A Phase 2, Open-Label, Multicenter Study of Ixazomib Plus Lenalidomide and Dexamethasone in Adult Japanese Patients With Relapsed and/or Refractory Multiple Myeloma
Phase: PHASE2
Conditions: Relapsed and/or Refractory Multiple Myeloma
Sponsor: Takeda

 
 
Title: A Phase 2, Open-Label, Multicenter Study of Ixazomib Plus Lenalidomide and 
Dexamethasone in Adult Japanese Patients With Relapsed and/or Refractory Multiple 
Myeloma 
 
NCT Number: NCT02917941 
Protocol Approve Date: 25-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). 
 
Note; This document was translated into English as the language on original version 
was Japanese. 

CONFIDENTIAL 
 
PROTOCOL 
A Phase 2, Open-Label, Multicenter Study of Ixazomib Plus Lenalidomide and Dexamethasone in 
Adult Japanese Patients With Relapsed and/or Refractory Multiple Myeloma 
 
Sponsor: 
Takeda Pharmaceutical Company Limited. 
4-1-1 Doshomachi, Chuo-ku, Osaka 540-8645 
Study Number: 
C16028 
IND Number: 
Not Applicable 
EudraCT Number: 
Not Applicable 
Compound: 
MLN9708, ixazomib citrate 
Date: 
25 November 2016 
(English version: 27 
December 2016) 
Amendment Number: Amendment 01 
 
Amendment History 
Date 
Amendment Number 
Region 
5 August 2016 
Original 
All sites 
25 November 2016 
Amendment 01 
All sites 
Note: This study will be continued as a post-marketing clinical study after a marketing approval of ixazomib was obtained in Japan. 
In the protocol, the term "study" will be replaced by "post-marketing clinical study" as appropriate, and the protocol is continuously 
used.  
 
CONFIDENTIAL PROPERTY OF TAKEDA 
This document is a confidential communication of Takeda. Acceptance of this document 
constitutes the agreement by the recipient that no information contained herein will be published 
or disclosed without written authorization from Takeda except to the extent necessary to obtain 
informed consent from those persons to whom the drug may be administered. Furthermore, the 
information is only meant for review and compliance by the recipient, his or her staff, and 
applicable institutional review committee and regulatory agencies to enable conduct of the study. 
 
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CONFIDENTIAL 
1.0 
ADMINISTRATIVE INFORMATION AND PRINCIPLES OF CLINICAL 
STUDIES 
1.1 
Contacts and Responsibilities of Study-Related Activities 
See the protocol annex. 
1.2 
Principles of Clinical Studies  
This study will be conducted with the highest respect for the individual participants in accordance 
with the requirements of this clinical study protocol and also in accordance with the following: 
• The ethical principles that have their origin in the Declaration of Helsinki. 
• International Conference on Harmonisation (ICH) E6 Good Clinical Practice: Consolidated 
Guideline. 
• All applicable laws and regulations, including, without limitation, data privacy laws, clinical 
trial disclosure laws, and regulations. 
1.3 
Protocol Amendment 01 Summary of Changes  
The primary purpose of this amendment is to describe the procedures to be changed in order to 
continue this study as a post-marketing clinical study after a marketing approval of ixazomib was 
obtained in Japan, and to correct typographical errors and inconsistencies found in the protocol 
before this amendment. Further details of this amendment are provided in Appendix J. 
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CONFIDENTIAL 
TABLE OF CONTENTS 
1.0 
ADMINISTRATIVE INFORMATION AND PRINCIPLES OF CLINICAL 
STUDIES ........................................................................................................................ 2 
1.1 
Contacts and Responsibilities of Study-Related Activities .......................................... 2 
1.2 
Principles of Clinical Studies ..................................................................................... 2 
1.3 
Protocol Amendment 01 Summary of Changes .......................................................... 2 
2.0 
STUDY SUMMARY ...................................................................................................... 8 
3.0 
LIST OF ABBREVIATIONS ........................................................................................ 10 
4.0 
INTRODUCTION ......................................................................................................... 12 
4.1 
Background ............................................................................................................. 12 
4.2 
Rationale for the Proposed Study ............................................................................. 13 
5.0 
STUDY OBJECTIVES AND ENDPOINTS .................................................................. 15 
5.1 
Objectives ................................................................................................................ 15 
5.1.1 
Primary Objective .............................................................................................. 15 
5.1.2 
Secondary Objectives ......................................................................................... 15 
5.2 
Endpoints................................................................................................................. 15 
5.2.1 
Primary Endpoint ............................................................................................... 15 
5.2.2 
Secondary Endpoints .......................................................................................... 15 
6.0 
STUDY DESIGN .......................................................................................................... 16 
6.1 
Overview of Study Design ....................................................................................... 16 
6.2 
Number of Patients .................................................................................................. 17 
6.3 
Duration of Study .................................................................................................... 17 
6.3.1 
Duration of an Individual Patient’s Study Participation ...................................... 17 
6.3.2 
End of Study ...................................................................................................... 17 
6.3.3 
Total Study Duration .......................................................................................... 17 
7.0 
STUDY POPULATION ................................................................................................ 18 
7.1 
Inclusion Criteria ..................................................................................................... 18 
7.2 
Exclusion Criteria .................................................................................................... 19 
8.0 
STUDY DRUG ............................................................................................................. 22 
8.1 
Study Treatment Administration .............................................................................. 22 
8.1.1 
Ixazomib: Study Drug ........................................................................................ 22 
8.1.2 
Lenalidomide: Concomitant Study Therapy ....................................................... 22 
8.1.3 
Dexamethasone: Concomitant Study Therapy .................................................... 23 
8.2 
Dose Modification Guidelines .................................................................................. 23 
8.2.1 
Dose Adjustments for Rash:  Ixazomib and Lenalidomide .................................. 24 
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CONFIDENTIAL 
8.2.2 
Dose Adjustments for Hematologic Toxicity:  Ixazomib and Lenalidomide ....... 25 
8.2.3 
Ixazomib Treatment Modification ...................................................................... 27 
8.2.4 
Lenalidomide Treatment Modification ............................................................... 28 
8.2.5 
Dexamethasone Treatment Modification ............................................................ 29 
8.2.6 
Criteria for Toxicity Recovery Before Beginning the Next Cycle of Treatment .. 30 
8.3 
Excluded Concomitant Medications and Procedures ................................................ 31 
8.4 
Permitted Concomitant Medications and Procedures ................................................ 31 
8.5 
Precautions and Restrictions .................................................................................... 32 
8.6 
Management of Clinical Events ............................................................................... 33 
8.6.1 
Prophylaxis Against Risk of Reactivation of Herpes Infection ............................ 33 
8.6.2 
Thromboembolism Prophylaxis.......................................................................... 33 
8.6.3 
Nausea and/or Vomiting ..................................................................................... 33 
8.6.4 
Diarrhea ............................................................................................................. 34 
8.6.5 
Erythematous Rash With or Without Pruritus ..................................................... 34 
8.6.6 
Thrombocytopenia ............................................................................................. 35 
8.6.7 
Neutropenia ....................................................................................................... 35 
8.6.8 
Fluid Deficit ....................................................................................................... 35 
8.6.9 
Hypotension ....................................................................................................... 35 
8.6.10 Posterior Reversible Encephalopathy Syndrome ................................................. 35 
8.6.11 Transverse Myelitis ............................................................................................ 36 
8.6.12 Progressive Multifocal Leukoencephalopathy .................................................... 36 
8.6.13 Overdose ............................................................................................................ 36 
8.7 
Blinding and Unblinding .......................................................................................... 36 
8.8 
Description of Investigational Agents ...................................................................... 36 
8.9 
Packaging and Labeling ........................................................................................... 37 
8.10 
Storage, Handling, and Accountability ..................................................................... 37 
8.10.1 Concomitant Study Therapy ............................................................................... 38 
8.11 
Other Protocol-Specified Materials .......................................................................... 38 
9.0 
STUDY CONDUCT...................................................................................................... 39 
9.1 
Study Personnel and Organizations .......................................................................... 39 
9.2 
Arrangements for Recruitment of Patients ................................................................ 39 
9.3 
Study Enrollments ................................................................................................... 39 
9.3.1 
Enrollment Procedures ....................................................................................... 39 
9.4 
Study Procedures ..................................................................................................... 40 
9.4.1 
Informed Consent............................................................................................... 40 
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CONFIDENTIAL 
9.4.2 
Patient Demographics ........................................................................................ 40 
9.4.3 
Medical History ................................................................................................. 40 
9.4.4 
Physical Examination ......................................................................................... 40 
9.4.5 
Eastern Cooperative Oncology Group Performance Status ................................. 40 
9.4.6 
Height and Weight ............................................................................................. 40 
9.4.7 
Vital Signs ......................................................................................................... 41 
9.4.8 
Pregnancy Test................................................................................................... 41 
9.4.9 
Skeletal Survey .................................................................................................. 41 
9.4.10 Skeletal-Related Events...................................................................................... 41 
9.4.11 Serum Free Light Chain Assay ........................................................................... 42 
9.4.12 Immunofixation of Serum and Urine .................................................................. 42 
9.4.13 Bone Marrow Evaluation ................................................................................... 42 
9.4.14 Response Assessment......................................................................................... 42 
9.4.15 Concomitant Medications and Procedures .......................................................... 43 
9.4.16 Adverse Events .................................................................................................. 43 
9.4.17 Clinical Laboratory Evaluations ......................................................................... 43 
9.4.18 Radiographic Disease Assessment ...................................................................... 44 
9.4.19 β2-Microglobulin ............................................................................................... 44 
9.4.20 Quantification of M-Protein ............................................................................... 45 
9.5 
Completion of Study Treatment for Individual Patients ............................................ 45 
9.6 
Completion of Study for Individual Patients............................................................. 45 
9.7 
Discontinuation of Treatment With Study Treatment ............................................... 45 
9.8 
Withdrawal of Patients From Study ......................................................................... 45 
9.9 
Study Compliance .................................................................................................... 46 
9.10 
Posttreatment Follow-up Assessments (Progression-Free Survival and Overall 
Survival) .................................................................................................................. 46 
10.0 
ADVERSE EVENTS .................................................................................................... 47 
10.1 
Definitions ............................................................................................................... 47 
10.1.1 Pretreatment Event Definition ............................................................................ 47 
10.1.2 Adverse Event Definition ................................................................................... 47 
10.1.3 Serious Adverse Event Definition ...................................................................... 47 
10.2 
Procedures for Recording and Reporting Adverse Events and Serious 
Adverse Events ........................................................................................................ 48 
10.3 
Monitoring of Adverse Events and Period of Observation ........................................ 49 
10.4 
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events ......... 50 
10.5 
Product Complaints and Medication Errors (Including Overdose) ............................ 50 
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CONFIDENTIAL 
10.6 
Safety Reporting to Investigators, IRBs and Regulatory Authorities......................... 51 
11.0 
STUDY-SPECIFIC COMMITTEES ............................................................................. 52 
12.0 
DATA HANDLING AND RECORDKEEPING ............................................................ 53 
12.1 
eCRFs ...................................................................................................................... 53 
12.2 
Record Retention ..................................................................................................... 53 
13.0 
STATISTICAL METHODS .......................................................................................... 55 
13.1 
Statistical and Analytical Plans ................................................................................ 55 
13.1.1 Analysis Sets...................................................................................................... 55 
13.1.2 Analysis of Demographics and Other Baseline Characteristics ........................... 55 
13.1.3 Efficacy Analysis ............................................................................................... 55 
13.1.4 Safety Analysis .................................................................................................. 57 
13.2 
Interim Analysis and Criteria for Early Termination ................................................ 57 
13.3 
Determination of Sample Size .................................................................................. 57 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE............................................... 58 
14.1 
Study-Site Monitoring Visits ................................................................................... 58 
14.2 
Protocol Deviations.................................................................................................. 58 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections ................................ 58 
15.0 
ETHICAL ASPECTS OF THE STUDY ........................................................................ 59 
15.1 
IRB Approval .......................................................................................................... 59 
15.2 
Subject Information, Informed Consent, and Subject Authorization ......................... 59 
15.3 
Subject Confidentiality ............................................................................................ 60 
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy ................................. 61 
15.4.1 Publication ......................................................................................................... 61 
15.4.2 Clinical Trial Registration .................................................................................. 61 
15.4.3 Clinical Trial Results Disclosure ........................................................................ 61 
15.5 
Insurance and Compensation for Injury .................................................................... 61 
16.0 
REFERENCES .............................................................................................................. 62 
12.2 
77 
 
LIST OF IN-TEXT TABLES 
Table 8.a 
Dose Reduction Steps for Ixazomib ................................................................... 24 
Table 8.b 
Dose Reduction Steps for Lenalidomide ............................................................. 24 
Table 8.c 
Dose Reduction Steps for Dexamethasone ......................................................... 24 
Table 8.d 
Dose Reduction Steps for Ixazomib and Lenalidomide for Rash ......................... 25 
Table 8.e 
Ixazomib and Lenalidomide Dose Adjustment for Thrombocytopenia ................ 26 
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CONFIDENTIAL 
Table 8.f 
Ixazomib and Lenalidomide Dose Adjustment for Neutropenia .......................... 27 
Table 8.g 
Ixazomib Treatment Modification (Delays, Reductions, and Discontinuations) 
Due to Adverse Events ....................................................................................... 28 
Table 8.h 
Lenalidomide Treatment Modification (Delays, Reductions, and 
Discontinuations) Due to Non-Hematologic Adverse Events .............................. 29 
Table 8.i 
Dexamethasone Treatment Modification (Delays, Reductions, and 
Discontinuations) Due to Adverse Events........................................................... 30 
Table 8.j 
Ixazomib Capsules ............................................................................................. 36 
Table 9.a 
Response Assessment......................................................................................... 43 
Table 9.b 
Hematology and Chemistry Tests ....................................................................... 44 
 
LIST OF APPENDICES 
Appendix A 
Schedule of Events ............................................................................................. 64 
Appendix B 
Responsibilities of the Investigator ..................................................................... 68 
Appendix C 
Investigator Consent to Use of Personal Information .......................................... 69 
Appendix D 
Eastern Cooperative Oncology Group (ECOG) Scale for Performance Status..... 70 
Appendix E 
Multiple Myeloma Diagnostic Criteria ............................................................... 71 
Appendix F 
Cockcroft-Gault Equation .................................................................................. 72 
Appendix G 
International Staging System Staging Criteria and Durie-Salmon Criteria .......... 73 
Appendix H 
Response Criteria ............................................................................................... 74 
Appendix I 
Changes in Procedures in Study Protocol after Shifting to the Post-marketing 
Clinical Study .................................................................................................... 76 
Appendix J 
Detailed Description of Amendments to Text ..................................................... 78 
 
