeloma································································· 22
1.4.2
Clinical Studies in Patients With Newly Diagnosed Multiple 
Myeloma································································· 25
1.4.3
Clinical Trials in Other Tumor Types ································ 26
1.4.4
Nonclinical Pharmacology Studies ··································· 27
1.5
Known and Anticipated Risks and Benefits of MLN9708····················· 27
1.5.1
Known and Anticipated Risks········································· 27
1.5.2
Anticipated benefits ···················································· 30
1.6
Concomitant medications·························································· 30
1.6.1
Lenalidomide ··························································· 31
1.6.2
Dexamethasone ························································· 31
1.7
Study plan rationale ································································ 31
1.7.1
Rationale for starting to plan this study······························ 31
1.7.2
Rationale for using a fixed dose ······································ 32
1.7.3
Rationale for including an MLN9708 + Rd cohort ················· 33
1.7.4
Rationale for the initial doses and cohorts··························· 33
1.7.5
Rationale for once-weekly dosing ···································· 34
2.
OBJECTIVES··············································································· 35
2.1
Primary Objective ·································································· 35
2.2
Secondary Objective(s) ···························································· 35


Product: MLN9708
Protocol Number: TB-MC010034
Date: 22 November 2016
Page 13 of 102
CONFIDENTIAL
3.
EXPERIMENTAL PLAN ································································· 36
3.1
Study Design········································································ 36
3.2
Study Centers ······································································· 37
3.3
Number of Subjects ································································ 37
3.4
Estimated Study Duration ························································· 37
3.4.1
Study Duration for Participants ······································· 37
3.5
Study Committees·································································· 38
3.5.1
ESEC····································································· 38
4.
SUBJECT ELIGIBILITY·································································· 39
4.1
Inclusion Criteria ··································································· 39
4.2
Exclusion Criteria ·································································· 40
5.
SUBJECT ENROLLMENT······························································· 43
5.1
Enrollment Procedures····························································· 44
5.2
RevMate® Registration ···························································· 44
6.
TREATMENT PROCEDURES··························································· 46
6.1
MLN9708 ··········································································· 46
6.2
Concomitant medications·························································· 46
6.2.1
Lenalidomide (
5 mg) ·························· 46
6.2.2
Dexamethasone (
4 mg) ·························· 47
6.3
Dosage, administration method, dosing schedule ······························ 47
6.3.1
MLN9708 administration·············································· 47
6.3.2
Lenalidomide Administration (Rd Concomitant Cohort 
Only) ····································································· 47
6.3.3
Dexamethasone Administration (Rd Concomitant Cohort 
Only) ····································································· 48
6.4
Criteria for Beginning the Next Cycle of Treatment ··························· 48
6.4.1
MLN9708 Monotherapy··············································· 48
6.4.2
MLN9708 in Combination With Rd·································· 49
6.4.3
Criteria for Dose Delays ··············································· 49
6.5
Dose Modification·································································· 50
6.5.1
MLN9708 Monotherapy··············································· 50
6.5.2
MLN9708 in combination with Rd··································· 51
6.6
Cohort Transition and Early Stopping Guidelines ······························ 58
6.6.1
Cohort Transition ······················································· 58
6.6.2
Early Stopping Guidelines············································· 60
6.7
DLT ·················································································· 60
6.7.1
DLT Assessment Period················································ 60
6.7.2
DLT-Evaluable Subjects ··············································· 60
CCI
CCI


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6.7.3
Definitions of DLT ····················································· 60
6.8
Permitted Concomitant Medications and Procedures ·························· 61
6.9
Excluded Concomitant Medications and Procedures··························· 61
7.
STUDY PROCEDURES ·································································· 63
7.1
Subject Screening ·································································· 63
7.2
Examinations, observations, and evaluations ··································· 63
7.2.1
Screening period························································ 63
7.2.2
Treatment period························································ 65
7.2.3
End of study····························································· 68
7.2.4
Laboratory tests························································· 70
7.2.5
Volume of blood collected············································· 71
7.2.6
Pharmacokinetic sample collection time points····················· 71
7.2.7
Assessment of antitumor activity ····································· 72
8.
REMOVAL AND REPLACEMENT OF SUBJECTS·································· 73
8.1
Removal of Subjects ······························································· 73
8.2
Replacement of Subjects ·························································· 74
9.
SAFETY DATA COLLECTION, RECORDING, AND REPORTING··············· 75
9.1
Definitions ·········································································· 75
9.1.1
Adverse Events ························································· 75
9.1.2
Serious Adverse Events················································ 75
9.2
All Adverse Events Reporting Procedures ······································ 76
9.3
Serious Adverse Event Reporting Procedures··································· 77
10. STATISTICAL CONSIDERATIONS ···················································· 79
10.1
Endpoints and Analysis Set ······················································· 79
10.1.1
Primary Endpoint······················································· 79
10.1.2
Secondary Endpoints··················································· 79
10.1.3
Analysis Set ····························································· 79
10.2
Sample Size Considerations······················································· 79
10.3
Interim Analysis and Early Stopping Guidelines ······························· 80
10.4
Statistical Methods of Analysis ··················································· 80
10.4.1
Safety endpoints ························································ 80
10.4.2
Efficacy endpoints······················································ 81
10.4.3
Pharmacokinetic analysis·············································· 81
11. REGULATORY OBLIGATIONS ························································ 82
11.1
Quality Control of Data and Quality Assurance ································ 82
11.2
Informed Consent ·································································· 82
11.3
Institutional Review Board························································ 83


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11.4
Subject Confidentiality ···························································· 83
11.5
Dissemination of New Information ·············································· 84
12. ADMINISTRATIVE AND LEGAL OBLIGATIONS·································· 85
12.1
Protocol Amendments and Study Termination·································· 85
12.2
Source Data and Essential Documents··········································· 85
12.3
Data Handling and Retention of Records········································ 86
12.3.1
Data Handling··························································· 86
12.3.2
Retention of Records··················································· 86
12.4
Language ············································································ 87
12.5
Publication Policy ·································································· 87
12.6
Compensation······································································· 88
12.7
Financing············································································ 88
13. REFERENCES ············································································· 89
·············································································· 91
······················································· 92
·················· 95
····················· 96
············································ 97
·································· 98
························································ 99
···································· 100
 
··········································· 102
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


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1.
BACKGROUND AND RATIONALE
1.1
Multiple myeloma
Multiple myeloma is a disease in which the plasma cells proliferate monoclonally in the 
bone marrow and become malignant (myeloma cells). Multiple myeloma gets its name 
because the myeloma cells infiltrate the bone marrow and form tumors in multiple 
locations. Humoral factors such as cytokines that are produced by the interaction of the 
bone marrow interstitial cells with the myeloma cells and monoclonal immunoglobulin 
(M-protein), which is produced by the myeloma cells, result in complications such as 
bone marrow failure, bone destruction, hypercalcemia, and renal failure. Multiple 
myeloma frequently occurs in the elderly. In the US, it is the second-leading hematologic 
malignancy: approximately 5 to 7 new cases of multiple myeloma are diagnosed per 
100,000 people each year (this works out to approximately 20,000 people total), and 
11,000 people die of malignant myeloma each year (accounting for about 2% of all 
cancer deaths). The situation is similar in Europe (Jemal et al, 2005; NCCN Guidelines, 
Version 1, 2012). In Japan, approximately 2 to 3 new cases of multiple myeloma are 
diagnosed per 100,000 people each year, and the total number of patients with multiple 
myeloma is estimated to be 13,000 (MHLW 2008 Patient Survey). In 2009, the number 
of deaths due to multiple myeloma was 4,084 in all (2,089 males and 1,995 females), 
meaning that multiple myeloma accounted for 1.2% of all cancer deaths (National Cancer 
Center, Center for Cancer Control and Information Services, Cancer Statistics in Japan 
2010). In Japan, multiple myeloma is treated in virtually the same way as in the US and
Europe. In the US and Europe, diagnosis and treatment guidelines have been 
promulgated by the NCCN, the British Committee for Standards in Haematology, and the 
UK Myeloma Forum. The NCCN Guidelines (Version 1, 2012) recommend a treatment 
regimen that includes bortezomib or an immunomodulator (thalidomide or lenalidomide) 
in the frontline setting. Patients deemed eligible for autologous stem cell transplants 
(ASCT) subsequently receive ASCT with high-dose chemotherapy. Bortezomib, 
thalidomide, lenalidomide, and other antitumor agent combination therapies are listed as 
salvage therapies. In Japan, the Japanese Society of Myeloma Guidelines (Version 2) 
issued in 2008, and these guidelines recommend almost the same treatments as those 
recommended in the US and Europe.


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Although treatments involving thalidomide, bortezomib, lenalidomide, and ASCT with 
high-dose chemotherapy have yielded better results – the 5-year survival was 25% in 
1975, but rose to 34% in the period from 1999 to 2005 (NCCN Guidelines, Version 1, 
2012). However, most patients, both in Japan and in other countries, experience re-
exacerbation during treatment. Salvage therapies are only effective in the short term; in 
the end, the patients stop responding to treatment. New and better drugs are therefore 
needed.
1.2
MLN9708
MLN9708 is an inhibitor of the 20S proteasome currently under development by 
Millennium Pharmaceuticals, Inc (MPI) in the United States. Inhibition of the 20S 
proteasome has been validated as a therapeutic target for the treatment of malignancies by 
the efficacy of the first-in-class proteasome inhibitor, bortezomib (Velcade®) in multiple 
myeloma and other hematologic malignancies. MPI has been developing MLN9708 for 
the better efficacy, safety, and convenience of bortezomib. 
MLN9708 is the citrate ester of the biologically active dipeptide boronic acid, MLN2238.
In aqueous solution or in blood, MLN9708 rapidly hydrolyzes to MLN2238, the active 
form that selectively and reversibly inhibits the proteasome. Similar to bortezomib, 
MLN2238 binds the β5 subunit of the 20S proteasome; however, it has a shorter 
dissociation half-life than bortezomib which contributes to wide distribution to tissues, 
and expected to demonstrate stronger antitumor activity. Nonclinical study showed 
greater antitumor activity against various xenograft models compared to bortezomib. 
MLN9708 has been formulated for both intravenous (IV) and oral (PO) administration, 
and oral formulation is used for development for multiple myeloma.
1.3
Nonclinical Studies 
MLN9708 is primarily examined as MLN2238 in the nonclinical studies since MLN9708 
rapidly hydrolyzes to the active form, MLN2238 after dosing.


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1.3.1
Pharmacology
There are several features of MLN2238, such as sustained pharmacodynamics effects and 
activity in bortezomib-refractory lymphoma xenograft models, that suggest it may have 
activity that extends beyond that seen with bortezomib.
1.3.1.1
In Vitro Pharmacology
MLN2238 inhibits β5 site 20S proteasome activity in vitro, with a concentration 
producing 50% inhibition (IC50) of 3.4 nmol/L Potency is reduced roughly 10-fold 
versus β1 (IC50= 31 nmol/L) and 1,000-fold versus β2 (IC50 = 3,500 nmol/L). MLN2238 
was also tested for inhibition against a panel of 103 kinases, 18 receptors 
(neurotransmitter, ion channel, brain and gut receptors), and 9 serine proteases. In all 
cases, the IC50 values were ≥10 µmol/L. Furthermore, MLN2238 demonstrated potent 
cell growth inhibition activity against MDA-MB-231 human breast cancer cells.
1.3.1.2
In Vivo Pharmacology
To determine the activity of MLN2238 in vivo, pharmacodynamics studies were 
performed in immunocompromised mice bearing either CWR22 human prostate or WSU-
DLCL2 (human diffuse large B-cell lymphoma) tumors. In CRW22 xenografts, there 
was a clear dose response seen in both tumor 20S proteasome inhibition and in changes 
in the protein markers of proteasome inhibition (GADD34 and ATF-3). In WSU-DLCL2 
xenografts, increased expression of protein markers of proteasome inhibition was resulted 
with MLN2238, and observed greater tumor proteasome inhibition compared to 
bortezomib. MLN2238 demonstrated stronger antitumor activity in 3 human lymphoma 
xenograft models including WSU-DLCL (as compared to bortezomib). In the case of the 
CWR22 xenograft model, significant antitumor activity was seen with both IV and PO 
dosing.
1.3.2
Pharmacokinetics
The pharmacokinetic properties of MLN2238, the active form of MLN9708, were studied 
in severe combined immunodeficient (SCID) mice bearing human CWR22 tumor 
xenografts, Sprague-Dawley rats, beagle dogs, and cynomolgus monkeys. Because of the 


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extensive red blood cell (RBC) partitioning of MLN2238, both blood and plasma 
pharmacokinetic parameters were determined in these studies. MLN2238 had a very low 
blood clearance (CLb) and a moderate blood volume of distribution at steady-state (Vss,b) 
after IV administration. The concentration-versus-time curve of MLN2238 displayed a 
distinct biexponential profile with a steep initial distribution phase and a long terminal 
elimination half-life (t1/2) (>24 hours) in all species tested. MLN2238 had higher plasma 
clearance (CLp) and a larger plasma Vss (Vss,p) than in CLb and Vss, b, largely because of 
the extensive RBC partitioning.
The pharmacokinetic properties of MLN2238 after oral administration were studied in 
rats and dogs. The plasma oral bioavailability was 41% in rats and nearly 100% in dogs. 
A clinical prototype formulation of the MLN9708 capsule demonstrated that MLN2238 
had excellent oral bioavailability and an excellent absorption profile in dogs. In addition, 
interindividual variability (coefficient of variation) in maximum plasma concentration 
(Cmax) and area under the concentration versus time curve from 0 to 24 hours (AUC0-24hr) 
after PO administration was low to moderate, similar to that after IV administration. The 
terminal t1/2 after oral administration was also similar to that after IV administration.
Metabolism appears to be a major route of elimination for MLN2238 and urinary 
excretion of the parent drug was negligible (< 5% of dose). In vitro study demonstrated 
that MLN2238 was metabolized by multiple cytochrome P450 (CYP) isozymes and non-
CYP enzymes and proteins. The rank order of relative biotransformation activity of each 
of the 5 major human CYP isozymes was 3A4 (34.2%) >1A2 (30.7%) >2D6 (14.7%) 
>2C9 (12.1%) >2C19 (negligible). All metabolites found in human liver microsome 
studies were also found in rat and dog liver microsomal studies, supporting the use of rats 
and dogs as appropriate species for toxicology studies. MLN2238 is neither an inhibitor 
of CYP isozymes 1A2, 2C9, 2C19, 2D6, and 3A4 (IC50 >30 µM, with an estimated 
inhibition dissociation constant [Ki] >15 µmol/L), nor a time-dependent inhibitor of 
CYP3A4/5 (up to 30 µmol/L). The potential for MLN9708 treatment to produce 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 a strong CYP3A4 inducer 
because of the possible contribution of CYP3A4- and CYP1A2-mediated metabolism to 
the elimination of MLN9708 in humans.


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MLN2238 may be a low-affinity substrate of para-glycoprotein (P-gp), breast cancer 
resistance protein (BCRP), and multidrug resistance protein 2 (MRP2). MLN2238 
however is not an inhibitor of P-gp, BCRP, and MRP2 transporters (IC50 > 100 µmol/L).
Consequently, the potential for MLN2238 to cause DDIs with substrates or inhibitors of 
P-gp, BCRP, and MRP2 is low.
1.3.3
Safety Pharmacology
In exploratory safety pharmacology studies, MLN2238 was a weak inhibitor of the 
cloned cardiac potassium (K+) human ether à-go-go-related gene (hERG) channel, with 
an IC50 of 59.6 µM, which exceeds, by approximately 200-fold, the plasma Cmax
(111 ng/mL [0.3 µM]) predicted to occur in humans at the optimally efficacious dose 
after IV administration.
In the Good Laboratory Practice (GLP) compliant, 1-cycle, repeat-dose, PO toxicology 
study in beagle dogs, an increase in corrected QT interval (QTc) was seen in male dogs at 
nontolerated doses, and a potential increase in QTc was seen in male dogs at tolerated 
doses. However, increased QTc was not seen in female dogs at any dose, despite the fact 
that female dogs had plasma Cmax values similar to those of male dogs. Additionally, in a 
GLP-compliant, 2-cycle, repeat-dose, IV toxicology study in beagle dogs, no increase in 
QTc was seen in either male or female dogs at any dose, even though dogs in the IV study 
had higher plasma MLN2238 concentration values than did the male dogs in the PO study. 
These data suggest that MLN2238 has a low potential for prolonging the QT interval in 
vivo. In the GLP-compliant, repeat-dose toxicology studies in beagle dogs, no effects on 
clinical signs or physical examination findings indicative of impaired respiratory or CNS 
function were noted at tolerated doses ( ≤ 0.14 mg/kg) after IV or PO administration. 
Detailed neurologic examinations MLN2238-related changes in neurologic parameters, 
primarily observed as changes in mental status (very low arousal) and changes in gait 
(ataxia) were observed at nontolerated doses (≥ 0.18 mg/kg). Similar findings were not 
observed at tolerated doses with any consistency.


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1.3.4
Toxicology Study
1.3.4.1
In Vitro Toxicology
MLN2238 was not mutagenic in a GLP-compliant bacterial reverse mutation assay 
(Ames assay).
1.3.4.2
In Vivo Toxicology
After repeated IV and PO administration of MLN2238, the exposures that were tolerated 
in rats were similar to those tolerated in dogs, indicating similar species sensitivity. The 
target tissues for dogs and rats were similar and consisted of the bone marrow, peripheral 
ganglia, and intestines. Higher exposures were achieved in the IV study compared to the 
PO study, and it is likely that the differences seen in peripheral white blood cell counts 
and bone marrow hypocellularity between the 2 studies reflected differences in exposure 
and not differences in toxicologic response after PO versus IV administration. Similarly, 
the lower exposures achieved after PO versus IV administration likely account for the 
lack of peripheral nervous system effects seen in the PO study. The toxicologic effects 
seen in rats (bone marrow hypocellularity with corresponding thrombocytopenia and 
neutropenia, degeneration of peripheral ganglia with secondary degeneration of 
peripheral nerves and spinal cord dorsal column, intestinal mucosal hyperplasia, and 
hepatocellular hypertrophy and vacuolization) are qualitatively similar to what was 
observed previously in rodents treated with bortezomib.
See MLN9708 Investigator’s Brochure for more detail.
1.4
Clinical Experience
No clinical studies evaluating MLN9708 have been conducted in Japan to date. Safety, 
tolerability, pharmacokinetics, and disease response are assessed in 7 phase 1 or phase 
1/2 studies (Table 1-1). IV and PO administration are being evaluated with a weekly and 
a twice-weekly dosing schedule. MLN9708 is given on Days 1, 8, and 15 of a 28-day 
cycle in the once weekly dosing schedule, and the drug is given on Days 1, 4, 8, and 11 of 
a 21-day cycle in the twice-weekly dosing schedule. As of 12 October 2011, preliminary 
data have been obtained from 247 subjects enrolled across 7 ongoing studies.


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Table 1-1. Summary of Overseas Studies
Phase 1 Study
Study C16001
IV, single agent, twice weekly, solid tumors 
Study C16002
IV, single agent, weekly, lymphoma
Study C16003
PO, single agent, twice weekly, relapsed or refractory multiple myeloma
Study C16004
PO, single agent, weekly, relapsed or refractory multiple myeloma
Study C16007
PO, single agent, weekly, relapsed or refractory light-chain amyloidosis
Phase 1/2 Study
Study C16005
PO, combination with Rda, weekly, newly diagnosed multiple myeloma
Study C16006
PO, combination with melphalan and prednisolone, weekly and twice weekly, 
newly diagnosed multiple myeloma
a Lenalidomide, 25 mg once daily for 21 consecutive days; dexamethasone, 40 mg once weekly
In addition to these ongoing studies, phase 1/2 study (Study C16008) in newly diagnosed 
multiple myeloma patients and global phase 3 study (Study C16010) in relapsed or 
refractory multiple myeloma patients are currently planned.
Table 1-2. Summary of Planned Overseas Clinical Studies
Phase 1/2 Study
Study C16008
PO, combination with Rd, twice weekly, newly diagnosed multiple myeloma
Phase 3 Study
Study C16010
PO, combination with Rd, weekly, relapsed or refractory multiple myeloma
1.4.1
Clinical Studies in Relapsed or Refractory Multiple Myeloma
Two ongoing clinical trials, Studies C16003 and C16004, investigate single-agent 
MLN9708 in patients with relapsed or refractory multiple myeloma.
In Study C16003 (0.24, 0.48, 0.80, 1.20, 1.68, 2.23 mg/m2; twice-weekly), 56 patients 
were enrolled as of 12 October 2011 and received treatment for 1 to 28 cycles (median,
3.5 cycles). One patient achieved complete response, 5 patients achieved a partial 
response, and 29 patients achieved minor response. 
In Study C16003, 1 of 3 patients experienced a protocol-defined DLT (Grade 3 rash) at a 
dose of 2.23 mg/m2, and an additional patient at this dose experienced Grade 4 
thrombocytopenia at DLT. The intermediate dose of 2.0 mg/m2 was set as a new dose 


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group approximately half way between the 2 existing dose levels of 2.23 mg/m2 and 
1.68 mg/m2. Given that none of the 6 patients treated at the 2.0 mg/m2 group experienced 
a DLT, the maximum tolerated dose (MTD) of MLN9708 administered twice weekly was 
determined to be 2.0 mg/m2.
Overall, 98% of patients experienced a treatment-emergent adverse event. Peripheral 
neuropathy was limited to Grade 1 or 2 in 10% of patients; with all of these patients 
reporting baseline Grade 1 peripheral neuropathy at study entry. The most common 
(≥20%) treatment-emergent adverse events are shown in Table 1-3.
Table 1-3.  Most Common (≥20%) Treatment-Emergent Adverse Events 
(Study C16003, N=56)
Treatment-Emergent Adverse Events
Most Common (≥20%) Any Grade
Fatigue (57%)
Skin rash (all terms) (50%)
Thrombocytopenia (41%)
Diarrhea (36%)
Nausea (34%)
Vomiting and fever (30% each)
Cough (25%)
Anorexia (23%)
Neutropenia (21%)
Drug-Related Grade 3 in 2 Patients
Thrombocytopenia (n = 19)
Neutropenia (n = 8)
Fatigue (n = 5)
Rash (all terms) (n = 5)
Data cutoff 12 October 2011
Fifteen patients have experienced drug-related serious adverse events involving 
thrombocytopenia, anemia, neutropenia, febrile neutropenia, nausea, vomiting, 
abdominal pain, chest pain (noncardiac), orthostatic hypotension, hypotension, 
hypophosphatemia, hyperuricemia, fever, chills, rash, pneumonia, hypoxia, pulmonary 
hypertension, fall, headache, fatigue, or dehydration. Five patients discontinued therapy 
due to a treatment-emergent adverse event; 3 patients due to events considered at least 
possibly related to MLN9708 (thrombocytopenia, pulmonary hypertension, and pruritic 
rash) and remaining 2 patients due to events related to disease progression (spinal cord 


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compression and bone pain). There have been 2 on study deaths reported as not related to 
MLN9708.
In Study C16004 (0.24, 0.48, 0.80, 1.20, 1.68, 2.23, 2.97, and 3.95 mg/m2, weekly), 32 
patients were enrolled as of 12 October 2011 and received treatment for 1 to 11 cycles 
(median, 2 cycles). One patient achieved a VGPR and one patient achieved a PR.
In Study C16004, 2 of 3 patients experienced protocol-defined DLT (Grade 3 rash, Grade 
3 nausea, vomiting, and diarrhea) at a dose of 3.95 mg/m2. Additional patients were 
enrolled and treated at 2.97 mg/m2. One of 6 patients treated at 2.97 mg/m2 experienced 
a DLT (Grade 3 nausea, vomiting, and diarrhea). The MTD of MLN9708 administered 
weekly was determined to be 2.97 mg/m2.
Overall, 97% of patients experienced a treatment-emergent adverse event. Peripheral 
neuropathy was limited to Grade 1 or 2 in 3 patients; with all patients reporting baseline 
Grade 1 peripheral neuropathy at study entry. The most common (20%) treatment-
emergent adverse events are shown in Table 1-4.
Table 1-4. Most Common (20%) Treatment-Emergent Adverse Events
(Study C16004, N=32)
Treatment-Emergent Adverse Events
Most Common (20%) Any Grade
Fatigue (50%)
Thrombocytopenia (34%)
Nausea (38%)
Diarrhea (31%)
Vomiting (28%)
Drug-Related Grade 3 in 2 Patients
Thrombocytopenia (n = 4; 1 Grade 4 and 3 Grade 3)
Neutropenia and diarrhea (n = 3 each)
Data cutoff 12 October 2011
There have been 2 drug-related serious adverse events (diarrhea, dehydration, and 
dizziness). Six patients discontinued MLN9708 due to a treatment-emergent adverse 
event considered at least possibly related to MLN9708 (thrombocytopenia, rash, 
neutropenia, diarrhea, nausea, vomiting, and abdominal pain). There has been one on
study death reported which was considered related to disease progression.


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1.4.2
Clinical Studies in Patients With Newly Diagnosed Multiple Myeloma
Two ongoing clinical trials of Studies C16005 and C16006 in patients with newly 
diagnosed multiple myeloma are currently ongoing.
In Study C16005 where MLN9708 is administered weekly (1.68, 2.23, 2.97, and 
3.95 mg/m2) in combination with lenalidomide and dexamethasone (Rd), 15 patients have 
been enrolled as of 12 October 2011 and completed 1 to 9 treatment cycles (median, 5
cycles). No DLTs were seen at doses up to 2.23 mg/m2. Three of 3 patients treated at the 
3.95 mg/m2 dose cohort experienced Grade 3 nausea and vomiting despite adequate 
antiemetic therapy; one of which additionally experienced Grade 2 syncope and in 
another patient the dose of lenalidomide was compromised such that they received < 80% 
of the planned doses. Subsequent patients were treated at one dose level below 
(2.97 mg/m2) where one of 6 patients experienced a DLT (Grade 3 rash). The MTD of 
weekly MLN9708 in combination with Rd was established at 2.97mg/m2. However with 
this dose, 3 of 6 patients experienced Grade 2 and 3 rash and had to discontinue 
lenalidomide. Therefore, the recommended dose was determined to be 2.23 mg/m2 plus 
Rd in the phase 2 portion of the combination trial and phase 3 Rd combination trial.
To date, all 15 response-evaluable patients have achieved PR to therapy including 
4 CRs, 4 VGPRs, and 7 PRs; 14 out of 15 patients achieved PR after Cycle 1, and all 15 
achieved PR after Cycle 2.
Overall, all 15 patients experienced a treatment-emergent adverse event. Peripheral 
neuropathy was limited to Grade 1 or 2 in 3 patients. The most common (20%) 
treatment-emergent adverse events are shown in Table 1-5.


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Table 1-5. Most Common (20%) Treatment-Emergent Adverse Events
(Study C16005, N=15)
Treatment-Emergent Adverse Events
Most Common (20%) Any Grade
Fatigue (60%)
Vomiting (53%)
Anemia (40%)
Diarrhea and nausea (33% each)
Insomnia, peripheral edema, and thrombocytopenia 
(27% each)
Drug-Related Grade 3 in 2 Patients
Rash and vomiting (n = 2 each)
Data cutoff 12 October 2011
No death has been reported in Study C16005. One patient discontinued MLN9708 due to 
an unrelated treatment-emergent adverse event. Four patients have experienced drug-
related serious adverse event involving nausea, vomiting, dehydration, dizziness, fainting, 
orthostatic hypotension, hypotension, deep vein thrombosis, atrial fibrillation, and muscle 
weakness.
In Study C16006, MLN9708 is administered in weekly and twice-weekly schedules in 
combination with melphalan and prednisone, and 6 patients have been enrolled as of 12 
October 2011. There has not been any serious adverse event, drug discontinuation due to 
treatment-emergent adverse event, or death reported to date.
1.4.3
Clinical Trials in Other Tumor Types
In Study C16001 conducted in patients with solid tumors, MLN9708 (IV, twice-weekly) 
is administered, and a total of 111 patients have been treated as of 12 October 2011. One 
partial response in a patient with head and neck cancer has been reported. MTD in Study 
C16001 was determined to be 1.76 mg/m2. In Study C16002 conducted in patients with 
lymphoma, MLN9708 (IV, twice-weekly) is administered, and a total of 21 patients have 
been treated as of 12 October 2011. Three patients have achieved PR.
In Study C16007 conducted in patients with amyloidosis, MLN9708 (PO, weekly) is 
administered, and a total of 6 patients have been treated as of 12 October 2011. As of the 
data cut, 2 patients achieved VGPR and one patient achieved PR. Treatment-emergent 
adverse events occurring in at least 2 patients include diarrhea and peripheral edema 


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(3 patients each), anemia, fatigue, nausea, and thrombocytopenia (2 patients each). As of 
12 October 2011, no subjects died or discontinued study treatment due to adverse events.
1.4.4
Nonclinical Pharmacology Studies
Pharmacokinetics of MLN2238 after IV weekly or twice-weekly MLN9708 dosing is 
multi-exponential with the rapid initial phase largely over by 4 hours followed by much 
slower disposition phases. The plasma MLN2238 concentration decreases by almost 
90% in the initial phase of 4 hours. The mean t1/2 after multiple IV dosing of MLN9708 
ranges from 4 to 8 days. Plasma MLN2238 exposures appear to increase proportionally 
with increasing dose over the MLN9708 IV dose range of 0.5 to 2.34 mg/m2. Oral 
MLN9708 is bioavailable and MLN2238 is rapidly absorbed with a Tmax of 0.5 to 8 hours. 
The mean terminal half-life after multiple dosing of oral MLN9708 ranges from 4 to 7 
days. MLN2238 exposures appear to increase proportionally with increasing dose over 
the oral MLN9708 dose range of 0.8 to 2.23 mg/m2. Blood 20S proteasome inhibition is 
dose dependent and immediate confirming target inhibition by MLN9708. Maximal 20S 
inhibition is approximately 60% to 62% for 1.76 mg/m2 twice-weekly IV dose and 60% 
to 72% for 2.23 mg/m2 twice-weekly oral dose. 
1.5
Known and Anticipated Risks and Benefits of MLN9708
1.5.1
Known and Anticipated Risks
Hematological Toxicities
Reversible thrombocytopenia, neutropenia, and anemia have been reported to date 
primarily at the higher doses tested. In addition to monitoring for recovery of blood 
counts, anemia, neutropenia, and thrombocytopenia induced by administration of 
MLN9708 should be managed in a similar manner to that used for myelosuppression 
resulting from standard cytotoxic chemotherapeutic agents. Administration of MLN9708 
should be modified as noted in each specific protocol with reinitiation of therapy at a 
reduced level from where thrombocytopenia, neutropenia, or anemia was noted has been 
instituted in the clinical studies.