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CONFIDENTIAL 
2.0 
STUDY SUMMARY 
Name of Sponsor(s): 
Takeda Pharmaceutical Company Limited. 
Compound: 
Investigational Drug Code: MLN9708 
Generic Name: ixazomib citrate 
Title of Protocol:  A Phase 2, Open-Label, Multicenter 
Study of Ixazomib Plus Lenalidomide and Dexamethasone 
in Adult Japanese Patients With Relapsed and/or Refractory 
Multiple Myeloma 
IND No.:  
Not Applicable 
EudraCT No.:  
Not Applicable 
Study Number:  C16028 
Phase:  2 
Study Design: 
This is a phase 2, open label, single arm, multicenter study to evaluate the efficacy and safety of ixazomib plus 
lenalidomide and dexamethasone (LenDex) in Japanese patients with relapsed and/or refractory multiple myeloma 
(MM).  The patient population will consist of adult men and women who have a confirmed diagnosis of MM, who 
have received 1 to 3 prior lines of therapy, and who meet other outlined eligibility criteria.  
Patients will receive study drug (ixazomib 4.0 mg) on Days 1, 8, and 15 plus lenalidomide (25 mg) on Days 1 through 
21 and dexamethasone (40 mg) on Days 1, 8, 15, and 22 of a 28-day cycle.  Patients may continue to receive treatment 
until progressive disease (PD) or unacceptable toxicity, whichever comes first.  Dose modifications may be made 
based on toxicities.  Patients with a low creatinine clearance < 60 mL/min will receive a reduced lenalidomide dose of 
10 mg once daily on Days 1 through 21 of a 28-day cycle.  The lenalidomide dose may be escalated to 15 mg once 
daily after 2 cycles if the patient is not responding to treatment and is tolerating the treatment.  If renal function 
normalizes (ie, creatinine clearance ≥ 60 mL/min) and the patient continues to tolerate this treatment, lenalidomide 
may then be escalated to 25 mg once daily. 
Patients will be seen at regular treatment cycle intervals while they are participating in the study: four times a 
treatment cycle for the first 2 cycles, twice a treatment cycle for the 3rd cycle, and then once a treatment cycle for the 
remainder of their participation in the active treatment and, if applicable, the PFS and OS follow-up phases of the 
study. 
Response will be assessed by investigator according to the International Myeloma Working Group (IMWG) criteria 
for all patients every 4 weeks until PD. Central laboratory data will be used for serum M-protein, urine M-protein and 
serum free light chain. All patients will be followed for survival after progression. Patients will be contacted every 12 
weeks until death or termination of the study by the sponsor. 
The study will be closed at 24 months from the enrollment of the last patient. 
Primary Objective: 
• To determine very good partial response (VGPR) or better (VGPR + complete response [CR]) rate in 
response-evaluable analysis set*. 
*Defined as patients who received at least one dose of ixazomib and had measurable disease at baseline, and at least 
one post baseline response assessment. 
Secondary Objectives: 
• To determine progression-free survival (PFS) 
• To determine overall response rate (ORR) (partial response [PR] or better) 
• To determine duration of response (DOR) 
• To determine time to progression (TTP)  
• To determine safety 
• To determine overall survival (OS)  
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CONFIDENTIAL 
Subject Population: 
Japanese adult patients with a confirmed diagnosis of symptomatic MM and relapsed and/or refractory disease will be 
enrolled in this study. 
Number of Subjects:  approximately 30 
Number of Sites:  approximately 20 
Dose Level(s): 
Patients will receive study drug (ixazomib 4.0 mg) on Days 
1, 8, and 15 plus lenalidomide (25 mg) on Days 1 through 
21 and dexamethasone (40 mg) on Days 1, 8, 15, and 22 of a 
28-day cycle. 
Route of Administration: 
oral 
Duration of Treatment: 
Patients may continue to receive treatment until PD or 
unacceptable toxicity, whichever comes first (The 
maximum treatment period will be 24 months after the last 
patient is enrolled). 
Period of Evaluation: 
The duration of the study, including enrollment, 
treatment, and follow-up, will be approximately 30 
months. 
Main Criteria for Inclusion: 
Male or female Japanese patients 20 years of age or older, who have diagnosed MM and have received 1 to 3 prior 
therapies. Patients must have measurable disease defined by at least 1 of the following 3 measurements based on 
central laboratory data: 1) Serum M-protein: ≥ 1 g/dL (≥10 g/L). 2) Urine M-protein: ≥ 200 mg/24 hours. 3) Serum 
free light chain assay:  involved free light chain level ≥ 10 mg/dL (≥ 100 mg/L) provided that the serum free light 
chain ratio is abnormal.  
Main Criteria for Exclusion: 
Patients who were refractory to lenalidomide or proteasome inhibitor-based therapy at any line, who experienced rash 
or pruritus requiring systemic medication within 14 days before enrollment, or who are diagnosed with 
Waldenstrom’s macroglobulinemia, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal 
gammopathy, and skin changes) syndrome, plasma cell leukemia, primary amyloidosis, myelodysplastic syndrome, or 
myeloproliferative syndrome. 
Main Criteria for Evaluation and Analyses: 
The primary endpoint for this study is VGPR or better (CR + VGPR) rate in response-evaluable analysis set.  
Secondary endpoints for this study are PFS, ORR, DOR, TTP, safety (adverse events, laboratory tests and vital signs), 
and OS. 
Statistical Considerations: 
VGPR or better rate and the 2-sided 95% confidence interval (CI) in response-evaluable analysis set will be evaluated 
as primary analysis of the primary endpoint.  Primary analysis is estimated to occur approximately 12 months from the 
enrollment of the last patient.  Final analysis is estimated to occur approximately 24 months from the enrollment of the 
last patient.   
Sample Size Justification: 
The sample size of
will provide
% probability of the point estimate of VGPR or better rate over the threshold 
rate, assuming expected CR + VGPR rate of 
% and threshold rate of 
%. The target number of patients is 
estimated to be 30, assuming a drop-out rate of 
%. 
Note: This study will be continued as a post-marketing clinical study after a marketing approval of ixazomib was 
obtained in Japan. In the protocol, the term "study" will be replaced by "post-marketing clinical study" as appropriate, 
and the protocol is continuously used. 
CCI
CCI
CCI
CC
I
C
CI
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CONFIDENTIAL 
3.0 
LIST OF ABBREVIATIONS 
5-HT3
5-hydroxytryptamine 3 serotonin receptor
ADL
activities of daily living
AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
BUN
blood urea nitrogen
CBC
complete blood count
CI
confidence interval
CO2
carbon dioxide
CR
complete response
CRO
contract research organization
CT
computed tomography
CYP
cytochrome P450
Del
deletion
DNA
deoxyribonucleic acid
DOR
duration of response
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EOT
End of Treatment (visit)
FAS
full analysis set
FCBP
female patients of childbearing potential
FDA
United States Food and Drug Administration
FLC
free light chain
GCP
Good Clinical Practice
G-CSF
granulocyte colony stimulating factor
GVHD
graft-versus-host disease
HBcAb
hepatitis B core antibody
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
IMiD
immunomodulatory drugs
IMWG
International Myeloma Working Group
IRB
institutional review board
IUD
intrauterine device
IV
intravenous; intravenously
LenDex
lenalidomide and dexamethasone
LDH
lactate dehydrogenase
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CONFIDENTIAL 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHRA 
Medicines and Healthcare products Regulatory Agency 
MM 
multiple myeloma 
MRI 
magnetic resonance imaging 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NDMM 
newly diagnosed multiple myeloma 
ORR 
overall response rate 
OS 
overall survival 
PD 
progressive disease (disease progression) 
PET 
positron emission tomography 
PFS 
progression-free survival 
PMDA 
Pharmaceuticals and Medical Devices Agency 
PML 
progressive multifocal leukoencephalopathy 
POEMS 
polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin 
changes 
PR 
partial response  
PRES 
posterior reversible encephalopathy syndrome 
PTE 
pretreatment event 
RNA 
ribonucleic acid 
RRMM 
relapsed and/or refractory multiple myeloma 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
sCR 
stringent complete response 
SD 
stable disease 
SPEP 
serum protein electrophoresis 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TEN 
toxic epidermal necrolysis 
Tmax 
time to first occurrence of maximum (peak) concentration 
TSH 
thyroid stimulating hormone 
TTP 
time to progression 
ULN 
upper limit of the normal range 
UPEP 
urine protein electrophoresis 
VGPR 
very good partial response 
WBC 
white blood cell 
WHO 
World Health Organization 
 