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Gastrointestinal Toxicities
Reversible diarrhea, nausea, vomiting, anorexia, constipation, and abdominal pain have 
been reported. Patients should be monitored for gastrointestinal toxicity and should be 
given appropriate supportive care that includes fluids for volume depletion and 
antibiotics for any associated infection. Other supportive measures such as loperamide or 
other antidiarrheal agents may be considered for diarrhea only if it is established that 
there is no active infection or anti-emetics including 5-HT3 antagonists are recommended.
Peripheral Neuropathy
Mild and reversible peripheral neuropathy has been reported. Therefore, patients on 
MLN9708 should be monitored for symptoms of neuropathy, such as a burning sensation, 
hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain, or weakness. In 
cases of new or worsening sensory peripheral neuropathy, with or without pain, 
administration of MLN9708 should be modified as noted in each specific protocol.
Reinitiation of therapy at a reduced level from where symptoms were noted may be 
considered.
Lymphopenia
Reversible lymphopenia has been reported primarily at the higher doses tested.
Infrequent incidences of herpes zoster have been reported.
If lymphopenia is noted, patients may be at an increased risk of infection. In particular, 
lymphopenia can be associated with reactivation of herpes zoster and herpes simplex 
viruses. Initiation of antiviral therapy should be considered if infection occurs and 
prophylaxis therapy should then be initiated following the course of therapy for the 
infection and through the following courses of treatment with MLN9708.
Acute Phase Response
Acute phase response, characterized by increases in total WBC, neutrophils, monocytes, 
and fibrinogen, was observed in nonclinical studies. These can be monitored in the clinic 
by clinical chemistry and vital sign evaluations. Therefore, patients should be observed 
for fever and metabolic changes.


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Fever
Cases of fever without neutropenia have been reported in the clinical studies; however, 
the relationship of onset of fever to MLN9708 is not yet completely established in 
humans. Patients may receive supportive care agents in response to fever that are 
associated with MLN9708.
Tumor Lysis Syndrome
Because MLN9708 is a cytotoxic agent and can rapidly kill malignant cells, patients with 
a high tumor burden prior to treatment should be monitored for the complications of 
tumor lysis syndrome with appropriate laboratory studies and supportive care.
Elevated Creatinine
Modest transient increases in creatinine and reversible renal failure have been reported.
In some situations this has been severe, requiring temporary dialysis. Appropriate 
supportive care that includes IV fluids to prevent volume depletion according to standard 
medical practice is recommended. Non-steroidal anti-inflammatory drugs are not 
recommended given they may in and of themselves have an association to renal 
dysfunction.
Erythematous Rash With or Without Pruritis
Rash with or without pruritus has been reported with MLN9708 primarily at the higher 
doses tested. The rash has been transient and has resolved with standard symptomatic 
measures such as oral, topical, or IV anti-histamines or corticosteroids.
Cough, Dyspnea, Peripheral Edema, Pneumonia/Pneumonitis, and Headache
Cases of cough, dyspnea, peripheral edema, pneumonia/pneumonitis, and headache have 
been reported in the clinical studies; however, the relationship of onset to MLN9708 is 
not yet completely established in humans. Standard supportive care and additional 
monitoring should be performed as clinically indicated.
Fatigue
Cases of profound fatigue have been reported in the clinical trials. Standard supportive 
care are recommended.


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For more detailed information regarding the risks associated with MLN9708, refer to the 
MLN9708 Investigator’s Brochure.
MLN9708, like Velcade®, is a modified dipeptidyl boronic acid derived from leucine and 
phenylalanine. MLN9708 is in the early stages of investigation in humans; therefore, its 
safety profile in humans is not yet fully known. For more detailed information regarding 
the risks associated with Velcade®, refer to the Velcade® 3 mg (bortezomib) for Injection 
Package Insert. 
1.5.2
Anticipated benefits
MLN9708 is a 20S proteasome inhibitor that has a mechanism of action similar to that of 
bortezomib, the clinical efficacy of which has been verified both in Japan and overseas.
MLN9708 demonstrates antitumor activity superior to that of bortezomib in some tumor 
models, and has exhibited antitumor activity even in bortezomib-resistant models. It is 
therefore hoped that MLN9708 will be effective in previously treated patients. In 
overseas clinical studies of MLN9708, patients have achieved partial response on 
MLN9708 monotherapy. In addition, since patients have achieved complete response
(CR), very good partial response (VGPR), and partial response (PR) in clinical studies of 
MLN9708 with Rd in patients with newly diagnosed multiple myeloma, MLN9708 is 
expected to exhibit antitumor activity in patients with newly diagnosed multiple myeloma 
as well. Furthermore, although most existing therapeutic medications for multiple 
myeloma are injectable formulations, oral formulation of MLN9708 may improve patient 
convenience.
1.6
Concomitant medications
In Japan, lenalidomide (
5 mg) has been approved for the treatment 
of relapsed or refractory multiple myeloma, and dexamethasone 
4 mg) has been approved for the treatment of multiple myeloma. The Rd combination 
therapy is one treatment option for relapsed or refractory multiple myeloma.
CCI
CCI


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1.6.1
Lenalidomide
Lenalidomide is an immunomodulator that was discovered by 
in the US. It is a 
derivative of thalidomide, which is known to be teratogenic in man. Lenalidomide is 
known to manifest its antitumor activity through, for example, a cytokine production 
modulating action and an angiogenic tumor cell proliferation inhibiting action. Since the 
results of toxicity studies suggest that lenalidomide might be teratogenic, the 
lenalidomide proper management procedures (
) for preventing fetuses from 
being exposed to lenalidomide should be observed.
In this study, subjects will be registered in accordance with the lenalidomide proper 
management procedures when supplying lenalidomide to subjects receiving MLN9708 
plus Rd. The registration system for this study is described in “5.2
Registration”
1.6.2
Dexamethasone
Dexamethasone is a corticosteroid that, in addition to exhibiting anti-inflammatory and 
anti-allergy effects, also possesses various pharmacological effects, including inhibition 
of immune response and the metabolism of, for example, fats and sugars.
Dexamethasone also acts to inhibit the proliferation of multiple myeloma cells by 
inducing apoptosis, and it is known that dexamethasone can increase the effects of 
immunomodulators or chemotherapy agents that kill myeloma cells.
1.7
Study plan rationale
1.7.1
Rationale for starting to plan this study
As described in “1.1 Multiple myeloma,” the current treatments for relapsed or refractory 
multiple myeloma are all unsatisfactory. All are only effective in the short term, and 
ultimately result in treatment non-responsiveness. New, superior medications are 
therefore needed. In addition, most existing therapies are based on injectable 
formulations that require hospital visit and are therefore relatively inconvenient for
patients. MLN9708 is a 20S proteasome inhibitor that possesses a mechanism of action 
similar to that of bortezomib, an existing therapeutic medication for multiple myeloma, 
CCI
CCI
PPD


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and that can be taken orally. In nonclinical studies, MLN9708 exhibited antitumor 
activity superior to that of bortezomib in some tumor models, and exhibited antitumor 
activity in bortezomib resistant models as well, and it is therefore hoped that MLN9708 
will be effective in patients who have not responded to previous treatments. MLN9708 
was well-tolerated in an overseas phase 1 study in patients with relapsed or refractory 
multiple myeloma. Responders, including complete responders, were found, and the 
results of this study therefore suggest that MLN9708 will be useful. Based on the results 
that have been obtained in overseas clinical studies, including this phase 1 study, a global 
phase 3 study of the concomitant use of MLN9708 with Rd in relapsed or refractory 
multiple myeloma (Study C16010) has been planned, and Japan is expected to participate 
in this study as well. Therefore, a phase 1 study has been planned as the first clinical 
study of MLN9708 in Japan to confirm the tolerability and safety of MLN9708 alone and 
MLN9708 in combination with Rd in relapsed or refractory multiple myeloma.
1.7.2
Rationale for using a fixed dose
The results of a population pharmacokinetic analysis in 137 subjects who received 
MLN9708 in overseas studies suggest that neither body surface area nor body weight 
appreciably affect MLN9708 clearance or distribution volume. It was concluded that 
body surface area does not affect the Cmax or AUC, so changing to a fixed dose would be 
appropriate. In addition, since it has been decided that fixed doses will be used in future 
overseas clinical studies, we concluded that it would be appropriate to use a fixed dose in 
this Japanese phase 1 study as well. When converting the dose from a body surface area 
dose to a fixed dose, we used 1.86 m2, which was the mean body surface area of the 
subjects who participated in overseas clinical studies of bortezomib in multiple myeloma 
that were conducted by MPI. Converting 2.97 mg/m2, which was the MTD both in 
MLN9708 monotherapy and in the combined use of MLN9708 with Rd, was converted 
into a fixed dose, yielded a fixed dose of 5.5 mg, and converting 2.23 mg/m2, which is the 
recommended dose of MLN9708 when used in combination with Rd, yielded a fixed 
dose of 4.0 mg.


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1.7.3
Rationale for including an MLN9708 + Rd cohort
Since this study will be the first clinical study of MLN9708 in Japan, we decided to first 
investigate the tolerability, safety and pharmacokinetics of MLN9708 in monotherapy. 
However, in the treatment of relapsed or refractory multiple myeloma, proteasome 
inhibitors, immunomodulators and steroid combination therapies are commonly used. 
The combined use of bortezomib, lenalidomide and low-dose dexamethasone (VRd)
therapy in multiple myeloma has been confirmed to be safe and effective (Anderson et al, 
2010; Kumar et al, 2010; Richardson et al, 2010a; Richardson et al, 2010b). MLN9708, a 
new proteasome inhibitor, is expected to possess pharmacological efficacy and safety 
superior to that of bortezomib. In study C16005, a study of the combined use of 
MLN9708 with Rd, not only did 15 of 15 subjects achieve PR or better response, but 
good safety results were obtained in all subjects as well. Given this result, a global phase 
3 study of the combined use of MLN9708 with Rd (study C16010) is currently being 
planned. Consequently, in this study, in addition to investigating MLN9708 monotherapy, 
we decided to also investigate MLN9708 when used in combination with Rd. For the 
dosages of Rd, we used the dosages used in overseas clinical studies in which the efficacy 
and safety of VRd therapy were confirmed. Comparison of the efficacy and safety of 
dexamethasone in 445 newly diagnosed multiple melanoma patients overseas between a 
group of 223 patients who received high-dose dexamethasone (40 mg/day on Days 1-4, 
9-12, and 17-20) and a group of 222 patients who received low-dose dexamethasone 
(40 mg/day on Days 1, 8, 15, and 22) revealed that low-dose dexamethasone afforded a 
level of efficacy similar to that obtained with high-dose dexamethasone (Rajkumar et al, 
2010). Weekly low-dose dexamethasone was therefore selected.
1.7.4
Rationale for the initial doses and cohorts
In study C16004, Grade 3 adverse events were reported in 2 of 6 subjects at the MTD of 
2.97 mg/m2 (equivalent to 5.5 mg), but Grade 3 or higher adverse events were not 
reported at the next lowest dose of 2.23 mg/m2 (equivalent to 4.0 mg). Therefore, in this 
study, we decided to use 4.0 mg at the initial dose (cohort 1). For the MLN9708 + Rd 
cohort (cohort 2), we selected a dose of 4.0 mg + Rd, which was the recommended dose 
in the MLN9708 + Rd phase 3 study and the phase 2 part of study C16005, and was the 
next dose level below the MTD of 2.97 mg/m2 (equivalent to 5.5 mg) in study C16005.


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Furthermore, we have also established a monotherapy cohort that will receive 5.5 mg 
(cohort 3) and a MLN9708 + Rd cohort that will receive 5.5 mg + Rd (cohort 4) in order 
to confirm the tolerability in Japanese at the dose equivalent to the MTD overseas once 
the tolerability of 4.0 mg and 4.0 mg + Rd have been confirmed.
1.7.5
Rationale for once-weekly dosing
Based on the nonclinical and clinical study results, we selected a 28-day MLN9708 
dosing cycle with weekly oral dosing on Days 1, 8, and 15 and no dose given on Day 22. 
In a mouse model, peak antitumor activity was obtained with weekly dosing, and the 
results of multiple-dose toxicity studies also support the case for weekly dosing. 
MLN9708 weekly dosing was confirmed to be tolerable in study C16004 in relapsed or 
refractory multiple myeloma.
Since the global phase 3 study that is currently being planned (study C16010) will also 
employ a similar dosing method, we have decided to confirm the tolerability of such a 
dosing method in this study.


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2.
OBJECTIVES
2.1
Primary Objective
To evaluate the tolerability, safety, and pharmacokinetics of MLN9708 alone or in 
combination with Rd in patients with relapsed and/or refractory multiple myeloma.
2.2
Secondary Objective(s)
To evaluate the antitumor activity of MLN9708 in patients with relapsed and/or
refractory multiple myeloma.


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3.
EXPERIMENTAL PLAN 
3.1
Study Design
This is a phase 1, multicenter, single-arm, open-label, dose-escalation study to evaluate 
the tolerability, safety, and pharmacokinetics of MLN9708 administered alone or in 
combination with Rd in patients with relapsed and/or refractory multiple myeloma. This 
study consists of the following 4 cohorts.
●
Cohort 1: MLN9708 4.0 mg
●
Cohort 2: MLN9708 4.0 mg + Rd
●
Cohort 3: MLN9708 5.5 mg
●
Cohort 4: MLN9708 5.5 mg + Rd
Three subjects will be enrolled sequentially from cohorts 1 (MLN9708 4.0 mg alone) to 4. 
If a DLT occurs in one subject during DLT-assessment period, 3 additional subjects will 
be enrolled in the applicable cohort to evaluate the tolerability in a total of 6 subjects. If 
DLT occurs in 2 of the 3 subjects, the given dosage is considered intolerable. If DLT 
occurs in 2 of the 6 subjects, the sponsor will determine the tolerability to the given 
dosage after discussing with the Efficacy and Safety Evaluation Committee (ESEC).  
The sponsor will evaluate the tolerability of MLN9708 on the basis of the safety data 
including DLT incidences during the DLT-assessment period.  The sponsor will decide 
whether the next cohort will be studied and the dose of the next cohort in consultation 
with the ESEC, if necessary. If the current cohort is considered tolerable, the next cohort 
will be in the order of cohorts 2 (MLN9708 4.0 mg + Rd), 3 (MLN9708 5.5 mg alone), 
and 4 (MLN9708 5.5 mg + Rd).  Even if a dosage is considered tolerable and transition to 
the next cohort is considered feasible, the next cohort may not be studied based on the 
results of the overseas clinical studies and the current study.
The additional written informed consent for extended treatment will be obtained before 
the first dose of MLN9708 in Cycle 2 from the subjects who meet the criteria in “6.4
Criteria for Beginning the Next Cycle of Treatment” and have no safety concern. 
Subjects who do not give the consent will undergo end of study (EOS) visit on 29 days 
after the last dose of MLN9708 in Cycle 1. The subjects giving the consent can continue 


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the study treatment up to 12 cycles unless they meet the criteria in “8.1 Removal of 
Subjects” including evidence of progressive disease (PD) and intolerable toxicity. 
Subjects may remain on treatment after the 12 cycles if the investigator considers it 
beneficial for the subjects.
All subjects should undergo EOS visit on 29 days after the last dose of MLN9708.
The overall study design is described in “Study Design and Treatment Schema” (page 8).
3.2
Study Centers
The study is planned at 5 study centers.
3.3
Number of Subjects
Approximately 12 to 24 subjects (3 to 6 subjects in each cohort) will be enrolled in the 
study.
If any significant protocol deviation that affects DLT assessment is observed or a subject 
could not complete the protocol-specified MLN9708 treatment during the DLT-
assessment period for reasons other than DLTs, the subject will be excluded from the 
DLT assessment, and additional subject(s) may be enrolled. Moreover, if there seems to 
be needs for additional data for safety or pharmacokinetics evaluation, the sponsor may 
decide to enroll additional subjects. See “10.2 Sample Size Considerations for the 
sample size justification.
3.4
Estimated Study Duration
The study will be conducted between March 2012 and March 2019.
3.4.1
Study Duration for Participants
Study duration for patients will last for up to approximately 14 months, including 
maximum of 4 weeks screening period, maximum 12 cycles of treatment period 
(approximately 12 months), and 4 weeks follow-up after the last dose. Subjects may 
remain on treatment after the 12 cycles if the investigator and the sponsor determine that 
the subjects would derive benefit from continued therapy beyond 12 months.


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3.5
Study Committees
3.5.1
ESEC
An ESEC will be formed before starting the study and will be composed of 3 medical 
experts/oncologists who are not the investigators or the sponsor staff of this study.
The ESEC may evaluate the safety of MLN9708 and the appropriateness to continue this 
study upon the sponsor’s request. Further details will be provided in the ESEC charter.


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4.
SUBJECT ELIGIBILITY
Investigators must ensure that subjects meet all the eligibility criteria (inclusion 
criteria/exclusion criteria).
4.1
Inclusion Criteria
Patients must give written consent to the participation and meet ALL of the following 
inclusion criteria to be eligible for the study.
[Disease Related]
1)
Japanese patients with multiple myeloma according to diagnostic criteria shown 
in Appendix E(1)
2)
Previously treated with 2 or more regimens including all the following drugs(1)
●
bortezomib
●
thalidomide or lenalidomide
●
corticosteroids
3)
Patients who have relapsed following the previous therapy or failed to continue 
the treatment due to their intolerability to the last treatment regimen for 
myeloma(1)
4)
Measurable disease defined by at least one of the following 3 measurements(1)
●
Serum M-protein: ≥ 1 g/dL (≥ 10 g/L)
●
Urine M-protein: ≥ 200 mg/24 hours
●
Serum free light chain (FLC) assay: involved FLC level ≥ 10 mg/dL
(≥100 mg/L), provided that the serum FLC ratio is abnormal.
5)
Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2(1,2)
[Demographic]
6)
Patients 20 years or older at giving their informed consent(1)
7)
Patients must be able to stay in the hospital for Cycle 1 treatment(2)
[Laboratory Values]
Patients must meet the following laboratory criteria at screening.  Patients must not 
receive granulocyte colony stimulating factor (G-CSF) or blood transfusion within 7 days 
before the test of neutrophil and platelet counts:


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8)
Absolute neutrophil count (ANC): ≥1,000/mm3(2)
9)
Platelet count: ≥75,000/mm3(2)
10) Total bilirubin:  ≤1.5 × the upper limit of normal range (ULN)(2)
11) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST):  
≤ 3 × ULN(2)
12) Creatinine clearance: calculated by using Cockcroft-Gault formula (Appendix 
F)
MLN9708 monotherapy cohort: ≥ 30 mL/min(2)
MLN9708 with Rd cohort: ≥ 60 mL/min(2)
[General]
13) Patients recovered (Grade 1) from the toxicities of the prior treatments.(2)
ANC ≥1,000/mm3.
14) Life expectancy of at least 3 months, in the judgment of the investigator(2)
15) Patients conforming to proper management guidelines of lenalidomide(2)
(MLN9708 with Rd cohort only).
<Basis for setting the criteria>
(1) To enroll subjects who represent the intended indication population. 
(2) To minimize risks and ensure safety of subjects.
4.2
Exclusion Criteria
Patients meeting ANY of the following exclusion criteria cannot be enrolled in the study.
[Disease related]
1)
Patients with plasmacytoma only(2)
2)
Patients with plasma cell leukemia(2)
3)
Patients with central nervous system invasion(2)
[Medications]
4)
Radiotherapy within 14 days before enrollment(2)
5)
Other anti-tumor drug administration within 21 days before enrollment(2)
6)
Other investigational products administration within 21 days before enrollment 
(60 days from the last dose for carfilzomib)(2)
7)
Antibody treatment within 42 days before enrollment(2)


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8)
Systemic treatment with potent CYP1A2 inhibitors (fluvoxamine, enoxacin), 
potent CYP3A inhibitors (clarithromycin, telithromycin, itraconazole, 
voriconazole, ketoconazole), or potent CYP3A inducers (rifampin, rifabutin, 
carbamazepine, phenytoin, phenobarbital), or use of foods containing Ginkgo 
biloba extract, St. John’s Wort, or grapefruit within 14 days before enrollment(2)
9)
Treatment with corticosteroids greater than 10 mg of prednisolone per day. 
Inhaled and topical steroids are permitted(2)
[Other Medical Conditions]
10) Peripheral neuropathy ≥ Grade 2(1)
11) Diarrhea ≥ Grade 2(1)
12) Major surgery requiring general anesthesia within 14 days before enrollment(1)
13) Infection requiring systemic antibiotic treatment or other serious infections 
within 14 days before enrollment(1)
14) Evidence of concurrent uncontrolled cardiovascular conditions including 
hypertension, cardiac arrhythmias, New York Heart Association (NYHA) Class 
III or worse congestive heart failure, angina, myocardial infarction, or cerebral 
infarction within 6 months before enrollment(1)
15) QTc > 470 milliseconds on a 12-lead ECG obtained during the screening 
period(1)
16) Tested positive for human immunodeficiency virus (HIV) antibody, hepatitis B 
virus surface antigen (HBs antigen), or hepatitis C virus  (HCV) antibody during 
the screening period(1)
17) Hypersensitivity to MLN9708 (including excipients), boron, or boron-containing 
drugs (1)
18) Hypersensitivity to lenalidomide, or dexamethasone, or excipients contained in 
the formulation of each drug(1)(MLN9708 with Rd cohort only)
19) Known gastrointestinal diseases (difficulty swallowing, inflamed gastroenteritis, 
and Crohn disease), or gastrointestinal procedure (endoscopic procedure is 
permitted), that could interfere with the oral absorption or tolerance of the study 
treatment(2)
20) Uncontrolled diabetes mellitus(1)
21) A history of interstitial lung disease or lung fibrosis, or a current complication of 
interstitial lung disease or lung fibrosis diagnosed by chest imaging.(1)
22) Prior or current complications of deep vein thrombosis or pulmonary 
embolism(1) (MLN9708 with Rd cohort only)
23) Diagnosed or treated for another malignancy within 2 years before the first dose 
of MLN9708 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 complete resection(1) 


Product: MLN9708
Protocol Number: TB-MC010034
Date: 22 November 2016
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[General]
24) Patients who do not consent to use adequate contraceptive precautions (e.g. 
condoms and oral contraceptives) during the following term:(3)
•
For women with childbearing potential*, from when giving their consent 
through 3 months after the last dose of MLN9708, dexamethasone, or 
lenalidomide
•
For men having their partners with childbearing potential, from when giving 
their consent through 4 months after the last dose of MLN9708, 
dexamethasone, or lenalidomide
* Women with child-bearing potential are those who are premenopausal (menopause is defined as the 
time when there has been no menstrual periods for at least 1 year), or who have not had a bilateral tubal 
ligation, bilateral oophorectomy, or hysterectomy. The menstruation possibly interrupted by 
chemotherapy is not defined as menopause.
25) Pregnant (e.g. positive for pregnancy test) or lactating. Lactation is prohibited 
from the first dose through 6 weeks after the last dose of MLN9708, 
dexamethasone, and lenalidomide(3)
26) Use of an investigational medical device within 28 days before enrollment(2)
27) Any inabilities that could potentially interfere with the consent or completion of 
treatment according to this protocol(2)
28) Having difficulties in participation to this study by the investigator’s judgment(2)
<Basis for setting the criteria>
(1) To minimize risks and ensure safety of subjects. 
(2) To eliminate any impact on evaluation of MLN9708.
(3) For unclear potential of reproductive and developmental toxicity associated with 
MLN9708 and teratogenicity evident by lenalidomide in the Rd cohort.


Product: MLN9708
Protocol Number: TB-MC010034
Date: 22 November 2016
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5.
SUBJECT ENROLLMENT
The investigators must obtain written informed consent from all subjects before any study 
specific procedures are performed.
All subjects who enter into the screening period for the study (defined as the point at 
which the subject signs the informed consent) will receive a unique, 8-digits subject 
identification number (e.g. 34XXXYYY). The first 2 digits (i.e. 34) represent the 
protocol number, next 3 digits (XXX) represent the study center number, and the last 3 
digits (YYY) represent the subject number which is assigned in each study center. 
This number will be used to identify the subject throughout the study and must be used 
on all study documentation related to that subject. The subject identification number 
must remain the same throughout the entire clinical study; it must not be changed at the 
time of re-screening or re-enrollment. The number is assigned in sequential order of the 
subject’s consent at the site, in principle (e.g. 001, 002, 003).
Subjects must be registered within 28 days of the consent.
Subjects not meeting the eligibility criteria during the screening period cannot be enrolled.
However, subjects can be re-screened with the investigator’s discretion as long as they 
are not registered as a screen failure. When subjects are re-screened, the investigators 
must obtain additional written informed consent before the re-screening to reconfirm the 
subject’s consent for study participation. A subject cannot be re-screened more than once, 
and will be defined as a screen failure if subject is not qualified to undergo re-screening 
or is determined as a screen failure after the re-screening.
A subject will be defined as a screen failure, if the subject signs the informed consent but 
fails to enroll into the study. The investigators must document all screen failures and the 
reasons for the failure on the electronic case report form (eCRF).
For addition or replacement of subjects, refer to “8.2 Replacement of Subjects”.


Product: MLN9708
Protocol Number: TB-MC010034
Date: 22 November 2016
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5.1
Enrollment Procedures
After the completion of subject screening for each subject, the investigator enrolls the 
subject according to the following procedures:
The investigator ensures that a subject meets all the eligibility criteria and faxes a 
“subject registration sheet” to the Registration Center after confirming the necessary 
information is completed. The “subject registration sheet” may be the source data of the 
investigator’s judgment for the each eligibility criteria.
The Registration Center confirms that a subject meets the all inclusion criteria and does 
not meet any of the exclusion criteria, and then the Registration Center identifies the 
subject as an enrolled subject and faxes a “registration confirmation sheet” to the 
investigator. If a subject is considered ineligible by the Registration Center, the center 
will not identify the subject as an enrolled subject. A “registration confirmation sheet”
describing the “reason for ineligibility” will be faxed to the investigator. 
The investigator must retain a “subject registration sheet”, a “registration confirmation 
sheet”, and the “reason for ineligibility” as the source documents appropriately in the 
study centers.
The Registration Center will report above subject registration progress promptly to the 
sponsor.
MLN9708 (TB-MC010034) Subject Registration Center
Takeda Pharmaceutical Company Limited
Marunouchi Eiraku Building, 1-4-1 Marunouchi, Chiyoda-ku, Tokyo, Japan
5.2
Registration
The 
procedures must be followed when providing lenalidomide to the subjects 
in the MLN9708 with Rd cohort in the study.
CCI
CCI
PPD
PPD
PPD


Product: MLN9708
Protocol Number: TB-MC010034
Date: 22 November 2016
Page 45 of 102
CONFIDENTIAL
Before a patient is enrolled in this study, the patient must be registered in accordance with 
the 
, and it must be confirmed that the patient is eligible to receive 
lenalidomide.
If the patient is already registered in
, then no re-registration is necessary.
CCI
CCI


Product: MLN9708
Protocol Number: TB-MC010034
Date: 22 November 2016
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6.
TREATMENT PROCEDURES
6.1
MLN9708
MLN9708 is manufactured (including packaging and labeling) by MPI and supplied by 
Takeda Pharmaceutical Company.
Specifications and storage conditions for MLN9708 are presented below.
Table 6-1.  Specifications for MLN9708
Investigational Product
MLN9708
Formulation and strength
capsules
One capsule contains 2.3, 3.0, 4.0, or 5.5 mg of active boronic acid form of 
MLN9708 (MLN2238)
Packaging
foil-foil blisters
Packaging Unit
Three capsules per foil-foil blister, which is contained by 1 unit carton.
Storage
to be refrigerated at 2ºC to 8ºC
Manufacturer
Millennium Pharmaceuticals, Inc. (the United States)
See the Directions for Use located in the Pharmacy Manual for details on the labeling and 
storage of MLN9708. There is very limited experience with clinically significant 
overdose of MLN9708 and no specific antidotes exist for the treatment of MLN9708 
overdose.  General supportive care is recommended.
The maximum dose of MLN9708 previously used in monotherapy was 3.95 mg/m2 
weekly. 
6.2
Concomitant medications
The concomitant medications (MLN9708 + Rd cohort only) are described below. The 
concomitant medications will be dispensed at the study center.
6.2.1
Lenalidomide (
5 mg)
Lenalidomide (
5 mg) is an anti-angiogenic malignant tumor agent 
that is indicated for relapsed and/or refractory multiple myeloma and myelodysplastic 
CCI
CCI


Product: MLN9708
Protocol Number: TB-MC010034
Date: 22 November 2016
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CONFIDENTIAL
syndromes with 5q- syndrome. For detailed information about lenalidomide, refer to the 
latest version of the package insert for 
 5 mg.
6.2.2
Dexamethasone (
4 mg)
Dexamethasone (
4 mg) is a corticosteroid that is indicated for multiple 
myeloma. For detailed information on dexamethasone, refer to the latest version of the 
package insert for
4 mg.
6.3
Dosage, administration method, dosing schedule
6.3.1
MLN9708 administration
In this study, MLN9708 will be administered orally once weekly for 3 weeks (on Days 1, 
8, and 15 and skip Day 22) in a 28-day cycle for up to 12 cycles.
MLN9708 will be taken on an empty stomach at least 1 hour before or no sooner than 2 
hours after a meal.
In Cycle 1, MLN9708 will be given according to the dosage and administration specified 
in this study protocol; no interruption, delays, or reduction will be permitted.
Missed doses of MLN9708 in Cycle 2 and subsequent cycles can be taken as soon as the 
patient remembers provided that at least 3 days elapses between doses (until Day 4). If a 
patient vomits after taking MLN9708, the patient should not repeat the dose, but resume 
dosing at the time of the next schedule.
Once a dose is reduced, no re-escalation will be permitted.
6.3.2
Lenalidomide Administration (Rd Concomitant Cohort Only)
Lenalidomide will be administered as a single, daily oral dose of 25 mg/day on Days 1 to 
21 for 21 consecutive days followed by one week rest period in a 28-day cycle. This 
cycle will be repeated.
CCI
CCI
CCI
CCI


Product: MLN9708
Protocol Number: TB-MC010034
Date: 22 November 2016
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Lenalidomide should be taken at approximately the same time each day. Patients should 
be instructed to swallow lenalidomide capsules whole with water and not to break, chew, 
or open the capsules.
Lenalidomide and MLN9708 should be taken simultaneously. Lenalidomide should be 
used according to the package insert of 
5 mg.
A missed dose of lenalidomide can be taken as soon as the patient remembers provided 
that it is within 12 hours from the regular dosing schedule. A double dose should not be 
taken to make up for a missed dose. If enough time has elapsed that the missed dose is 
not taken within the same day, the missed dose should be skipped. 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 schedule.
6.3.3
Dexamethasone Administration (Rd Concomitant Cohort Only)
Dexamethasone will be administered as a single, oral dose of 40 mg/day weekly on Days 
1, 8, 15, and 22 of a 28-day cycle.
Dexamethasone will be taken at approximately the same time each day, approximately 1 
hour after MLN9708 and lenalidomide. Each dose of dexamethasone should be taken 
with food or milk. Dexamethasone should be used according to the package insert of 
4 mg.
Missed doses of dexamethasone can be taken as soon as the patient remembers provided 
that at least 3 days elapses between doses (until Day 4). If the patient vomits after taking 
a dose, the patient should not repeat the dose but resume dosing at the time of the next 
schedule.
6.4
Criteria for Beginning the Next Cycle of Treatment
6.4.1
MLN9708 Monotherapy
Treatment with MLN9708 will be repeated every 28 days as 1 cycle. For a new treatment 
cycle to begin, the patient must satisfy the following criteria:
CCI
CCI


Product: MLN9708
Protocol Number: TB-MC010034
Date: 22 November 2016
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CONFIDENTIAL
●
ANC must be 1,000 mm3
●
Platelet count must be 50,000 mm3
●
All other toxicity (except for alopecia) considered related to MLN9708 must be 
resolved to Grade 1 or to the patient’s baseline values
6.4.2
MLN9708 in Combination With Rd
Treatment of MLN9708 with Rd will be repeated every 28 days as 1 cycle. For a new 
treatment cycle to begin, the patient must satisfy the following criteria:
●
ANC must be 1,000 mm3
●
Platelet count must be 75,000 mm3
●
All other nonhematological toxicities (except for alopecia) considered related to 
MLN9708 or Rd must be resolved to Grade 1 or to the patient’s baseline values
6.4.3
Criteria for Dose Delays
If a subject fails to meet the criteria for beginning the next cycle of treatment, initiation of 
the next cycle should be delayed for one week for re-evaluation. If the subject still fails 
to meet the criteria, the subject should be re-evaluated weekly. The next cycle treatment 
can be initiated if the subject meets the criteria for initiating the next cycle within 3 
weeks of the scheduled initiation of the next cycle. The MLN9708 and lenalidomide 
starting doses for the next cycle are presented below.
●
Reinitiate with one dose level reduction
–
If MLN9708 or lenalidomide treatment was interrupted during the preceding cycle 
in accordance with “6.5 Dose Modification” and treatment could not be resumed 
within the same cycle
●
Reinitiate with the same dose level as the preceding cycle
–
If there was no need for dose adjustment in the preceding cycle
–
If MLN9708 or lenalidomide treatment was interrupted during the preceding cycle 
in accordance with “6.5 Dose Modification” and treatment could be resumed 
during the cycle
Should the start of the next cycle need to be delayed for more than 3 weeks because of 
incomplete recovery from treatment-related toxicity, the patient undergoes the EOS
exams, and treatment should be discontinued.


Product: MLN9708
Protocol Number: TB-MC010034
Date: 22 November 2016
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CONFIDENTIAL
6.5
Dose Modification
6.5.1
MLN9708 Monotherapy
6.5.1.1
Criteria for Dose Modification
Dose modifications of MLN9708 are not permitted in Cycle 1.
If dose modification is required in Cycle 2 or subsequent cycles, MLN9708 dose will be 
reduced by one level according to Table 6-2. If multiple toxicities are noted, the dose 
should be interrupted or reduced according to the most severe toxicity guidelines (Table 
6-3 and Table 6-4). Toxicity will be assessed according to the Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.03.
Table 6-2. Dose Reduction Levels of MLN9708
Initial dose
Level 1
Level 2
Level 3
Level 4
4.0 mg
3.0 mg
2.3 mg
Discontinue
‐
5.5 mg 
4.0 mg
3.0 mg
2.3 mg
Discontinue
6.5.1.1.1
Dose Modification for Hematological Toxicity
If platelet count is less than 30,000/mm3 or ANC is less than 750/mm3 in Cycle 2 or 
subsequent cycles, MLN9708 dose should be interrupted.  If the platelet count is 
recovered to at least 30,000/mm3 and ANC is recovered to at least 750/mm3 within the 
same cycle, MLN9708 may be reinitiated with one dose level reduction.  If the subject 
meets the criteria for retreatment by delaying the initiation of the subsequent cycle, the 
subjects may be retreated with MLN9708 with one dose level reduction (See “6.4 Criteria 
for Beginning the Next Cycle of Treatment”).
Table 6-3. Dose Modification of MLN9708 for Hematological Toxicities
Criteria
Action
Within-cycle Dose Modifications (Days 8 and 15)
If platelet count < 30,000/mm3 or 
ANC < 750/mm3
Interrupt MLN9708, follow CBC weekly.  Upon 
recovery, MLN9708 may be reinitiated with one 
dose level reduction.  
ANC = absolute neutrophil count, CBC = complete blood count


Product: MLN9708
Protocol Number: TB-MC010034
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6.5.1.1.2
Dose Modification for Non-hematological Toxicity
If non-hematological toxicities shown in Table 6-4 occur in Cycle 2 and subsequent 
cycles, MLN9708 should be interrupted. Upon recovery, MLN9708 may be reinitiated 
with one dose level reduction. For Grade 4 non-hematological toxicities, MLN9708 
should be discontinued permanently.
Table 6-4. Dose Modification of MLN9708 for Non-hematological Toxicities
Criteria
Action
Peripheral Neuropathy:
Grade 2 peripheral neuropathy with pain
MLN9708 therapy should be interrupted until 
toxicities have resolved to Grade 1 or baseline.  
Upon recovery, MLN9708 may be reinitiated with 
one dose level reduction.
Grade 3 non-hematological toxicities 
MLN9708 therapy should be interrupted until 
toxicities have resolved to Grade 1 or baseline.  
Upon recovery, MLN9708 may be reinitiated with 
one dose level reduction.
Grade 4 non-hematological toxicities
Discontinue MLN9708.  
With agreement by the sponsor, investigators may 
consider restarting the therapy for patients continue 
to clinically benefit from the therapy.
6.5.2
MLN9708 in combination with Rd
6.5.2.1
Criteria for Dose Modification
Dose modifications of MLN9708 are not permitted in Cycle 1. Dose modifications of Rd
should be avoided as much as possible. If a subject experiences an adverse event(s) 
considered strongly related to lenalidomide or dexamethasone and the investigator 
considers it difficult to continue the treatment with Rd, the investigator and the sponsor 
will discuss the alternative dose modification.
If dose modification is required in Cycle 2 or subsequent cycles, MLN9708, lenalidomide, 
or dexamethasone dose will be modified levels according to Table 6-5. If multiple 
toxicities are noted, the dose should be modified or delayed according to the most severe 
toxicity guidelines (Table 6-6 through Table 6-11). Once a dose is reduced, no re-
escalation will be permitted.


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Protocol Number: TB-MC010034
Date: 22 November 2016
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Each adverse event should be attributed to a specific drug, if possible, so that the dose 
can be modified accordingly. Reduction of one agent and not the other is appropriate if 
toxicity is related primarily to one of the agents. Toxicity will be assessed according to 
the CTCAE version 4.03.
Table 6-5. Dose Reduction Levels for MLN9708, lenalidomide and dexamethasone
Drug
Initial dose
Level 1
Level 2
Level 3
Level 4
MLN9708
4.0 mg
3.0 mg
2.3 mg
Discontinue
‐
5.5 mg
4.0 mg
3.0 mg
2.3 mg
Discontinue
lenalidomide
25 mg
15 mg
10 mg
5 mg
Discontinue
dexamethasone
40 mg
20 mg
8 mg
Discontinue
-
6.5.2.2
Dose Modification for Hematological Toxicity
6.5.2.2.1
Dose Modification for Thrombocytopenia
If platelet count is less than 30,000/mm3 in Cycle 2 or subsequent cycles, lenalidomide 
dose should be interrupted.  If the platelet count is recovered to at least 30,000/mm3
within the same cycle, lenalidomide may be reinitiated with one dose level reduction.  
MLN9708 dose can be kept as is.  If the subject meets the criteria for retreatment with 
delaying the initiation of the subsequent cycle, the subjects may be retreated with 
lenalidomide with one dose level reduction (See “6.4 Criteria for Beginning the Next 
Cycle of Treatment”).
If thrombocytopenia occurs more than once, MLN9708 or lenalidomide dose will be 
modified at each occurrence according to Table 6-6 to continue the treatment. In some 
severe situations, both MLN9708 and lenalidomide may be interrupted or reduced if 
needed based on discussion between the investigator and the sponsor.


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Protocol Number: TB-MC010034
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Table 6-6. MLN9708 and Lenalidomide Dose Modification for Thrombocytopenia
Platelets
Action 
First fall to < 30,000/mm3
Interrupt lenalidomide treatment, follow CBC 
weekly
Return to ≥30,000/mm3 within the same cycle
Resume lenalidomide at 15 mg
Second fall:  Subsequent drop below 30,000/mm3
Interrupt MLN9708, follow CBC weekly
Return to ≥30,000/mm3 within the same cycle
Resume MLN9708 at reduced dose by 1 level 
(Level 1)
Third fall:  Subsequent drop below 30,000/mm3
Interrupt lenalidomide treatment, follow CBC 
weekly
Return to ≥30,000/mm3 within the same cycle
Resume lenalidomide at 10 mg
Fourth fall:  Subsequent drop below 30,000/mm3
Interrupt MLN9708, follow CBC weekly
Return to ≥30,000/mm3 within the same cycle
Resume MLN9708 at reduced dose by 1 level 
(Level 2)
Do not dose MLN9708 below 2.3 mg
Fifth fall:  Subsequent drop below 30,000/mm3
Interrupt lenalidomide, follow CBC weekly
Return to ≥30,000/mm3 within the same cycle
Resume lenalidomide at 5 mg
Do not dose lenalidomide below 5 mg
CBC = complete blood count
6.5.2.2.2
Dose Modification for Neutropenia
If ANC count is less than 1,000/mm3 in Cycle 2 or subsequent cycles, lenalidomide dose 
should be interrupted.  If the ANC is recovered to at least 1,000/mm3 within the same 
cycle, lenalidomide may be reinitiated with one dose level reduction.  MLN9708 dose 
can be kept as is.  If the subject meets the criteria for retreatment by delaying the 
initiation of the subsequent cycle, the subjects may be retreated with lenalidomide with 
one dose level reduction (See section “6.4 Criteria for Beginning the Next Cycle of 
Treatment”).
If neutropenia occurs more than once, MLN9708 or lenalidomide dose will be modified 
according to Table 6-7 to continue the treatment.  G-CSF is not permitted in Cycle 1 
unless Grade 4 neutropenia occurs (See section 6.9 Excluded Concomitant Medications 
and Procedures).  In some severe situations, both lenalidomide and MLN9708 may be 
interrupted or reduced if needed based on discussion between the investigator and the 
sponsor.


Product: MLN9708
Protocol Number: TB-MC010034
Date: 22 November 2016
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Table 6-7. MLN9708 and Lenalidomide Dose Modification for Neutropenia
Absolute Neutrophil Count
Action 
First fall to < 1,000/mm3
Interrupt lenalidomide treatment, follow CBC 
weekly
Returns to ≥1,000/mm3 within the same cycle
Resume lenalidomide at 15 mg
Second fall: Subsequent drop below 1,000/mm3
Interrupt MLN9708, follow CBC weekly
Returns to ≥1,000/mm3 within the same cycle
Resume MLN9708 at reduced dose by 1 level 
(Level 1)
Third fall: Subsequent drop below 1,000/mm3
Interrupt lenalidomide treatment, follow CBC 
weekly
Returns to ≥1,000/mm3 within the same cycle
Resume lenalidomide at 10 mg
Fourth fall: Subsequent drop below 1,000/mm3
Interrupt MLN9708, follow CBC weekly
Returns to ≥1,000/mm3 within the same cycle
Resume MLN9708 at reduced dose by 1 level 
(Level 2)
Do not dose MLN9708 below 2.3 mg
Fifth fall: Subsequent drop below 1,000/mm3
Interrupt lenalidomide, follow CBC weekly
Returns to ≥1,000/mm3 within the same cycle
Resume lenalidomide at 5 mg
Do not dose lenalidomide below 5 mg
CBC = complete blood count
6.5.2.3
Dose Modification for Non-hematological Toxicity
6.5.2.3.1
Dose Modification for Rash
If Grade 2 or 3 rash occurs in Cycle 2 or subsequent cycles, lenalidomide dose should be 
interrupted.  If the rash is recovered to Grade 1 or lower within 2 weeks, lenalidomide 
may be reinitiated with one dose level reduction.  MLN9708 dose can be kept as is.  If 
rash occurs more than once, MLN9708 or lenalidomide dose will be reduced according to 
Table 6-8 to continue the treatment.  In some severe situations, both lenalidomide and 
MLN9708 may be interrupted or reduced if needed based on discussion between the 
investigator and the sponsor.


Product: MLN9708
Protocol Number: TB-MC010034
Date: 22 November 2016
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Table 6-8. MLN9708 and Lenalidomide Dose Modification for Rash
Rash
Action
Grade 2 or 3
Interrupt lenalidomide treatment
Recovers to < Grade 2 within 2 weeks
Resume lenalidomide at 15 mg
If does not recover to < Grade 2 in 2 weeks
OR for subsequent occurrence of Grade 2 or 3 rash
Interrupt MLN9708
Recovers to < Grade 2 within 2 weeks
Resume MLN9708 at reduced dose by 1 level 
(Level 1)
If does not recover to < Grade 2 in 2 weeks
OR for subsequent occurrence of Grade 2 or 3 rash
Interrupt lenalidomide treatment
Recovers to < Grade 2 within 2 weeks
Resume lenalidomide at 10 mg
If does not recover to < Grade 2 in 2 weeks
OR for subsequent occurrence of Grade 2 or 3 rash
Interrupt MLN9708  
Recovers to < Grade 2 within 2 weeks
Resume MLN9708 at reduced dose by 1 level 
(Level 2)
Do not dose MLN9708 below 2.3 mg
If does not recover to < Grade 2 in 2 weeks
OR for subsequent occurrence of Grade 2 or 3 rash
Interrupt lenalidomide treatment
Recover to < Grade 2 within 2 weeks
Resume lenalidomide at 5 mg
Do not dose lenalidomide below 5 mg
6.5.2.3.2
MLN9708 Treatment Modification
MLN9708 dose adjustments are allowed based on clinical and laboratory findings. Dose 
reduction levels of MLN9708 for toxicity are indicated in Table 6-5. Treatment 
modifications due to MLN9708-related non-hematological toxicities are outlined in Table 
6-9. 


Product: MLN9708
Protocol Number: TB-MC010034
Date: 22 November 2016
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Table 6-9. MLN9708 Treatment Modification Due to Non-hematological Toxicities
Adverse Event (Severity)
Action on MLN9708
Further Considerations
Grade 2 peripheral 
neuropathy with pain
•
Hold MLN9708 until resolution 
to Grade ≤ 1 or baseline
•
MLN9708 may be reinitiated 
with one dose level reduction.
Grade 3 non-hematological 
toxicity
•
Hold MLN9708 until resolution 
to Grade ≤1 or baseline  
•
MLN9708 may be reinitiated 
with one dose level reduction
Grade 4 non-hematological 
toxicities 
•
Consider permanently 
discontinuing MLN9708
With agreement by the sponsor, 
investigators may consider restarting 
the therapy for patients continue to 
benefit from the therapy
6.5.2.3.3
Lenalidomide Treatment Modification
Lenalidomide dose adjustments are allowed based on clinical and laboratory findings.  
Dose reduction levels of lenalidomide for toxicity are indicated in Table 6-5.  Treatment 
modifications due to lenalidomide-related adverse events are outlined in Table 6-10.


Product: MLN9708
Protocol Number: TB-MC010034
Date: 22 November 2016
Page 57 of 102
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Table 6-10. Lenalidomide Treatment Modification Guidelines Due to Non-
hematological Toxicities
Adverse Event (Severity)
Action on Lenalidomide
Further Considerations
Grade 3/4 toxicities judged to be 
related to lenalidomide  (other 
than the toxicities listed below)
•
Hold lenalidomide treatment, 
and restart at the next lower 
dose level when toxicity has 
resolved to Grade 2
Do not dose below 5 mg
Renal dysfunction
•
Dose reduction, interruption, 
or discontinuation per 
lenalidomide package insert 
Care should be taken in dose 
selection/modification in the 
elderly as they are more likely to 
have decreased renal function
Monitor renal function regularly
Grade 2 thrombosis/embolism
•
Hold lenalidomide and start 
anticoagulation therapy; 
restart at investigator’s 
discretion after adequate 
anticoagulation; maintain dose 
level (No dose modification)
For patients treated with Rd, 
thromboprophylaxis such as 
aspirin according to the 
institutional standard of care is 
recommended
Angioedema, Stevens-Johnson 
Syndrome (SJS), and Toxic 
Epidermal Necrolysis (TEN)
Grade 2/3 skin rash
•
Hold or discontinue 
lenalidomide
Grade 4 exfoliative or bullous 
rash or if SJS or TEN suspected
•
Permanently discontinue 
lenalidomide
Any grade angioedema
•
Permanently discontinue 
lenalidomide
Any grade tumor Lysis syndrome
•
Hold lenalidomide in the same 
cycle.  Upon recovery, 
lenalidomide can be restarted 
at the same dose used before 
interruption.
Monitor closely and take 
appropriate medical precautions.
6.5.2.3.4
Dexamethasone Treatment Modification
Dexamethasone dose adjustments are outlined in Table 6-5. Treatment modifications due 
to dexamethasone-related adverse events are outlined in Table 6-11.


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Table 6-11. Dexamethasone Treatment Modification Guidelines Due to Non-
hematological Toxicities
Adverse Event (Severity)
Action on Dexamethasone
Gastrointestinal
Dyspepsia, gastric, or duodenal 
ulcer, gastritis Grade 1-2 
(requiring medical management)
If symptoms persist, reduce dexamethasone by 1 
dose level as needed.
> Grade 2
Hold dexamethasone until symptoms adequately 
controlled.  Restart and reduce 1 dose level of 
current dose.  
Cardiovascular
Edema > Grade 2 (limiting 
function and unresponsive to 
therapy or anasarca)
Diuretics as needed and reduce dexamethasone 
by 1 dose level.  If edema persists despite these 
measures, reduce 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 
Reduce dexamethasone dose by 1 dose level.  If 
weakness persists despite these measures, reduce 
dose by 1 dose level.  Discontinue 
dexamethasone and do not resume if symptoms 
persist.  
Metabolic
Hyperglycemia > Grade 2
Treatment with insulin or oral hypoglycemics as 
needed.  If uncontrolled despite these measures, 
decrease dose by 1 dose level until levels are 
satisfactory.
Acute pancreatitis
Discontinue dexamethasone.
6.6
Cohort Transition and Early Stopping Guidelines
6.6.1
Cohort Transition
Three subjects will be initially enrolled into each dose level in order starting with cohort 
1. The sponsor will evaluate the tolerability of MLN9708 dosage in each cohort on the 
basis of the DLT incidences in consultation with the ESEC, if necessary.
Even if a dosage is considered tolerable and transition to the next cohort is considered 
feasible, the next cohort may not be studied based on the results of the overseas clinical 
studies and the current study.


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1. Cohort Transition From Cohort 1 to Cohort 2
If no DLT occurs during the DLT assessment period for cohort 1 (the initial dose through 
before Cycle 2), the dosage will be considered tolerable. If a DLT occurs in one subject
during the DLT assessment period, 3 additional subjects will be enrolled into a given dose 
level to evaluate tolerability in a total of 6 subjects. If DLTs occur in no more than 1 of 
the 6 subjects, then this dosage will be considered tolerable. If DLTs occur in 2 of 3 
subjects, then this dosage will be considered intolerable. If DLTs occur in 2 of 6 subjects, 
the sponsor will determine the tolerability of this dosage in consultation with the ESEC.
Even if a dosage is considered tolerable, the appropriateness of transition to cohort 2 will 
be determined by the sponsor in consultation with the ESEC as necessary.
2. Cohort Transition From Cohort 2 to Cohort 3
If no DLT occurs during the DLT assessment period for cohort 2, the dosage will be 
tolerable. If a DLT occurs in one subject during the DLT assessment period, 3 additional
subjects will be enrolled into a given dose level to evaluate tolerability in a total of 6 
subjects. If DLTs occur in no more than 1 of the 6 subjects, then this dosage will be 
considered tolerable. If DLTs occur in 2 of 3 subjects, then this dosage will be considered 
intolerable. If DLTs occur in 2 of 6 subjects, then the sponsor will determine the 
tolerability of this dosage in consultation with the ESEC. Even if a dosage is considered 
tolerable, the appropriateness of transition to cohort 3 will be determined by the sponsor 
in consultation with the ESEC as necessary. If the cohort 2 dosage is found to be 
intolerable, the sponsor will determine the appropriateness of transition to cohort 3 based 
on the data obtained from cohort 1 and cohort 2 in consultation with the ESEC.
3. Cohort Transition From Cohort 3 to Cohort 4
If no DLTs occur during the DLT assessment period for cohort 3, the dosage will be
tolerable. If a DLT occurs in one subject during the DLT assessment period, 3 additional
subjects will be enrolled into a given dosage level to evaluate tolerability in a total of 6 
subjects. If DLTs occur in no more than 1 of the 6 subjects, then this dosage will be 
considered tolerable. If DLTs occur in 2 of 3 subjects, then this dosage will be considered 
intolerable. If DLTs occur in 2 of 6 subjects, then the sponsor will determine the 
tolerability of this dosage in consultation with the ESEC. Even if a dosage is considered 


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tolerable, the appropriateness of transition to cohort 4 will be determined by the sponsor 
based on the data obtained from cohort 2, in consultation with the ESEC as necessary.
6.6.2
Early Stopping Guidelines
Should the start of the next cycle need to be delayed for more than 3 weeks because of 
incomplete recovery from treatment-related toxicity (6.4.3 Criteria for Dose Delays), the 
patient undergoes the EOS exams, and treatment should be discontinued.
6.7
DLT
6.7.1
DLT Assessment Period
DLTs will be assessed from the first dose until Cycle 2 Day 1 of MLN9708 treatment.
6.7.2
DLT-Evaluable Subjects
DLT-evaluable subjects are defined as follows:
•
DLTs 1 during DLT-assessment period.
OR
•
Received 3 doses of MLN9708 specified for the applicable cohort and completed 
the DLT-assessment period.
Subjects whose treatment with MLN9708 was interrupted or reduced in Cycle 1 for 
reasons other than DLTs are not eligible for DLT assessment in principle.
6.7.3
Definitions of DLT
DLT will be defined as any of the following AEs that are considered possibly related to 
MLN9708. Toxicity will be accessed according to the CTCAE version 4.03.
1.
Grade 4 neutropenia (ANC < 500/mm3 ) lasting more than 7 consecutive days.
2.
Grade 3 or greater neutropenia (ANC < 1,000/mm3 ) with fever and/or infection, 
where fever is defined as axillary temperature ≥ 38.0ºC.
3.
Grade 4 thrombocytopenia (platelets < 25,000/mm3) lasting more than 7 consecutive 
days.
4.
Grade 3 or greater thrombocytopenia (< 50,000/mm3) with clinically significant 
bleeding, or which requires blood transfusion.


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5.
A platelet count 10,000/mm3.
6.
Grade 2 peripheral neuropathy with pain or Grade 3 or greater peripheral neuropathy.
7.
Any other Grade 3 or greater nonhematologic toxicities with the following 
exceptions:
•
Grade 3 or greater arthralgia/myalgia.
•
Grade 3 or greater fatigue lasting less than 7 days.
•
Grade 3 nausea and/or emesis which can be controlled with anti-emetic therapies 
including anti-emetic prophylaxis. Anti-emetic prophylaxis is defined as an anti-
emetic regimen that employs a 5-HT3 antagonist given in standard doses and 
according to standard schedules. Dexamethasone should not be administered as 
an anti-emetic.
•
Diarrhea that is controlled with appropriate supportive care
8.
A delay of more than 14 days in the initiation of Cycle 2 treatment because of a lack 
of adequate recovery of MLN9708 related hematological or nonhematologic 
toxicities.
9.
Other Grade 2 or greater MLN9708 related nonhematologic toxicities that, in the 
opinion of the investigator, require permanent discontinuation of MLN9708.
10. Inability to give at least 80% of the planned lenalidomide doses (Rd combination 
cohort only) due to the adverse events related to MLN9708.
When a subject experiences any of the above DLTs, MLN9708 therapy should be 
interrupted within the same cycle after DLT. With agreement by the sponsor, 
investigators may consider restarting the MLN9708 therapy from next cycle for subjects 
continue to clinically benefit from the therapy. MLN9708 should be reinitiated in 
accordance with “6.4.3 Criteria for Dose Delays”.
The sponsor will consult with the ESEC for the final decision if determination of DLT or 
subjects’ eligibility for DLT-assessment is difficult.
6.8
Permitted Concomitant Medications and Procedures
Throughout the study, investigators may prescribe any concomitant medications or
perform procedures deemed necessary to provide adequate supportive care except for 
those listed in "6.9 Excluded Concomitant Medications and Procedures
6.9
Excluded Concomitant Medications and Procedures
The following medications and procedures are prohibited during the study.


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●
Systemic treatment with strong inhibitors of CYP3A inducers (rifampicin, rifabutin, 
carbamazepine, phenytoin, phenobarbital), or use/ intake of foods containing St. 
John's Wort during the study.
●
Any antineoplastic treatment other than Rd administered concomitantly with 
MLN9708 in the Rd combination cohort. Treatment with corticosteroids 10 mg of 
prednisolone per day or less is permitted.
●
Radiotherapy (note that, in general, the requirement for local radiation therapy 
indicates disease progression).
●
Myeloid growth factors (e.g., G-CSF, granulocyte macrophage-colony stimulating 
factor [GM-CSF] is not permitted in Cycle 1 unless Grade 4 neutropenia occurs. 
Their use should follow published guidelines and/or institutional practice, however, 
alternative usage may be reviewed with the Millennium clinician or study clinician 
designee.
●
Platelet transfusions to help patients meet eligibility criteria of ANC and platelet 
counts are not allowed prior to MLN9708 dosing on Cycle 1 Day 1 (within 7 days 
before the test).


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7.
STUDY PROCEDURES
MLN9708 treatment must be initiated within 7 days after the enrollment. Refer to 
Appendix A for an outline of procedures required at each visit.
7.1
Subject Screening
Before any protocol-specified procedure, all subjects must sign and date the informed 
consent form.
The investigator will be expected to create and maintain a screening log for all potential 
study candidates that includes information about the potential candidate (sex, date of 
birth), date, and outcome of the screening process (e.g., enrollment into study, reason for 
ineligibility or refused to participate).
All existing test results (e.g., HIV, hepatitis B virus [HBV], HCV), diagnostic imaging 
results (e.g., X-ray, CT, MRI) and bone marrow test results, for example, obtained prior 
to the date of consent acquisition may be used as data at the time of screening, provided 
the subject's consent is obtained.
7.2
Examinations, observations, and evaluations
The investigator will conduct examinations, observations, and evaluations of the subject 
according to the following procedures from the informed consent until the end of 
treatment visit. The subject assessments/observations will all be performed by the same 
investigator, in principle.
7.2.1
Screening period
All of the following exams, observations, and evaluations will be performed within 28 
days before first dose, unless otherwise specified. Subjects meeting all of the eligibility 
criteria specified in "4 SUBJECT ELIGIBILITY" prior to subject enrollment will be 
enrolled to this study in accordance with Section 5 “SUBJECT ENROLLMENT."
●
Informed consent
●
Assessment of eligibility, according to the inclusion/exclusion criteria


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●
Subject background (including medical history, concomitant disease, details of 
multiple myeloma diagnosis [date of diagnosis, histological type, current clinical 
stage] (see Appendix H), history of prior-treatment for multiple myeloma 
[chemotherapy, radiotherapy, transplantation, surgery])
–
For past medical history, the following clinically significant diseases and 
procedures that have resolved or ended before the initial dose.
1.
Diseases listed in the exclusion criteria (all such diseases that have resolved 
or ended prior to enrollment)
2.
Diseases or procedures experienced by the patient in the last 3 months other 
than those described in #1, except for transient diseases (e.g., upper 
respiratory tract inflammation, cold, headache)
3.
Other diseases that could affect the MLN9708 evaluation
–
"Concomitant disease" refers to any symptoms or diseases being experienced by 
the subject at the time of the first study treatment, and includes all clinically 
significant laboratory tests, 12-lead ECGs, and physical examination finding 
abnormalities. Concurrent illnesses will be investigated in detail (and diagnosis 
terms obtained wherever possible).
●
ECOG performance status (see Appendix B)
●
Vital signs (sitting blood pressure, pulse rate and axillary temperature, and 
transcutaneous oxygen saturation [SpO2]
●
Height, weight
●
12-lead ECG (QRS, QT, QTc, PR and heart rate)
‒
The 12-lead ECG is performed with the subject at rest in a supine position.
●
Laboratory tests: See Table 7-1 for the test parameters.
–
Hematology tests
–
Chemistry tests
–
Urinalysis
–
Virus tests (HIV antibody, HBs antigen, HCV antibody. The test results will not 
be recorded in the eCRF.)
–
β2-microglobulin
–
Immunoglobulin quantitation (IgG, IgM, IgA, IgD)
–
FLC
●
Serum M-protein (protein fraction test by electrophoresis; immunofixation)
●
Urine M-protein by 24-hour urine collection (protein fraction test by electrophoresis; 
immunofixation)
●
Pregnancy test (serum or urine; only if the subject is of childbearing potential)
●
Serious adverse events (see “9.1.1 Adverse Events” through “9.3 Serious Adverse 
Event Reporting Procedures”)


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●
X-rays
–
Chest
–
Bone (head, cervical vertebrae, thoracic vertebrae, lumbar vertebrae, pelvis, both 
upper arms, both forearms, both femurs, both lower legs); in two directions for 
each, except for the pelvis
–
If bone X-ray is performed within 8 weeks before the first dose, the X-ray results 
may be used as screening data.
●
CT/MRI (chest, abdomen)
–
Unless a patient shows hypersensitivity to contrast or concern for potential 
aggravation of renal dysfunction, all CT/MRI should be performed with contrast.
–
When CT/MRI scan is performed within 8 weeks before the first dose of 
MLN9708, it may be used as screening data.
●
Bone marrow aspirate: Percentage of plasma cells in bone marrow (Note: When 
collecting the sample, anatomical locations that are irradiated in the past should be 
avoided.)
7.2.2
Treatment period
Study treatment must be initiated within 7 days after enrollment. If study treatment 
cannot be initiated within 7 days, the patient may be rescreened after obtaining additional 
informed consent. For details, see “5 SUBJECT ENROLLMENT.” Hospitalization is 
generally required from the first dose of MLN9708 through the start of Cycle 2. However, 
if a subject wishes to return home temporarily and the investigator confirms that the 
subject’s symptoms are stable based on the available data collected in the study to that 
point, then the subject may return home temporarily, provided this does not interfere with 
the study observations/tests.
See “6.3 Dosage, administration method, dosing schedule” for more details on the 
administration of MLN9708 and Rd. Unless otherwise specified, the following 
procedures must be followed before administering MLN9708 in each cycle. See 
Appendix A for the acceptable test, observation, and examination time windows.
●
Obtaining informed consent to extended treatment
–
Written consent to the extended administration of MLN9708 will be obtained prior 
to Cycle 2 treatment from subjects who meet the criteria specified in “6.4 Criteria 
for Beginning the Next Cycle of Treatment” and who have experienced no safety 
concerns.