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4.0 
INTRODUCTION 
4.1 
Background 
Multiple myeloma (MM) is a malignant disease where monoclonal plasma cells proliferate mainly 
in the bone marrow.  MM causes hematopoietic deterioration, increase of monoclonal 
immunoglobulin (M-protein) produced in myeloma cells, bone destruction, hypercalcemia, and 
results in renal failure, which is one of the major causes of death.  It constitutes approximately 1% 
of all reported neoplasms and approximately 13% of hematologic cancers worldwide [1].  The  
American Cancer Society estimates that there will be 26,850 new cases of MM, with 
approximately 11,240 deaths, in the United States in 2015 [2].  In Europe, the estimated annual 
incidence is 38,900 new cases of MM, with approximately 24,300 deaths in 2012 [3].  Although 
less common in Asian countries, MM is a growing health problem with an incidence that is 
approaching that of Western countries and a larger population base [4][5].  The National Cancer 
Center Japan estimates that there will be 8,600 new cases of MM, with approximately 4,200 deaths, 
in Japan in 2015 [6].  MM is generally regarded as incurable at present, although some data have 
suggested an increasing cure-fraction in front-line patients [7].  Responses to currently available 
therapies are transient, despite the marked improvement in treatment options, and most patients 
receive multiple lines of therapy, including combination regimens, over the course of their disease 
[8]. 
The treatment of MM has undergone important changes over the recent past due to advances in 
understanding the disease biology and improvements in treatment strategies.  While historic 
treatment approaches focused on cytotoxic drugs, such as alkylating agents, anthracyclines, and 
corticosteroids, the introduction of the first-in-class proteasome inhibitor, bortezomib, and the 
immunomodulatory drugs (IMiDs), thalidomide and lenalidomide, have improved treatment 
outcomes [9][10][11][12].  These agents, alone and in combination with steroids or cytotoxic 
agents, are now among the recommended standard of care throughout the MM treatment pathway 
[13][14].  As of July 2016, bortezomib and lenalidomide are available for the treatment for the 
both newly diagnosed multiple myeloma (NDMM) and relapsed and/or refractory multiple 
myeloma (RRMM) in Japan.  In addition, pomalidomide, panobinostat and carfilzomib are 
approved for RRMM.  
Despite the increase in the number of therapeutic options, MM remains incurable and there is a 
need for new and better agents.  Patients who were refractory to the initial therapy or relapse 
demonstrate variable response to subsequent treatments with decreasing likelihood and duration of 
response (DOR).  Patients ultimately become refractory to approved therapies and have no 
alternative treatment options.  In an effort to further target the proteasome with increased activity 
in MM and other cancers, ixazomib has been developed, a small molecule 20S proteasome 
inhibitor. 
Ixazomib refers to the biologically active boronic acid form of the drug substance.  The drug 
substance is administered as a stable citrate ester, ixazomib citrate, a prodrug of ixazomib.  In 
physiological conditions, ixazomib citrate rapidly hydrolyzes to the biologically active boronic 
acid, ixazomib, that potently, reversibly, and selectively inhibits the proteasome.  In contrast to 
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bortezomib, ixazomib demonstrates a faster dissociation rate from the proteasome that may result 
in enhanced tumor penetration, exhibits antitumor activity in a broader range of tumor xenografts, 
and has more prolonged tissue penetration.  The clinical benefit of ixazomib has been studied in 
Millennium-sponsored clinical studies and ixazomib is being developed globally for the treatment 
options for RRMM, NDMM, and systemic AL amyloidosis.  In November 2015, ixazomib in 
combination with lenalidomide and dexamethasone received FDA approval for the treatment of 
patients with multiple myeloma who have received at least 1 prior therapy; therefore, ixazomib is 
available commercially in the United States. 
The pivotal study for ixazomib in patients with RRMM is an ongoing phase 3 global, randomized, 
double-blind, placebo-controlled study (Study C16010).  The objective of the study is to evaluate 
efficacy and safety of ixazomib in combination with lenalidomide + dexamethasone (LenDex) in 
comparison with placebo in combination with LenDex in patients with multiple myeloma who had 
received at least one prior therapy.  The results of the primary analysis of efficacy for the overall 
population showed that there was a statistically significant and clinically meaningful prolongation 
of progression-free survival (PFS) as assessed by the independent review committee, the primary 
endpoint,  in the ixazomib + LenDex regimen compared to the placebo + LenDex regimen.  The 
median PFS was 20.6 months in the ixazomib + LenDex regimen and 14.7 months in the placebo + 
LenDex regimen (hazard ratio = 0.742; p = 0.012) [15].  In addition, the ixazomib + LenDex 
regimen provided clinical benefit in terms of better disease control (demonstrated by significant 
improvements in complete response (CR) and overall response rates) and longer disease control 
(demonstrated by significant improvement in time to progression and by longer duration of 
response).  Ixazomib in combination with LenDex is a well-tolerated regimen, and ixazomib does 
not add clinically significant toxicity to the LenDex background therapy. 
4.2 
Rationale for the Proposed Study 
In Study C16010, the results of the primary analysis of efficacy for the overall population showed 
that there was a statistically significant and clinically meaningful prolongation of PFS in the 
ixazomib + LenDex regimen compared to the placebo + LenDex regimen.  In the Japanese 
subpopulation, the consistency of the results of PFS between overall population and Japanese 
subpopulation was not denied.  However, it was proposed that an additional evaluation be 
necessary for the efficacy of ixazomib in Japanese RRMM patients. 
This study, therefore, was planned to evaluate the efficacy and safety of ixazomib when 
administered with LenDex in Japanese patients with RRMM.  The primary objective of this study 
is to determine the very good partial response (VGPR) or better  rate in response-evaluable 
analysis set. 
The study treatments in this study are identical to the ones in Study C16010. Patients will receive 
ixazomib 4.0 mg on Days 1, 8, and 15 plus lenalidomide (25 mg) on Days 1 through 21 and 
dexamethasone (40 mg) on Days 1, 8, 15, and 22 of a 28-day cycle.  The results of Study C16010 
showed that this combination regimen was effective in prolonging PFS and improving response to 
treatment, resulting in long-term benefit in patients with RRMM.  This combination regimen was 
also well tolerated, with clinically manageable TEAEs.   
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In Study TB-MC010034, a phase 1 study in Japan, it was shown that ixazomib at a dose of 4.0 mg 
as a single agent or in combination with LenDex was safe and tolerable in Japanese patients with 
RRMM. 
Based on the above results, the favorable benefit-risk profile of ixazomib at 4.0 mg in combination 
with LenDex supports the appropriateness of the selection of the doses and schedules of the 
combination therapy in patients with RRMM in this study. 
This study will be continued as a post-marketing clinical study after a marketing approval of 
ixazomib was obtained in Japan. In the study protocol, the term "study" will be replaced by 
"post-marketing clinical study" as appropriate. The details of changes in study procedures to be 
made after shifting to the post-marketing clinical study are found in Appendix I. 
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5.0 
STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Objectives 
5.1.1 Primary Objective 
• To determine VGPR or better (VGPR + CR) rate in response-evaluable analysis set* 
*Defined as patients who received at least one dose of ixazomib and had measurable disease at 
baseline, and at least one post baseline response assessment. 
5.1.2 Secondary Objectives 
• To determine progression-free survival (PFS) 
• To determine overall response rate (ORR) (partial response [PR] or better) 
• To determine duration of response (DOR) 
• To determine time to progression (TTP)  
• To determine safety 
• To determine overall survival (OS)  
5.2 
Endpoints 
5.2.1 Primary Endpoint 
• VGPR or better rate in response-evaluable analysis set 
5.2.2 Secondary Endpoints 
• PFS, defined as the time from the date of first study drug administration to the date of first 
documentation of PD or death from any cause, whichever occurs first 
• ORR 
• DOR, defined as the time from the date of first documentation of response to the date of first 
documentation of PD 
• TTP, defined as the time from the date of first study drug administration to the date of first 
documentation of PD 
• Safety including treatment-emergent adverse events (TEAEs), laboratory parameters, and vital 
signs 
• OS, defined as the time from the date of first study drug administration to the date of death 
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6.0 
STUDY DESIGN 
6.1 
Overview of Study Design 
This is a phase 2, open-label, single arm, multicenter study to evaluate the efficacy and safety of 
ixazomib plus lenalidomide and dexamethasone in Japanese patients with relapsed and/or 
refractory multiple myeloma (MM).  The patient population will consist of adult men and women 
who have a confirmed diagnosis of MM, who have received 1 to 3 prior lines of therapy, and who 
meet other outlined eligibility criteria (see Section 7.0).  Approximately 30 patients will be 
enrolled in the study. 
General eligibility criteria may be assessed prior to the formal Screening period if it is part of 
standard clinical practice.  However, per the Schedule of Events, formal screening will occur 
during the Screening period, which may last for up to 28 days prior to enrollment.  A Takeda 
clinician will confirm patient eligibility prior to enrollment.  Determination of disease progression 
as an entry criterion may be based on patient data obtained during or following the patient’s most 
recent prior antineoplastic therapy. 
Patients will receive study drug (ixazomib 4.0 mg) on Days 1, 8, and 15 plus lenalidomide (25 mg) 
on Days 1 through 21 and dexamethasone (40 mg) on Days 1, 8, 15, and 22 of a 28-day cycle.  
Patients may continue to receive treatment until progressive disease (PD) or unacceptable toxicity, 
whichever comes first.  Dose modifications may be made based on toxicities.  Patients with a low 
creatinine clearance < 60 mL/min will receive a reduced lenalidomide dose of 10 mg.  The 
lenalidomide dose may be escalated to 15 mg after 2 cycles if the patient is not responding to 
treatment and is tolerating the treatment.  If renal function normalizes (ie, creatinine clearance 
≥ 60 mL/min) and the patient continues to tolerate this treatment, lenalidomide may then be 
escalated to 25 mg. 
Patients will be seen at regular treatment cycle intervals while they are participating in the study:  
four times a treatment cycle for the first 2 cycles, twice a treatment cycle for the 3rd cycle, and then 
once a treatment cycle for the remainder of their participation in the active treatment and, if 
applicable, the PFS (every 4 weeks) and OS (every 12 weeks) follow-up phases of the study. 
Response will be assessed by investigator according to the IMWG criteria for all patients every 4 
weeks until PD. Central laboratory data will be used for serum M-protein, urine M-protein and 
serum free light chain.  All patients will be followed for survival after progression.  Patients will be 
contacted every 12 weeks until death or termination of the study by the sponsor. 
Patients will attend an End of Treatment (EOT) visit approximately 30 days after receiving their 
last dose of study treatment (ixazomib, lenalidomide or dexamethasone) and will continue to be 
followed for other follow-up assessments specified in the Schedule of Events.  Patients 
discontinuing study treatment prior to PD will continue to be assessed for PD during the PFS 
follow-up portion of the study. 
Analysis is planned to be performed twice during the study. The primary analysis is planned to be 
performed using the data obtained at approximately 12 months from the enrollment of the last 
patient.  The final analysis is planned to be performed after the final database lock using the data 
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obtained at approximately 24 months from the enrollment of the last patient.  The timing of 
analysis may be changed or additional analysis may be added upon request of the regulatory 
authorities. See Section 13.0 for the details. 
6.2 
Number of Patients 
Approximately 30 patients will be enrolled in this study from approximately 20 study sites. 
6.3 
Duration of Study 
6.3.1 Duration of an Individual Patient’s Study Participation 
Patients may remain on treatment until the occurrence of PD or unacceptable toxicity.  The 
maximum treatment period will be 24 months after the last patient is enrolled. Patients who stop 
treatment for any reason other than PD will continue in PFS follow-up and be seen every 4 weeks 
until documented PD.  After PD, all patients will continue to the OS follow-up phase and be 
contacted every 12 weeks until death or until the sponsor terminates the study. 
Refer to Section 10.3 for adverse event monitoring period after the last dose of the study treatment. 
6.3.2 End of Study 
The final analysis is planned to be performed using the data obtained at approximately 24 months 
from the enrollment of the last patient.  The study will be closed at 24 months from the enrollment 
of the last patient, and all the patients will be off study treatment.  After that, the patients may be 
treated with the available drugs at investigator discretion outside of the study. The sponsor will not 
supply study drug beyond the time period. 
6.3.3 Total Study Duration 
The duration of the study will be approximately 30 months, including 6 months for the enrollment 
period, 24 months from the enrollment of the last patient for the treatment and follow-up period. 
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7.0 
STUDY POPULATION 
7.1 
Inclusion Criteria 
Each patient must meet all of the following inclusion criteria to be enrolled in the study: 
1. Male or female Japanese patients 20 years of age or older. 
2. Multiple myeloma diagnosed according to standard criteria either currently or at the time of 
initial diagnosis (See Appendix E for the standard criteria) 
NOTE:  The initial diagnosis must be symptomatic MM, although the relapsed disease does not 
need to be symptomatic. 
3. Patients must have measurable disease defined by at least 1 of the following 3 measurements 
based on central laboratory data: 
Serum M-protein:  ≥1 g/dL (≥ 10 g/L). 
Urine M-protein:  ≥200 mg/24 hours. 
Serum free light chain assay:  involved free light chain level ≥10 mg/dL (≥ 100 mg/L), provided 
that the serum free light chain ratio is abnormal. 
4. Patients with RRMM who have received 1 to 3 prior therapies. 
NOTE:  This patient population includes the following 3 categories of patients: 
Patients who relapsed from their therapy(s) but were not refractory to any previous therapy. 
Patients who were refractory to all lines of previous therapy(s) (ie, patients who have never 
responded to any therapies received). 
Patients who were relapsed from at least 1 line of therapy AND additionally were refractory to at 
least 1 line of therapy. For the purposes of this study, refractory MM is defined as PD on therapy or 
PD within 60 days after the last dose of a given therapy. 
A line of therapy is defined as 1 or more cycles of a planned treatment program.  This may consist 
of 1 or more planned cycles of single-agent therapy or combination therapy, as well as a sequence 
of treatments administered in a planned manner.  For example, a planned treatment approach of 
induction therapy followed by autologous stem cell transplantation, followed by maintenance is 
considered 1 line of therapy. [16]  Autologous and allogenic transplants are permitted. 
5. Patients must meet the following clinical laboratory criteria: 
Absolute neutrophil count (ANC) ≥ 1,000/mm3, hemoglobin ≥ 8 g/dL and platelet 
count ≥ 75,000/mm3.  Platelet transfusions to help patients meet eligibility criteria are not allowed 
within 3 days prior to screening. 
Total bilirubin ≤ 1.5 x the upper limit of the normal range (ULN). 
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN. 
Calculated creatinine clearance ≥ 30 mL/min. 
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6. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. 
7. Patients who received prior allogenic transplant must have no active graft-versus-host disease 
(GVHD). 
8. Patients who meet the following conditions: 
Female patients who: 
Are postmenopausal for at least 24 months before the screening visit, OR 
Are surgically sterile, OR 
Females of childbearing potential must (see Section 8.5 for definition): 
1) Have a negative pregnancy test with a sensitivity of at least 25 mIU/mL within 10 to 14 
days and again within 24 hours prior to starting Cycle 1 of lenalidomide 
2) Agree to practice true abstinence or to begin TWO reliable methods of birth control (1 
highly effective method and 1 additional effective method AT THE SAME TIME) for at 
least 28 days before starting study treatment through 90 days after the last dose of study 
treatment. 
3) Agree to ongoing pregnancy testing 
4) Adhere to the guidelines of the RevMate program 
Male patients, even if surgically sterilized (ie, status postvasectomy), must: 
Agree to avoid sexual intercourse completely 90 days after the last dose of study treatment. 
Agree to practice true abstinence or to practice effective barrier contraception during the entire 
study treatment period and 90 days after the last dose of study treatment if their partner is of 
childbearing potential, even if they have had a successful vasectomy, AND 
Adhere to the guidelines of the RevMate program 
9. Thromboembolism prophylaxis is required based on published standard or institutional 
standard of care. 
10. Voluntary written consent must be given before performance of any study-related procedure 
not part of standard medical care, with the understanding that consent may be withdrawn by 
the patient at any time without prejudice to future medical care. 
11. Patient is willing and able to adhere to the study visit schedule and other protocol 
requirements. 
7.2 
Exclusion Criteria 
Patients meeting any of the following exclusion criteria are not to be enrolled in the study: 
1. Patients who were refractory to lenalidomide or proteasome inhibitor-based therapy at any 
line. 
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NOTE:  Refractory disease is defined as PD on treatment or PD within 60 days after the last dose 
of a given therapy.  Patients who progressed the disease after 60 days from the last dose of a given 
therapy will be considered relapsed and are eligible for inclusion in the study. 
Patients who were refractory to thalidomide-based therapy are eligible. 
2. Female patients who are breast feeding or pregnant. 
3. Failure to have fully recovered (ie, ≤ Grade 1 toxicity) from the effects of prior chemotherapy 
(except for hair loss) regardless of the interval since last treatment. 
4. Major surgery within 14 days before enrollment. 
5. Radiotherapy within 14 days before enrollment. 
6. Central nervous system involvement. 
7. Infection requiring systemic antibiotic therapy or other serious infection within 14 days before 
enrollment. 
8. Rash or pruritus requiring systemic medication within 14 days before enrollment. 
9. Diagnosis of Waldenstrom’s macroglobulinemia, POEMS (polyneuropathy, organomegaly, 
endocrinopathy, monoclonal gammopathy, and skin changes) syndrome, plasma cell leukemia, 
primary amyloidosis, myelodysplastic syndrome, or myeloproliferative syndrome. 
10. Evidence of current uncontrolled cardiovascular conditions, including uncontrolled 
hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, 
unstable angina, or myocardial infarction within the past 6 months before enrollment. 
11. Systemic treatment with strong CYP3A inducers (rifampicin, carbamazepine, phenytoin), or 
St. John’s wort within 14 days before enrollment. 
12. Ongoing or active systemic infection, known human immunodeficiency virus (HIV) positive, 
known hepatitis B surface antigen seropositive or known hepatitis C virus (HCV)-RNA 
positive. 
NOTE: Patients who have positive hepatitis B core antibody (HBcAb) can be enrolled but must 
have hepatitis B virus (HBV)-DNA negative.  Patients who have positive hepatitis C antibody can 
be enrolled but must have HCV-RNA negative.  
13. Comorbid systemic illnesses or other severe concurrent disease which, in the judgment of the 
investigator, would make the patient inappropriate for entry into this study or interfere 
significantly with the proper assessment of safety and toxicity of  the prescribed regimens (eg, 
peripheral neuropathy that is Grade 1 with pain or Grade 2 or higher of any cause). 
14. Psychiatric illness/social situation that would limit compliance with study requirements. 
15. Known allergy to any of the study medications, their analogues, or excipients in the various 
formulations of any agent. 
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16. Inability to swallow oral medication, inability or unwillingness to comply with the drug 
administration requirements, or gastrointestinal condition that could interfere with the oral 
absorption or tolerance of treatment. 
17. Diagnosed or treated for another malignancy within 2 years before enrollment or previously 
diagnosed with another malignancy and have any evidence of residual disease.  Patients with 
nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have 
undergone complete resection. 
18. Patients who have participated in the clinical trial of ixazomib, or have been treated with 
ixazomib. 
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8.0 
STUDY DRUG 
8.1 
Study Treatment Administration 
All protocol-specific criteria for administration of study treatment must be met and documented 
prior to drug administration.  Study treatment will be administered only to eligible patients under 
the supervision of the investigator or identified subinvestigator(s).  Patients should be monitored 
for toxicity and doses of the appropriate treatment drug or study treatment should be modified as 
needed to accommodate patient tolerance to treatment; this may include symptomatic treatment, 
dose interruptions, and adjustments of dose. 
All doses must be taken as outlined in the Schedule of Events.  Eligible patients may take study 
treatment at home as directed. 
8.1.1 Ixazomib: Study Drug 
Study drug will be supplied as single capsules at 3 different dose strengths, containing 4.0, 3.0, and 
2.3 mg of ixazomib.  Ixazomib capsules will be provided by the sponsor. 
Ixazomib will be given as a single, oral dose of 4.0 mg weekly (Days 1, 8, and 15) for 3 weeks on, 
followed by 1 week off in a 28-day cycle.  Ixazomib should be taken on an empty stomach, at least 
1 hour before or no sooner than 2 hours after food.  A total of approximately 240 mL of water 
should be taken with the capsules.  Patients should be instructed to swallow ixazomib capsules 
whole with water and not to break, chew, or open the capsules. 
Missed doses can be taken as soon as the patient remembers as long as the next scheduled dose is 
72 hours or more away.  A double dose should not be taken to make up for a missed dose.  If the 
patient vomits after taking a dose, the patient should not repeat the dose but should resume dosing 
at the time of the next scheduled dose. 
Patients who take more than the prescribed dose of ixazomib should be instructed to seek 
emergency medical care if needed and contact study staff immediately. 
8.1.2 Lenalidomide: Concomitant Study Therapy 
Lenalidomide will be given as a single, daily oral dose of 25 mg for 21 days (Days 1 through 21) in 
a 28-day cycle.  Patients with a low creatinine clearance < 60 mL/min will receive a reduced 
lenalidomide dose of 10 mg once daily.  The lenalidomide dose may be escalated to 15 mg once 
daily after 2 cycles if the patient is not responding to treatment and is tolerating the treatment.  If 
renal function normalizes (ie, creatinine clearance ≥ 60 mL/min) and the patient continues to 
tolerate this treatment, lenalidomide may then be escalated to 25 mg once daily. 
Administration of lenalidomide will be at approximately the same time each day.  Patients should 
be instructed to swallow lenalidomide capsules whole with or without food and not to break, chew, 
or open the capsules. 
If a dose of lenalidomide is missed, it should be taken as soon as possible on the same day.  If it is 
missed for the entire day, it should not be made up. 
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If the patient vomits after taking a dose, the patient should not repeat the dose but should resume 
dosing at the time of the next scheduled dose. 
Patients who take more than the prescribed dose of lenalidomide should be instructed to seek 
emergency medical care if needed and contact study staff immediately. 
8.1.3 Dexamethasone: Concomitant Study Therapy 
Dexamethasone will be given as an oral dose of 40 mg/day weekly on Days 1, 8, 15, and 22 in a 
28-day cycle. 
Dexamethasone should be taken at approximately the same time preferably with food/milk to 
avoid stomach irritation.  If a dose of dexamethasone was missed, the dose should be taken as soon 
as the patient remembers it.  If enough time has elapsed that it is almost time for the next dose 
(within 6 hours), the missed dose should be skipped and the next dose is to be taken according to 
the regular dosing schedule.  A double dose should not be taken to make up for a missed dose.  If 
the patient vomits after taking a dose, the patient should not repeat the dose but should resume 
dosing at the time of the next scheduled dose. 
Patients who take more than the prescribed dose of dexamethasone should be instructed to seek 
emergency medical care if needed and contact study staff immediately. 
8.2 
Dose Modification Guidelines 
Toxicities are to be assessed according to the NCI Common Terminology Criteria for Adverse 
Events (CTCAE), version 4.03 (effective on 14 June 2010) [17].  Each adverse event should be 
attributed to a specific drug, if possible, so that the dose modifications can be made accordingly. 
Only 1 dose adjustment per cycle will be performed for a given agent when toxicity is suspected to 
be related primarily to that agent. Reduction of 1 agent and not the other is appropriate if the 
toxicity is suspected to be related primarily to 1 of the agents, however, dose reduction of multiple 
agents may be considered after consultation with Takeda clinician. Guidelines for dose 
modification within cycles are provided in Sections 8.2.1 through 8.2.5. Prior to beginning the next 
cycle of treatment, refer to the guidelines in Section 8.2.6. Further clarification can be obtained in 
consultation with Takeda clinician. If multiple toxicities are noted, the dose adjustments and/or 
delays should be made according to the most severe toxicity guidelines. 
Alternative dose modifications may be recommended in order to maximize exposure of study 
treatment while protecting patient safety. It is also recommended that the investigator consult with 
the Takeda clinician before the dose modifications, if possible. 
Dose reduction steps for ixazomib, lenalidomide, and dexamethasone are described in Table 8.a, 
Table 8.b, and Table 8.c, respectively. 
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Table 8.a 
Dose Reduction Steps for Ixazomib 
Starting Dose 
First Dose Reduction 
Second Dose Reduction 
Third Dose Reduction 
4.0 mg 
3.0 mg 
2.3 mg 
Discontinue 
 