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●
Medical interview (including confirmation of treatment compliance): Day 1 of each 
Cycle
●
ECOG performance status: See Appendix B
–
Cycle 1:  Days 1, 8, and 15
–
Cycles 2 and subsequent cycles:  Day 1
●
Vital signs (sitting blood pressure, pulse rate and axillary temperature, SpO2)
–
Cycle 1:  Days 1, 8 and 15
–
Cycles 2 to 12:  Days 1 and 15
–
Cycle 13 and subsequent cycles:  Day 1
●
Body weight
–
Cycle 1: Before MLN9708 dosing on Day 1. If a patient’s body weight at 
screening is measured within 3 days before the first dose, then this measurement 
may be used for the Cycle 1 Day 1 data.
–
Cycle 2 and subsequent cycles: Day 1 of each cycle. Measurements taken within 
3 days before dosing will be accepted.
●
12-lead ECG (QRS, QT, QTc, PR and heart rate)
–
Day 1 of Cycle 1: Before dosing
–
Day 15 of Cycle 1: Before dosing, 30 minutes (± 10 min) after dosing, 1 hour 
(± 15 min) after dosing, and 4 hours (± 45 min) after dosing
–
Day 16 of Cycle 1: 24 hours (± 1 hr) after dosing on Day 15
●
Laboratory tests: See Table 7-1 for the test parameters.
–
Hematology tests
●
Cycle 1: Days 1, 8, 15 and 22
●
Cycles 2 and 3: Days 1, 8 and 15
●
Cycles 4 to 12: Days 1 and 15
●
Cycle 13 and subsequent cycles: Day 1
If a screening test is performed within 3 days before the first dose, the results 
may be used as the Cycle 1 Day 1 data.
–
Chemistry tests
●
Cycle 1: Days 1, 8, 15 and 22
●
Cycles 2 and 3: Days 1, 8 and 15
●
Cycles 4 to 12: Days 1 and 15
●
Cycle 13 and subsequent cycles: Day 1
If a screening test is performed within 3 days before the first dose, the result 
may be used as the data as Cycle 1 Day 1 data. Hemoglobin A1c (HbA1c) will 
be measured only on Day 1 of each cycle.


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–
Urinalysis: Day 1 of each cycle
–
Immunoglobulin quantitation (IgG, IgM, IgA, IgD): Day 1 of each cycle
–
FLC: FLC will be measured as appropriate if a response assessment requires 
confirmation or disease progression is suspected (see Appendix G).
●
Serum M-protein (electrophoresis protein fraction test): Performed on Day 1 of each 
cycle. If a screening test is performed within 7 days before the first dose, the results 
may be used as the Cycle 1 Day 1 data.
●
Urine M-protein (electrophoresis protein fraction test): 
Subjects whose urine M-protein is detected only in urine at screening
–
Measurement by 24-hour urine collection 
●
Urine samples will be collected prior to MLN9708 dosing on Cycle 1 Day 1.
If a screening test is performed within 7 days before the first dose, the results 
may be used as the Cycle 1 Day 1 data.
●
Samples will be collected every 2 cycles prior to MLN9708 dosing on Day 1 
of Cycles 3 and subsequent cycles (Cycles 3, 5, 7, 9, 11 and on [odd-numbered 
cycles]). It will be acceptable to collect samples between Days 23 and 28 of 
the preceding cycle.
–
Measurement by casual urine 
●
Samples will be collected every 2 cycles prior to MLN9708 dosing on Day 1
of Cycles 2 and subsequent cycles (Cycles 2, 4, 6, 8, 10, 12 and on [even-
numbered cycles]).
Subjects whose urine M-protein is detected in serum and urine at screening
–
Measurement by 24-hour urine collection.
●
Urine samples will be collected prior to MLN9708 dosing on Cycle 1 Day 1.  
If a screening test is performed within 7 days before the first dose, the results 
may be used as the Cycle 1 Day 1 data.
●
If a response assessment requires confirmation or disease progression is 
suspected (see Appendix G), a urine M-protein measurement will be collected 
as appropriate using 24-hour urine collection.
●
Immunofixation
–
Immunofixation will be performed only if it is necessary to confirm response (see
Appendix G).
●
Pregnancy test (serum or urine, only for women of childbearing potential): Day 1 of 
each cycle
●
Concomitant drugs/therapies
–
All drugs or medical procedures used from the first dose of MLN9708 to the tests 
performed at EOS visit. At subject visits after the subject has become an 
outpatient, subjects will be asked about drugs or medical procedures he/she has 
received (other than Rd in the MLN9708 + Rd cohort).


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●
Adverse events: See “9.1.1 Adverse Events” to “9.3 Serious Adverse Event Reporting 
Procedures.”
●
Pharmacokinetics: See “7.2.6 Pharmacokinetic sample collection time points.”
●
X-rays
–
Bone (head, cervical vertebrae, thoracic vertebrae, lumbar vertebrae, pelvis, both 
upper arms, both forearms, both femurs, both lower legs); in two directions for 
each, except for the pelvis
–
X-rays will be performed as appropriate if osteolytic lesions are found at screening 
and there are concerns about bone lesions increasing or new bone lesions 
developing during the study.
●
CT/MRI (head, abdomen):
–
If soft tissue plasmacytoma is found at screening, a CT/MRI scan will be 
performed every 2 cycles before MLN9708 dosing on Day 1 of Cycle 3 and 
subsequent cycles (Cycles 3, 5, 7, 9, 11 and on [odd-numbered cycles]). It will be 
acceptable to perform the scan between Days 23 and 28 of the preceding cycle.
A scan may be performed as appropriate if disease progression is suspected or a 
response assessment requires confirmation if necessary outside a specified cycle 
(see Appendix G).
–
All diagnostic imaging scans will be performed using contrast media, except for 
subjects who are hypersensitive to contrast media or shows concern for potential 
aggravation of renal dysfunction.
●
Bone marrow aspiration: Percentage of plasma cells in bone marrow (Note: When 
collecting the sample, anatomical locations that are irradiated in the past should be 
avoided.)
Bone marrow puncture will be performed as appropriate if a response assessment 
requires confirmation or when disease progression is suspected (see Appendix G).
7.2.3
End of study
The following assessments will be performed on Day 29 after the last dose (acceptable 
time window + 21days) for subjects who have received MLN9708. These assessments 
will be performed before any poststudy therapy is provided. If tests, observations, or 
examinations are not going to be performed due to some unavoidable circumstance, such 
as complete withdrawal of subject consent or because follow-up is not possible or the 
patient has died or is in poor condition, the reason for this will be recorded in the source 
documents and the study completed. In such cases, the missing tests, observations, or 
examinations that is to be conducted on Day 29 after the last dose will not be considered 
protocol deviations.


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CONFIDENTIAL
●
ECOG performance status: See Appendix B
●
Vital signs (sitting blood pressure, pulse rate and axillary temperature, SpO2)
●
Body weight
●
12-lead ECG (QRS, QT, QTc, PR and heart rate)
–
The 12-lead ECG will be performed with the patient at rest in a supine position.
●
Laboratory tests: See Table 7-1 for the test parameters.
–
Hematology tests
–
Chemistry tests
–
Urinalysis
–
Immunoglobulin quantitation (IgG, IgM, IgA, IgD)
–
FLC
●
Serum M-protein (protein fraction test by electrophoresis)
●
Urine M-protein by 24-hour urine collection (protein fraction test by electrophoresis):
Performed only for subjects whose urine M-protein is detected at screening.
●
Immunofixation
–
Performed when response confirmation is necessary.
●
Pregnancy test (serum or urine; only if the patient is of childbearing potential)
●
Adverse events: See “9.1.1 Adverse Events” to “9.3 Serious Adverse Event Reporting 
Procedures”)
●
X-rays
–
Bone (head, cervical vertebrae, thoracic vertebrae, lumbar vertebrae, pelvis, both 
upper arms, both forearms, both femurs, both lower legs); in two directions for 
each, except for the pelvis
–
X-rays will be performed as appropriate if osteolytic lesions are found at screening.
●
CT/MRI (chest, abdomen)
–
If soft tissue plasmacytoma is found at screening, a CT/MRI scan will be 
performed.
–
All diagnostic imaging scans will be performed using contrast media, except for 
subjects who are hypersensitive to contrast media or shows concern for potential 
aggravation of renal dysfunction.


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7.2.4
Laboratory tests
The laboratory tests listed in “Table 7-1.  Study Test Parameters” will be performed at the 
study center. The investigator will retain the laboratory test criteria, including the history.
Table 7-1.  Study Test Parameters
Hematology
Chemistry
Urinalysis
Others
RBC count
Sodium
PH
β2-microglobulini
Hemoglobin
Potassium
Occult blood
IgG
Hematocrit
Chlorine
Sugar
IgM
Platelet count
Total protein
Specific gravity
IgA
WBC count
Albumin
Ketone bodies
IgDg
WBC differentials
Calcium
Urobilinogen
FLC
• Neutrophils
Inorganic phosphorus
Bilirubin
MLN2238 plasma 
concentration
• Eosinophils
Magnesium
Urinary sediment
Serum M-protein (protein 
fractionation by 
electrophoresis, 
immunofixation)
• Basophils
Glucosea
Nitrite
• Lymphocytes
HbA1c
Qualitative urinary 
protein
Urine M-protein (protein 
fractionation by 
electrophoresis, 
immunofixation)
• Monocytes
Urea nitrogen
Quantitative urinary 
proteinh
Creatinine
Pregnancy testb (serum or 
urine)
Uric acid
Total bilirubin
ALPc
LDHd
AST (SGOTe)
ALT (SGPTf)
a At screening and for Cycle 1, the samples will be collected at fasting (at least 4 hours after food)
b Only for women of childbearing potential
c Alkali phosphatase
d Lactate dehydrogenase
e Serum glutamate oxaloacetate transaminase
f Serum glutamate pyruvate transaminase
g Performed only for subjects suspected of having IgD-type multiple myeloma
h The amount of protein will be measured by 24-hour urine collection at screening and study completion. The amount 
of protein will be measured by 24-hour urine collection or casual urine at the specified time points (see 7.2.2) for 
subjects whose urine M-protein was detected at screening.
i β2-microglobulin performed only at screening


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7.2.5
Volume of blood collected
The volume of blood collected each time for the following parameters is shown below.
●
Pharmacokinetics
–
Plasma MLN2238 concentration: 3 mL in total
7.2.6
Pharmacokinetic sample collection time points
The blood samples used for the pharmacokinetic assessments will be collected in 
accordance with “Table 7-2. Pharmacokinetic Sample Collection Time Points.” 
Information on sample collection, processing, storage conditions, and shipping methods 
is shown in the sampling handling manuals.
The pharmacokinetic blood samples at predose will be collected before MLN9708, Rd
dosing in the MLN9708 + Rd cohort as well.


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Table 7-2. Pharmacokinetic Sample Collection Time Points
Cycle
Test Day
Time
Allowable Time Window
Cycle 1
Day 1
Predose
-1 hour
15 minutes postdose
±3 minutes
30 minutes postdose
±5 minutes
60 minutes postdose
±15 minutes
90 minutes postdose
±15 minutes
2 hours postdose
±15 minutes
4 hours postdose
±45 minutes
8 hours postdose
±1 hour
Day 2
24 hours postdose
±1 hour
Day 3
48 hours postdose
±2 hours
Day 5
96 hours postdose
±4 hours
Day 8
168 hours postdose
(before dosing on Day 8)
-4 hours
Day 15
Predose
-1 hour
15 minutes postdose
±3 minutes
30 minutes postdose
±5 minutes
60 minutes postdose
±15 minutes
90 minutes postdose
±15 minutes
2 hours postdose
±15 minutes
4 hours postdose
±45 minutes
8 hours postdose
±1 hour
Day 16
24 hours postdose
±1 hour
Day 17
48 hours postdose
±2 hours
Day 19
96 hours postdose
±4 hours
Day 22
168 hours postdose
±4 hours
Cycle 2
Day 1
Predose (336 hours postdose)
-1 hour
7.2.7
Assessment of antitumor activity
Antitumor activity will be evaluated at Cycles 3, 5, 7, 9 and 11 and whenever possible at 
EOS visit, in accordance with Appendix G, based on the Uniform Response Criteria for 
Multiple Myeloma of the International Myeloma Working Group, using the results 
obtained from serum and urine M-protein measurements, FLC measurements, percentage 
of plasma cells in bone marrow, and X-ray and CT/MRI measurements performed at the 
time points specified in the study protocol.


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8.
REMOVAL AND REPLACEMENT OF SUBJECTS
8.1
Removal of Subjects
Subjects have the right to withdraw fully or partially from the study at any time and for 
any reason.
Withdrawal of full consent for a study means that the subject does not wish to receive 
further study treatment and does not wish to or is unable to continue further study 
participation.  Any subject may withdraw full consent to participate in the study at any 
time during the study.  The investigator will discuss with the subject the most appropriate 
way to withdraw to ensure the subject’s health.  
Withdrawal of partial consent means that the subject does not wish to take investigational 
product any longer but is still willing to collaborate in providing further data by 
continuing on study (e.g. participate in all subsequent study visits or procedures).  
Subjects may withdraw partial consent to continue receiving investigational product at 
any time during the study.  These subjects should continue the schedule of study 
observations.  
Subjects who discontinue the investigational product by investigator’s discretion or 
reasons other than the subject’s withdrawal of consent also must continue the schedule of 
study observations.  
All the procedures should be completed for the subject who discontinued the study by 
any reasons except the withdrawal of full-consent, lost to follow-up or death.  If study 
observations cannot be performed due to unavoidable circumstances, such as the 
worsening of the subject’s condition, the reasons must be documented on the source 
documents and no further follow-up is necessary.  In this case, the missing of protocol-
specified tests or assessments between the day of the last dose of the investigational 
product and the 29th day after the last dose will not be considered as any protocol 
deviations.
Reasons for removal from investigational product or observation might include:


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●
withdrawal of full consent
●
withdrawal of partial consent
●
no consent for extended treatment
●
administrative decision by the investigator or the sponsor
●
pregnancy (refer to Appendix D) 
●
ineligibility
●
important protocol deviation
●
patient noncompliance
●
adverse event 
●
disease progression
●
death
●
lost to follow-up.
8.2
Replacement of Subjects
Subjects in this study who have not received study treatment may be replaced.
If any major protocol deviation that potentially affects DLT assessment for reasons other 
than safety concerns as DLT occurs during DLT assessment period, the subject will be 
excluded from the DLT assessment and additional subjects may be enrolled in this cohort.  
Additional patients may also be enrolled throughout the study if there seems to be a need 
for additional data for safety or pharmacokinetics evaluation.


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9.
SAFETY DATA COLLECTION, RECORDING, AND REPORTING
9.1
Definitions
9.1.1
Adverse Events
An adverse event is any untoward medical occurrence or unintended signs, symptoms, or 
disease (including abnormal laboratory findings) appears in a subject which does not 
necessarily have a causal relationship to the study treatment.  Adverse events may include 
the onset of new illness and worsening of pre-existing conditions. 
The worsening of pre-existing medical condition indicates that the condition becomes
worse in severity, frequency, or duration, or has an association with a significantly worse 
outcome.  A pre-existing condition that has not worsened during the study, and a non-
emergent medical procedure such as elective cosmetic surgery is not considered an 
adverse event.
Disease progression itself is not considered as an adverse event; however, signs and 
symptoms of disease progression will be recorded as adverse events.  If a new primary 
malignancy appears, it will be regarded as an adverse event.
The investigator is responsible for reviewing laboratory test results and determining 
whether an abnormal value in an individual study subject represents a change from values 
before the study.  In general, abnormal laboratory findings without clinical significance 
(based on the investigator's judgment) should not be recorded as adverse events; however, 
laboratory value changes requiring therapy or adjustment in prior therapy are regarded as 
adverse events.
9.1.2
Serious Adverse Events
A serious adverse event is defined as an adverse event that
●
is fatal
●
is life threatening (places the subject at immediate risk of death)
●
requires in-patient hospitalization or prolongation of existing hospitalization
●
results in persistent or significant disability/incapacity


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●
is a congenital anomaly/birth defect
●
is other significant medical hazard
A hospitalization meeting the regulatory definition for “serious” is any inpatient hospital 
admission that includes a minimum of an overnight stay in a health care facility.  Any 
adverse event that does not meet the definitions of serious (e.g., emergency room visit, 
outpatient surgery, or requires urgent investigation) may be considered by the investigator 
to meet the “other significant medical hazard” criterion for classification as a serious 
adverse event.
9.2
All Adverse Events Reporting Procedures
The investigator is responsible for ensuring that all adverse events (as defined in "Section 
9.1 Definitions" and as further specified below) observed by the investigator or reported 
by subjects are collected and recorded in the subjects’ medical records, in the eCRF, and, 
for serious adverse events, on the serious adverse event report form.  These adverse 
events will include the following:
●
All non-serious adverse events (as defined in "Section 9.1.1 Adverse Events") that 
occur after initiation of investigational product to an end-of-study.  
●
All serious adverse events (as defined in "Section 9.1.2 Serious Adverse Events") that 
occur after the subject has signed the informed consent form to an 
end-of-study, and treatment-related serious adverse events that occur after the end-of-
study.
The following adverse event attributes must be assigned by the investigator.  The sponsor 
may ask the investigator to provide follow-up information, extracts from medical record, 
or eCRFs.
●
Adverse event diagnosis or syndrome(s) ( signs or symptoms if not known)
●
Event description (with detail appropriate to the event)
●
Dates of onset and resolution
●
Severity
●
Assessment of relatedness to the study treatment
●
Action taken
●
Outcome


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If applicable, the relationship of the adverse event to the study treatment will be assessed 
by Yes or No.
CTCAE version 4.03 will be used for grading adverse events.  
Adverse events requiring follow-up as determined by the investigator will be followed 
until resolved or considered stable.  If the investigator judged that further follow-up is not 
necessary or follow-up is not possible before the adverse event is resolved or stable, 
follow-up may be terminated.
It will be left to the investigator’s clinical judgment to determine whether an adverse 
event is related and of sufficient severity to require the subject’s removal from treatment 
or from the study.  A subject may also voluntarily withdraw from treatment due to what 
he or she perceives as an intolerable adverse event.  If either of these situations arises, the 
subject should be strongly encouraged to undergo an end-of-study assessment and be 
under medical supervision until symptoms cease or the condition becomes stable.
9.3
Serious Adverse Event Reporting Procedures
All serious adverse events that occur after the subject has signed the informed consent 
form must be reported to the sponsor within 24 hours of discovery or notification of the 
event.  Initial serious adverse event information and all amendments or additions must be 
recorded on a serious adverse event report form and submitted to the sponsor.  Copies of 
relevant medical records should be submitted to the sponsor as soon as they become 
available; autopsy reports should be provided for deaths if available.  
Serious adverse events occurring after the end of the study and thought to be possibly 
related to the study treatment will be collected and reported within 24 hours of discovery 
or notification of the event.  
If a subject is permanently withdrawn from the treatment or from the study because of a 
serious adverse event, this information must be included in the initial or follow-up serious 
adverse event report form as well as the eCRF.


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As a principle, initial information of a serious adverse event must be recorded on a 
predefined serious adverse event report form [initial report] and faxed by the investigator 
to the sponsor.  The original initial report must be submitted to the study monitor.  
The principal investigator should submit detailed information without delay after 
notification of initial information.  As a principle, detailed report(s) must be recorded on a 
predefined serious adverse event report form and faxed to the sponsor.  The original 
detailed report(s) must be submitted to the study monitor.  If amendment is needed, the 
amendment should be reported according to the same procedure.
An operator of the Emergency Center for Safety Information is also available for contact 
24 hours 365 days. 
Emergency center for safety information (available 24 hours 365 days)
The principal investigator should inform the head of the medical institution of all serious 
adverse events occurring at the center in accordance with procedures required at the 
center and notify the sponsor according to this protocol.  
Determination of expectedness will be based on the contents in the latest investigator’s 
brochure (including information on the adverse events that have already been reported to 
the medical institution).
PPD
PPD
PPD


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10.
STATISTICAL CONSIDERATIONS
10.1
Endpoints and Analysis Set
10.1.1
Primary Endpoint
●
DLTs, adverse events, body weight, vital signs, 12-lead ECGs, laboratory tests
●
MLN2238 plasma concentration
10.1.2
Secondary Endpoints
●
Numbers of subjects achieving CR, VGPR, and PR
10.1.3
Analysis Set
DLT Analysis Set:
The DLT analysis set will consist of DLT evaluable subjects who received at least one 
dose of MLN9708 (see 6.7.2).
Safety Analysis Set:
The safety analysis set will consist of all subjects who received at least one dose of 
MLN9708.
Response Evaluable Analysis Set:
The response evaluable analysis set will consist of all subjects who received at least one 
dose of MLN9708, have measurable disease at baseline, and at least one postbaseline 
response assessment.
Pharmacokinetic analysis set:
The pharmacokinetic analysis set will consist of all subjects who received at least one 
dose of MLN9708 and has evaluable pharmacokinetic data.
10.2
Sample Size Considerations
The planned number of subjects in this study is 3 to 6 for each cohort (12 to 24 in total).


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The sample size was selected with reference to the preceding overseas clinical studies 
and the “Anti-Malignant Tumor Drug Clinical Assessment Guidelines” (PFSB/ELD 
Notification No. 1101001, dated November 1, 2005). The sample size was not selected 
based on a statistical rationale.
10.3
Interim Analysis and Early Stopping Guidelines
No interim analysis is planned in this study.
10.4
Statistical Methods of Analysis
The demographic data and all endpoints data will be analyzed.  Summary statistics 
(numbers of subjects, mean, median, standard deviation, maximum, minimum) will be 
calculated for continuous data. Frequencies and proportions will be tabulated for 
categorical data.
Details are presented in the statistical analysis plan.
10.4.1
Safety endpoints
Unless otherwise specified, the following safety endpoints will be analyzed for the 
subjects in the safety analysis set.
10.4.1.1
DLT
DLTs will be summarized in the DLT analysis set.
10.4.1.2
Adverse events
The incidence and percentage of treatment-emergent adverse events will be summarized 
by system organ class (SOC) and preferred term (PT) of ICH Medical Dictionary for 
Regulatory Activities (MedDRA) and by grade.  In addition, the following adverse events 
will be summarized by the same method.  Severity will be graded with CTCAE version 
4.03.
●
Serious adverse events
●
Adverse events leading to permanent discontinuation of study treatment
●
Treatment-related adverse events


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●
Treatment-related serious adverse events
●
Treatment-related adverse events leading to permanent discontinuation of study 
treatment
10.4.1.3
Laboratory tests
Summary statistics will be calculated for the changes in continuous data from baseline to 
postdose assessment.  In addition, the shift from baseline to the postdose worst grade will 
be tabulated for selected laboratory parameters in accordance with CTCAE version 4.03.
10.4.1.4
Other safety analyses
Vital signs, 12-lead ECGs, body weight, ECOG performance status, etc. will be 
summarized.
10.4.2
Efficacy endpoints
Unless otherwise specified, the following efficacy endpoint analyses will be performed 
for subjects in the response evaluable analysis set.
10.4.2.1
Tumor response
The numbers of patients achieving CR, VGPR and PR will be assessed in accordance 
with the International Myeloma Working Group Uniform Response Criteria for Multiple 
Myeloma. Where possible, the objective response rate (CR + VGPR + PR) will also be 
summarized.
10.4.3
Pharmacokinetic analysis
In the pharmacokinetic analysis set, non- compartment model analysis will be performed 
based on the MLN2238 plasma concentration profile, and the pharmacokinetic 
parameters (e.g., Cmax, AUC) will be calculated.  The summary statistics will also be 
calculated for each parameter by dose.  In addition to calculating the summary statistics 
of the MLN2238 plasma concentration at each blood sample collection time, specified in 
the study protocol, by dose, figures of profiles (both individual and mean concentration) 
will also be prepared by dose.  Furthermore, a compartment model analysis may be 
performed based on the MLN2238 plasma concentration profile.


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11.
REGULATORY OBLIGATIONS
11.1
Quality Control of Data and Quality Assurance 
This study will be conducted in compliance with “Ministerial Ordinance Concerning the 
Standards for the Conduct of Clinical Trials of Medicinal Products” (Ministry of Health, 
Labour and Welfare [MHLW] Ordinance No. 28, 27 March 1997) including relevant 
MHLW notifications (J-GCP), Pharmaceutical Affairs Law, and the protocol of this study, 
and based on the Helsinki Declaration, the protection of the human rights of subjects will 
be given first priority. 
Quality control of data will be conducted following the sponsor’s standard operating 
procedures related to the conduct of clinical studies.  The sponsor’s audit, which is 
independent of and separate from routine monitoring or quality control functions, will 
ascertain, for quality assurance of a clinical trial, whether the clinical trial is conducted in 
compliance with the J-GCP, the protocol, and the operating procedures.
11.2
Informed Consent
An initial generic informed consent template form is provided for the principal 
investigator to prepare the informed consent document to be used at the site.  Updates to 
the template will be communicated by letter from the sponsor to the principal investigator.  
The written informed consent document should be prepared in Japanese.
Before a subject’s participation in the clinical study, the investigator is responsible for 
obtaining written informed consent from the subject after fully informing the aims, 
methods, anticipated benefits, and potential hazards of the study and before any protocol-
specific screening procedures or any investigational products are administered.
The acquisition of informed consent should be documented in the subject’s medical 
records, and the informed consent form should be signed and personally dated by the 
subject, by the investigator and by the person who conducted the informed consent 
discussion.  The original signed informed consent form should be retained in accordance 
with institutional policy, and a copy of the signed consent form should be provided to the 
subject or legally acceptable representative.  


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If a potential subject is illiterate or visually impaired, the investigator must provide an 
impartial witness to read the informed consent form to the subject and must allow for 
questions.  Thereafter, both the subject and the witness must sign the informed consent 
form to attest that informed consent was freely given and understood.  
11.3
Institutional Review Board
A copy of the protocol, proposed informed consent form, other written subject 
information, and any proposed advertising material must be submitted to the institutional 
review board (IRB) for written approval.  A copy of the written approval of the protocol 
and informed consent document must be received by the sponsor before recruitment of 
subjects into the study and shipment of investigational product.
The sponsor must submit and, where necessary, obtain approval from the IRB for 
protocol amendments and changes to the informed consent document if applicable.  The 
investigator should notify the head of the medical institution of deviations from the 
protocol or serious adverse events occurring at the site and other adverse event reports 
received from the sponsor, in accordance with local procedures.
The investigator will be responsible for obtaining annual approval/renewal of the head of 
the medical institution throughout the duration of the study.  Copies of the investigator’s 
reports and the head of the medical institution’s continuance of approval must be sent to 
the sponsor.  
11.4
Subject Confidentiality
The investigator must ensure that the subject’s confidentiality is maintained:  
●
On the eCRFs or other documents submitted to the sponsor, subjects should be 
identified by the subject identification number only.  
●
On the serious adverse event forms submitted to the sponsor, subjects should be 
identified by a subject study number only.  
●
Documents that are not for submission to the sponsor (e.g., signed informed consent 
forms) should be kept in strict confidence by the investigator.
In compliance with J-GCP, it is required that the investigator and institution permit 
authorized representatives (study monitors or auditors) of the company, of the regulatory 


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agency(s), and the IRB direct access to review the subject’s original medical records for 
verification of study-related procedures and data.  Direct access includes examining, 
analyzing, verifying, and reproducing any records and reports that are important to the 
evaluation of the study.  The investigator is obligated to inform and obtain the consent of 
the subject to permit named representatives to have access to his/her study-related records 
without violating the confidentiality of the subject.
11.5
Dissemination of New Information
When information important to the proper conduct of the clinical study becomes 
available such as on diseases, impairment, and deaths suspected to be due to the effect of 
the investigational product, onset of infections suspected to be due to the use of the 
investigational product, and other information related to the investigational product 
quality, efficacy, and safety, the sponsor will promptly notify the investigators, the heads 
of medical institution, medical experts, and the ESEC in writing and take necessary 
measures. Of note, the sponsor will finish the report to the ESEC at the end of October 
2016.
Once it is determined that the information provided by the sponsor may affect a subject’s
willingness to continue participation, the investigator should promptly provide the 
information to the subjects, document, and ensure his/her willingness to continue 
participation.  When the sponsor requires the investigator to ensure the subject’s 
willingness to continue participation, or the investigator obtains information that may 
affect a subject’s willingness to continue participation as well, the investigator will ensure 
the subject’s willingness to continue participation.