Table 8.b 
Dose Reduction Steps for Lenalidomide 
Starting Dosea 
First Dose Reduction 
Second Dose Reduction 
Third Dose Reduction 
25 mg 
15 mg 
10 mg 
5 mg 
a  Patients with renal dysfunction (creatinine clearance < 60 mL/min) will receive lenalidomide from the starting dose 
of 10 mg, first dose reduction of 5 mg, and discontinued at the second dose reduction. 
Table 8.c 
Dose Reduction Steps for Dexamethasone 
Starting Dose 
First Dose Reduction 
Second Dose Reduction 
Third Dose Reduction 
40 mg 
20 mg 
8 mg 
Discontinue 
 
8.2.1 Dose Adjustments for Rash:  Ixazomib and Lenalidomide 
Ixazomib or lenalidomide dose adjustments for rash will be presented as follows: 
• Occurrence of Grade 2 rash 
Supportive care and prophylaxis are recommended (see Section 8.6.5). 
 Occurrence or recurrence of Grade 2 rash manageable by supportive care 
 Continues ixazomib and lenalidomide at the same dose with supportive care including 
prophylaxis.  
 If becomes not manageable, see below. 
 Occurrence of Grade 2 rash which is not manageable by supportive care 
 Withhold ixazomib and lenalidomide until rash recovers to ≤ Grade 1. Following 
recovery within the same cycle (including potential delay for next cycle), resume 
ixazomib and lenalidomide at the same dose.  In recurrence, reduce the drug according to 
Table 8.d  
• Occurrence or recurrence of Grade 3 rash 
 Supportive care and prophylaxis are recommended. Reduce the drug according to Table 8.d. 
 
In this study, "events manageable by supportive care" means the ones for which symptomatic 
treatment allows for continued study treatment without dose interruptions or reductions, while 
"events not manageable by supportive care" means the ones that cannot be managed only by 
supportive care, and require dose interruptions or reductions. 
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In severe situations, alternative dose modification may be made as needed.  Angioedema and 
Grade 4 rash have been reported after the use of lenalidomide, and in such case, lenalidomide 
should be discontinued [18].  Refer to Table 8.h for dose modification of lenalidomide if 
angioedema, Stevens-Johnson syndrome, or toxic epidermal necrolysis (TEN) is observed. 
Table 8.d 
Dose Reduction Steps for Ixazomib and Lenalidomide for Rash 
Reduction 
Action on Ixazomib and Lenalidomide 
Example of Dose Reduction 
Dose of 
Ixazomib 
Dose of Lenalidomidea 
1st reduction 
Withhold ixazomib and lenalidomide until rash recovers 
to ≤ Grade 1.  When recovery within the same cycle, 
resume ixazomib at the next lower dose and 
lenalidomide at the same dose. 
3.0 mg 
25 mg (10 mg) 
2nd reduction 
Withhold ixazomib and lenalidomide until rash recovers 
to ≤ Grade 1.  When recovery within the same cycle, 
resume ixazomib at the same dose and lenalidomide at 
the next lower dose. 
3.0 mg 
15 mg (5 mg) 
3rd reduction 
Withhold ixazomib and lenalidomide until rash recovers 
to ≤ Grade 1.  When recovery within the same cycle, 
resume ixazomib at the next lower dose and 
lenalidomide at the same dose. 
2.3 mg 
15 mg (5 mg) 
4th reduction 
Withhold ixazomib and lenalidomide until rash recovers 
to ≤ Grade 1.  When recovery within the same cycle, 
resume ixazomib at the same dose and lenalidomide at 
the next lower dose. 
2.3 mg 
10 mg (discontinue) 
a  Dose of lenalidomide in a parenthesis is for patients with renal dysfunction (creatinine clearance < 60 mL/min)  
8.2.2 Dose Adjustments for Hematologic Toxicity:  Ixazomib and Lenalidomide 
A decision regarding which study treatment requires dose reduction will be dependent upon the 
toxicity, its onset, and time course. Ixazomib or lenalidomide will be adjusted according to each 
criterion on the occurrence of:  thrombocytopenia (refer to Table 8.e), or neutropenia (refer to 
Table 8.f). When dose reduction is required, the reduction steps for ixazomib and lenalidomide are 
described in Table 8.a and Table 8.b, respectively. 
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Table 8.e 
Ixazomib and Lenalidomide Dose Adjustment for Thrombocytopenia 
Platelet Count 
Action on Ixazomib 
Action on Lenalidomide 
Action 
First fall to < 30,000/mm3 
Interrupt treatment 
Interrupt treatment 
Follow complete blood 
count (CBC) weekly 
Return to ≥ 30,000/mm3 
within the same cycle 
Resume and maintain 
dose level  
Resume at next lower 
dose level 
Eg, if lenalidomide dose was 
25 mg, reduce to 15 mg 
Second fall to < 30,000/mm3 
Interrupt treatment 
Interrupt treatment 
Follow CBC weekly 
Return to ≥ 30,000/mm3 
within the same cycle 
Resume at next lower 
dose level 
Resume and maintain 
dose level 
Eg, if ixazomib dose was 
4 mg, reduce to 3 mg 
Third fall to < 30,000/mm3 
Interrupt treatment 
Interrupt treatment 
Follow CBC weekly 
Return to ≥ 30,000/mm3 
within the same cycle 
Resume and maintain 
dose level 
Resume at next lower 
dose level 
Eg, if lenalidomide dose was 
15 mg, reduce to 10 mg 
Fourth fall to < 30,000/mm3 
Interrupt treatment 
Interrupt treatment 
Follow CBC weekly 
Return to ≥ 30,000/mm3 
within the same cycle 
Resume at next lower 
dose level 
Resume and maintain 
dose level 
Eg, if ixazomib dose was 
3 mg, reduce to 2.3 mg 
Do not reduce below 2.3 mg 
Fifth fall to < 30,000/mm3 
Interrupt treatment 
Interrupt treatment 
Follow CBC weekly 
Return to ≥ 30,000/mm3 
within the same cycle 
Resume and maintain 
dose level 
Resume at next lower 
dose level 
Eg, if lenalidomide dose was 
10 mg, reduce to 5 mg 
Do not reduce below 5 mg 
 
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Table 8.f 
Ixazomib and Lenalidomide Dose Adjustment for Neutropenia 
Absolute Neutrophil Count 
Action on Ixazomib 
Action on 
Lenalidomide 
Action 
First fall to < 500/mm3 
Interrupt treatment 
Interrupt treatment 
Follow CBC weekly; see Section 
8.4 for myeloid growth factor 
recommendations 
Return to ≥ 500/mm3 within 
the same cycle 
Resume and maintain 
dose level 
Resume at next lower 
dose level 
Eg, if lenalidomide dose was 
25 mg, reduce to 15 mg 
Second fall to < 500/mm3 
Interrupt treatment 
Interrupt treatment 
Follow CBC weekly; see Section 
8.4 for myeloid growth factor 
recommendations 
Return to ≥ 500/mm3 within 
the same cycle 
Resume at next lower 
dose level 
Resume and 
maintain dose level 
Eg, if ixazomib dose was 4 mg, 
reduce to 3 mg 
Third fall to < 500/mm3 
Interrupt treatment 
Interrupt treatment 
Follow CBC weekly; see Section 
8.4 for myeloid growth factor 
recommendations 
Return to ≥ 500/mm3 within 
the same cycle 
Resume and maintain 
dose level 
Resume at next lower 
dose level 
Eg, if lenalidomide dose was 
15 mg, reduce to 10 mg 
Fourth fall to < 500/mm3 
Interrupt treatment 
Interrupt treatment 
Follow CBC weekly; see Section 
8.4 for myeloid growth factor 
recommendations 
Return to ≥ 500/mm3 within 
the same cycle 
Resume at next lower 
dose level 
Resume and 
maintain dose level 
Eg, if ixazomib dose was 3 mg, 
reduce to 2.3 mg 
Do not reduce below 2.3 mg 
Fifth fall to < 500/mm3 
Interrupt treatment 
Interrupt treatment 
Follow CBC weekly; see Section 
8.4 for myeloid growth factor 
recommendations 
Return to ≥ 500/mm3 within 
the same cycle 
Resume and maintain 
dose level 
Resume at next lower 
dose level 
Eg, if lenalidomide dose was 
10 mg, reduce to 5 mg 
Do not reduce below 5 mg 
 
8.2.3 Ixazomib Treatment Modification 
Dose modification of ixazomib is allowed based on clinical and laboratory findings.  Treatment 
modifications due to ixazomib-related AEs are outlined in Table 8.g.  Sequential dose reductions 
of ixazomib from the starting dose of 4.0 mg once daily are recommended depending on toxicity as 
indicated in Table 8.a. 
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Table 8.g 
Ixazomib Treatment Modification (Delays, Reductions, and Discontinuations) 
Due to Adverse Events 
Adverse Event (Severity) 
Action on Ixazomib 
Further Considerations 
Grade 1 peripheral neuropathy  
No action 
Grade 1 signs & symptoms:  
asymptomatic, without pain or loss of 
function, clinical or diagnostic 
observations only 
Grade 1 peripheral neuropathy with 
pain or Grade 2 
Hold ixazomib until resolution to 
Grade ≤ 1 or baseline 
After resolution, resume ixazomib 
and maintain dose level 
Grade 2 signs & symptoms:  
moderate symptoms, limiting 
instrumental activities of daily living 
(ADL)  
Grade 2 peripheral neuropathy with 
pain or Grade 3 
Hold ixazomib until resolution to 
Grade ≤ 1 or baseline 
Reduce ixazomib to next lower dose 
upon recovery 
Grade 3 signs & symptoms:  severe 
symptoms, limiting self care ADL, 
assistive device indicated 
Grade 4 peripheral neuropathy 
Discontinue ixazomib 
 