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12.
ADMINISTRATIVE AND LEGAL OBLIGATIONS
12.1
Protocol Amendments and Study Termination
Protocol amendments, except where necessary to eliminate an immediate hazard to 
subjects, must be made only with the prior approval by the sponsor.  The head of the 
medical institution must be informed of amendments and give approval if applicable.  
The medical institution must send a copy of the approval letter from the head of the 
medical institution to the sponsor.
Both the sponsor and the principal investigator reserve the right to terminate the study, 
according to the study contract.  The principal investigator should notify the head of the 
medical institution in writing of the study’s completion or early termination and send a 
copy of the notification to the sponsor.
12.2
Source Data and Essential Documents
The study center must comply with inspection by sponsor’s study monitors, auditors, IRB, 
and regulatory authorities and make available for direct inspection all clinical study-
related records.
After coordinating the method, timing, and schedule for source data verification 
beforehand with the investigator and clinical study management office of the study center, 
the study monitor will confirm through direct access that all clinical study-related records 
are in order and are stored appropriately and that the contents are accurate and complete.
Source data verification by study monitors will be conducted in accordance with 
“Monitoring Plan” to be provided separately.
In this study, an eCRF may be used as source data.
●
eligibility
●
medical and surgical history
●
reason for discontinuation or change of study treatment
●
purpose of the use of concomitant medications
●
reason for study termination


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●
investigator’s comments
●
presence or absence of adverse events, intermittence (repeated appearance and 
disappearance), severity, seriousness, and relationship with investigational product 
No study document should be destroyed without prior written agreement between the 
sponsor and the medical institution.  Should the medical institution wish to assign the 
management of study records to another party or move them to another location, he/she 
must notify the sponsor in writing of the new responsible person and/or the new location.
12.3
Data Handling and Retention of Records
12.3.1
Data Handling
All data capture for this study will be eCRF using electronic data capture (EDC) system.  
Case report form is taken as synonymous with eCRF.  The sponsor offers the training to 
investigators and clinical research coordinators for eCRF completion guidelines and/or 
acquiring EDC access privileges.
The sponsor ensures that the data is compliance with the protocol and J-GCP and creates 
electronic queries for the medical institution to resolve any questions.
The principal investigator review all eCRF data including the response to queries and 
data changes, then the principal investigator will sign off eCRF electronically 
(eSignature) as indicating approval for the all entries on eCRF.  The principal investigator 
is responsible for the accuracy and reliability of eCRF data.
Sponsor’s clinical data management department may correct the data for the following 
eCRF issues with notification to the sites.
●
Revision of administrative data such as visit no. on eCRF generated by unscheduled 
visit or re-examination.
●
Deletion of the entry in “Other” option and change to another option if the entry in 
“Other” option should be filled in correct option.
12.3.2
Retention of Records
The medical institution must maintain the following records (including documents) till 
the day on which manufacturing or import approval of the test product is obtained (or the 


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day 3 years after the date of notification in case of a notification pursuant to Article 24, 
Paragraph 3) or the day 3 years after the date of premature termination or completion of 
the clinical study, whichever is the later.
1)
Source documents
2)
The contract, informed consent forms, written information and other documents 
prepared by persons engaged in the medical institution pursuant to the J-GCP or 
their copies.
3)
The protocol, documents obtained from the institutional review board pursuant 
to Article 32, Paragraphs 1, 2, and 3, and other documents obtained pursuant to 
the J-GCP.
4)
Records of investigational product control and other study-related duties.
The sponsor will obtain the following data via electronic means from a third-party 
measurement service.  The electronic data provided by the third-party measurement 
service will be used as source documents.
12.4
Language
The eCRF must be completed in English.
All written information and other material to be used by subjects and investigative staff
must use vocabulary and language that are clearly understood.  
12.5
Publication Policy
Authorship of any publications resulting from this study will be determined on the basis 
of the Uniform Requirement for Manuscripts Submitted to Biomedical Journals, which 
states:
●
Authorship credit should be based on (1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; (2) drafting the 
article or revising it critically for important intellectual content; (3) final approval of 
the version to be published.  Authors should meet conditions 1, 2, and 3.
●
When a large, multicenter group has conducted the work, the group should identify 
the individuals who accept direct responsibility for the manuscript.  These individuals 
should fully meet the criteria for authorship defined above.
●
Acquisition of funding, collection of data, or general supervision of the research 
group, alone, does not justify authorship.


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●
All persons designated as authors should qualify for authorship, and all those who 
qualify should be listed.
●
Each author should have participated sufficiently in the work to take public 
responsibility for appropriate portions of the content.
All publications (e.g., manuscripts, abstracts, oral/slide presentations, book chapters) 
based on this study must be submitted to the sponsor for corporate review.  The Clinical 
Study Agreement among the institution, the principal investigator, and the sponsor will 
detail the procedures for, and timing of, sponsor’s review of publications.
12.6
Compensation 
Subjects will be treated and/or compensated for any study-related illness/injury pursuant 
to the information provided in the compensation for injury section of the informed 
consent document, which describes any compensation that will be provided during the 
study.  However, if the liability for damages is determined to be due to deliberateness or 
negligence on the he part of research facilities and/or due to deliberateness or gross 
negligence on the part of subjects, the compensation will be adjusted accordingly or 
waived altogether.
12.7
Financing 
The financial aspects of the study should be documented in an agreement between the 
sponsor and the institution.


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13.
REFERENCES
Anderson K, Weller E, Lonial S, Jakubowiak A, Jagannath S, Raje N, et al. Lenalidomide, 
bortezomib, and dexamethasone in patients with newly diagnosed multiple myeloma 
(MM): Updated Results of a Multicenter Phase I/II Study after Longer Follow-up. J Clin 
Oncol. (ASCO Meeting Abstracts) 2010;28(15s):suppl; abstr 8016.
Bladé J, Samson D, Reece D, Apperley J, Bjorkstrand B, Gahrton G, et al. Criteria for 
evaluating disease response and progression in patients with multiple myeloma treated by 
high-dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of 
the EBMT. European Group for Blood and Marrow Transplant. British Journal of 
Haematology 1998;102(5):1115-23.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine.  
Nephron 1976;16(1):31-41.
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.
Durie BG. Staging and kinetics of multiple myeloma. Semin Oncol 1986;13:300-309.
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;36:842-854.
Greipp PR, Miguel JS, Durie BG, Crowley JJ, Barlogie B, Bladé J, et al. International 
staging system for multiple myeloma. J Clin Oncol 2005;23(15):3412-3420.
Jemal A, Murray T, Ward E, Samuels A, Tiwari RC, Ghafoor A, et al. Cancer statistics, 
2005. CA Cancer J Clin 2005;55(1):10-30.
Kumar S, Flinn I, Richardson P, Hari P, Callander N, Noga S, et al. Novel Three- and 
Four-Drug Combination Regimens of Bortezomib, Dexamethasone, Cyclophosphamide, 
and Lenalidomide, for Previously Untreated Multiple Myeloma: Results From the Multi-
Center, Randomized, Phase 2 EVOLUTION Study. Blood (ASH Annual Meeting 
Abstracts) 2010;116(21):abstr 621.
National Comprehensive Cancer Network. V.1.2012. NCCN Clinical Practice Guidelines 
in Oncology: Multiple Myeloma. 2012
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 openlabel 
randomised controlled trial. Lancet Oncol 2010;11(1):29-37.
Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, et al. A Phase 2 
Study of Bortezomib in Relapsed, Refractory Myeloma. New England Journal of 
Medicine 2003;348(26):2609-17.


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Richardson PG, Weller E, Lonial S, Jakubowiak AJ, Jagannath S, Raje NS, et al. 
Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with 
newly diagnosed multiple myeloma. Blood 2010a;116(5):679-86.
Richardson PG, Jagannath S, Jakubowiak AJ, et al. Phase II Trial of lenalidomide, 
bortezomib, and dexamethasone in patients (pts) with relapsed and relapsed/refractory 
multiple myeloma (MM): updated efficacy and safety data after >2 years of follow-up 
[abstract]. Blood 2010b;116:Abstract 3049.
The following references are available in Japanese.
MLN9708 Investigator’s brochure (Edition 1.0) Takeda Bio Development Center Ltd.
Ministry of Health, Labour and Welfare. Patients survey 2008. Accessed on 12 December, 
2011.
http://www.mhlw.go.jp/toukei/saikin/hw/kanja/10syoubyo/suiihyo12.html
Common Terminology Criteria for Adverse Events v4.03［CTCAE］14 June 2010）
Japan Society of Myeloma. Guidelines for diagnosis and treatment for multiple myeloma 
Edtion 2. 11 November 2008.
National Cancer Center; Center for Cancer Control and Information Services. 01 October 
2006 (Updated on 30 November 2010). Accessed on 12 December, 2011.
http://ganjoho.jp/public/statistics/pub/statistics01.html


Summary of Changes for Protocol Amendment
A Phase 1 Study of MLN9708 in Japanese Patients with Relapsed and/or Refractory 
Multiple Myeloma
Version 3.2 →Version 3.3
Protocol Number:  TB-MC010034
Date of Amendment:  22 November 2016


Protocol Change Memo
A Phase 1 Study of MLN9708 in Japanese Patients with Relapsed and/or Refractory Multiple Myeloma
Date for version 3.3:  22 November 2016
1
Section
Replaced
With
Rationale
Header
Date: 18 November 2015
Date: 22 November 2016
New version.
Title Page
Version/Date: Version 3.2    18 November 2015
Version/Date: Version 3.3    22 November 2016
New version.
Document History
Document History
Version 1:  12 January 2012
Version 2:  7 February 2012
Version 2.1:  7 March 2012
Version 2.2:  11 September 2012
Version 3:  4 December 2013
Version 3.1:  4 December 2014
Document History
Version 1:  12 January 2012
Version 2:  7 February 2012
Version 2.1:  7 March 2012
Version 2.2:  11 September 2012
Version 3:  4 December 2013
Version 3.1: 4 December 2014
Version 3.2:  18 November 2015
Document history 
is updated.
3. EXPERIMENTAL 
PLAN
3.4 Estimated Study 
Duration
The study will be conducted between March 2012 and 
March 2017.
The study will be conducted between March 2012 and 
March 2019.
Extended the 
estimated study 
duration according 
to the progress of 
the study.
6. TREATMENT 
PROCEDURES
6.9 Excluded 
Concomitant 
Medications and 
Procedures

Systemic treatment with strong inhibitors of 
CYP1A2 (fluvoxamine, enoxacin), strong inhibitors 
of CYP3A (clarithromycin, telithromycin, 
itraconazole, voriconazole, ketoconazole) or strong 
CYP3A inducers (rifampicin, rifabutin, 
carbamazepine, phenytoin, phenobarbital), or use/ 
intake of foods containing Ginkgo biloba extract, St.
John's wort, or grapefruit during the study.

Systemic treatment with strong CYP3A inducers 
(rifampicin, rifabutin, carbamazepine, phenytoin, 
phenobarbital), or use/ intake of foods containing St.
John's wort during the study.
The inhibitors of 
CYP1A2 and
CYP3A does not 
affect on 
pharmacokinetics 
of MLN 9708 
based on the study 
results.
    : Amended texts


Protocol Change Memo
A Phase 1 Study of MLN9708 in Japanese Patients with Relapsed and/or Refractory Multiple Myeloma
Date for version 3.3:  22 November 2016
2
Section
Replaced
With
Rationale
11. REGULATORY 
OBLIGATIONS
11.5. Dissemination 
of New Information
When information important to the proper conduct of the 
clinical study becomes available such as on diseases, 
impairment, and deaths suspected to be due to the effect 
of the investigational product, onset of infections 
suspected to be due to the use of the investigational 
product, and other information related to the 
investigational product quality, efficacy, and safety, the 
sponsor will promptly notify the investigators, the heads
of medical institution, medical experts, and the ESEC in 
writing and take necessary measures.
When information important to the proper conduct of the 
clinical study becomes available such as on diseases, 
impairment, and deaths suspected to be due to the effect of
the investigational product, onset of infections suspected to 
be due to the use of the investigational product, and other 
information related to the investigational product quality, 
efficacy, and safety, the sponsor will promptly notify the 
investigators, the heads of medical institution, medical 
experts, and the ESEC in writing and take necessary
measures.  Of note, the sponsor will finish the report to 
the ESEC at the end of October 2016.
Report of new
information to 
ESEC was finished.
    : Amended texts


Summary of Changes for Protocol Amendment
A Phase 1 Study of MLN9708 in Japanese Patients with Relapsed and/or Refractory 
Multiple Myeloma
Version 3.1 →Version 3.2
Protocol Number:  TB-MC010034
Date of Amendment:  18 November 2015


Protocol Change Memo
A Phase 1 Study of MLN9708 in Japanese Patients with Relapsed and/or Refractory Multiple Myeloma
Date for version 3.2:  18 November 2015
1
Section
Replaced
With
Rationale
Header
Product: MLN9708
Protocol Number: TB-MC010034
Date: 4 December 2014
Product: MLN9708
Protocol Number: TB-MC010034
Date: 18 November 2015
New version.
Document History
Document History
Version 1:  12 January 2012
Version 2:  7 February 2012
Version 2.1:  7 March 2012
Version 2.2:  11 September 2012
Version 3:  4 December 2013
Document History
Version 1:  12 January 2012
Version 2:  7 February 2012
Version 2.1:  7 March 2012
Version 2.2:  11 September 2012
Version 3:  4 December 2013
Version 3.1:  4 December 2014
Document history 
is updated.
3. EXPERIMENTAL 
PLAN
3.4 Estimated Study 
Duration
The study will be conducted between March 2012 and 
March 2016.
The study will be conducted between March 2012 and 
March 2017.
Extended the 
estimated study 
duration according 
to the progress of 
the study.
    : Amended texts


Summary of Changes for Protocol Amendment
A Phase 1 Study of MLN9708 in Japanese Patients with Relapsed and/or Refractory 
Multiple Myeloma
Version 3 →Version 3.1
Protocol Number:  TB-MC010034
Date of Amendment:  4 December 2014


Protocol Change Memo
A Phase 1 Study of MLN9708 in Japanese Patients with Relapsed and/or Refractory Multiple Myeloma
Date for version 3.1:  4 December 2014
1
Section
Replaced
With
Rationale
Header
Product: MLN9708
Protocol Number: TB-MC010034
Date: 4 December 2013
Product: MLN9708
Protocol Number: TB-MC010034
Date: 4 December 2014
New version.
Title Page
Clinical Study Sponsor: Takeda Bio Development Center
Company Limited
1-7-12, Marunouchi, Chiyoda-ku, Tokyo, 100-0005, 
Japan
Version/Date: Version 3    4 December 2013
Confidentiality Notice
This document contains confidential information of 
Takeda Bio Development Center Limited.
This document must not be disclosed to anyone other 
than the study staff and members of the institutional
review board.
The information in this document cannot be used for any 
purpose other than the evaluation or conduct of the 
clinical study without the prior written consent of Takeda 
Bio Development Center Limited.
If you have questions regarding how this document may 
be used or shared, or other study-related questions,
contact the Clinical Study Sponsor.
Clinical Study Sponsor: Takeda Pharmaceutical Company 
Limited
1-1, Doshomachi 4-chome, Chuo-ku, Osaka, 540-8645, 
Japan
Version/Date: Version 3.1    4 December 2014
This document contains confidential information of Takeda 
Pharmaceutical Company Limited.
This document must not be disclosed to anyone other than 
the study staff and members of the institutional review 
board.
The information in this document cannot be used for any 
purpose other than the evaluation or conduct of the clinical 
study without the prior written consent of Takeda 
Pharmaceutical Company Limited.
If you have questions regarding how this document may be 
used or shared, or other study-related questions, contact the 
Clinical Study Sponsor.
Description 
adjustment and new 
version.
    : Amended texts
PPD
PPD


Protocol Change Memo
A Phase 1 Study of MLN9708 in Japanese Patients with Relapsed and/or Refractory Multiple Myeloma
Date for version 3.1:  4 December 2014
2
Section
Replaced
With
Rationale
Document History
Document History
Version 1:  12 January 2012
Version 2:  7 February 2012
Version 2.1:  7 March 2012
Version 2.2:  11 September 2012
Document History
Version 1:  12 January 2012
Version 2:  7 February 2012
Version 2.1:  7 March 2012
Version 2.2:  11 September 2012
Version 3:  4 December 2013
Document history 
is updated.
Protocol Summary
Sponsor:  Takeda Bio Development Center Limited
Sponsor:  Takeda Pharmaceutical Company Limited
Description 
adjustment.
3. EXPERIMENTAL 
PLAN
3.4 Estimated Study 
Duration
The study will be conducted between March 2012 and 
March 2015.
The study will be conducted between March 2012 and 
March 2016.
Extended the 
estimated study 
duration according 
to the progress of 
the study.
5. SUBJECT 
ENROLLMENT
5.1 Enrollment 
Procedures
MLN9708 (TB-MC010034) Subject Registration 
Center
Takeda Bio Development Center Limited
Sapia Tower, 1-7-12 Marunouchi, Chiyoda-ku, Tokyo, 
Japan
MLN9708 (TB-MC010034) Subject Registration Center
Takeda Pharmaceutical Company Limited
Marunouchi Eiraku Building, 1-4-1 Marunouchi, 
Chiyoda-ku, Tokyo, Japan
Description 
adjustment.
    : Amended texts
PPD
PPD
PPD
PPD
PPD
PPD


Protocol Change Memo
A Phase 1 Study of MLN9708 in Japanese Patients with Relapsed and/or Refractory Multiple Myeloma
Date for version 3.1:  4 December 2014
3
Section
Replaced
With
Rationale
6. TREATMENT 
PROCEDURES
6.1 MLN9708
MLN9708 is manufactured (including packaging and 
labeling) by MPI and supplied by Takeda Bio 
Develoment Center.
MLN9708 is manufactured (including packaging and 
labeling) by MPI and supplied by Takeda Pharmaceutical 
Company.
Description 
adjustment.
14. APPENDICES
Appendix D. 
Pregnancy 
Notification 
Worksheet
Fax to: Clinical Development DIV, Takeda Bio 
Development Center Company Limited
Fax to: Clinical Development DIV, Takeda Pharmaceutical 
Company Limited
Description 
adjustment.
    : Amended texts


 
 
 
Summary of Changes for Protocol Amendment 
A Phase 1 Study of MLN9708 in Japanese Patients with Relapsed and/or Refractory  
Multiple Myeloma 
 
Version 2.2 → Version 3 
 
 
 
 
 
Protocol Number:  TB-MC010034 
Date of Amendment:  4 December 2013 
 


Protocol Change Memo 
A Phase 1 Study of MLN9708 in Japanese Patients with Relapsed and/or Refractory Multiple Myeloma 
Date for version 3:  4 December 2013 
1 
Section 
Replaced 
With 
Rationale 
Header 
Product: MLN9708 
Protocol Number: TB-MC010034 
Date: 11 September 2012 
Product: MLN9708 
Protocol Number: TB-MC010034 
Date: 4 December 2013 
New version. 
Title Page 
Version/Date: Version 2.2    11 September 2012 
Version/Date: Version 3    4 December 2013 
New version. 
Document History 
Document History 
Version 1:  12 January 2012 
Version 2:  7 February 2012 
Version 2.1:  7 March 2012 
 
Document History 
Version 1:  12 January 2012 
Version 2:  7 February 2012 
Version 2.1:  7 March 2012 
Version 2.2:  11 September 2012 
 
Document history 
is updated. 
Overview of Study 
Design 
 
The sponsor will evaluate the tolerability of MLN9708 
dosage on the basis of the safety data including DLT 
incidences during the DLT-assessment period.  The 
sponsor will decide whether the next cohort will be 
studied and the dose of the next cohort in consultation 
with the ESEC, if necessary.  If the current cohort is 
considered tolerable, the next cohort will be in the order 
of cohorts 2 (MLN9708 4.0 mg plus Rd), 3 (MLN9708 
5.5 mg alone), and 4 (MLN9708 5.5 mg plus Rd).   
The sponsor will evaluate the tolerability of MLN9708 
dosage on the basis of the safety data including DLT 
incidences during the DLT-assessment period.  The 
sponsor will decide whether the next cohort will be studied 
and the dose of the next cohort in consultation with the 
ESEC, if necessary.  If the current cohort is considered 
tolerable, the next cohort will be in the order of cohorts 2 
(MLN9708 4.0 mg plus Rd), 3 (MLN9708 5.5 mg alone), 
and 4 (MLN9708 5.5 mg plus Rd).  Even if a dosage is 
considered tolerable and transition to the next cohort is 
considered feasible, the next cohort may not be studied 
based on the results of the overseas clinical studies and the 
current study. 
Added description 
for the case where 
the next cohort will 
not be studied. 
     : Amended texts 
 


Protocol Change Memo 
A Phase 1 Study of MLN9708 in Japanese Patients with Relapsed and/or Refractory Multiple Myeloma 
Date for version 3:  4 December 2013 
2 
Section 
Replaced 
With 
Rationale 
3. EXPERIMENTAL 
PLAN 
3.1 Study Design 
The sponsor will evaluate the tolerability of MLN9708 
dosage on the basis of the safety data including DLT 
incidences during the DLT-assessment period.  The 
sponsor will decide whether the next cohort will be 
studied and the dose of the next cohort in consultation 
with the ESEC, if necessary.  If the current cohort is 
considered tolerable, the next cohort will be in the order 
of cohorts 2 (MLN9708 4.0 mg plus Rd), 3 (MLN9708 
5.5 mg alone), and 4 (MLN9708 5.5 mg plus Rd).   
The sponsor will evaluate the tolerability of MLN9708 
dosage on the basis of the safety data including DLT 
incidences during the DLT-assessment period.  The 
sponsor will decide whether the next cohort will be studied 
and the dose of the next cohort in consultation with the 
ESEC, if necessary.  If the current cohort is considered 
tolerable, the next cohort will be in the order of cohorts 2 
(MLN9708 4.0 mg plus Rd), 3 (MLN9708 5.5 mg alone), 
and 4 (MLN9708 5.5 mg plus Rd).  Even if a dosage is 
considered tolerable and transition to the next cohort is 
considered feasible, the next cohort may not be studied 
based on the results of the overseas clinical studies and the 
current study. 
Added description 
for the case where 
the next cohort will 
not be studied. 
3. EXPERIMENTAL 
PLAN 
3.4 Estimated Study 
Duration 
The study will be conducted between March 2012 and 
September 2014. 
The study will be conducted between March 2012 and 
March 2015. 
Extended the 
estimated study 
duration according 
to the progress of 
the study. 
6. TREATMENT 
PROCEDURES 
6.6  Cohort 
Transition and Early 
Stopping Guidelines 
6.6.1 Cohort 
Transition 
N/A 
Even if a dosage is considered tolerable and transition to 
the next cohort is considered feasible, the next cohort may 
not be studied based on the results of the overseas clinical 
studies and the current study. 
Added description 
for the case where 
the next cohort will 
not be studied. 
     : Amended texts 
 


 
 
 
Summary of Changes for Protocol Amendment 
A Phase 1 Study of MLN9708 in Japanese Patients with Relapsed and/or Refractory  
Multiple Myeloma 
 
Version 2.1 → Version 2.2 
 
 
 
 
 
Protocol Number:  TB-MC010034 
Date of Amendment:  11 September 2012 
 


Protocol Change Memo 
A Phase 1 Study of MLN9708 in Japanese Patients with Relapsed and/or Refractory Multiple Myeloma 
Date for version 2.2:  11 September 2012 
1 
Section 
Replaced 
With 
Rationale 
Header 
Product: MLN9708 
Protocol Number: TB-MC010034 
Date: 7 March 2012 
Product: MLN9708 
Protocol Number: TB-MC010034 
Date: 11 September 2012 
New version. 
Title Page 
Key Sponsor Contact:  
 
 
Deleted 
New template. 
Title Page 
Version/Date: Version 2.1    7 March 2012 
Version/Date: Version 2.2     11 September 2012 
New version. 
Document History 
Document History 
Version 1: 12 January 2012 
Version 2: 7 February 2012 
Document History 
Version 1: 12 January 2012 
Version 2: 7 February 2012 
Version 2.1: 7 March 2012 
Document history 
is updated. 
6. TREATMENT 
PROCEDURES 
6.5.2.2.2 Dose 
Modification for 
Neutropenia 
If ANC count is less than 1,000/mm3 in Cycle 2 or 
subsequent cycles, lenalidomide dose should be 
interrupted.   
...*snip*... 
G-CSF is not permitted in Cycle 1 unless Grade 4 
neutropenia occurs (See section 6.8 Excluded 
Concomitant Medications and Procedures). 
If ANC count is less than 1,000/mm3 in Cycle 2 or 
subsequent cycles, lenalidomide dose should be 
interrupted.   
...*snip*... 
G-CSF is not permitted in Cycle 1 unless Grade 4 
neutropenia occurs (See section 6.9 Excluded Concomitant 
Medications and Procedures). 
Description 
amendment 
     : Amended texts 
 
PPD
PPD
PPD
PPD


Protocol Change Memo 
A Phase 1 Study of MLN9708 in Japanese Patients with Relapsed and/or Refractory Multiple Myeloma 
Date for version 2.2:  11 September 2012 
2 
Section 
Replaced 
With 
Rationale 
6. TREATMENT 
PROCEDURES 
6.5.2.3.2 MLN9708 
Treatment 
Modification 
Table 6-9 
Adverse Event (Severity): Grade 2 peripheral 
neuropathywith pain, Grade 3 non-hematological 
toxicity 
Action on MLN9708: Reduce MLN9708 by 1 dose level 
Table 6-9 
Adverse Event (Severity): Grade 2 peripheral 
neuropathywith pain, Grade 3 non-hematological toxicity
Action on MLN9708: MLN9708 may be reinitiated with 
one dose level reduction. 
Clear explanation 
6. TREATMENT 
PROCEDURES 
6.7.3 Definitions of 
DLT 
7. Any other Grade 3 or greater nonhematologic toxicities 
with the following exceptions: 
...*snip*... 
•Grade 3 or greater nausea and/or emesis without the use 
of optimal anti-emetic prophylaxis. Optimal anti-emetic 
prophylaxis is defined as an anti-emetic regimen that 
employs a 5-HT3 antagonist given in standard doses and 
according to standard schedules. Dexamethasone should 
not be administered as an anti-emetic. 
•Diarrhea that does not require treatment 
7. Any other Grade 3 or greater nonhematologic toxicities 
with the following exceptions: 
...*snip*... 
•Grade 3 nausea and/or emesis which can be controlled 
with anti-emetic therapies including anti-emetic 
prophylaxis. Anti-emetic prophylaxis is defined as an anti-
emetic regimen that employs a 5-HT3 antagonist given in 
standard doses and according to standard schedules.  
Dexamethasone should not be administered as an anti-
emetic. 
• Grade 3 Diarrhea that is controlled with appropriate 
supportive care 
In ver 2.1 PRT, the 
sponsor's intention 
was not described 
clear enough. 
Therefore to avoid 
any potential 
misinterpratation, 
we decided to 
amend the 
description to be 
more specific. 
6. TREATMENT 
PROCEDURES 
6.8 Permitted 
Concomitant 
Medications and 
Procedures 
N/A 
6.8 Permitted Concomitant Medications and Procedures 
Throughout the study, investigators may prescribe any 
concomitant medications or perform procedures deemed 
necessary to provide adequate supportive care except for 
those listed in “6.9 Excluded Concomitant Medications and 
Procedures” 
Added new section 
for clarification 
     : Amended texts 
 


Protocol Change Memo 
A Phase 1 Study of MLN9708 in Japanese Patients with Relapsed and/or Refractory Multiple Myeloma 
Date for version 2.2:  11 September 2012 
3 
Section 
Replaced 
With 
Rationale 
7. STUDY 
PROCEDURES 
7.2.2 Treatment 
period 
• 
Body weight 
– 
Cycle 1:  Before MLN9708 dosing on Day 1.  
If a patient's body weight has been measured 
within 3 days before the first dose, then this 
measurement may be used for the Cycle 1 Day 
1 data. 
• 
Body weight 
– 
Cycle 1:  Before MLN9708 dosing on Day 1.  
If a patient's body weight at screening is 
measured within 3 days before the first dose, 
then this measurement may be used for the Cycle 
1 Day 1 data.  
Clear explanation 
7. STUDY 
PROCEDURES 
7.2.2 Treatment 
period 
• 
Urine M-protein (electrophoresis protein fraction 
test):  
...*snip*... 
Subjects whose urine M-protein has been detected 
in serum and urine at screening 
–Measurement by 24-hour urine collection. 
• 
If a response assessment requires confirmation or 
disease progression is suspected (see Appendix G), a 
urine M-protein measurement will be collected as 
appropriate using 24-hour urine collection. 
• 
Urine M-protein (electrophoresis protein fraction 
test):  
...*snip*... 
Subjects whose urine M-protein has been detected in 
serum and urine at screening 
–Measurement by 24-hour urine collection. 
• 
Urine samples will be collected prior to MLN9708 
dosing on Cycle 1 Day 1.  If a screening test is 
performed within 7 days before the first dose, the 
results may be used as the Cycle 1 Day 1 data. 
• 
If a response assessment requires confirmation or 
disease progression is suspected (see Appendix G), a 
urine M-protein measurement will be collected as 
appropriate using 24-hour urine collection. 
Clear explanation 
7. STUDY 
PROCEDURES 
7.2.3 End of study 
 
Urine M-protein by 24-hour urine collection 
(protein fraction test by electrophoresis):  
Performed only for subjects whose urine M-protein 
was detected by immunofixation and electrophoresis 
protein fraction test at screening. 
 
Urine M-protein by 24-hour urine collection (protein 
fraction test by electrophoresis):  Performed only for 
subjects whose urine M-protein is detected at 
screening. 
Correction of 
errors. 
     : Amended texts 
 


Protocol Change Memo 
A Phase 1 Study of MLN9708 in Japanese Patients with Relapsed and/or Refractory Multiple Myeloma 
Date for version 2.2:  11 September 2012 
4 
Section 
Replaced 
With 
Rationale 
7. STUDY 
PROCEDURES 
7.2.6 
Pharmacokinetic 
sample collection 
time points 
Table 7-2 
Cycle 2 
Day 1 
Predose 
 
Table 7-2 
Cycle 2 
Day 1 
Predose (336 hours postdose) 
 
Clear explanation 
8. REMOVAL AND 
REPLACEMENT OF 
SUBJECTS 
8.1 Removal of 
Subjects 
Subjects have the right to withdraw fully or partially from 
the study at any time and for any reason. 
...*snip*... 
In this case, the missing of protocol-specified tests or 
assessments on the 29th day after the last dose of the 
investigational product will not be considered as any 
protocol deviations. 
Subjects have the right to withdraw fully or partially from 
the study at any time and for any reason. 
...*snip*... 
In this case, the missing of protocol-specified tests or 
assessments between the day of the last dose of the 
investigational product and the 29th day after the last dose 
will not be considered as any protocol deviations. 
Clear explanation 
14. APPENDICES 
Appendix A.  
Schedule of 
Assessments 
 
 
Cycle 1 
Day1 
EOS 
Urine M-protein 
Measurement (24hr 
Urine Collection) 
Xm 
X 
  
 
 
Cycle 1 
Day 1 
EOS 
Urine M-protein 
Measurement (24hr 
Urine Collection) 
▲m 
▲ 
  
Correction of 
errors. 
14. APPENDICES 
Appendix A.  
Schedule of 
Assessments 
 
 
EOS 
CT/MRI 
(chest,abdomen)o 
X 
  
 
 
EOS 
CT/MRI 
(chest,abdomen)o 
Xo 
  
Description 
amendment. 
     : Amended texts 
 


Protocol Change Memo 
A Phase 1 Study of MLN9708 in Japanese Patients with Relapsed and/or Refractory Multiple Myeloma 
Date for version 2.2:  11 September 2012 
5 
Section 
Replaced 
With 
Rationale 
14. APPENDICES 
Appendix A.  
Schedule of 
Assessments 
Note 
Footnote 
▲For a patient with M-protein detected only in urine at 
screening, spot urine is to be performed every 2 
cycles for urine M-protein predose of MLN9708 on 
Day 1 of Cycle 3 and subsequent cycles (Cycle 3, 5, 
7, 9, 11, and so on [odd-numbered cycles]) (Urine 
collection during Days 23 through 28 of previous 
cycle is acceptable).   
For subjects whose M-protein has been detected in 
serum and urine at screening, if a response assessment 
requires confirmation or disease progression (see 
Appendix G) is suspected, a urine M-protein 
measurement will be collected as appropriate 
Footnote 
▲For a patient with M-protein detected only in urine at 
screening, spot urine is to be performed every 2 cycles 
for urine M-protein predose of MLN9708 on Day 1 of 
Cycles 1, 3 and subsequent cycles (Cycle 3, 5, 7, 9, 11, 
and so on [odd-numbered cycles]) (Urine collection 
during Days 23 through 28 of previous cycle is 
acceptable).  Also conduct at EOS visit. 
For subjects whose M-protein is detected in serum and 
urine at screening, urine samples will be collected prior 
to MLN9708 dosing on Cycle 1 Day 1.  If a response 
assessment requires confirmation or disease 
progression (see Appendix G) is suspected, a urine M-
protein measurement will be collected as appropriate.  
Also conduct at EOS visit. 
Clear explanation 
     : Amended texts 


 
 
 
Summary of Changes for Protocol Amendment 
A Phase 1 Study of MLN9708 in Japanese Patients with Relapsed and/or Refractory  
Multiple Myeloma 
 
Version 2 → Version 2.1 
 
 
 
 
 
Protocol Number:  TB-MC010034 
Date of Amendment:  7 March 2012 
 


Protocol Change Memo 
A Phase 1 Study of MLN9708 in Japanese Patients with Relapsed and/or Refractory Multiple Myeloma 
Date for version 2.1:  7 March 2012 
1 
Section 
Replaced 
With 
Rationale 
Header 
Product: MLN9708 
Protocol Number: TB-MC010034 
Date: 7 February 2012 
Product: MLN9708 
Protocol Number: TB-MC010034 
Date: 7 March 2012 
New version. 
Title Page 
Key Sponsor Contact: Development Operations 2, 
Clinical Development Division  
Key Sponsor Contact: Development Operations, Clinical 
Development 
Reorganization due 
to conversion of 
business entity. 
Title Page 
Version/Date: Version 2    7 Febuary 2012 
Version/Date: Version 2.1     7 March 2012 
New version. 
Document History 
Document History 
Version 1: 12 January 2012 
Document History 
Version 1: 12 January 2012 
Version 2: 7 February 2012 
Document history 
is updated. 
1.6.1 Lenalidomide 
In this study, subjects will be registered in accordance 
with the
proper management procedures 
In this study, subjects will be registered in accordance with 
the lenalidomide proper management procedures 
 
Description 
amendment. 
5.2
Registration 
The
procedures must be followed when 
providing
to the subjects in the MLN9708 
with Rd cohort in the study. 
The
procedures must be followed when 
providing lenalidomide to the subjects in the MLN9708 
with Rd cohort in the study. 
Description 
amendment. 
6. TREATMENT 
PROCEDURES 
6.5.2.3.4 
Dexamethasone 
Treatment 
Modification  
Table 6-11 
Adverse Events 
CTCAE  
Action 
Others 
≥ Grade 3 
Hold dexamethasone 
until toxicity has 
resolved to ≤ Grade 2 
  
Table 6-11 
Deleted 
Correction of errors 
7 STUDY 
PROCEDURES 
7.2.1 Screening 
period 
• 
Subject background (including medical history, 
concomitant disease, details of multiple myeloma 
diagnosis [date of diagnosis, histological type, 
current clinical stage], history of prior-treatment for 
multiple myeloma [chemotherapy, radiotherapy, 
transplantation, surgery]) 
• 
Subject background (including medical history, 
concomitant disease, details of multiple myeloma 
diagnosis [date of diagnosis, histological type, current 
clinical stage] (see Appendix H), history of prior-
treatment for multiple myeloma [chemotherapy, 
radiotherapy, transplantation, surgery]) 
Clear explanation 
     : Amended texts 
 
CCI
CCI
CCI
CCI
CCI


Protocol Change Memo 
A Phase 1 Study of MLN9708 in Japanese Patients with Relapsed and/or Refractory Multiple Myeloma 
Date for version 2.1:  7 March 2012 
2 
Section 
Replaced 
With 
Rationale 
7 STUDY 
PROCEDURES 
7.2.1 Screening 
period 
• 
CT/MRI (chest, abdomen) 
Unless a patient shows hypersensitivity to contrast, all 
CT/MRI should be performed with contrast. 
• 
CT/MRI (chest, abdomen) 
Unless a patient shows hypersensitivity to contrast or 
concern for potential aggravation of renal dysfunction, all 
CT/MRI should be performed with contrast. 
Clear explanation 
7 STUDY 
PROCEDURES 
7.2.2 Treatment 
period 
• 
Vital signs (sitting blood pressure, pulse rate and 
axillary temperature, SpO2) 
‒ 
Cycle 1:  Days 1, 8 and 15 
‒ 
Cycles 2 and subsequent cycles:  Days 1 and 
15 
• 
Vital signs (sitting blood pressure, pulse rate and 
axillary temperature, SpO2) 
‒ 
Cycle 1:  Days 1, 8 and 15 
‒ 
Cycles 2 to 12:  Days 1 and 15 
‒ 
Cycle 13 and subsequent cycles:  Day 1 
Clear explanation 
7 STUDY 
PROCEDURES 
7.2.2 Treatment 
period 
• 
Body weight 
Cycle 1:  Before MLN9708 dosing on Day 1.  If a 
patient’s body weight has been measured within 3 days 
before the first dose, then this measurement may be used 
as the Cycle 1 Day 1 measurement.  
• 
Body weight  
Cycle 1:  Before MLN9708 dosing on Day 1.  If a 
patient’s body weight has been measured within 3 days 
before the first dose, then this measurement may be used 
for the Cycle 1 Day 1 data.  
Clear explanation t 
7 STUDY 
PROCEDURES 
7.2.2 Treatment 
period 
• 
Laboratory tests: Hematology tests 
‒ 
Cycles 4 and subsequent cycles:  Days 1 and 
15 
• 
Laboratory tests: Hematology tests 
‒ 
Cycles 4 to 12:  Days 1 and 15 
‒ 
Cycle 13 and subsequent cycles:  Day 1 
Clear explanation 
7 STUDY 
PROCEDURES 
7.2.2 Treatment 
period 
• 
Laboratory tests: Hematology test 
If a screening test has been performed within 3 days 
before the first dose, the test may be used as Cycle 1 
Day 1 test. 
• 
Laboratory tests: Hematology test 
If a screening test has been performed within 3 days 
before the first dose, the result may be used as Cycle 1 
Day 1 data. 
Clear explanation 
7 STUDY 
PROCEDURES 
7.2.2 Treatment 
period 
• 
Laboratory tests: Chemistry tests 
‒ 
Cycles 4 and subsequent cycles:  Days 1 and 
15 
• 
Laboratory tests: Chemistry tests 
‒ 
Cycles 4 to 12:  Days 1 and 15 
‒ 
Cycle 13 and subsequent cycles:  Day 1 
Clear explanation 
7 STUDY 
PROCEDURES 
7.2.2 Treatment 
period 
• 
Laboratory tests: Chemistry test 
If a screening test has been performed within 3 days 
before the first dose, the test may be used as Cycle 1 
Day 1 test. 
• 
Laboratory tests: Chemistry test 
If a screening test has been performed within 3 days 
before the first dose, the result may be used as Cycle 1 
Day 1 data. 
Clear explanation 
     : Amended texts 


Protocol Change Memo 
A Phase 1 Study of MLN9708 in Japanese Patients with Relapsed and/or Refractory Multiple Myeloma 
Date for version 2.1:  7 March 2012 
3 
Section 
Replaced 
With 
Rationale 
7 STUDY 
PROCEDURES 
7.2.2 Treatment 
period 
• 
Urine M-protein (electrophoresis protein fraction 
test):  
For subjects whose urine M-protein has been 
detected at screening, a urine M-protein 
measurement will be collected using 24-hour urine 
collection according to the schedule presented 
below.  For subjects whose M-protein has been 
detected only in the urine, urine M-protein will be 
measured by casual urine.  
‒ 
Measurement by 24-hour urine collection 
(Subjects whose urine M-protein has been 
detected in the urine at screening. 
*snip* 
• 
Urine samples will be collected prior to 
MLN9708 dosing on Day 1 of Cycles 3, 
5, 7, 9, and 11.  It will be acceptable to 
collect samples between Days 23 and 28 
of the preceding cycle. 
‒ 
Measurement by casual urine (Subjects whose 
M-protein has been detected only in urine at 
screening) 
• 
Samples will be collected prior to 
MLN9708 dosing on Day 1 of Cycles 2, 
4, 6, 8, 10, and 12. 
‒ 
If disease progression is suspected (see 
Appendix G), a urine M-protein measurement 
will be collected as appropriate using 24-hour 
urine collection. 
• 
Urine M-protein (electrophoresis protein fraction 
test):  
Subjects whose urine M-protein has been detected 
only in urine at screening 
‒ 
Measurement by 24-hour urine collection  
• 
Urine samples will be collected prior to 
MLN9708 dosing on Cycle 1 Day 1.  If a 
screening test has been performed within 7 
days before the first dose, the results may 
be used as the Cycle 1 Day 1 data. 
• 
Samples will be collected every 2 cycles 
prior to MLN9708 dosing on Day 1 of 
Cycles 3 and subsequent cycles (Cycles 3, 
5, 7, 9, 11 and on [odd-numbered cycles]).  
It will be acceptable to collect samples 
between Days 23 and 28 of the preceding 
cycle. 
‒ 
Measurement by casual urine  
• 
Samples will be collected every 2 cycles 
prior to MLN9708 dosing on Day 1 of 
Cycles 2 and subsequent cycles (Cycles 2, 
4, 6, 8, 10, 12 and on [even-numbered 
cycles]). 
Subjects whose urine M-protein has been detected 
in serum and urine at screening 
‒ 
Measurement by 24-hour urine collection. 
• 
If a response assessment requires 
confirmation or disease progression is 
suspected (see Appendix G), a urine M-
protein measurement will be collected as 
appropriate using 24-hour urine collection. 
Clear explanation 
     : Amended texts 


Protocol Change Memo 
A Phase 1 Study of MLN9708 in Japanese Patients with Relapsed and/or Refractory Multiple Myeloma 
Date for version 2.1:  7 March 2012 
4 
Section 
Replaced 
With 
Rationale 
7 STUDY 
PROCEDURES 
7.2.2 Treatment 
period 
• 
CT/MRI (head, abdomen): 
‒ 
If soft tissue plasmacytoma is found at 
screening, a CT/MRI scan will be performed 
every 2 cycles before MLN9708 dosing on 
Day 1 of Cycle 3, 5, 7, 9, and 11.  It will be 
acceptable to perform the scan between Days 
23 and 28 of the preceding cycle. A scan may 
be performed as appropriate if disease 
progression is suspected or a response 
assessment requires confirmation (see 
Appendix G) if necessary outside a specified 
cycle. 
‒ 
All diagnostic imaging scans will be performed 
using contrast media, except for subjects who 
are hypersensitive to contrast media. 
• 
CT/MRI (head, abdomen): 
‒ 
If soft tissue plasmacytoma is found at 
screening, a CT/MRI scan will be performed 
every 2 cycles before MLN9708 dosing on Day 
1 of Cycle 3 and subsequent cycles (Cycles 3, 5, 
7, 9, 11 and on [odd-numbered cycles]).  It will 
be acceptable to perform the scan between Days 
23 and 28 of the preceding cycle. A scan may be 
performed as appropriate if disease progression 
is suspected or a response assessment requires 
confirmation if necessary outside a specified 
cycle (see Appendix G). 
‒ 
All diagnostic imaging scans will be performed 
using contrast media, except for subjects who are 
hypersensitive to contrast media or shows 
concern for potential aggravation of renal 
dysfunction. 
Clear explanation 
7 STUDY 
PROCEDURES 
7.2.2 Treatment 
period 
• 
Bone marrow aspiration: Percentage of plasma cells 
in bone marrow (Note: When collecting the sample, 
anatomical locations that have been irradiated in the 
past should be avoided.) 
Bone marrow puncture will be performed as 
appropriate when disease progression is suspected 
(see Appendix G). 
• 
Bone marrow aspiration: Percentage of plasma cells in 
bone marrow (Note: When collecting the sample, 
anatomical locations that have been irradiated in the 
past should be avoided.) 
Bone marrow puncture will be performed as 
appropriate if a response assessment requires 
confirmation or when disease progression is suspected 
(see Appendix G). 
Clear explanation 
7 STUDY 
PROCEDURES 
7.2.3 End of study 
The following assessments will be performed on 
Day 29 after the last dose (acceptable time window) 
for subjects who have received MLN9708. 
The following assessments will be performed on Day 
29 after the last dose (acceptable time window + 
21days) for subjects who have received MLN9708. 
Correction of errors 
     : Amended texts 
 


Protocol Change Memo 
A Phase 1 Study of MLN9708 in Japanese Patients with Relapsed and/or Refractory Multiple Myeloma 
Date for version 2.1:  7 March 2012 
5 
Section 
Replaced 
With 
Rationale 
7 STUDY 
PROCEDURES 
7.2.3 End of study 
• 
CT/MRI (chest, abdomen) 
‒ 
If soft tissue plasmacytoma is found at 
screening, a CT/MRI scan will be performed. 
‒ 
All diagnostic imaging scans will be performed 
using contrast media, except for subjects who 
are hypersensitive to contrast media. 
• 
CT/MRI (chest, abdomen) 
‒ 
If soft tissue plasmacytoma is found at 
screening, a CT/MRI scan will be performed. 
‒ 
All diagnostic imaging scans will be performed 
using contrast media, except for subjects who are 
hypersensitive to contrast media or shows 
concern for potential aggravation of renal 
dysfunction. 
Clear explanation 
7 STUDY 
PROCEDURES 
7.2.4 Laboratory tests
Table 7-1.  Study Test Parameters Others 
Serum M-protein (protein fractionation by 
electrophoresis) 
Table 7-1.  Study Test Parameters Others 
Serum M-protein (protein fractionation by electrophoresis, 
immunofixation) 
Correction of errors 
7 STUDY 
PROCEDURES 
7.2.4 Laboratory tests
Table 7-1.  Study Test Parameters Others 
Urine M-protein (protein fractionation by electrophoresis)
Table 7-1.  Study Test Parameters Others 
Urine M-protein (protein fractionation by electrophoresis, 
immunofixation) 
Correction of errors 
9. SAFETY DATA 
COLLECTION, 
RECORDING, AND 
REPORTING 
9.3 Serious Adverse 
Event Reporting 
Procedures 
 
 
 
 
 
Change to reflect 
the new company 
name. 
13. REFERENCES 
N/A 
Durie BG. Staging and kinetics of multiple myeloma. 
Semin Oncol 1986;13:300-309. 
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;36:842-854. 
Greipp PR, Miguel JS, Durie BG, Crowley JJ, Barlogie B, 
Bladé J, et al. International staging system for multiple 
myeloma. J Clin Oncol 2005;23(15):3412-3420. 
Refernece in newly 
added Appendix H. 
     : Amended texts 
 
PPD
PPD
PPD


Protocol Change Memo 
A Phase 1 Study of MLN9708 in Japanese Patients with Relapsed and/or Refractory Multiple Myeloma 
Date for version 2.1:  7 March 2012 
6 
Section 
Replaced 
With 
Rationale 
14. APPENDICES 
Appendix A.  
Schedule of 
Assessments 
  
Day 
EOS 
Visit Windows (Day) 
+14 
  
Day 
EOS 
Visit Windows (Day) 
+21 
  
Correction of errors 
14. APPENDICES 
Appendix A.  
Schedule of 
Assessments 
  
 
Screening 
Chemistry 
X 
  
 
Screening 
Chemistryj 
Xh 
  
Clear explanation 
14. APPENDICE 
Appendix A.  
Schedule of 
Assessments 
  
Tests and 
Observation 
Cycle 2 and thereafter; 
Day 1 
FLC 
Xk 
  
Tests and 
Observation 
Cycle 2 and thereafter; 
Day 1 
FLCk 
(X)k 
  
Clear explanation 
14. APPENDICE 
Appendix A.  
Schedule of 
Assessments 
  
Tests and 
Observation 
Cycle 2 and thereafter 
Day 
15 
Vital Signs 
X 
Hematology 
X 
Chemistry 
X 
  
Tests and 
Observation 
Cycle 2 and thereafter 
Day 
15 
Vital Signs 
Xq 
Hematology 
Xq 
Chemistryi 
Xq 
Clear explanation 
14. APPENDICE 
Appendix A.  
Schedule of 
Assessments 
  
Tests and 
Observation 
Cycle 2 and thereafter; 
Day 1 
EOS 
Immunofixation 
(serum and urine) o
NA 
Xo 
  
 
Tests and 
Observation 
Cycle 2 and thereafter; 
Day 1 
EOS 
Immunofixation 
(serum and urine) l 
(X)l 
(X)l 
Clear explanation 
14. APPENDICE 
Appendix A.  
Schedule of 
Assessments 
  
Tests and 
Observation 
Cycle 2 and thereafter; 
Day 1 
Urine M-protein 
Measurement 
X 
24hr Urine 
Collectionm 
X 
  
Tests and Observation 
Cycle 2 and 
thereafter; Day 1 
Urine M-protein Measurement 
(Casual Urine Collection) 
● 
Urine M-protein Measurement (24hr 
Urine Collection) 
▲ 
Clear explanation 
     : Amended texts 


Protocol Change Memo 
A Phase 1 Study of MLN9708 in Japanese Patients with Relapsed and/or Refractory Multiple Myeloma 
Date for version 2.1:  7 March 2012 
7 
Section 
Replaced 
With 
Rationale 
14. APPENDICE 
Appendix A.  
Schedule of 
Assessments 
  
Tests and 
Observation 
Screening 
Cycle 2 and 
thereafter; Day 1
EOS 
Radiographic 
assessment 
(systemic) q 
Xq 
 
X 
CT/MRI 
(chest, abdomen) 
r 
Xr 
Xr 
X 
Bone Marrow 
Aspiration k 
X 
Xk 
 
  
Tests and 
Observation 
Screening
Cycle 2 and 
thereafter; Day 1
EOS 
Radiographic 
assessment 
(systemic) n 
Xn 
 
Xn 
CT/MRI 
(chest, abdomen) o
Xo 
Xo 
X 
Bone Marrow 
Aspiration k 
X 
(X)k 
 
  
Clear explanation 
14. APPENDICE 
Appendix A.  
Schedule of 
Assessments 
  
Tests and 
Observation 
Cycle 2 and 
thereafter 
EOS
Response Assessment
Xs 
Xs 
  
Tests and 
Observation 
Cycle 2 and 
thereafter 
EOS
Response Assessment
Xp 
Xp
  
Clear explanation 
14. APPENDICE 
Appendix A.  
Schedule of 
Assessments 
Note 
N/A 
Footnote 
●For a patient with M-protein detected only in urine at 
screening, spot urine is to be performed every 2 cycles 
for urine M-protein predose of MLN9708 on Day 1 of 
Cycle 2 and subsequent cycles (Cycle 2, 4, 6, 8, 10, 12, 
and so on [even-numbered cycles]).   
▲For a patient with M-protein detected only in urine at 
screening, spot urine is to be performed every 2 cycles 
for urine M-protein predose of MLN9708 on Day 1 of 
Cycle 3 and subsequent cycles (Cycle 3, 5, 7, 9, 11, and 
so on [odd-numbered cycles]) (Urine collection during 
Days 23 through 28 of previous cycle is acceptable).   
For subjects whose M-protein has been detected in serum 
and urine at screening, if a response assessment requires 
confirmation or disease progression (see Appendix G) is 
suspected, a urine M-protein measurement will be 
collected as appropriate 
Add footnotes 
     : Amended texts 


Protocol Change Memo 
A Phase 1 Study of MLN9708 in Japanese Patients with Relapsed and/or Refractory Multiple Myeloma 
Date for version 2.1:  7 March 2012 
8 
Section 
Replaced 
With 
Rationale 
14. APPENDICE 
Appendix A.  
Schedule of 
Assessments 
Footnote 
l For a patient with urine M-protein detected at screening, 
after Cycyle 2, samples will be collected every 2 cycles 
prior to MLN9708 dosing on Day 1 of Cycles 3, 5, 7, 9, 
and 11. It will be acceptable to collect samples between 
Days 23 and 28 of the preceding cycle. For a patient with 
M-protein detected only in urine at screenng, casual urine 
sample will be collected prior to MLN9708 dosing on 
Day 1 of Cycles 2, 4, 6, 8, 10, and 12 for urine M-protein.
 
l To be conducted if a response assessment requires 
confirmation (see Appendix G) during the MLN9708 
treatment. 
Clear explanation 
14. APPENDICE 
Appendix A.  
Schedule of 
Assessments 
Note 
 
m When assessing response, measure a urine M-protein 
using 24-hour urine collection. 
m If a screening test has been performed within 7 days 
before the first dose, the results may be used as the Cycle 1 
Day 1 data. 
Clear explanation 
14. APPENDICE 
Appendix A.  
Schedule of 
Assessments 
Note 
n To be performed every 2 cycles predose of MLN9708 
on Day 1 of Cycle 2, 3, 5, 7, 9, and 11.  It will be 
acceptable to collect samples between Days 23 and 28 of 
the preceding cycle. Samples may be colleced as 
appropriate outside a specified cycle if a response 
assessment requires confirmation or disease progression 
is suspected. 
n If bone X-rays have been performed within 8 weeks 
before the first dose, the X-ray results may be used as 
screening data.  Chest X-ray is to be performed only 
during the screening.  For any patient with documented 
osteolytic disease at screening, repeat the assessment again 
at EOS.  If there are symptoms or signs that suggest 
increased or new bone lesions during the study treatment, 
repeat the procedure as necessary at any point.  Repeat 
scans should use the same imaging modality throughout the 
study. 
Clear explanation 
     : Amended texts 
 


Protocol Change Memo 
A Phase 1 Study of MLN9708 in Japanese Patients with Relapsed and/or Refractory Multiple Myeloma 
Date for version 2.1:  7 March 2012 
9 
Section 
Replaced 
With 
Rationale 
14. APPENDICE 
Appendix A.  
Schedule of 
Assessments 
Note 
r When CT scans and MRIs are performed within 8 
weeks of the first dose of MLN9708, the scans maybe 
used as the screening data.  For patients with 
documented plasma cell neoplasms (plasmacytoma) in 
soft tissues, CT/MRI are to be performed predose of 
MLN9708 on Day 1 of Cycles 3, 5, 7, 9, and 11.  (CT 
scans and MRIs may be conducted on Days 23 through 
28 of previous cycle).  Also conduct at EOS visit.  If 
there are symptoms or signs that suggested increases or 
new bone lesions in the specified cycles, scans may be 
repeated at any point during the study.  Unless a patient 
shows hypersensitivity to contrast, CT/MRT should be 
performed with contrast.  Repeat scans should use the 
same imaging modality throughout the study. 
Unless a patient shows hypersensitivity to contrast, 
CT/MRT should be performed with contrast.  Repeat 
scans should use the same imaging modality throughout 
the study. 
o When CT scans and MRIs are performed within 8 weeks 
of the first dose of MLN9708, the scans maybe used as the 
screening data.  For patients with documented plasma cell 
neoplasms (plasmacytoma) in soft tissues, CT/MRI are to 
be performed predose of MLN9708 on Day 1 of Cycle 3 
and subsequent cycles (Cycles 3, 5, 7, 9, 11, and so on 
[odd-numbered cycles]).  (CT scans and MRIs may be 
conducted on Days 23 through 28 of previous cycle).  
Also conduct at EOS visit.  If there are symptoms or signs 
that suggested increases or new bone lesions (See 
Appendix G) in the specified cycles, scans may be repeated 
at any point during the study.  Unless a patient shows 
hypersensitivity to contrast or concerns for potential 
aggravation of renal dysfunction, CT/MRT should be 
performed with contrast.  Repeat scans should use the 
same imaging modality throughout the study. 
Unless a patient shows hypersensitivity to contrast or 
potentiality for aggravated renal dysfunction, CT/MRT 
should be performed with contrast.  Repeat scans should 
use the same imaging modality throughout the study. 
Clear explanation 
14. APPENDICE 
Appendix A.  
Schedule of 
Assessment 
Note 
s To be conducted at Cycles 3, 5, 7, 9, and 11 and at EOS 
as much as possible. 
p To be conducted every 2 cycles at Cycle 3 and 
subsequent cycles (Cycles 3, 5, 7, 9, 11 [odd-numbered 
cycles]) and at EOS as much as possible. 
Correction of errors 
and clear 
explanation 
14. APPENDICE 
Appendix A.  
Schedule of 
Assessments 
Note 
N/A 
q To be conducted until/up to 12 cycles. 
Clear explanation 
     : Amended texts 
 


Protocol Change Memo 
A Phase 1 Study of MLN9708 in Japanese Patients with Relapsed and/or Refractory Multiple Myeloma 
Date for version 2.1:  7 March 2012 
10 
Section 
Replaced 
With 
Rationale 
14. APPENDICE 
Appendix H.  
International Staging 
System for Multiple 
Myeloma and Durie 
& Salmon Myeloma 
Staging System 
N/A 
Added H. International Staging System and Durie & 
Salmon Myeloma Staging System 
Added staging 
system for clarity. 
     : Amended texts 


 
 
 
Summary of Changes for Protocol Amendment 
A Phase 1 Study of MLN9708 in Japanese Patients with Relapsed and/or Refractory  
Multiple Myeloma 
 
Version 1 → Version 2 
 
 
 
 
 
Protocol Number:  TB-MC010034 
Date of Amendment:  7 February 2012 
 


Protocol Change Memo 
A Phase 1 Study of MLN9708 in Japanese Patients with Relapsed and/or Refractory Multiple Myeloma 
Date for version 2:  7 February 2012 
1 
Section 
Replaced 
With 
Rationale 
Header 
Product: MLN9708 
Protocol Number: TB-MC010034 
Date: 12 January 2012 
Product: MLN9708 
Protocol Number: TB-MC010034 
Date: 7 February 2012 
New version. 
Title Page 
Version/Date: Version 1   12 January 2012 
Version/Date: Version 2   7 February 2012 
New version. 
Document History 
- 
Document History  
Version 1   7 February 2012 
Document history 
is updated. 
Protocol Summary 
Inclusion Criteria: 
4) Measurable disease defined by at least one 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 FLC 
level ≥ 10 mg/dL. 
4) Measurable disease defined by at least one 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 FLC 
level ≥ 10 mg/dL (≥ 100 mg/L), provided that the 
serum FLC ratio is abnormal. 
Clear explanation. 
Protocol Summary 
Exclusion Criteria: 
8) Systemic treatment with potent CYP1A2 inhibitors 
(fluvoxamine, enoxacin), potent CYP3A inhibitors 
(clarithromycin, telithromycin, itraconazole, 
voriconazole, ketoconazole), or potent CYP3A inducers 
(rifampin, rifabutin, carbamazepine, phenytoin, 
phenobarbital), or use of foods containing Ginkgo biloba 
extract, or St. John’s wort within 14 days before 
enrollment. 
8) Systemic treatment with potent CYP1A2 inhibitors 
(fluvoxamine, enoxacin), potent CYP3A inhibitors 
(clarithromycin, telithromycin, itraconazole, voriconazole, 
ketoconazole), or potent CYP3A inducers (rifampin, 
rifabutin, carbamazepine, phenytoin, phenobarbital), or use 
of foods containing Ginkgo biloba extract, St. John’s wort, 
or grapefruit within 14 days before enrollment. 
Response to the 
PMDA queries. 
Protocol Summary 
Exclusion Criteria: 
20) Uncontrolled diabetes mellitus. 
21) Prior or current complications of deep vein 
thrombosis or pulmonary embolism (MLN9708 with Rd 
cohort only). 
20) Uncontrolled diabetes mellitus. 
21) A history of interstitial lung disease or lung fibrosis, or 
a current complication of interstitial lung disease or lung 
fibrosis diagnosed by diagnostic chest imaging. 
22) Prior or current complications of deep vein thrombosis 
or pulmonary embolism (MLN9708 with Rd cohort only). 
Response to the 
PMDA queries. 
     : Amended texts 


Protocol Change Memo 
A Phase 1 Study of MLN9708 in Japanese Patients with Relapsed and/or Refractory Multiple Myeloma 
Date for version 2:  7 February 2012 
2 
Section 
Replaced 
With 
Rationale 
Protocol Summary 
Exclusion Criteria: 
23) Patients who do not consent to use adequate 
contraceptive precautions (e.g. condoms and oral 
contraceptives) from when giving their consent through 3 
months after the last dose of MLN9708, dexamethasone, 
or lenalidomide for women with childbearing potential 
and from giving their consent through 4 months after last 
dose of MLN9708, dexamethasone, or lenalidomide for 
men having their partners with childbearing potential.  
Menopause is defined as the time when there has been no 
menstrual periods for at least 1 year.  The menstruation 
is possibly interrupted by chemotherapy not defined as 
menopause. 
 