Grade 3 nonhematologic toxicity 
judged to be related to ixazomib 
Hold ixazomib until resolution to 
Grade ≤ 1 or baseline   
Symptomatic recommendations 
noted in Section 8.6 
If does not recover to ≤ Grade 1 or 
baseline within 4 weeks 
(including recurrence) 
Reduce ixazomib to next lower dose 
upon return to ≤ Grade 1 or baseline 
Monitor closely (especially at the 
time of recurrence), take appropriate 
medical precautions, and provide 
appropriate symptomatic care 
Grade 4 nonhematologic toxicities 
judged to be related to ixazomib 
Consider permanently discontinuing 
ixazomib 
Exception, in a case where the 
investigator determines the patient is 
obtaining a clinical benefit and has 
discussed this with the Takeda 
clinician 
 
8.2.4 Lenalidomide Treatment Modification 
Dose modification of lenalidomide is allowed based on clinical and laboratory findings.  
Treatment modifications due to lenalidomide-related AEs are outlined in Table 8.h.  Sequential 
dose reductions of lenalidomide from the starting dose of 25 mg daily (10 mg daily for patients 
with renal dysfunction) are recommended depending on toxicity as indicated in Table 8.b. 
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Table 8.h 
Lenalidomide Treatment Modification (Delays, Reductions, and 
Discontinuations) Due to Non-Hematologic Adverse Events 
Adverse Event (Severity) 
Action on Lenalidomide [18] 
Further Considerations 
Grade 3/4 toxicities judged to be 
related to lenalidomide 
Hold lenalidomide treatment, and 
restart at the next lower dose level 
when toxicity has resolved to 
≤ Grade 2 
Do not reduce below 5 mg daily 
Renal dysfunction 
Dose reduce per lenalidomide 
package insert for impaired renal 
function 
Care should be taken in dose 
selection/modification in the elderly 
as they are more likely to have 
decreased renal function. Monitor 
renal function regularly 
≥ Grade 2 thrombosis/embolism 
Hold lenalidomide and start 
anticoagulation therapy; restart at 
investigator’s discretion after 
adequate anticoagulation; maintain 
dose level 
See Section 8.6.2 for anticoagulation 
recommendations 
Angioedema, Stevens-Johnson 
Syndrome, and Toxic Epidermal 
Necrolysis (TEN) 
Permanently discontinue 
lenalidomide per package insert 
 
Grade 4 exfoliative or bullous rash  
Permanently discontinue 
lenalidomide per package insert 
 
Tumor lysis syndrome 
Dose modify as per lenalidomide 
package insert 
Monitor closely and take appropriate 
medical precautions 
 
8.2.5 Dexamethasone Treatment Modification 
Dose modification of dexamethasone is allowed based on clinical and laboratory findings.  
Treatment modifications due to dexamethasone-related AEs are outlined in Table 8.i.  Sequential 
dose reductions of dexamethasone from the starting dose of 40 mg once daily are recommended 
depending on toxicity as indicated in Table 8.c. 
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Table 8.i 
Dexamethasone Treatment Modification (Delays, Reductions, and 
Discontinuations) Due to Adverse Events 
Adverse Event (Severity) 
Action on Dexamethasone [19] 
Gastrointestinal 
disorder 
Dyspepsia, gastric, or duodenal ulcer, 
gastritis Grade 1-2 (requiring medical 
management) 
Treat with histamine-2 blockers, sucralfate, or 
omeprazole.  If symptoms persist despite these 
measures, decrease dexamethasone by 1 dose 
level. 
Dyspepsia, gastric, or duodenal ulcer, 
gastritis ≥ Grade 3 (requiring hospitalization 
or surgery) 
Hold dexamethasone until symptoms 
adequately controlled.  Restart and decrease 1 
dose level of current dose along with 
concurrent therapy with histamine-2 blockers, 
sucralfate, or omeprazole.  If symptoms persist 
despite these measures, discontinue 
dexamethasone and do not resume. 
Acute pancreatitis 
Discontinue dexamethasone and do not 
resume. 
Cardiovascular 
disorder 
Edema ≥ Grade 3 (limiting function and 
unresponsive to therapy or anasarca) 
Diuretics as needed and decrease 
dexamethasone by 1 dose level.  If edema 
persists despite these measures, decrease dose 
another level.  Discontinue dexamethasone 
and do not resume if symptoms persist despite 
second reduction. 
Neurological 
disorder 
Confusion or mood alteration ≥ Grade 3 
Hold dexamethasone until symptoms resolve.  
After the symptoms resolved, restart with 1 
dose level reduction.  If symptoms persist 
despite these measures, discontinue 
dexamethasone and do not resume. 
Musculoskeletal 
disorder 
Muscle weakness ≥ Grade 3 (interfering with 
function ± interfering with activities of daily 
living) 
Decrease dexamethasone dose by 1 dose level.  
If weakness persists despite these measures, 
decrease dose by 1 dose level.  Discontinue 
dexamethasone and do not resume if 
symptoms persist despite second reduction. 
Metabolic disorder 
Hyperglycemia ≥ Grade 3  
Treatment with insulin or oral hypoglycemics 
as needed.  If uncontrolled despite these 
measures, decrease dexamethasone dose by 
1 dose level until levels are satisfactory. 
 
8.2.6 Criteria for Toxicity Recovery Before Beginning the Next Cycle of Treatment 
The criteria for toxicity recovery before the patient can begin the next cycle of treatment are as 
follows: 
• ANC ≥ 1,000/mm3 
• platelet count ≥ 75,000/mm3 
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• other clinically significant nonhematologic toxicities ≤ Grade 1 or to the patient’s baseline 
condition. 
If a patient fails to meet the criteria above for beginning the next cycle of treatment, initiation of 
the next cycle should be delayed for 1 week.  At the end of that time, the patient should be 
re-evaluated to determine whether the criteria for retreatment have been met. 
If the beginning the next cycle of treatment are delayed more than 2 weeks, resume the study 
treatment at the next lower dose level (decide which agent will be reduced based on attribution or 
previous reductions).  In the case of the occurrence of rash, see Section 8.2.1 for dose adjustment 
of ixazomib and lenalidomide. The maximum delay before treatment should be discontinued 
(except in the case of investigator determined clinical benefit and discussion with the Takeda 
clinician) will be 3 weeks. 
If the patient does not recover completely from the treatment-related toxicity, see Sections 8.2.1 to 
8.2.5 for recommended dose reduction. 
8.3 
Excluded Concomitant Medications and Procedures 
The following medications are prohibited during the study: 
• Systemic treatment with any of the following drug metabolizing enzyme inducers is not 
permitted in this study. (Rationale:  If there were to be a drug-drug interaction with an inducer, 
the ixazomib exposure may be decreased.) 
Strong CYP3A inducers:  rifampin, carbamazepine, phenytoin 
• Excluded food products include St. John’s wort. 
The following procedures are prohibited during the study: 
• Any antineoplastic treatment with activity against MM, other than study treatment. 
• Radiation therapy (note that, in general, the requirement for local radiation therapy indicates 
PD).  Palliative radiotherapy for pain control in a preexisting lesion may be considered after 
discussion with the Takeda clinician. 
• Platelet transfusion to help patients meet eligibility criteria is not allowed within 3 days prior to 
study drug dosing. 
8.4 
Permitted Concomitant Medications and Procedures 
All necessary supportive care decided by investigator or identified subinvestigator(s) will be 
available to patients.  All blood products, concomitant medications and therapies administered 
from first dose of study treatment through 30 days after last dose of study treatment or initiation of 
the subsequent antineoplastic therapies whichever comes first will be recorded in the CRFs. 
The following medications and procedures are permitted during the study: 
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• Myeloid growth factors (eg, granulocyte colony stimulating factor [G-CSF]) are permitted.  
Their use should follow published guidelines and/or institutional practice; however, alternative 
usage may be reviewed with the Takeda clinician or study clinician designee. 
• Erythropoietin will be allowed in this study, but has an increased risk of deep vein thrombosis 
when administered with lenalidomide, and has not been approved for the treatment of anemia 
as a malignant disease in Japan.  Therefore, the use of erythropoietin should be minimized as 
much as possible. 
• Patients could be transfused with red blood cells and platelets as clinically indicated. 
• When digoxin was co-administered with lenalidomide, the digoxin plasma level  was increased 
[20].  Periodic monitoring of digoxin plasma levels in accordance with clinical judgment and 
based on standard clinical practice in patients receiving this medication is recommended 
during administration of lenalidomide. 
• Concomitant treatment with bisphosphonates will be permitted. 
• Supportive measures consistent with optimal patient care may be given throughout the study. 
8.5 
Precautions and Restrictions 
Nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided with impaired renal function 
given reported NSAID-induced renal failure in patients with decreased renal function. 
It is not known what effects ixazomib has on human pregnancy or development of the embryo or 
fetus.  Lenalidomide is structurally related to thalidomide.  Thalidomide is a known human 
teratogenic active substance that causes severe life-threatening birth defects.  Therefore, female 
patients participating in this study should avoid becoming pregnant, and male patients should 
avoid impregnating a female partner.  Female patients of childbearing potential (FCBP) and male 
patients should use effective methods of contraception through defined periods during and after 
study treatment as specified below.  FCBP is a female who:  1) has not undergone a hysterectomy 
or bilateral oophorectomy or 2) has not been naturally postmenopausal (amenorrhea following 
chemotherapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has 
not had menses at any time during the preceding 24 consecutive months). 
Any female patients of childbearing potential must either: 
• Agree to practice true abstinence for at least 28 days before starting study treatment through 90 
days after the last dose of study treatment, OR 
• Agree to practice 2 reliable methods of contraception, for at least 28 days before starting study 
treatment through 90 days after the last dose of study treatment 
• The 2 methods of reliable contraception must include 1 highly effective method and 
1 additional effective (barrier) method. The following are examples of highly effective and 
additional effective methods of contraception: 
Highly effective methods: 
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Intrauterine device (IUD) 
Hormonal (birth control pills, injections, implants) 
Tubal ligation 
Partner’s vasectomy 
Additional effective methods: 
Condom 
Diaphragm 
Cervical Cap 
• Must also adhere to RevMate program 
Male patients, even if surgically sterilized (ie, status postvasectomy), must: 
• Agree to practice true abstinence during the entire study treatment period and through 90 days 
after the last dose of study treatment, OR 
• Agree to use effective barrier contraception during the entire study treatment period and 
through 90 days after the last dose of study treatment if their partner is of childbearing potential, 
even if they have had a successful vasectomy, AND 
• Must also adhere to RevMate program 
8.6 
Management of Clinical Events 
8.6.1 Prophylaxis Against Risk of Reactivation of Herpes Infection 
Patients may be at an increased risk of opportunistic infection including reactivation of herpes 
zoster and herpes simplex viruses. Antiviral therapy such as acyclovir or valacyclovir should be 
considered. 
8.6.2 Thromboembolism Prophylaxis 
While on lenalidomide, patients should be on routine thromboprophylaxis [21].  Prophylactic 
therapy per published standard or institutional standard of care is required for all patients to 
prevent thromboembolic complications that may occur with lenalidomide-based regimens in 
combination with dexamethasone. 
8.6.3 Nausea and/or Vomiting 
Standard anti-emetics including 5-hydroxytryptamine 3 serotonin receptor (5-HT3) antagonists 
are recommended for emesis if it occurs once treatment is initiated; prophylactic anti-emetics may 
also be considered at the physician’s discretion.  Dexamethasone should not be administered as an 
anti emetic.  Fluid deficit should be corrected before initiation of study treatment and during 
treatment. 
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8.6.4 Diarrhea 
Prophylactic antidiarrheals will not be used in this protocol.  However, diarrhea should be 
managed according to clinical practice, including the administration of antidiarrheals once 
infectious causes are excluded.  Fluid intake should be maintained to avoid dehydration.  Fluid 
deficit should be corrected before initiation of treatment and during treatment. 
8.6.5 Erythematous Rash With or Without Pruritus 
Rash has been reported with both lenalidomide and ixazomib.  The lenalidomide-induced rash is 
characterized as generalized, maculopapular, morbilliform, urticarial, papular, often with pruritus.  
Serious skin reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, and 
erythema multiforme have been reported [18][22][23].  Lenalidomide interruption or 
discontinuation should be considered as described in the package insert and Section 8.2. 
Rash with ixazomib may range from limited erythematous areas, macular and/or small papular 
bumps that may or may not be pruritic over a few areas of the body, to a more generalized eruption 
that is predominately on the trunk or extremities.  Rash has been most commonly characterized as 
maculopapular or macular. 
To date, in the clinical studies of ixazomib (single dose or combination with other cancer 
therapies), rash is most commonly reported within the first 3 cycles of therapy.  The rash is often 
transient and self-limiting and is typically Grade 1 to 2 in severity. If rash occurs, consideration 
should be given to alternate causes of the rash such as concomitant medications, infections, etc. 
Symptomatic measures such as antihistamines or corticosteroids (oral or topical) have been 
successfully used to manage rash and have been used prophylactically in subsequent cycles.  The 
use of a topical, intravenous (IV), or oral steroid (eg, prednisone ≤ 10 mg per day or equivalent) is 
permitted.  Management of a Grade 3 rash may require IV antihistamines or corticosteroids.  
Administration of ixazomib (and/or other causative agent if given in combination) should be 
modified per protocol and reinitiated at a reduced level from where rash was noted (also per 
protocol). 
In line with clinical practice, dermatology consult and biopsy of Grade 3 or higher rash or any SAE 
involving rash is recommended at the discretion of the investigator.  Prophylactic measures should 
also be considered if a patient has previously developed a rash (eg, using a thick, alcohol-free 
emollient cream on dry areas of the body or oral or topical antihistamines).  
The rare risks of Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), drug reaction with 
eosinophilia and systemic symptoms (DRESS syndrome), and pemphigus vulgaris have been 
reported in oncology studies when ixazomib (or placebo) was given with concomitant medications 
that are known to cause rash (eg, Bactrim, lenalidomide, aspirin), and/or in the setting of 
confounding TEAEs.  These severe, potentially life-threatening or deadly conditions may involve 
rash with skin peeling and mouth sores and should be clinically managed according to standard 
medical practice.  Additional information regarding these reactions can be found in the IB. 
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8.6.6 Thrombocytopenia 
Blood counts should be monitored regularly as outlined in the protocol with additional testing 
obtained according to standard clinical practice.  Thrombocytopenia may be severe but has been 
manageable with platelet transfusions according to standard clinical practice.  Ixazomib or 
lenalidomide administration should be modified as per dose modification recommendations in the 
protocol when thrombocytopenia occurs (see Table 8.e).  Therapy can be reinitiated at a reduced 
level upon recovery of platelet counts.  A rare risk is thrombotic thrombocytopenic purpura, a rare 
blood disorder where blood clots form in small blood vessels throughout the body characterized by 
thrombocytopenia, petechiae, fever, or possibly more serious signs and symptoms.  Thrombotic 
thrombocytopenic purpura should be managed symptomatically according to standard medical 
practice. 
8.6.7 Neutropenia 
Blood counts should be monitored regularly as outlined in the protocol with additional testing 
obtained according to standard clinical practice.  Neutropenia may be severe but has been 
manageable.  Growth factor support is not required but may be considered according to standard 
clinical practice.  Ixazomib or lenalidomide administration should be modified as noted as per dose 
modification recommendations in the protocol when neutropenia occurs (see Table 8.f).  Therapy 
can be reinitiated at a reduced level upon recovery of absolute neutrophil counts. 
8.6.8 Fluid Deficit 
Dehydration should be avoided since lenalidomide is substantially excreted by kidney, and 
ixazomib may cause vomiting, diarrhea, and dehydration.  Acute renal failure has been reported in 
patients treated with ixazomib, commonly in the setting of the previously noted gastrointestinal 
toxicities and dehydration.  Fluid replacement should be performed before initiation of study 
treatment as needed during treatment to avoid dehydration. 
8.6.9 Hypotension 
Symptomatic hypotension and orthostatic hypotension with or without syncope have been 
reported with ixazomib.  Blood pressure should be closely monitored while the patient is on study 
treatment and fluid replacement should be performed as needed, especially in the setting of 
concomitant symptoms such as nausea, vomiting, diarrhea, or decreased appetite.  Patients taking 
medications and/or diuretics to manage their blood pressure (for either hypo- or hypertension) 
should be managed according to standard clinical practice, including considerations for dose 
adjustments of their concomitant medications during the course of the trial. 
8.6.10 Posterior Reversible Encephalopathy Syndrome 
One case of posterior reversible encephalopathy syndrome (PRES), which ultimately resolved, has 
been reported with ixazomib.  This condition is characterized by headache, seizures, and visual 
loss, as well as abrupt increase in blood pressure.  Diagnosis may be confirmed by magnetic 
resonance imaging (MRI) or computed tomography (CT).  If the syndrome is diagnosed or 
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suspected, symptom-directed treatment should be maintained until the condition is reversed by 
control of hypertension or other instigating factors. 
8.6.11 Transverse Myelitis 
One case of transverse myelitis has been reported with ixazomib.  It is not known whether 
ixazomib causes transverse myelitis; however, because it happened to a patient receiving ixazomib, 
the possibility that ixazomib may have contributed to transverse myelitis cannot be excluded.  
Transverse myelitis should be managed according to standard medical practice. 
8.6.12 Progressive Multifocal Leukoencephalopathy 
Progressive multifocal leukoencephalopathy (PML), which may be fatal, has occurred in less than 
1% of oncology patients receiving ixazomib in combination with other cancer therapies.  It is not 
known whether ixazomib causes PML; however, the possibility that ixazomib may have 
contributed to PML cannot be excluded.  In the event of occurrence of PML, ixazomib should be 
discontinued and supportive care provided as needed. 
8.6.13 Overdose 
An overdose is defined as a known deliberate or accidental administration of investigational drug, 
to or by a study patient, at a dose above that which is assigned to that individual patient according 
to the study protocol. If overdose occurs, consider close observation for hemodynamics and 
supportive care under hospitalization in study site.  Gastric lavage and administration of charcoal 
may be considered, but it should be kept in mind that ixazomib absorption is rapid, with an overall 
median Tmax of 1 hour. Ixazomib is not readily dialyzable.  Latest information can be found in the 
IB. 
8.7 
Blinding and Unblinding 
This is an open-label study. 
8.8 
Description of Investigational Agents 
The ixazomib drug products are provided in the 3 different dose strengths as shown in Table 8.j, 
and are differentiated by both capsule size and color. 
Table 8.j 
Ixazomib Capsules 
Dose Strength 
Capsule Size 
Capsule Color 
4.0 mg 
Size 3 
Ivory 
3.0 mg 
Size 4 
Light grey 
2.3 mg 
Size 4 
Flesh 
 
For additional details, please see the ixazomib IB and Pharmacy Manual. 
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8.9 
Packaging and Labeling 
The ixazomib capsules will be provided by Takeda.  The study drug labels will fulfill all 
requirements specified by governing regulations.  The formulation consists of 4.0-, 3.0-, and 
2.3-mg capsules for oral administration. 
The capsules are individually packaged using cold form foil-foil blisters that are in a child resistant 
carton.  There are 3 capsules in each wallet/carton. 
8.10 
Storage, Handling, and Accountability 
On receipt at the investigative site, study drug should remain in the blister and carton provided 
until use or dispensation.  The container should be stored in a refrigerator at 2°C to 8°C (36°F to 
46°F).  All excursions should be brought to the sponsor’s attention for assessment and 
authorization for continued use.  Ensure that the drug is used before the retest expiry date provided 
by sponsor.  Expiry extensions will be communicated accordingly with updated documentation to 
support the extended shelf life. 
Study drug dispensed to the patient should remain in the blister packaging and carton and 
refrigerated as noted above until the point of use.  Comprehensive instructions should be provided 
to the patient in order to ensure compliance with dosing procedures.  Patients should be given only 
1 cycle of study drug at a time, unless agreed upon by Takeda clinician.  Patients should be 
instructed to store the medication refrigerated (36°F to 46°F, 2°C to 8°C) for the duration of each 
cycle.  Patients should be instructed to return their empty cartons to the investigative site, rather 
than discarding them.  Reconciliation will occur accordingly when the patient returns for their next 
cycle of study drug.  Any extreme in temperature should be reported as an excursion and should be 
dealt with on a case-by-case basis. 
Because ixazomib is an anticancer agent, as with other potentially toxic compounds, caution 
should be exercised when handling the study drug.  Patients should be instructed not to chew, 
break, or open capsules.  In case of contact with broken capsules, raising dust should be avoided 
during the clean-up operation.  Ixazomib may be harmful by inhalation, ingestion, or skin 
absorption.  Gloves and protective clothing should be worn during clean-up and during return of 
broken capsules and powder to minimize skin contract.  The area should be ventilated and the site 
washed with soap and water after material pick up is complete.  The material should be disposed of 
as hazardous medical waste. 
In case of contact with the powder (eg, from a broken capsule), skin should be washed 
immediately with soap and copious amounts of water for at least 15 minutes.  In case of contact 
with the eyes, copious amounts of water should be used to flush the eyes for at least 15 minutes.  
Medical personnel should be notified. 
Patients are to be instructed on proper storage, accountability, and administration of study drug, 
including that study drug is to be taken as intact capsules. 
Refer to the Pharmacy Manual for additional instructions. 
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8.10.1 Concomitant Study Therapy 
8.10.1.1 Lenalidomide 
Lenalidomide will be supplied by the study site through the RevMate program. 
Lenalidomide capsules should be stored according to the instructions provided in the 
manufacturer’s package insert. 
8.10.1.2 Dexamethasone 
Dexamethasone will be supplied by the study site. 
Dexamethasone tablets should be stored according to the instructions provided in the 
manufacturer’s package insert. 
8.11 
Other Protocol-Specified Materials 
No other drugs or ancillary material are supplied for use in this trial. 
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9.0 
STUDY CONDUCT 
This trial will be conducted in compliance with the protocol, Good Clinical Practice (GCP), 
applicable regulatory requirements, and International Conference on Harmonisation (ICH) 
guidelines. 
9.1 
Study Personnel and Organizations 
The contact information for the Takeda clinician, the central laboratory, any additional clinical 
laboratories or vendors participating on the study as well as the list of investigators can be found in 
the protocol annex. 
9.2 
Arrangements for Recruitment of Patients 
Recruitment and enrollment strategies for this study may include recruitment from the 
investigator’s local practice, or referrals from other physicians.  If advertisements become part of 
the recruitment strategy, they will be reviewed by the institutional review board (IRB). 
9.3 
Study Enrollments 
After written informed consent has been obtained, the patient will be assigned an subject 
identification code. 
Patient eligibility will be confirmed by a Takeda clinician before enrollment by the investigator 
into the study. Re-enrollment of the same patient will not be permitted. If a patient discontinues 
from the study, that subject identification code will not be reused. 
The date of enrollment is defined as the date when the Registration Center faxes the “registration 
confirmation sheet” to the investigator. 
9.3.1 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 contact information on the Registration Center can be found in the protocol annex.  
The “subject registration sheet” may be the source data of the investigator’s judgment for the each 
eligibility criteria. 
The Registration Center, specifically the Takeda clinician, 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. 
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The investigator must retain the “subject registration sheet”, the “registration confirmation sheet”, 
and the “reason for ineligibility” as the source documents appropriately in the study sites. 
9.4 
Study Procedures 
Patients will be evaluated at scheduled visits during Screening, Treatment, End of Treatment 
(EOT), and Follow-Up. Refer to the Schedule of Events for the timing of assessments (Appendix 
A). Tests and procedures should be performed on schedule, but occasional changes are allowable 
(± 2 days) for holidays and other administrative reasons. If the study schedule is shifted, 
assessments must be shifted to ensure that collection of assessments is completed before dosing.  If 
extenuating circumstances prevent a patient from beginning treatment or completing a scheduled 
procedure or assessment within this time, the patient may continue the study only with the 
permission of the Takeda clinician. 
Additional details are provided as necessary in the following sections. 
9.4.1 Informed Consent 
Each patient must provide written informed consent before any study-required procedures are 
conducted, unless those procedures are performed as part of the patient’s standard care. 
9.4.2 Patient Demographics 
The date of birth, race, ethnicity, and sex of the patient are to be obtained during Screening. 
9.4.3 Medical History 
During the Screening period, a complete medical history will be compiled for each patient, 
including diagnosis (refer to Appendix E) and current staging (refer to Appendix G) of MM.  The 
history should include a review of all current medications, prior radiation or antineoplastic therapy, 
and the patient’s current smoking status. 
9.4.4 Physical Examination 
A complete physical examination and symptom-directed physical exam will be conducted at the 
time points specified in the Schedule of Events. 
9.4.5 Eastern Cooperative Oncology Group Performance Status 
Performance status will be assessed using the ECOG performance scale (refer to Appendix D) at 
the time points specified in the Schedule of Events. 
9.4.6 Height and Weight 
Height will only be assessed at the Screening visit.  Weight will be measured at the time points 
specified in the Schedule of Events. 
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9.4.7 Vital Signs 
Measurement of vital signs, including temperature, blood pressure, heart rate, and respiratory rate 
will be done at the time points specified in the Schedule of Events. 
9.4.8 Pregnancy Test 
Two pregnancy tests with sensitivity of at least 25 mIU/mL will be performed for all women of 
childbearing potential prior to initiation of study treatment.  The first pregnancy test must be 
performed within 10 to 14 days prior to the start of study treatment and the second pregnancy test 
must be performed within 24 hours prior to the start of study treatment of Cycle 1.  The results 
must be available and negative before the first dose of study treatment is administered. 
FCBP is a female who:  1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has 
not been naturally postmenopausal (amenorrhea following chemotherapy does not rule out 
childbearing potential) for at least 24 consecutive months (ie, has not had menses at any time 
during the preceding 24 consecutive months). 
FCBP with regular or no menstruation must have a pregnancy test weekly for the first 28 days and 
then every 28 days while on treatment (including breaks in therapy), at discontinuation of study 
treatment, and at Day 28 after the last dose of study treatment.  Females with irregular 
menstruation must have a pregnancy test weekly for the first 28 days and then every 14 days while 
on study (including breaks in therapy), at discontinuation of study treatment, and at Days 14 and 
28 after the last dose of study treatment.  All patients must be counseled about pregnancy 
precautions, risks of fetal exposure, and other risks in accordance with RevMate program. 
9.4.9 Skeletal Survey 
A complete skeletal survey, using roentgenography, will be performed at Screening (within 8 
weeks prior to enrollment) and annually in all patients.  If at any time the investigator believes 
there are symptoms or signs that suggest increased or new bone lesions, a repeat of the skeletal 
survey should be performed.  For imaging of symptomatic sites, plain films may be obtained for 
additional clarity. 
At the discretion of the investigator, CT scan, a positron emission tomography (PET) -CT scan, or 
whole body MRI may be done at Screening in place of a skeletal survey, provided that the same 
modality for assessment is used throughout the study. 
Radiographs will be analyzed locally and reports maintained with the patient source record for 
review. 
9.4.10 Skeletal-Related Events 
Selected skeletal-related events, defined as new fractures (excluding vertebral compression or rib 
fractures), irradiation of or surgery on bone, or spinal cord compression, will be captured from the 
start of the study treatment through death or study termination by the sponsor at the time points 
listed in the Schedule of Events. 
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9.4.11 Serum Free Light Chain Assay 
A blood sample for serum free light chain assay will be obtained at the time points specified in the 
Schedule of Events. 
9.4.12 Immunofixation of Serum and Urine 
Serum and urine samples for the analysis of immunofixation of immunoglobulins will be obtained 
at the time points specified in the Schedule of Events. 
9.4.13 Bone Marrow Evaluation 
Central Laboratory Evaluation 
Cytogenetics 
The sample of the bone marrow aspirate obtained at Screening (within 28 days before the first dose 
of study treatment) will be used for evaluation of cytogenetics that will cover a panel of high-risk 
abnormalities including the following:  del(13), +1q21, t(4;14), t(14;16), and del(17).  This sample 
will be submitted to the central laboratory (See a separately created manual).  The first or second 
pull of the bone marrow aspirate is the preferred specimen to be sent to the central laboratory for 
this analysis. 
Local Laboratory Evaluations 
Disease Assessment 
A bone marrow aspirate will be obtained at Screening for disease assessment and at any time bone 
marrow aspirate sample is obtained to assess CR or to investigate suspected PD.  This evaluation 
will be performed locally. 
Determination of the kappa/lambda ratio by immunohistochemistry or immunofluorescence 
should be performed to assess stringent CR (sCR) when a CR has been documented.  A bone 
marrow biopsy can additionally be performed per local standards for disease assessments. 
Cytogenetics 
An additional bone marrow aspirate or bone marrow sample may also be submitted for 
cytogenetics to be analyzed locally, according to local standards, if the site has capability to 
perform analysis and there is sufficient sample available.  The central laboratory cytogenetic 
results will be utilized for study analysis, whereas local laboratory cytogenetic results (where 
available) will only be utilized in instances when central laboratory results are not available. 
9.4.14 Response Assessment 
Patients will be assessed by investigator for disease response according to the IMWG criteria, 
version 2011 (refer to Appendix H)[16].  Central laboratory data will be used for serum M-protein, 
urine M-protein and serum free light chain.  
Response assessments should occur every cycle until PD.  The Takeda clinician will confirm the 
investigator assessment of PD prior to the investigator taking the patient off treatment. 
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Response and relapse categories are as follows: 
Table 9.a 
Response Assessment 
Complete response 
CR 
Subcategory:  stringent complete response 
sCR 
Partial response 
PR 
Subcategory:  very good partial response 
VGPR 
Stable disease 
SD 
Progressive disease 
PD 
 