24) Patients who do not consent to use adequate 
contraceptive precautions (e.g. condoms and oral 
contraceptives) during the following term:  
• For women with childbearing potential*, from when 
giving their consent through 3 months after the last 
dose of MLN9708, dexamethasone, or lenalidomide 
• For men having their partners with childbearing 
potential, from giving their consent through 4 months 
after last dose of MLN9708, dexamethasone, or 
lenalidomide  
* Women with child-bearing potential are those who are 
premenopausal (menopause is defined as the time when 
there has been no menstrual periods for at least 1 year), or 
who have not had a bilateral tube ligation, bilateral 
oophorectomy, or hysterectomy.  The menstruation is 
possibly interrupted by chemotherapy not defined as 
menopause.) 
Response to the 
PMDA queries. 
Protocol Summary 
Exclusion Criteria: 
24) Pregnant (e.g. positive for pregnancy test) or 
lactating.   
25) Pregnant (e.g. positive for pregnancy test) or lactating.  
Lactation is prohibited from the first dose through 6 weeks 
after the last dose of MLN9708, dexamethasone, and 
lenalidomide 
Response to the 
PMDA queries. 
Study Glossary 
NA 
SpO2 transcutaneous oxygen saturation 
Response to the 
PMDA queries. 
1. BACKGROUND 
AND RATIONALE 
1.7.2 Rationale for 
using a fixed dose 
When converting the dose from a body surface area dose 
to a fixed dose, we used 1.86 m2, which was the median 
body surface area of the subjects who participated in 
overseas clinical studies of bortezomib in multiple 
myeloma that were conducted by MPI. 
When converting the dose from a body surface area dose to 
a fixed dose, we used 1.86 m2, which was the mean body 
surface area of the subjects who participated in overseas 
clinical studies of bortezomib in multiple myeloma that 
were conducted by MPI. 
Response to the 
PMDA queries. 
     : Amended texts 
 


Protocol Change Memo 
A Phase 1 Study of MLN9708 in Japanese Patients with Relapsed and/or Refractory Multiple Myeloma 
Date for version 2:  7 February 2012 
3 
Section 
Replaced 
With 
Rationale 
4. SUBJECT 
ELIGIBILITY 
4.1 Inclusion Criteria
4) Measurable disease defined by at least one 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 FLC 
level ≥ 10 mg/dL. 
4) Measurable disease defined by at least one 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 FLC 
level ≥ 10 mg/dL (≥ 100 mg/L), provided that the 
serum FLC ratio is abnormal. 
Clear explanation. 
4. SUBJECT 
ELIGIBILITY 
4.2 Exclusion 
Criteria 
8) Systemic treatment with potent CYP1A2 inhibitors 
(fluvoxamine, enoxacin), potent CYP3A inhibitors 
(clarithromycin, telithromycin, itraconazole, 
voriconazole, ketoconazole), or potent CYP3A inducers 
(rifampin, rifabutin, carbamazepine, phenytoin, 
phenobarbital), or use of foods containing Ginkgo biloba 
extract, or St. John’s wort within 14 days before 
enrollment. 
8) Systemic treatment with potent CYP1A2 inhibitors 
(fluvoxamine, enoxacin), potent CYP3A inhibitors 
(clarithromycin, telithromycin, itraconazole, voriconazole, 
ketoconazole), or potent CYP3A inducers (rifampin, 
rifabutin, carbamazepine, phenytoin, phenobarbital), or use 
of foods containing Ginkgo biloba extract, St. John’s wort, 
or grapefruit within 14 days before enrollment. 
Response to the 
PMDA queries. 
4. SUBJECT 
ELIGIBILITY 
20) Uncontrolled diabetes mellitus. 
21) Prior or current complications of deep vein 
thrombosis or pulmonary embolism (MLN9708 with Rd 
cohort only). 
20) Uncontrolled diabetes mellitus. 
21) A history of interstitial lung disease or lung fibrosis, or 
a current complication of interstitial lung disease or lung 
fibrosis diagnosed by diagnostic chest imaging. 
22) Prior or current complications of deep vein thrombosis 
or pulmonary embolism (MLN9708 with Rd cohort only). 
Response to the 
PMDA queries. 
     : Amended texts 
 


Protocol Change Memo 
A Phase 1 Study of MLN9708 in Japanese Patients with Relapsed and/or Refractory Multiple Myeloma 
Date for version 2:  7 February 2012 
4 
Section 
Replaced 
With 
Rationale 
4.2 Exclusion 
Criteria 
23) Patients who do not consent to use adequate 
contraceptive precautions (e.g. condoms and oral 
contraceptives) from when giving their consent through 3 
months after the last dose of MLN9708, dexamethasone, 
or lenalidomide for women with childbearing potential 
and from giving their consent through 4 months after last 
dose of MLN9708, dexamethasone, or lenalidomide for 
men having their partners with childbearing potential.  
Menopause is defined as the time when there has been no 
menstrual periods for at least 1 year.  The menstruation 
is possibly interrupted by chemotherapy not defined as 
menopause. 
24) Patients who do not consent to use adequate 
contraceptive precautions (e.g. condoms and oral 
contraceptives) during the following term:  
• For women with childbearing potential*, from when 
giving their consent through 3 months after the last 
dose of MLN9708, dexamethasone, or lenalidomide 
• For men having their partners with childbearing 
potential, from giving their consent through 4 months 
after last dose of MLN9708, dexamethasone, or 
lenalidomide  
* Women with child-bearing potential are those who are 
premenopausal (menopause is defined as the time when 
there has been no menstrual periods for at least 1 year), or 
who have not had a bilateral tube ligation, bilateral 
oophorectomy, or hysterectomy.  The menstruation is 
possibly interrupted by chemotherapy not defined as 
menopause.) 
Response to the 
PMDA queries. 
4. SUBJECT 
ELIGIBILITY 
24) Pregnant (e.g. positive for pregnancy test) or 
lactating(3)   
25) Pregnant (e.g. positive for pregnancy test) or lactating.  
Lactation is prohibited from the first dose through 6 weeks 
after the last dose of MLN9708, dexamethasone, and 
lenalidomide(3) 
Response to the 
PMDA queries. 
6. TREATMENT 
PROCEDURES 
6.1 MLN9708 
  
Packaging 
PTP 
Packaging Unit Three capsules per PTP, which is contained 
by 1 unit carton. 
Packaging 
foil-foil blisters 
Packaging Unit 
Three capsules per foil-foil blister, which is 
contained by 1 unit carton. 
Correction of 
errors. 
     : Amended texts 
 


Protocol Change Memo 
A Phase 1 Study of MLN9708 in Japanese Patients with Relapsed and/or Refractory Multiple Myeloma 
Date for version 2:  7 February 2012 
5 
Section 
Replaced 
With 
Rationale 
6. TREATMENT 
PROCEDURES 
6.5.1.1.2 Dose 
Modification for 
Non-hematological 
Toxicity 
If non-hematological toxicities shown in Table 6-4 occur 
in within a cycle, MLN9708 should be interrupted.   
If non-hematological toxicities shown in Table 6 4 occur in 
Cycle 2 and subsequent cycles, MLN9708 should be 
interrupted.   
Correction of 
errors. 
6. TREATMENT 
PROCEDURES 
6.5.2.1 Criteria for 
Dose Modification 
Table 6-5. 
4.0 mg/day 
Table 6-5. 
4.0 mg 
All "mg/day" was replaced with "mg". 
Correction of 
errors. 
6. TREATMENT 
PROCEDURES 
6.5.2.2.1 Dose 
Modification for 
Thrombocytopenia 
Table 6-6. 
Fourth fall 
Resume MLN9708 at reduced dose by 1 level (Level 2). 
Do not dose MLN9708 2.3 mg or below. 
Table 6-6. 
Fourth fall 
Resume MLN9708 at reduced dose by 1 level (Level 2). 
Do not dose MLN9708 below 2.3 mg. 
Correction of 
errors. 
6. TREATMENT 
PROCEDURES 
6.5.2.2.1 Dose 
Modification for 
Thrombocytopenia 
Table 6-6. 
Fifth fall 
Resume lenalidomide at 5 mg. 
Do not dose lenalidomide 5 mg or below. 
Table 6-6. 
Fifth fall 
Resume lenalidomide at 5 mg 
Do not dose lenalidomide below 5 mg. 
Correction of 
errors. 
6. TREATMENT 
PROCEDURES 
6.5.2.2.2 Dose 
Modification for 
Neutropenia 
Table 6-7. 
Fourth fall 
Resume MLN9708 at reduced dose by 1 level (Level 2). 
Do not dose MLN9708 2.3 mg or below. 
Table 6-7. 
Fourth fall 
Resume MLN9708 at reduced dose by 1 level (Level 2). 
Do not dose MLN9708 below 2.3 mg. 
Correction of 
errors. 
     : Amended texts 
 


Protocol Change Memo 
A Phase 1 Study of MLN9708 in Japanese Patients with Relapsed and/or Refractory Multiple Myeloma 
Date for version 2:  7 February 2012 
6 
Section 
Replaced 
With 
Rationale 
6. TREATMENT 
PROCEDURES 
6.5.2.2.2 Dose 
Modification for 
Neutropenia 
Table 6-7. 
Fifth fall 
Resume lenalidomide at 5 mg. 
Do not dose lenalidomide 5 mg or below. 
Table 6-7. 
Fifth fall 
Resume lenalidomide at 5 mg 
Do not dose lenalidomide below 5 mg. 
Correction of 
errors. 
6. TREATMENT 
PROCEDURES 
6.5.2.3.1 Dose 
Modification for 
Rash 
Table 6-8. 
Fourth event 
Resume MLN9708 at reduced dose by 1 level (Level 2). 
Do not dose MLN9708 2.3 mg or below. 
Table 6-7. 
Fourth fall 
Resume MLN9708 at reduced dose by 1 level (Level 2). 
Do not dose MLN9708 below 2.3 mg. 
Correction of 
errors. 
6. TREATMENT 
PROCEDURES 
6.5.2.3.1 Dose 
Modification for 
Rash 
Table 6-8. 
Fifth event 
Resume lenalidomide at 5 mg. 
Do not dose lenalidomide 5 mg or below. 
Table 6-7. 
Fifth event 
Resume lenalidomide at 5 mg 
Do not dose lenalidomide below 5 mg. 
Correction of 
errors. 
6. TREATMENT 
PROCEDURES 
6.5.2.3.1 Dose 
Modification for 
Rash 
Table 6-8. 
Second thorough fifth event 
Recovers to < Grade 2. 
Table 6-8. 
Second thorough fifth event 
Recovers to < Grade 2 within 2 weeks. 
Correction of 
errors. 
6. TREATMENT 
PROCEDURES 
6.5.2.3.3 
Lenalidomide 
Treatment 
Modification 
Table 6-11. 
Dyspepsia, gastric, or duodenal ulcer, gastritis Grade 1-2 
(requiring medical management) 
Grade 4 
Table 6-11. 
Dyspepsia, gastric, or duodenal ulcer, gastritis Grade 1-2 
(requiring medical management) 
> Grade 2 
Correction of 
errors. 
     : Amended texts 
 


Protocol Change Memo 
A Phase 1 Study of MLN9708 in Japanese Patients with Relapsed and/or Refractory Multiple Myeloma 
Date for version 2:  7 February 2012 
7 
Section 
Replaced 
With 
Rationale 
6. TREATMENT 
PROCEDURES 
6.8 Excluded 
Concomitant 
Medications and 
Procedures 
Systemic treatment with strong inhibitors of CYP1A2 
(fluvoxamine, enoxacin), strong inhibitors of CYP3A 
(clarithromycin, telithromycin, itraconazole, 
voriconazole, ketoconazole) or strong CYP3A inducers 
(rifampicin, rifabutin, carbamazepine, phenytoin, 
phenobarbital), or use/ intake of foods containing Ginkgo 
biloba extract, or St. John's wort during the study. 
Systemic treatment with strong inhibitors of CYP1A2 
(fluvoxamine, enoxacin), strong inhibitors of CYP3A 
(clarithromycin, telithromycin, itraconazole, voriconazole, 
ketoconazole) or strong CYP3A inducers (rifampicin, 
rifabutin, carbamazepine, phenytoin, phenobarbital), or 
use/ intake of foods containing Ginkgo biloba extract, St. 
John's wort, or grapefruit during the study. 
Response to the 
PMDA queries. 
6. TREATMENT 
PROCEDURES 
6.8 Excluded 
Concomitant 
Medications and 
Procedures 
Any antineoplastic treatment for multiple myeroma other 
than Rd administered concomitantly with MLN9708 in 
the Rd combination cohort.  Treatment with 
corticosteroids 10 mg of prednisolone per day or less is 
permitted. 
Any antineoplastic treatment other than Rd administered 
concomitantly with MLN9708 in the Rd combination 
cohort.  Treatment with corticosteroids 10 mg of 
prednisolone per day or less is permitted. 
Clear explanation. 
7. STUDY 
PROCEDURES 
7.2.1 Screening 
period 
Subject background (including medical history, 
concomitant disease, details of multiple myeloma 
diagnosis [date of diagnosis, histological type, current 
clinical stage], history of prior-treatment) 
Subject background (including medical history, 
concomitant disease, details of multiple myeloma diagnosis 
[date of diagnosis, histological type, current clinical stage], 
history of prior-treatment for multiple myeloma 
[chemotherapy, radiotherapy, transplantation, surgery]) 
Clear explanation. 
7. STUDY 
PROCEDURES 
7.2.1 Screening 
period 
Vital signs (sitting blood pressure, pulse rate, and axillary 
temperature) 
Vital signs (sitting blood pressure, pulse rate, axillary 
temperature, and transcutaneous oxygen saturation [SpO2])
Response to the 
PMDA queries. 
7. STUDY 
PROCEDURES 
7.2.1 Screening 
period 
• 
Laboratory tests:  
(snip) 
– 
Virus tests 
• 
Laboratory tests:  
(snip) 
- 
Virus tests (HIV antibody, HBs antigen, HCV 
antibody.  The test results will not be recorded in the 
eCRF.) 
Clear explanation. 
     : Amended texts 
 


Protocol Change Memo 
A Phase 1 Study of MLN9708 in Japanese Patients with Relapsed and/or Refractory Multiple Myeloma 
Date for version 2:  7 February 2012 
8 
Section 
Replaced 
With 
Rationale 
7. STUDY 
PROCEDURES 
7.2.1 Screening 
period 
• 
X-rays 
– 
Chest, bone (head, cervical vertebrae, thoracic 
vertebrae, lumbar vertebrae, pelvis, both upper arms, 
both forearms, both femurs, both lower legs); in two 
directions for each, except for the pelvis 
– 
If bone X-ray is performed within 8 weeks before the 
first dose, the X-ray results may be used as screening 
data. 
• 
X-rays 
– 
Chest 
– 
Bone (head, cervical vertebrae, thoracic vertebrae, 
lumbar vertebrae, pelvis, both upper arms, both 
forearms, both femurs, both lower legs); in two 
directions for each, except for the pelvis 
– 
If bone X-ray is performed within 8 weeks before the 
first dose, the X-ray results may be used as screening 
data. 
Clear explanation. 
7. STUDY 
PROCEDURES 
7.2.2 Treatment 
period 
• 
Vital signs (sitting blood pressure, pulse rate, and 
axillary temperature) 
• 
Vital signs (sitting blood pressure, pulse rate, axillary 
temperature, and SpO2) 
Response to the 
PMDA queries. 
7. STUDY 
PROCEDURES 
7.2.2 Treatment 
period 
• 
X-rays 
– 
Chest, bone (head, cervical vertebrae, thoracic 
vertebrae, lumbar vertebrae, pelvis, both upper arms, 
both forearms, both femurs, both lower legs); in two 
directions for each, except for the pelvis 
– 
X-rays will be performed as appropriate if osteolytic 
lesions are found at screening and there are concerns 
about bone lesions increasing or new bone lesions 
developing during the study. 
• 
X-rays 
– 
Bone (head, cervical vertebrae, thoracic vertebrae, 
lumbar vertebrae, pelvis, both upper arms, both 
forearms, both femurs, both lower legs); in two 
directions for each, except for the pelvis 
– 
X-rays will be performed as appropriate if osteolytic 
lesions are found at screening and there are concerns 
about bone lesions increasing or new bone lesions 
developing during the study. 
Correction of 
errors. 
7. STUDY 
PROCEDURES 
7.2.3 End of study 
Vital signs (sitting blood pressure, pulse rate, and axillary 
temperature) 
Vital signs (sitting blood pressure, pulse rate, axillary 
temperature, and SpO2) 
Response to the 
PMDA queries. 
     : Amended texts 
 


Protocol Change Memo 
A Phase 1 Study of MLN9708 in Japanese Patients with Relapsed and/or Refractory Multiple Myeloma 
Date for version 2:  7 February 2012 
9 
Section 
Replaced 
With 
Rationale 
7. STUDY 
PROCEDURES 
7.2.3 End of study 
• 
X-rays 
– 
Chest, bone (head, cervical vertebrae, thoracic 
vertebrae, lumbar vertebrae, pelvis, both upper arms, 
both forearms, both femurs, both lower legs); in two 
directions for each, except for the pelvis 
– 
X-rays will be performed as appropriate if osteolytic 
lesions are found at screening. 
• 
X-rays 
– 
Bone (head, cervical vertebrae, thoracic vertebrae, 
lumbar vertebrae, pelvis, both upper arms, both 
forearms, both femurs, both lower legs); in two 
directions for each, except for the pelvis 
– 
X-rays will be performed as appropriate if osteolytic 
lesions are found at screening. 
Correction of 
errors. 
7. STUDY 
PROCEDURES 
7.2.4 Laboratory tests
Table 7-1 footnote 
i β2-microglobulin, HIV antibody, HBs antigen, and HCV 
antibody test are performed only at screening 
Table 7-1 footnote 
i β2-microglobulin test is performed only at screening 
Clear explanation. 
9. SAFETY DATA 
COLLECTION, 
RECORDING, AND 
REPORTING 
9.3 Serious Adverse 
Event Reporting 
Procedures 
Emergency center for safety information (available 24 
hours 365 days) 
 
Emergency center for safety information (available 24 
hours 365 days) 
 
 
Clear explanation. 
14. APPENDICES 
Appendix A.  
Schedule of 
Assessments 
Radiographic assessment (systemic)q 
q If bone X-rays is performed within 8 weeks before the 
first dose, the X-ray results may be used as screening 
data.  For any patient with documented osteolytic 
disease at screening, repeat the assessment again at EOS.  
If there are symptoms or signs that suggest increased or 
new bone lesions during the study treatment, repeat the 
procedure as necessary at any point.  Repeat scans 
should use the same imaging modality throughout the 
study. 
Radiographic assessmentq 
q If bone X-rays is performed within 8 weeks before the 
first dose, the X-ray results may be used as screening data.  
Chest X-ray is to be performed only during the screening.  
For any patient with documented osteolytic disease at 
screening, repeat the assessment again at EOS.  If there 
are symptoms or signs that suggest increased or new bone 
lesions during the study treatment, repeat the procedure as 
necessary at any point.  Repeat scans should use the same 
imaging modality throughout the study. 
Clear explanation. 
     : Amended texts 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD

SAP_001.pdf: 
 
 
Title: A Phase 1 Study of MLN9708 in Japanese Patients with Relapsed and/or 
Refractory Multiple Myeloma 
 
NCT Number: TBD 
Statistical analysis plan Approve Date: 12-FEB-2014 
 
Certain information within this statistical analysis plan has been redacted (ie, specific 
content is masked irreversibly from view with a black/blue bar) to protect either 
personally identifiable information or company confidential information. 
 
This may include, but is not limited to, redaction of the following: 
 
Named persons or organizations associated with the study. 
 
Patient identifiers within the text, tables, or figures or in by-patient data listings. 
 
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. 
 
If needed, certain appendices that contain a large volume of personally identifiable 
information or company confidential information may be removed in their entirety if it 
is considered that they do not add substantially to the interpretation of the data (eg, 
appendix of investigator’s curriculum vitae). 
 


 
STATISTICAL ANALYSIS PLAN 
APPROVAL SHEET 
 
Product 
MLN9708 (ixazomib citrate) 
Protocol Number 
TB-MC010034 
Study Title 
A Phase 1 Study of MLN9708 in Japanese Patients with Relapsed and/or 
Refractory Multiple Myeloma 
Author 
 
Date Prepared 
12 February 2014 
Version 
2.0 
 
Approval signature 
Signature 
Date 
 
Development Operations 
Signature 
Date 
 
Biostatistics 
 
PPD
PPD
PPD


Product:  MLN9708 (ixazomib citrate) 
Statistical Analysis Plan:  TB-MC010034 
Date:  12 February 2014 
Page 1 of 24 
CONFIDENTIAL 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
A Phase 1 Study of MLN9708 in Japanese Patients with Relapsed and/or Refractory 
Multiple Myeloma 
MLN9708 (ixazomib citrate) 
 
Protocol Number:  TB-MC010034 
 
 
 
Version: 
2.0 
Date: 
12 February 2014 
Biostatistician: 
 
PPD


Product:  MLN9708 (ixazomib citrate) 
Statistical Analysis Plan:  TB-MC010034 
Date:  12 February 2014 
Page 2 of 24 
CONFIDENTIAL 
1. 
LIST OF ABBREVIATIONS 
Abbreviation or Term 
Definition/Explanation 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
BSA 
body surface area 
BUN 
blood urea nitrogen 
CR 
complete response 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
dose limiting toxicity 
DOR 
duration of response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EOS 
end of study 
ESEC 
Efficacy and Safety Evaluation Committee 
HbA1c 
hemoglobin A1c 
LDH 
lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
ORR 
objective response rate 
PD 
progressive disease 
PK 
pharmacokinetic 
PR 
partial response 
PT 
preferred term 
QTc 
corrected QT interval 
QTcB 
corrected QT interval by Bazetts  formula 
QTcF 
corrected QT interval by Fridericias  formula 
RBC 
red blood cell 
Rd  
lenalidomide and dexamethasone 
sCR 
stringent complete response 
SD 
stable disease 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
VGPR 
very good partial response 
WBC 
white blood cell 


Product:  MLN9708 (ixazomib citrate) 
Statistical Analysis Plan:  TB-MC010034 
Date:  12 February 2014 
Page 3 of 24 
CONFIDENTIAL 
2. 
TABLE OF CONTENTS 
Page 
1. 
LIST OF ABBREVIATIONS ······························································· 2 
2. 
TABLE OF CONTENTS ···································································· 3 
3. 
INTRODUCTION ············································································ 5 
4. 
STUDY OBJECTIVES ······································································ 5 
4.1 
Primary Objective ···································································· 5 
4.2 
Secondary Objective ································································· 5 
5. 
STUDY OVERVIEW ········································································ 5 
5.1 
Summary of Study Design ·························································· 5 
5.2 
Sample Size Considerations ························································· 7 
6. 
STUDY ENDPOINTS ······································································· 7 
6.1 
Primary Endpoint ····································································· 7 
6.2 
Secondary Endpoints ································································· 7 
7. 
ANALYSIS SETS ············································································ 8 
7.1 
Safety Analysis Set ··································································· 8 
7.2 
Dose Limiting Toxicity (DLT) Analysis Set ······································· 8 
7.3 
Response Evaluable Analysis Set··················································· 8 
7.4 
Pharmacokinetic (PK) Analysis Set ················································ 8 
8. 
DATA HANDLING ·········································································· 8 
8.1 
Handling of Missing Data ··························································· 8 
8.2 
Handling of Partial Date ····························································· 8 
8.3 
Definition of Baseline Values ······················································· 9 
8.4 
Windowing of Visits ································································· 9 
9. 
STATISTICAL METHODS OF ANALYSIS ·············································· 9 
9.1 
General Principles ···································································· 9 
9.2 
Enrollment and Disposition of Subjects ········································· 10 
9.2.1 
Subject Disposition ····················································· 10 
9.2.2 
Analysis Sets ···························································· 10 
9.2.3 
Protocol Deviations and Treatment Compliance ···················· 10 
9.3 
Demographic and Other Baseline Characteristics ······························· 11 
9.4 
Safety Analyses ····································································· 13 
9.4.1 
Extent of Exposure ····················································· 13 
9.4.2 
Adverse Events ························································· 14 


Product:  MLN9708 (ixazomib citrate) 
Statistical Analysis Plan:  TB-MC010034 
Date:  12 February 2014 
Page 4 of 24 
CONFIDENTIAL 
9.4.3 
Clinical laboratory ······················································ 15 
9.4.4 
12-Lead Electrocardiograms ·········································· 16 
9.4.5 
Vital Signs ······························································· 17 
9.4.6 
Eastern Cooperative Oncology Group (ECOG) Performance 
Status ····································································· 17 
9.5 
Efficacy Analyses ·································································· 18 
9.5.1 
Tumor Response ························································ 18 
10. LISTING····················································································· 19 
11. APENDICES ················································································ 20 
12. REFERENCES ············································································· 20 
13. DOCUMENT HISTORY ·································································· 21 
 


Product:  MLN9708 (ixazomib citrate) 
Statistical Analysis Plan:  TB-MC010034 
Date:  12 February 2014 
Page 5 of 24 
CONFIDENTIAL 
3. 
INTRODUCTION  
The purpose of this statistical analysis plan is to provide details of the statistical analyses 
that have been outlined within the protocol for MLN9708 study TB-MC010034.  The 
scope of this plan includes the final analysis that is planned and will be performed by the 
Biostatistics department or designee. 
4. 
STUDY OBJECTIVES 
4.1 
Primary Objective 
To evaluate the tolerability, safety, and pharmacokinetics of MLN9708 alone or in 
combination with lenalidomide and dexamethasone (Rd) in patients with relapsed and/or 
refractory multiple myeloma. 
4.2 
Secondary Objective 
To evaluate the antitumor activity of MLN9708 in patients with relapsed and/or 
refractory multiple myeloma. 
5. 
STUDY OVERVIEW 
5.1 
Summary of Study Design 
This is a phase 1, multicenter, single-arm, open-label, dose-escalation study to evaluate 
the tolerability, safety, and pharmacokinetics of MLN9708 administered alone or in 
combination with Rd in patients with relapsed and/or refractory multiple myeloma.  
This study consists of the following 4 cohorts. 
● Cohort 1:  MLN9708 4.0 mg 
● Cohort 2:  MLN9708 4.0 mg + Rd 
● Cohort 3:  MLN9708 5.5 mg 
● Cohort 4:  MLN9708 5.5 mg + Rd 
Three subjects will be enrolled sequentially from cohorts 1 (MLN9708 4.0 mg alone) to 4.  
If dose-limiting toxicity (DLT) occurs in 1 subject during DLT-assessment period, 3 
additional subjects will be enrolled in the applicable cohort to evaluate the tolerability in 
a total of 6 subjects.  If DLT occurs in 2 of the 3 subjects, the given dosage is considered 
intolerable.  If DLT occurs in 2 of the 6 subjects, the sponsor will determine the 
tolerability to the given dosage after discussing with the Efficacy and Safety Evaluation 
Committee (ESEC). 


Product:  MLN9708 (ixazomib citrate) 
Statistical Analysis Plan:  TB-MC010034 
Date:  12 February 2014 
Page 6 of 24 
CONFIDENTIAL 
The sponsor will evaluate the tolerability of MLN9708 on the basis of the safety data 
including DLT incidences during the DLT-assessment period.  The sponsor will decide 
whether the next cohort will be studied and the dose of the next cohort in consultation 
with the ESEC, if necessary.  If the current cohort is considered tolerable, the next 
cohort will be in the order of cohorts 2 (MLN9708 4.0 mg + Rd), 3 (MLN9708 5.5 mg 
alone), and 4 (MLN9708 5.5 mg + Rd).  Even if a dosage is considered tolerable and 
transition to the next cohort is considered feasible, the next cohort may not be studied 
based on the results of the overseas clinical studies and the current study. 
The additional written informed consent for extended treatment will be obtained before 
the first dose of MLN9708 in Cycle 2 from the subjects who meet the criteria for 
beginning the next cycle of treatment and have no safety concern.  Subjects who do not 
give the consent will undergo end of study (EOS) visit on 29 days after the last dose of 
MLN9708 in Cycle 1.  The subjects giving the consent can continue the study treatment 
up to 12 cycles unless they meet the criteria of subject removal including evidence of 
progressive disease (PD) and intolerable toxicity.  Subjects may remain on treatment 
after the 12 cycles if the investigator considers it beneficial for the subjects. 
All subjects should undergo EOS visit on 29 days after the last dose of MLN9708. 
The overall study design is described in Table 5-1. “Study Design and Treatment 
Schema”. 


Product:  MLN9708 (ixazomib citrate) 
Statistical Analysis Plan:  TB-MC010034 
Date:  12 February 2014 
Page 7 of 24 
CONFIDENTIAL 
Table 5-1.  Study Design and Treatment Schema 
 
5.2 
Sample Size Considerations 
The planned number of subjects in this study is 3 to 6 for each cohort (12 to 24 in total). 
The sample size was selected with reference to the preceding overseas clinical studies 
and the “Anti-Malignant Tumor Drug Clinical Assessment Guidelines” (PFSB/ELD 
Notification No. 1101001, dated November 1, 2005).  The sample size was not selected 
based on a statistical rationale. 
6. 
STUDY ENDPOINTS 
6.1 
Primary Endpoint 
● DLTs, adverse events, body weight, vital signs, 12-lead electrocardiograms (ECGs), 
laboratory tests. 
● MLN2238 plasma concentration. 
6.2 
Secondary Endpoints 
● Number of subjects achieving CR, VGPR, and PR. 
Screening Period 
Subject Enrollment 
Treatment Period 
Cohort 1:  MLN9708 4.0 mg 
Study Day 
MLN9708 
Cycle 1* 
Day 1 
Day 8 Day 15 Day 22 
X 
X 
X 
- 
* Repeat the same administration schedule for Cycle 2 and after 
Cohort 2:  MLN9708 4.0 mg + Rd 
Study Day 
MLN9708 
Cycle 1* 
Day 1 
Day 8 Day 15 Day 22 
X 
X 
X 
- 
Lenalidomide 
Day 1 - 21 
Dexamethasone 
X 
X 
X 
X 
Cohort 3:  MLN9708 5.5 mg 
Study Day 
MLN9708 
Cycle 1* 
Day 1 
Day 8 Day 15 Day 22 
X 
X 
X 
- 
Cohort 4:  MLN9708 5.5 mg + Rd 
Study Day 
MLN9708 
Cycle 1* 
Day 1 
Day 8 Day 15 Day 22 
X 
X 
X 
- 
Lenalidomide 
Day 1 - 21 
Dexamethasone 
X 
X 
X 
X 
Tolerable  
Move up to next cohort 
Tolerable  
Move up to next cohort 
Tolerable  
Move up to next cohort 
The sponsor will decide whether the next cohort will be studied and the dose of 
the next cohort in consultation with Efficacy and Safety Evaluation committee, if 
necessary, after 28 days (until observation of Day 29 of treatment period) have 
past since the first dose. 
End of Study Visit (29 days after the last dose) 


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7. 
ANALYSIS SETS 
7.1 
Safety Analysis Set 
The safety analysis set will consist of all subjects who received at least one dose of study 
treatment.  Subjects will be analyzed according to the treatment received.  Safety 
analysis set will be used for all safety analyses unless otherwise specified. 
7.2 
Dose Limiting Toxicity (DLT) Analysis Set 
The DLT analysis set will consist of all subjects who experienced at least one DLT during 
DLT-assessment period (i.e., from the first dose to start of dose in cycle 2), or who 
received 3 planned doses of MLN9708 and completed the DLT-assessment period.  DLT 
analysis set will be used for DLT analyses. 
7.3 
Response Evaluable Analysis Set 
The response evaluable analysis set will consist of all subjects who received at least one 
dose of study treatment, have measurable disease at baseline, and at least one post-
baseline tumor assessment.  Response evaluable analysis set will be the primary analysis 
set for the analyses of response. 
7.4 
Pharmacokinetic (PK) Analysis Set 
The PK analysis set will consist of all subjects who had at least one evaluable 
concentration data and received at least one dose of study treatment.  Unless otherwise 
specified, the PK analysis set will be used for all PK analyses. 
8. 
DATA HANDLING 
8.1 
Handling of Missing Data 
Missing values by drop-out or error will be removed from analysis and not be imputed.  
However, estimation of pharmacokinetic parameters will be performed as much as 
possible, even if there are missing values.  PK data below the lower limit of quantitation 
will be treated as “zero”. 
8.2 
Handling of Partial Date 
For initial diagnosis or each last prior event (antineoplastic therapy, radiation therapy, 
bone marrow transplant or stem cell transplant, and any surgical procedures) with the 
dates that are partially missing, the following rules will be applied: 


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 If only month and year are provided, the 1st of the month will be used if the year 
and the month are the same as those for the first dose of study treatment.  
Otherwise, the 15th will be used. 
 If only year is provided and it is the same as the year of the first dose of study 
treatment, the 1st of January will be used.  Otherwise, the 1st of July will be 
used. 
The listing will be prepared based on original date (e.g., 2007/01/UN / 2007/UN/UN). 
8.3 
Definition of Baseline Values 
Unless otherwise specified, the baseline value is defined as the value collected at the time 
closest to, but prior to, the first dose of any study treatment. 
8.4 
Windowing of Visits 
If some multiple values are observed in the same time window, the value on the closer 
day to the target date will be adopted.  If the difference between the observed dates and 
the target date is same, later value is adopted for safety evaluation.  However, the actual 
dates of these values should be used in the listings and individual plots. 
9. 
STATISTICAL METHODS OF ANALYSIS 
9.1 
General Principles 
● Tables will be tabulated by the following groups unless otherwise specified; 
 monotherapy treatment group 
 combination treatment group 
 total of all subjects 
● Listings and figures are provided by treatment group unless otherwise specified. 
● Continuous variables will be summarized descriptively using summary statistics (n, 
mean, standard deviation, median, max, and min). 
● Categorical variables will be summarized using frequencies and percentages. 
● The analyses will not be performed for N=1. 
● The National Cancer Institute-Common Terminology Criteria for Adverse Events 
(CTCAE) Version 4.03 will be used for grading the adverse events and clinical 
laboratory abnormalities. 
● International uniform response criteria for multiple myeloma (Durie et al, 2006) will 
be used for evaluating the tumor response. 