CR must be confirmed with follow-up assessments of serum protein electrophoresis (SPEP), urine 
protein electrophoresis (UPEP), immunofixation of blood and urine, and serum free light chains as 
outlined in Appendix H.  One bone marrow assessment has to occur to document CR; no second 
bone marrow confirmation is needed. 
Note that in order to determine a response of sCR, bone marrow, immunohistochemistry, or 
immunofluorescence for kappa/lambda ratio, as well as serum free light chain assay, should be 
performed for all patients suspected to be in CR to meet this response category’s requirements. 
Patients with measurable disease in either SPEP or UPEP or both will be assessed for response 
only based on these 2 tests and not by the free light chain assay.  Free light chain response criteria 
are only applicable to patients without measurable disease in the serum or urine, and to fulfill the 
requirements of the category of sCR. 
9.4.15 Concomitant Medications and Procedures 
Concomitant medications and therapy will be recorded from the first dose of study treatment 
through 30 days after last dose of study treatment or initiation of the subsequent antineoplastic 
therapies whichever comes first. If an AE is still on follow-up, the concomitant medications and 
therapy will be recorded during the follow-up period.  See Section 8.3 for a list of prohibited 
concomitant medications and therapies and Section 8.4 for a list of allowed concomitant 
medications and therapies. 
9.4.16 Adverse Events 
Monitoring of AEs, serious and nonserious, will be conducted throughout the study as specified in 
the Schedule of Events.  Refer to Section 10.0 for details regarding definitions, documentation, 
and reporting of pretreatment events (PTEs), AEs, and SAEs. 
9.4.17 Clinical Laboratory Evaluations 
Clinical laboratory evaluations will be performed by the central laboratory.  Central laboratory 
results should be used for confirmation of patient eligibility.  For dosing decisions, local 
hematology and chemistry laboratory results may be used; however, samples must still be sent to 
the central laboratory as well.  Hematology and chemistry panels may be collected within 3 days 
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before Day 1 dosing and within 24 hours before Days 8, 15 and 22 dosing, where required.  Local 
laboratory evaluations may be done more frequently at the investigator’s discretion, ie, for acute 
management of adverse events. 
In the instance when local laboratory results are used and central laboratory results are 
subsequently available, a retrospective review will be completed by the Takeda clinician to 
determine any significant difference between those results. In the event of a significant difference, 
the Takeda clinician will consider regarding recommended actions for the site/patient. 
Blood samples for analysis of the following hematology and chemistry will be obtained as 
specified in the Schedule of Events.  Blood samples will be collected before the study treatment 
administration. 
Table 9.b 
Hematology and Chemistry Tests 
Hematology 
Chemistry 
Hemoglobin 
Hematocrit 
Platelet Count  
WBC Count with Differential 
blood urea nitrogen (BUN) 
Creatinine 
Total bilirubin 
Uric Acid 
lactate dehydrogenase (LDH) 
Alkaline phosphatase 
AST 
ALT 
Albumin 
Glucose  
Sodium 
Potassium 
Chloride 
carbon dioxide (CO2) 
Magnesium 
Calcium 
Phosphate 
Thyroid Stimulating Hormone (TSH) 
 
9.4.18 Radiographic Disease Assessment 
For patients with documented extramedullary disease, other assessments and scans such as a CT, 
PET-CT or MRI scan may be required to better delineate the lesion sites and measurements of 
extramedullary disease.  Follow-up scans should be performed at Screening (within 8 weeks prior 
to enrollment), every other cycle during treatment, and every 8 weeks during the PFS follow-up 
period, until disease progression. 
All follow-up scans should use the same imaging modality used at Screening. 
Radiographs will be analyzed locally and the reports will be maintained as the patient source 
record for review. 
9.4.19 β2-Microglobulin 
A blood sample for central laboratory evaluation will be collected at Screening for serum β2 
microglobulin testing. 
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9.4.20 Quantification of M-Protein 
A blood sample and urine sample will be obtained at Screening and at the time points specified in 
the Schedule of Events. 
9.5 
Completion of Study Treatment for Individual Patients 
Patients will be considered to have completed study treatment if they receive the study treatment 
until PD or until discontinuation for unacceptable toxicity, withdrawal of consent, or death.  
Takeda clinician will review the source data documenting PD prior to the investigator taking the 
patient off treatment or stopping disease assessments due to PD.  Patients will attend an EOT visit 
approximately 30 days after receiving their last dose of the study treatment and will continue to be 
followed for other follow-up assessments specified in the Schedule of Events.  Refer to the 
Schedule of Events for EOT visit assessments. 
9.6 
Completion of Study for Individual Patients 
Patients will be considered to have completed the study if they are followed until death or until the 
sponsor terminates the study. 
9.7 
Discontinuation of Treatment With Study Treatment 
Treatment with study treatment may also be discontinued for any of the following reasons: 
• Adverse event 
• Protocol deviation 
• Study terminated by sponsor 
• Withdrawal by patient 
• Lost to follow-up 
• PD 
• Other 
Prior to the investigator taking the patient off treatment, the investigator is required to submit the 
rationale to the Takeda clinician for review. 
Once study treatment has been discontinued, all study procedures outlined for the EOT visit will 
be immediately completed as specified in the Schedule of Events.  The primary reason for study 
treatment discontinuation will be recorded on the eCRF. 
9.8 
Withdrawal of Patients From Study 
A patient may be withdrawn from the study for any of the following reasons: 
• Study terminated by sponsor 
• Withdrawal by patient 
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• Lost to follow-up 
• Death 
• Other 
The consequence of study withdrawal is that no new information will be collected from the 
withdrawn patient and added to the existing data or any database.  However, every effort will be 
made to follow all patients for safety. 
9.9 
Study Compliance 
Study drug will be administered or dispensed only to eligible patients under the supervision of the 
investigator or subinvestigator(s).  The investigational product administrator will maintain records 
of study drug receipt and dispensing. 
9.10 
Posttreatment Follow-up Assessments (Progression-Free Survival and Overall 
Survival) 
Patients who stop treatment for any reason other than PD will continue to have PFS follow-up 
visits.  The PFS follow-up should occur every 4 weeks until the occurrence of PD, and 
radiographic disease assessments are to be performed every 8 weeks.  All subsequent 
antineoplastic therapies will be recorded, regardless if they are initiated before or after PD.  
Patients who start an alternative antineoplastic therapy prior to PD will continue to be followed for 
PD. 
Patients who stop treatment due to PD will continue to have OS visits/assessments.  During the OS 
follow-up, assessments can be made over the phone and do not require a clinic visit.  Data may be 
collected by methods that include but are not limited to telephone, e-mail, and mail.  The OS 
follow-up should be conducted every 12 weeks after documented PD until death or termination of 
the study by the sponsor.  All subsequent antineoplastic therapies will be recorded during the OS 
follow-up period. 
Information for new primary malignancy should be collected during the study, including the PFS 
and OS follow-up periods. 
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10.0 
ADVERSE EVENTS 
10.1 
Definitions 
10.1.1 Pretreatment Event Definition 
A pretreatment event (PTE) is any untoward medical occurrence in a patient or subject who has 
signed informed consent to participate in a study but before administration of any study 
medication; it does not necessarily have to have a causal relationship with study participation. 
10.1.2 Adverse Event Definition 
An adverse event (AE) means any untoward medical occurrence in a patient or subject who 
received a pharmaceutical product (or a study drug); the untoward medical occurrence does not 
necessarily have a causal relationship with this treatment.  An AE can therefore be any unfavorable 
or unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product whether or not it is related to the 
medicinal product.  This includes any newly occurring event, or a previous condition that has 
increased in severity or frequency since the administration of study drug. 
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is not 
considered a clinically significant change from baseline by the investigator. 
10.1.3 Serious Adverse Event Definition 
A serious adverse event (SAE) means any untoward medical occurrence at any dose that: 
• Results in death. 
• Is life-threatening (refers to an AE in which the patient was at risk of death at the time of the 
event. It does not refer to an event which hypothetically might have caused death if it were 
more severe). 
• Requires inpatient hospitalization or prolongation of existing hospitalization (see Section 
10.2 on planned hospitalizations). 
• Results in persistent or significant disability or incapacity. (Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions). 
• Is a congenital anomaly/birth defect. 
• Is a medically important event.  This refers to an AE that may not result in death, be 
immediately life threatening, or require hospitalization, but may be considered serious when, 
based on appropriate medical judgment, may jeopardize the patient, require medical or 
surgical intervention to prevent 1 of the outcomes listed above, or involves suspected 
transmission via a medicinal product of an infectious agent.  Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
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development of drug dependency or drug abuse; any organism, virus, or infectious particle 
(eg, prion protein transmitting transmissible spongiform encephalopathy), pathogenic or 
nonpathogenic, is considered an infectious agent. 
In this study, intensity for each AE, including any lab abnormality, will be determined using the 
NCI CTCAE, Version 4.03, effective date 14 June 2010 [17].  Clarification should be made 
between an SAE and an AE that is considered severe in intensity (Grade 3 or 4), because the terms 
serious and severe are NOT synonymous.  The general term severe is often used to describe the 
intensity (severity) of a specific event; the event itself, however, may be of relatively minor 
medical significance (such as a Grade 3 headache).  This is NOT the same as serious, which is 
based on patient/event outcome or action criteria described above, and is usually associated with 
events that pose a threat to a patient’s life or ability to function.  A severe AE (Grade 3 or 4) does 
not necessarily need to be considered serious.  For example, a white blood cell count of 1,000/mm3 
to less than 2,000/mm3 is considered Grade 3 (severe) but may not be considered serious.  
Seriousness (not severity) serves as a guide for defining regulatory reporting obligations. 
10.2 
Procedures for Recording and Reporting Adverse Events and Serious 
Adverse Events 
All AEs spontaneously reported by the patient and/or in response to an open question from study 
personnel or revealed by observation, physical examination, or other diagnostic procedures will be 
recorded on the appropriate page of the eCRF (see Section 10.3 for the period of observation).  
Any clinically relevant deterioration in laboratory assessments or other clinical finding is 
considered an AE.  When possible, signs and symptoms indicating a common underlying 
pathology should be noted as 1 comprehensive event. 
Regardless of causality, SAEs and serious PTEs (as defined in Section 10.1) must be reported (see 
Section 10.3 for the period of observation) by the investigator to the Emergency Reception Center 
for Safety Information (contact information provided below).  This should be done by e-mailing or 
faxing the SAE Form within 24 hours after becoming aware of the event.  The SAE Form, created 
and designated by Takeda, or the equivalent form specified by each study site shall be used.  If the 
first SAE report was filed, the original SAE Form should be submitted to Takeda later.  If 
applicable, copies of relevant records also need to be submitted to Takeda when they became 
available.  The investigator should give the detailed information about the SAE to Takeda in a 
timely manner after he/she sent the first report.  The details of subsequent SAE information should 
be reported according to the above-stated reporting procedures.  Follow-up information on the 
SAE or serious PTE may be requested by Takeda.  SAE report information must be consistent with 
the data provided on the eCRF. 
SAE Reporting Contact Information (the Emergency Reception Center for Safety Information) 
Bell Medical Solutions, Inc. 
 
PPD
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Planned hospital admissions or surgical procedures for an illness or disease that existed before the 
patient was enrolled in the trial are not to be considered AEs unless the condition deteriorated in an 
unexpected manner during the trial (eg, surgery was performed earlier or later than planned). 
For both serious and nonserious AEs, the investigator must determine both the severity (toxicity 
grade) of the event and the relationship of the event to study treatment administration. For serious 
PTEs, the investigator must determine both the severity (toxicity grade) of the event and the 
causality of the event in relation to study procedures. 
Severity (toxicity grade) for each AE, including any lab abnormality, will be determined using the 
NCI CTCAE, Version 4.03, effective date 14 June 2010 [17]. 
The relationship between the event and study treatment administration (ie, its causality) will be 
determined by the investigator responding yes (related) or no (unrelated) to this question:  “Is there 
a reasonable possibility that the AE is associated with the study treatment (any of ixazomib, 
lenalidomide, or dexamethasone) ?” 
10.3 
Monitoring of Adverse Events and Period of Observation 
AEs, both nonserious and serious, will be reported and monitored throughout the study as follows:  
• AEs will be reported during the period from the first dose of study treatment through 30 days 
after administration of the last dose of study treatment, or the start of subsequent antineoplastic 
therapy, whichever occurs first, and recorded in the eCRFs.  Even after this period, 
skeletal-related events (refer to Section 9.4.10 for details) and new primary malignancies must 
be reported during the period from the first dose of study treatment through death or 
termination of the study by the sponsor. 
• All AEs should be followed until resolution or until become a chronic condition. This will not 
necessarily be done, however, if the investigator considers it is clinically appropriate to 
discontinue the follow-up or if the subject is lost to follow-up. 
• SAEs 
Serious PTEs will be reported to the Emergency Reception Center for Safety Information from the 
time of the signing of the informed consent form up to the first dose of study treatment, and will 
not be recorded in the eCRF. 
Related and unrelated treatment-emergent SAEs will be reported to the Emergency Reception 
Center for Safety Information during the period from the first dose of study treatment through 
30 days after administration of the last dose of study treatment, or the start of subsequent 
antineoplastic therapy, whichever occurs first, and recorded in the eCRF.  After this period, only 
related SAEs must be reported to the Emergency Reception Center for Safety Information. The 
information on new primary malignancy, even though it was obtained after this period, must be 
provided to the Emergency Reception Center for Safety Information during the period from the 
first dose of study treatment through death or termination of the study by the sponsor, regardless of 
whether the malignancy is related to the study treatment. 
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All serious PTEs and SAEs should be monitored until they are resolved or are clearly determined 
to be due to a patient’s stable or chronic condition or intercurrent illness(es). 
10.4 
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events 
If a female patient becomes pregnant or suspects that she is pregnant while participating in this 
study or within 90 days after the last dose of study treatment, she must inform the investigator 
immediately and permanently discontinue study treatment.  The sponsor must also be contacted 
immediately by faxing a completed Pregnancy Form to the Emergency Reception Center for 
Safety Information (see Section 10.2).  The pregnancy must be followed for the final pregnancy 
outcome. 
If a female partner of a male patient becomes pregnant during the male patient’s participation in 
this study or within 90 days after the last dose of study treatment, the sponsor must also be 
contacted immediately by faxing a completed Pregnancy Form to the Emergency Reception 
Center for Safety Information (see Section 10.2).  Every effort should be made to follow the 
pregnancy for the final pregnancy outcome. 
10.5 
Product Complaints and Medication Errors (Including Overdose) 
A product complaint is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product.  Individuals who 
identify a potential product complaint situation should immediately report this to “Dohmen Life 
Sciences” addresses provided below. 
A medication error is a preventable event that involves an identifiable patient and that leads to 
inappropriate medication use, which may result in patient harm.  Whereas overdoses and 
underdoses constitute medication errors, doses missed inadvertently by a patient do not.  All 
medication error (including overdose) should be recorded on eCRF by the principal investigator or 
subinvestigator.  Individuals who identify a potential medication error (including overdose) 
situation should immediately report this via the phone numbers or e-mail addresses provided 
below. 
Product complaints in Japan can be reported to study monitor (CRA) as well as “Dohmen Life 
Sciences”. 
Call Center 
Phone Number 
E-mail 
Fax 
Business Hours 
Dohmen Life 
Science Services 
  