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9.2 
Enrollment and Disposition of Subjects 
9.2.1 
Subject Disposition 
9.2.1.1 
Items 
Items for subject enrollment 
● Subjects screened 
● Subjects enrolled 
Items for subject disposition 
● MLN9708 administration: [Received, Never received] 
● Lenalidomide administration: [Received, Never received] 
● Dexamethasone administration: [Received, Never received] 
● Study treatment completion: [Ongoing, Discontinuation, #Reasons] 
● Study status: [Ongoing, Completed Safety Follow-up, Discontinued Without Safety 
Follow-up] 
9.2.1.2 
Methods 
The following tabulations will be prepared: 
● Subject enrollment (Subjects screened) 
● Subject disposition (Subjects enrolled) 
9.2.2 
Analysis Sets 
9.2.2.1 
Items 
Every analysis set defined in Section 7 “ANALYSIS SETS”. 
9.2.2.2 
Methods 
The number of subjects included in and excluded from each analysis set will be tabulated 
for all subjects enrolled. 
9.2.3 
Protocol Deviations and Treatment Compliance 
9.2.3.1 
Items 
The following categories of important protocol deviations: 
● EN : Entered study even though entry criteria was not satisfied 
● XM : Received an excluded concomitant treatment 
● NW : Developed withdrawal criteria but was not withdrawn 
● TA : Received the wrong treatment or incorrect dose 
● TC : Other Treatment Compliance 


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● OS : Off-schedule procedures (other than TA or TC) 
● MD : Missing data (other than TA or TC) 
● OT : Other Deviations 
9.2.3.2 
Methods 
The number of subjects with any important protocol deviations and each important 
protocol deviation will be tabulated for all subjects enrolled. 
9.3 
Demographic and Other Baseline Characteristics 
9.3.1.1 
Items 
Items for demographic and baseline characteristics 
● Sex 
● Age 
● Age group: [< 65, ≥ 65 years] 
● Height 
● Weight 
● Body Surface Area (BSA) 
BSA will be calculated using the following formula: 
 BSA (m2) = Height (cm)0.5 * Weight (kg)0.5 / 60 
● Eastern Cooperative Oncology Group (ECOG) performance status: [0, 1, 2] 
● Medical and surgical history: [Yes, No] 
Items for disease characteristics 
● Disease type: [IgG (Kappa, Lambda), IgA (Kappa, Lambda), IgD (Kappa, Lambda), 
IgE (Kappa, Lambda), IgM (Kappa, Lambda), Other] 
● Stage at initial diagnosis (Durie-Salmon Stage): [IA, IB, IIA, IIB, IIIA, IIIB, 
Unknown] 
● Stage at initial diagnosis (International Staging System Stage): [I, II, III, Unknown] 
● Duration from initial diagnosis to first dose 
● Duration from last prior antineoplastic therapy to first dose 
● Duration from last prior radiation therapy to first dose 
● Duration from last prior bone marrow transplant or stem cell transplant to first dose 
● Duration from last prior surgical procedures to first dose 
Duration will be calculated using the following formula: 
 Duration (months) = (Date of first dose - Date of initial diagnosis or each last 
prior event) * 12 / 365.25 
● Evidence of lytic bone disease at initial diagnosis: [Yes, No, Unknown] 
● Evidence of extramedullary disease at initial diagnosis: [Yes, No, Unknown] 
● Stage at study entry (Durie-Salmon Stage): [IA, IB, IIA, IIB, IIIA, IIIB, Unknown] 


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● Stage at study entry (International Staging System Stage): [I, II, III, Unknown] 
● Serum creatinine (in summary statistics) 
● Serum creatinine by category: [≤ 2, > 2 mg/dL] 
● Creatinine clearance by category: [< 30; 30 ≤ , < 60; ≥ 60 mL/min] 
Creatinine clearance will be calculated using the Cockcroft-Gault formulas as follows: 
 For male subjects: 
Creatinine clearance (mL/min) = (140 - Age [years]) * Weight (kg) / (72 * Serum 
creatinine [mg/dL]) 
 For female subjects: 
Creatinine clearance (mL/min) = 0.85 * (140 - Age [years]) * Weight (kg) / (72 * 
Serum creatinine [mg/dL]) 
● Kappa/Lambda ratio by category: [< 1, ≥ 1] 
● Serum M-protein (total M-protein) 
● 24 hour urine M-protein (urine total M-protein) 
● Beta-2-microglobulin by category: [< 2.5; 2.5 ≤ , ≤ 5.5; > 5.5 mg/L] 
● Albumin by category: [< 3.5, ≥ 3.5 g/dL] 
● Corrected calcium 
Corrected calcium will be calculated using the following formulas: 
 Corrected calcium (mmol/L) = 0.25 * (Serum calcium [mg/dL] - 0.8 * (Albumin 
[g/dL] - 4)), when Albumin (g/dL) is ≤ 4. 
 Corrected calcium (mmol/L) = 0.25 * Serum calcium (mg/dL), when Albumin 
(g/dL) is > 4. 
● Subjects with bone marrow aspirate: [Available, Unable to detect, Not available] 
● Bone marrow aspirate results (% Plasma cells) 
● Skeletal survey results at screening: [Within Normal Limits, Abnormal not clinically 
significant, Abnormal clinically significant] 
● Lytic bone lesions at screening: [Yes, No, Indeterminate] 
● Chest X-Ray results at screening: [Not done, Done (Within Normal Limits, Abnormal 
not clinically significant, Abnormal clinically significant, Not evaluated/Inevaluable)] 
● CT/MRI results at screening: [Within Normal Limits, Abnormal not clinically 
significant, Abnormal clinically significant] 
● Plasmacytomas at screening: [Yes, No, Indeterminate] 
● Prior antineoplastic therapy: [Yes, No] 
● Prior radiation therapy: [Yes, No] 
● Prior bone marrow transplant or stem cell transplant: [Yes, No] 
● Prior surgical procedures: [Yes, No] 
9.3.1.2 
Methods 
The following tabulations will be prepared: 
● Demographic and other baseline characteristics (safety analysis set) 


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● Disease characteristics (safety analysis set) 
9.4 
Safety Analyses 
9.4.1 
Extent of Exposure 
9.4.1.1 
Items 
Items for summary of exposure 
● Number of treated cycles (in summary statistics) 
● Number of treated cycles: [≥ 1, ≥ 2, ≥ 3,…≥ 13] 
● Total amount of dose taken 
● Number of doses taken 
● Dose intensity 
Dose intensity will be calculated using the following formula: 
 Dose Intensity (mg/cycle) = Total amount of dose taken (mg) / Number of treated 
cycles 
● Relative dose intensity 
Relative dose intensity will be calculated using the following formula: 
 Relative Dose Intensity (%) = (Total amount of dose taken [mg] / Total amount of 
dose expected per initial dose [mg]) * 100 
 
● Dosing compliance 
Dosing compliance will be calculated using the following formula: 
 Dosing compliance (%) = (Total amount of dose taken [mg] / Total amount of 
dose expected [mg]) * 100 
The dose expected is defined as the scheduled dose level for a dosing day when the 
action on drug is not "held" or "discontinued". 
Items for change in exposure 
● Subjects with any dose reduced prescribed: [#Reasons] 
● Subjects with any dose reduced non-prescribed: [#Reasons] 
● Subjects with any dose held: [#Reasons] 
● Subjects with any dose missed: [#Reasons] 
● Subjects with any dose delayed: [#Reasons] 
● Subjects with any dose discontinued permanently: [#Reasons] 
9.4.1.2 
Methods 
The following tabulations will be prepared: 
● Summary of exposure to MLN9708 (Safety analysis set) 
● Summary of exposure to Lenalidomide (Safety analysis set) 
● Summary of exposure to Dexamethasone (Safety analysis set) 


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● Change in exposure to MLN9708 (Safety analysis set) 
● Change in exposure to Lenalidomide (Safety analysis set) 
● Change in exposure to Dexamethasone (Safety analysis set) 
9.4.2 
Adverse Events 
9.4.2.1 
Items 
● Treatment-emergent adverse events (TEAEs) 
● Treatment-related adverse events 
● Serious treatment-emergent adverse events 
● Serious treatment- related adverse events 
● Treatment-emergent adverse events leading to permanent discontinuation of study 
treatment 
● Treatment-related adverse events leading to permanent discontinuation of study 
treatment 
● Dose limiting toxicities (DLTs) 
9.4.2.2 
Methods 
TEAEs are defined as adverse events or events resulting from exacerbation of 
complications that have occurred after the first dose of MLN9708. 
Treatment-related adverse events are defined as TEAEs that relationship to study 
treatment is assessed as “Yes”. 
The Medical Dictionary for Regulatory Activities (MedDRA) version 16.0 will be used to 
code all adverse events to a system organ class (SOC) and a preferred term (PT). 
The following tabulations will be prepared: 
● Summary of treatment-emergent adverse events (Safety analysis set) 
● Summary of treatment-related adverse events (Safety analysis set) 
● Subject incidence of treatment-emergent adverse events by system organ class and 
preferred term by grade (Safety analysis set) 
● Subject incidence of treatment-related adverse events by system organ class and 
preferred term by grade (Safety analysis set) 
● Subject incidence of serious treatment-emergent adverse events by system organ class 
and preferred term by grade (Safety analysis set) 
● Subject incidence of serious treatment-related adverse events by system organ class 
and preferred term by grade (Safety analysis set) 
● Subject incidence of treatment-emergent adverse events leading to permanent 
discontinuation of study treatment by system organ class and preferred term by grade 
(Safety analysis set) 


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● Subject incidence of treatment-related adverse events leading to permanent 
discontinuation of study treatment by system organ class and preferred term by grade 
(Safety analysis set) 
● Subject incidence of treatment-emergent adverse events by preferred term in 
descending order of frequency (Any vs. grade 3 or higher events) (Safety analysis set) 
● Subject incidence of treatment-related adverse events by preferred term in descending 
order of frequency (Any vs. grade 3 or higher events) (Safety analysis set) 
● Subject incidence of serious treatment-emergent adverse events by preferred term in 
descending order of frequency (Safety analysis set) 
● Subject incidence of serious treatment-related adverse events by preferred term in 
descending order of frequency (Safety analysis set) 
● Subject incidence of treatment-emergent adverse events leading to permanent 
discontinuation of study treatment by preferred term in descending order of frequency 
(Safety analysis set) 
● Subject incidence of treatment-related adverse events leading to permanent 
discontinuation of study treatment by preferred term in descending order of frequency 
(Safety analysis set) 
● Subject incidence of dose limiting toxicities by preferred term in descending order of 
frequency by safety evaluation committee in cycle 1 (DLT analysis set) 
A subject counts once for each SOC and PT for its worst grade. 
All “by SOC and PT” and “by PT” tabulations are prepared by descending order of 
frequency for total of treatment groups and by alphabetical order. 
Serious adverse event that occurred prior to first dose of MLN9708 will be presented in 
the listing. 
9.4.3 
Clinical laboratory 
9.4.3.1 
Items 
● Hematology 
● Chemistry (including corrected calcium) 
● Urinalysis 
9.4.3.2 
Methods 
For the purposes of summarization in the tables, listings and figures, all laboratory values 
will be converted to standardized units. 
The textbook range (Pagana KD and Pagana TJ, 2011) will be used for the grading of 
differential. 
The following tables will be prepared for all evaluable clinical laboratory abnormalities: 


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● Subject incidence of hematology abnormalities at post-baseline by grade (Safety 
analysis set) 
● Subject incidence of chemistry abnormalities at post-baseline by grade (Safety 
analysis set) 
● Subject incidence of urinalysis abnormalities at post-baseline by grade (Safety 
analysis set) 
● Maximum grade shift from baseline for hematology (Safety analysis set) 
● Maximum grade shift from baseline for chemistry (Safety analysis set) 
● Maximum grade shift from baseline for urinalysis (Safety analysis set) 
The following table will be prepared for all categorical values: 
● Worst category shift from baseline for urinalysis (Safety Analysis Set) 
The following tables and figures will be prepared for all continuous values: 
● Summary of maximum/minimum post-baseline values for hematology (Safety 
analysis set) 
● Summary of maximum/minimum post-baseline values for chemistry (Safety analysis 
set) 
● Summary of maximum/minimum post-baseline values for urinalysis (Safety analysis 
set) 
● Line plot of hematology by subject (Safety analysis set) 
● Line plot of chemistry by subject (Safety analysis set) 
● Line plot of urinalysis by subject (Safety analysis set) 
9.4.4 
12-Lead Electrocardiograms 
9.4.4.1 
Items 
ECG interpretation, heart rate, PR, QRS, QT, QTcB, and QTcF. 
(QTcB and QTcF which are calculated at site will not be used for analyses and will be 
presented on the listing only.) 
QTcB and QTcF will be calculated using the following formulas: 
 
QTcB = QT / (RR0.5) 
 
QTcF = QT / (RR0.33) 
where RR = 60 / heart rate (bpm) 
9.4.4.2 
Methods 
The following table will be prepared for ECG interpretation: 
● Shift table of ECG interpretation by visit (Safety analysis set) 


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The following tables and figures will be prepared for heart rate, PR, QRS, QT, QTcB, and 
QTcF: 
● Summary of maximum/minimum post-baseline values for 12-lead ECGs (Safety 
analysis set) 
● Line plot of 12-lead ECGs by subject (Safety analysis set) 
The following tables will be prepared for QT, QTcB, and QTcF: 
● Category of QT, QTcB, and QTcF by visit (Safety analysis set) 
● Category of change from baseline of QT, QTcB, and QTcF by visit (Safety analysis 
set) 
The categories of QT, QTcB, and QTcF are as follows: 
● ≤ 450 msec; 450 < , ≤ 480 msec; 480 < , ≤ 500 msec; > 500 msec 
The categories of change from baseline of QT, QTcB, and QTcF are as follows: 
● ≤ 30 msec; 30 < , ≤ 60 msec; > 60 msec 
9.4.5 
Vital Signs 
9.4.5.1 
Items 
Temperature, pulse, systolic blood pressure, diastolic blood pressure, SpO2, and weight. 
9.4.5.2 
Methods 
The following tables and figures will be prepared for each item: 
● Summary of maximum/minimum post-baseline values for vital signs (Safety analysis 
set) 
● Summary of maximum/minimum post-baseline values for weight (Safety analysis set) 
● Line plot of vital signs by subject (Safety analysis set) 
● Line plot of weight by subject (Safety analysis set) 
9.4.6 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
9.4.6.1 
Items 
ECOG performance status. 
9.4.6.2 
Methods 
The following table will be prepared: 
● Eastern Cooperative Oncology Group performance status by visit (Safety analysis set) 


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9.5 
Efficacy Analyses 
9.5.1 
Tumor Response 
Tumor response will be assessed using the International uniform response criteria for 
multiple myeloma (Durie et al, 2006). 
9.5.1.1 
Items 
● Best response: [CR (including sCR), PR (including VGPR), SD, PD, Not Evaluable] 
Best response for a subject is the best observed post-baseline tumor response.  All 
response categories require two consecutive assessments made at anytime before the 
institution of any new therapy. 
● Objective response rate (ORR) 
ORR is defined as the rate of subjects with sCR, CR, VGPR, or PR in response 
evaluable analysis set. 
● Duration of response (DOR) 
DOR is defined as the time from the date of first documentation of objective tumor 
response (sCR, CR, VGPR, or PR) to the date of first subsequent documentation of 
PD or death due to disease progression, whichever comes first in subjects who have 
the documentation of objective tumor response.  Subjects who are alive at the data 
cutoff date without the documentation of PD will be censored at the date of the last 
tumor assessment. 
DOR will be calculated using the following formulas: 
DOR = Date of first documentation of PD or death - Date of first subsequent 
documentation of objective tumor response + 1 
● Time to response 
Time to response is defined as the time from the date of first dose of study treatment 
to the date of first documentation of objective tumor response (sCR, CR, VGPR, or 
PR) in subjects who responded. 
Time to response will be calculated using the following formulas: 
Time to response = Date of first documentation of objective tumor response - Date of 
first dose of study treatment 
● Time to progression (TTP) 
TTP is defined as the time from the date of first dose of study treatment to the date of 
first documentation of PD or death caused by progression, whichever comes first.  
Subjects who are alive at the data cutoff date without the documentation of PD will be 
censored at the date of the last tumor assessment, but if the subjects have not had the 
last tumor assessment, then will be censored at the following day of first dose of study 
treatment. 
TTP will be calculated using the following formulas: 
TTP = Date of first documentation of PD or death - Date of first dose of study 
treatment + 1 
● Maximum M-protein change: [-100%; -100% < , ≤ -90%; -90% < , ≤ -75%; -75% < , 
≤ -50%; -50% < , ≤ -25%; -25% < , ≤ 25%; 25% <] 


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Maximum M-protein change is the largest percent change from baseline among all 
post-baseline measures of the Total M-protein.  For subjects with measurable serum 
M-protein at baseline, it is the percent change from baseline to the best (lowest) post-
baseline value in serum M-protein.  For subjects with non-measurable serum M-
protein but measurable urine M-protein at baseline, it is the percent change from 
baseline to the best (lowest) post-baseline value in urine M-protein. 
9.5.1.2 
Methods 
For all items, the following table will be prepared using Response Evaluable Analysis 
Set: 
 Summary of Tumor Response (Response Evaluable Analysis Set). 
For ORR, frequencies and percentages with 2-sided 95% exact confidence interval using 
the F distribution method given in Collett (2002) will be presented. 
DOR, time to response, and TTP will be summarized descriptively.  For DOR and TTP,  
Kaplan-Meier method will be used. 
For best response and maximum M-protein change, frequencies and percentages will be 
presented by category. 
10. 
LISTING 
● Deaths on study 
● Treatment-emergent adverse events 
● Treatment-related adverse events 
● Serious adverse events 
● Adverse events leading to permanent discontinuation of study treatment 
● Dose limiting toxicities by safety evaluation committee in cycle 1 
● Dose limiting toxicities by investigator 
● Hematology 
● Chemistry (including corrected calcium) 
● Urinalysis 
● Beta-2-microglobulin 
● Serum free light chain 
● Serum M-protein 
● Serum immunofixation 
● Quantitative immunoglobulins 
● Spot urine M-protein 
● 24-hour urine M-protein 
● Urine immunofixation 
● Bone marrow evaluations: Aspiration 


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● Chest X-ray 
● Skeletal survey 
● CT/MRI 
● Plasmacytoma evaluation 
● Vital signs 
● Pregnancy test 
● 12-lead ECGs 
● Eastern Cooperative Oncology Group performance status 
● Subject disposition (including informed consent for extended administration) 
● Screen failures 
● Important protocol deviations 
● Analysis sets 
● Demographics 
● Medical and surgical history 
● Disease characteristics 
● Prior therapy 
● Prior radiation therapy 
● Prior transplant procedure 
● Prior surgery 
● Tumor response (Investigator response assessment) 
● Overall efficacy 
● Summary of exposure to MLN9708 
● Summary of exposure to Lenalidomide 
● Summary of exposure to Dexamethasone 
● Exposure to MLN9708 by visit 
● Exposure to Lenalidomide by visit 
● Exposure to Dexamethasone by visit 
● Concomitant medications 
● Concomitant procedures 
● Grade 3 or higher clinical laboratory abnormalities 
11. 
APENDICES 
● Appendix A: Pharmacokinetics Analysis Plan 
12. 
REFERENCES 
● Collett D. Modelling Binary Data, Second Edition. Chapman & Hall. 2002:408p. 
● Durie BG, Harousseau JL, Miguel JS, Blade J, Barlogie B, Anderson K, et al. 
International uniform response criteria for multiple myeloma. Leukemia 
2006;20(9):1467-73. 


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● National Cancer Institute. Common Terminology Criteria for Adverse Events 
(CTCAE) Version 4.03. NIH Publication. 2010:78p 
● Pagana KD. and Pagana TJ. Mosbys Diagnostic and Laboratory Test  Reference Tenth 
Edition. Mosby Elsevier. 2011:1152p. 
13. 
DOCUMENT HISTORY 
Version 
Date 
Author 
Remarks 
1.0 
11 April 2012 
 
Original version 
2.0 
12 February 2014 
 
"BSA" and "EOS" have been added to the list in 
section 1. 
Description of the study design has been corrected 
in section 5.1. 
Some descriptions have been corrected in section 7, 
8, and 9. 
"8.2 Handling of Partial Date" has been added in 
section 8. 
"total of monotherapy treatment groups" and "total 
of combination treatment groups" have been deleted 
in section 9.1. 
To use "International uniform response criteria for 
multiple myeloma (Durie et al, 2006)" for 
evaluating the tumor response has been added in 
section 9.1. 
"MLN9708 completion", "Lenalidomide 
completion", "Dexamethasone completion", and 
"Study completion" have been deleted from items 
for subject disposition in section 9.2.1.1. 
"Study treatment completion" has been added to 
items for subject disposition in section 9.2.1.1. 
"Study status" has been added to items for subject 
disposition in section 9.2.1.1. 
Methods have been changed in section 9.2.1.2. 
"BSA" and formula for calculating it have been 
added to items for demographic and baseline 
characteristics in section 9.3.1.1. 
"Duration from last prior antineoplastic therapy to 
first dose", "Duration from last prior radiation 
therapy to first dose", "Duration from last prior bone 
marrow transplant or stem cell transplant to first 
dose", "Duration from last prior any surgical 
procedures to first dose", and formula for 
calculating them have been added to items for 
disease characteristics in section 9.3.1.1. 
"Evidence of lytic bone disease" has been changed 
to "Evidence of lytic bone disease at initial 
diagnosis" in section 9.3.1.1. 
"Evidence of extramedullary disease" has been 
changed to "Evidence of extramedullary disease at 
initial diagnosis" in section 9.3.1.1. 
"Serum creatinine and by category" has been deleted 
PPD
PPD


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in section 9.3.1.1. 
"Serum creatinine (in summary statistics)" and 
"Serum creatinine by category" have been added in 
section 9.3.1.1. 
The Cockcroft-Gault formulas for calculating 
creatinine clearance have been added in section 
9.3.1.1. 
"Detection of M-protein" has been deleted from 
items for disease characteristics in section 9.3.1.1. 
"Kappa/Lambda ratio" has been changed to " 
Kappa/Lambda ratio by category" in section 9.3.1.1. 
"Serum M-protein" has been changed to "Serum M-
protein (total M-protein)" in section 9.3.1.1. 
"Urine M-protein" has been changed to "24 hour 
urine M-protein (urine total M-protein)" in section 
9.3.1.1. 
"β2-microglobin by category" has been changed to 
"Beta-2-microglobulin by category" in section 
9.3.1.1. 
"Serum albumin by category" has been changed to 
"Albumin by category" in section 9.3.1.1. 
Formulas for calculating corrected calcium have 
been added in section 9.3.1.1. 
"Number of subjects with bone marrow aspirate" has 
been changed to "Subjects with bone marrow 
aspirate" in section 9.3.1.1. 
"Bone marrow aspirate results" has been changed to 
"Bone marrow aspirate results (% Plasma cells)" in 
section 9.3.1.1. 
"Skeletal survey results" has been changed to 
"Skeletal survey results at screening" in section 
9.3.1.1. 
"Lytic bone lesions at screening" has been added in 
section 9.3.1.1. 
"Chest X-Ray results" has been changed to "Chest 
X-Ray results at screening" in section 9.3.1.1. 
"MRI/CT results" has been changed to "CT/MRI 
results at screening" in section 9.3.1.1. 
"Plasmacytomas at screening" has been added in 
section 9.3.1.1. 
"Number of prior antineoplastic therapy" has been 
deleted in section 9.3.1.1. 
"Prior antineoplastic therapy" has been added in 
section 9.3.1.1. 
Items for concomitant medications have been 
deleted in section 9.3.1.1. 
Methods have been changed in section 9.3.1.2. 
"Number of doses taken" has been added in section 
9.4.1.1. 
Formulas for calculating dose intensity, relative dose 
intensity, and dosing compliance have been added in 


Product:  MLN9708 (ixazomib citrate) 
Statistical Analysis Plan:  TB-MC010034 
Date:  12 February 2014 
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CONFIDENTIAL 
section 9.4.1.1. 
Definition for dose expected has been added in 
section 9.4.1.1. 
The MedDRA version 15.0 for coding all adverse 
events to a SOC and a PT has been changed to 
version 16.0 in section 9.4.2.2. 
To use "The textbook range (Pagana KD and Pagana 
TJ, 2011)" for grading of differential has been added 
in section 9.4.3.2. 
"Subject incidence of hematology abnormalities by 
grade (Safety analysis set)" has been changed to 
"Subject incidence of hematology abnormalities at 
post-baseline by grade (Safety analysis set)" in 
section 9.4.3.2. 
"Subject incidence of chemistry abnormalities by 
grade (Safety analysis set)" has been changed to 
"Subject incidence of chemistry abnormalities at 
post-baseline by grade (Safety analysis set)" in 
section 9.4.3.2. 
"Subject incidence of urinalysis abnormalities by 
grade (Safety analysis set)" has been changed to 
"Subject incidence of urinalysis abnormalities at 
post-baseline by grade (Safety analysis set)" in 
section 9.4.3.2. 
"Shift table of urinalysis (Safety Analysis Set)" has 
been changed to "Shift table of urinalysis by visit 
(Safety Analysis Set)" in section 9.4.3.2. 
"RR" has been deleted from items in section 9.4.4.1. 
Formulas for calculating QTcB and QTcF have been 
added in section 9.4.4.1. 
Definitions for "ORR", "DOR", "time to response", 
"TTP", "Best response", and "Maximum M-protein 
change" have been changed in section 9.5.1.1. 
Methods for "ORR", "DOR", "time to response", 
"TTP", "Best response", and "Maximum M-protein 
change" have been changed in section 9.5.1.2. 
"Adverse events" has been deleted in section 10. 
"Treatment-emergent adverse events" has been 
added in section 10. 
"Adverse events leading to permanent 
discontinuation of investigational product" has been 
changed to "Adverse events leading to permanent 
discontinuation of study treatment" in section 10. 
"Dose limiting toxicities" has been deleted in section 
10. 
"Dose limiting toxicities by safety evaluation 
committee in cycle 1" and "Dose limiting toxicities 
by investigator" have been added in section 10. 
"Chemistry" has been changed to "Chemistry 
(including corrected calcium)" in section 10. 
"Urine M-protein" has been deleted in section 10. 
"Spot urine M-protein" and "24-hour urine M-


Product:  MLN9708 (ixazomib citrate) 
Statistical Analysis Plan:  TB-MC010034 
Date:  12 February 2014 
Page 24 of 24 
CONFIDENTIAL 
protein" have been added in section 10. 
"Pregnancy test" has been added in section 10. 
"Subject disposition" has been changed to "Subject 
disposition (including informed consent for 
extended administration)" in section 10. 
"Prior radiation" has been changed to "Prior 
radiation therapy" in section 10. 
"Investigator response assessment (IMWG)" has 
been changed to "Tumor response (Investigator 
response assessment)" in section 10. 
"Overall efficacy" has been added in section 10. 
"Concomitant medications" has been added in 
section 10. 
"Concomitant procedures" has been added in section 
10. 
"Summary of tumor response" has been deleted in 
section 10. 
"MLN9708 dosing" has been changed to "Exposure 
to MLN9708 by visit" in section 10. 
"Lenalidomide dosing" has been changed to 
"Exposure to Lenalidomide by visit" in section 10. 
"Dexamethasone dosing" has been changed to 
"Exposure to Dexamethasone by visit" in section 10. 
"Bone marrow evaluations" has been changed to 
"Bone marrow evaluations: Aspiration" in section 
10. 
"β2-microglobulin" has been changed to"Beta-2-
microglobulin" in section 10. 
"12-Lead Electrocardiograms" has been changed 
to"12-lead ECGs" in section 10. 
"ECOG performance status" has been changed to 
"Eastern Cooperative Oncology Group performance 
status" in section 10. 
"Grade 3 or higher clinical laboratory abnormalities" 
has been added in section 10. 
The section "12 REFERENCES" has been added.