 
 
 
 
 
Product complaints or medication errors in and of themselves are not AEs and may or may not be 
associated with an AE.  If a product complaint or a medication error results in an AE or SAE, an 
additional report describing the AE or SAE should also be completed and sent to the Emergency 
Reception Center for Safety Information (refer to Section 10.2). 
PPD
PPD
PPD
PPD
PPD
PPD
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10.6 
Safety Reporting to Investigators, IRBs and Regulatory Authorities 
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, investigators, IRBs or the head 
of each study site.  Relative to the first awareness of the event by/or further provision to the 
sponsor or sponsor’s designee, SUSARs will be submitted to the regulatory authorities as an 
expedited report within 7 days for fatal and life-threatening events and 15 days for other serious 
events, unless otherwise required by national regulations.  The sponsor will also prepare an 
expedited report for other safety issues where these might materially alter the current benefit-risk 
assessment of an investigational medicinal product or that would be sufficient to consider changes 
in the investigational medicinal product’s administration or in the overall conduct of the trial. 
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11.0 
STUDY-SPECIFIC COMMITTEES 
No steering committee, data safety monitoring committee, or clinical endpoint committee will be 
used in this study. 
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12.0 
DATA HANDLING AND RECORDKEEPING 
The full details of procedures for data handling will be documented in the Data Management Plan.  
If selected for coding, AEs, PTEs, medical history, and concurrent conditions will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA).  Drugs will be coded using the 
World Health Organization (WHO) Drug Dictionary. 
12.1 
eCRFs 
Completed eCRFs are required for each subject who receives study drug.  The sponsor or its 
designee will allow the study sites to have access to eCRFs and will make arrangements to train 
appropriate site staff in the use of the eCRF.  These forms are used to transmit the information 
collected in the performance of this study to the sponsor, CRO partners, and regulatory authorities.  
eCRFs should be prepared in English. 
Any change of, modification of, or addition to the data on the eCRFs should be made by the 
investigator or appropriate site personnel.  These corrections of eCRFs are recorded as audit trails 
that capture the information before and after correction, correctors' names, correction dates and 
reasons for each correction. 
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated.  Furthermore, the principal investigator must retain 
full responsibility for the accuracy and authenticity of all data entered on the eCRFs. 
The sponsor or its designee must review eCRFs for accuracy and completeness when visiting the 
study site.  The sponsor or its designee will be permitted to review subjects' medical and hospital 
records pertinent to the study to ensure the accuracy of eCRFs.  The completed eCRFs are the sole 
property of the sponsor and should not be made available in any form to third parties, except for 
authorized representatives of appropriate governmental health or regulatory authorities, without 
written permission of the sponsor. 
12.2 
Record Retention 
The investigator and the head of the study site agree to keep the records stipulated in Section 12.1 
and those documents that include (but are not limited to) the study-specific documents, the 
identification log of all participating subjects, medical records, source worksheets, all original 
signed and dated informed consent forms, electronic copies of eCRFs, including the audit trails, 
and detailed records of drug disposition.  The investigator and the head of the study site must retain 
the essential documents until the following date of 1) or 2), whichever occurs later.  However, if 
the sponsor requests a longer time period for retention, the head of the study site should discuss 
how long and how to retain those documents with the sponsor. 
1) The day when a marketing approval of the study drug was obtained (or the day 3 years after 
the notification of early termination of the study). 
2) The day 3 years after the date of early termination or completion of the study. 
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In addition, the investigator and the head of the study site should retain the essential relevant 
documents until the receipt of a sponsor-issued notification to state the retention is no longer 
required. 
Refer to the Clinical Study Site Agreement for the sponsor’s requirements on record retention.  
The investigator and the head of the study site should contact and receive written approval from 
the sponsor before disposing of any such documents. 
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13.0 
STATISTICAL METHODS 
13.1 
Statistical and Analytical Plans 
A statistical analysis plan (SAP) will be prepared and finalized prior to database lock.  This 
document will provide further details regarding the definition of analysis variables and analysis 
methodology to address all study objectives. 
A data review will be conducted prior to database lock.  This review will assess the accuracy and 
completeness of the study database, subject evaluability, and appropriateness of the planned 
statistical methods. 
Analysis is planned to be performed twice during the study.  The primary analysis is planned to be 
performed using the data obtained at approximately 12 months from the enrollment of the last 
patient.  The final analysis is planned to be performed after the final database lock using the data 
obtained at approximately 24 months from the enrollment of the last patient.  The timing of 
analysis may be changed or additional analysis may be added upon request of the regulatory 
authorities. 
13.1.1 Analysis Sets 
In this study, the following three analysis sets ("full analysis set (FAS)", "response-evaluable 
analysis set" and "safety analysis set") are defined.  The definition of each analysis set is as 
follows: 
• FAS:  All subjects who received at least one dose of the study drug during the treatment period. 
• Response-evaluable analysis set: All FAS subjects with measurable disease at baseline, and at 
least one post baseline response assessment. 
• Safety analysis set:  All subjects who received at least one dose of the study drug during the 
treatment period. 
The sponsor will verify the validity of the definitions of the analysis sets as well as the rules for 
handling data, consulting a medical expert as needed. If necessary, the SAP will be supplemented 
with handling rules that were not specified in the planning stage before finalization. 
13.1.2 Analysis of Demographics and Other Baseline Characteristics 
The key demographics and other baseline characteristics will be summarized. 
13.1.3 Efficacy Analysis 
(1) Primary endpoint and the analytical methods 
[Primary endpoint] 
VGPR or better (CR + VGPR) rate in response-evaluable analysis set 
[Primary analysis] 
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The VGPR or better (CR + VGPR) rate and the 2-sided 95% confidence interval (CI) will be 
provided in the response-evaluable analysis set. 
[Sensitivity analysis] 
The VGPR or better (CR + VGPR) rate and the 2-sided 95% CI will be provided in FAS. 
Non-evaluable subjects in FAS will be included in the analysis as not VGPR or CR. 
(2) Secondary endpoints and their analytical methods 
[Secondary endpoints] 
• PFS 
• ORR 
• DOR 
• TTP 
• OS 
[Analytical Method] 
For the PFS, the Kaplan-Meier survival curve [and the 25th, 50th (median), and 75th percentiles, if 
estimable] will be calculated with their 2-sided 95% CIs in FAS.  PFS is defined as the time from 
the date of first study drug administration to the date of first documentation of PD or death from 
any cause, whichever occurs first.  
The overall response rate and the 2-sided 95% CI will be calculated for the response-evaluable 
analysis set and FAS.  Non-evaluable subjects in FAS will be included in the analysis as 
non-responders. 
For the DOR, the Kaplan-Meier survival curve [and the 25th, 50th (median), and 75th percentiles, if 
estimable] will be calculated with their 2-sided 95% CIs for the subjects who responded to the 
study treatment among the FAS.  DOR is defined as the time from the date of first documentation 
of response to the date of first documentation of PD. 
For the TTP, the Kaplan-Meier survival curve [and the 25th, 50th (median), and 75th percentiles, if 
estimable] will be calculated with their 2-sided 95% CIs in FAS.  TTP is defined as the time from 
the date of first study drug administration to the date of first documentation of PD. 
For the OS, the Kaplan-Meier survival curve [and the 25th, 50th (median), and 75th percentiles, if 
estimable] will be calculated with their 2-sided 95% CIs in FAS. OS is defined as the time from the 
date of first study drug administration to the date of death. 
(1) Data conversion and handling of missing data 
Details will be provided in the SAP. 
(2) Significance level and confidence coefficient 
Confidence coefficient: 95% (2-sided) 
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13.1.4 Safety Analysis 
The following analyses will be performed using the safety analysis set. 
(1) Treatment-emergent Adverse Events 
Treatment-emergent adverse event (TEAE) is defined as any AE that occurs after administration 
of the first dose of any study drug through 30 days after the last dose of any study drug. 
The frequency of TEAEs listed below will be calculated.  All TEAEs will be coded using the 
MedDRA, and tabulated by the System Organ Class and Preferred Terms. 
• All TEAEs 
• Drug-related TEAEs 
• Grade 3 or higher TEAEs 
• Grade 3 or higher drug-related TEAEs 
• All TEAEs by grade 
• Drug-related TEAEs by grade 
• TEAEs leading to any study drug discontinuation 
• Serious TEAEs 
• All TEAEs over time 
(2) Laboratory values, vital signs 
For continuous variables, the observed values and the changes from baseline will be summarized 
for each visit using descriptive statistics.  Case plots will also be presented for the observed values. 
For categorical variables, shift tables showing the number of patients in each category at baseline 
and each post-baseline visit will be provided. 
13.2 
Interim Analysis and Criteria for Early Termination 
The primary analysis is planned to be performed using the data obtained at approximately 12 
months from the enrollment of last patient.  The continuation or discontinuation of the study will 
not be determined by this analysis.  However, the timing of analysis may be changed or additional 
analysis may be added upon request of the regulatory authorities.  
13.3 
Determination of Sample Size 
Assuming the expected VGPR or better rate is
% and the threshold rate is
% based on the 
results of Study C16010, a sample size of 
would be necessary to provide  a point estimate of 
VGPR or better rate higher than the threshold rate with
% probability.  Assuming a drop-out 
ratio of 
%, the target number of patients has been set to 30.  The expected response rate and the 
threshold assumptions are based on VGPR or better rate in ixazomib + LenDex arm and placebo + 
LenDex arm in Study C16010 (intent-to-treat population, primary analysis). 
CCI
CCI
CCI
CCI
CC
I
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14.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
14.1 
Study-Site Monitoring Visits 
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed.  Source documents will be reviewed for verification of data 
recorded on the eCRFs.  Source documents are defined as original documents, data, and records.  
The investigator and the head of the study site guarantee access to source documents by the 
sponsor or its designee (CRO) and by the IRB. 
All aspects of the study and its documentation will be subject to review by the sponsor or designee, 
including the Investigator’s Binder, study medication, subject medical records, informed consent 
documentation, and review of eCRFs and associated source documents.  It is important that the 
investigator and other study personnel are available during the monitoring visits and that sufficient 
time is devoted to the process. 
14.2 
Protocol Deviations 
The investigator or subinvestigator can deviate and change from the protocol for any medically 
unavoidable reason, for example, to eliminate an immediate hazard to study subjects, without a 
prior written agreement with the sponsor or a prior approval from IRB.  In the event of a deviation 
or change, the principal investigator should notify the sponsor and the head of the site of the 
deviation or change as well as its reason in a written form, and then retain a copy of the written 
form.  When necessary, the principal investigator may consult and agree with the sponsor on a 
protocol amendment.  If the protocol amendment is appropriate, the amendment proposal should 
be submitted to the head of the site as soon as possible and an approval from IRB should be 
obtained. 
The investigator should document all protocol deviations. 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections 
The study site also may be subject to quality assurance audits by the sponsor or designees.  In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit.  The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study.  In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the FDA, the United Kingdom Medicines and Healthcare 
products Regulatory Agency [MHRA], the Pharmaceuticals and Medical Devices Agency of 
Japan [PMDA]).  If the study site is contacted for an inspection by a regulatory body, the sponsor 
should be notified immediately.  The investigator and the head of the study site guarantee access 
for quality assurance auditors to all study documents as described in Section 14.1. 
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15.0 
ETHICAL ASPECTS OF THE STUDY 
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of Helsinki, 
and the ICH Harmonised Tripartite Guideline for GCP.  Each investigator will conduct the study 
according to applicable local or regional regulatory requirements and align his or her conduct in 
accordance with the “Responsibilities of the Investigator” that are listed in Appendix B.  The 
principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities. 
15.1 
IRB Approval 
IRBs must be constituted according to the applicable local requirements of each participating 
region.  The sponsor or designee will require documentation noting all names and titles of 
members who make up the respective IRB.  If any member of the IRB has direct participation in 
this study, written notification regarding his or her abstinence from voting must also be obtained. 
The sponsor or designee will supply relevant documents for submission to the respective IRB for 
the protocol’s review and approval.  This protocol, the Investigator’s Brochure, a copy of the 
informed consent form, and, if applicable, subject recruitment materials and/or advertisements and 
other documents required by all applicable laws and regulations, must be submitted to a central or 
local IRB for approval.  The IRB’s written approval of the protocol and subject informed consent 
must be obtained and submitted to the sponsor or designee before commencement of the study (ie, 
before signing a contract for the clinical study).  The IRB approval must refer to the study by exact 
protocol title, number, and version date; identify versions of other documents (eg, informed 
consent form) reviewed; and state the approval date.  The sponsor will notify site once the sponsor 
has confirmed the adequacy of site regulatory documentation.  Until the site receives notification, 
no protocol activities including assignment of patients may occur. 
Study sites must adhere to all requirements stipulated by their respective IRB.  This may include 
notification to the IRB regarding protocol amendments, updates to the informed consent form, 
recruitment materials intended for viewing by subjects, local safety reporting requirements, 
reports and updates regarding the ongoing review of the study at intervals specified by the 
respective IRB, and submission of the investigator’s final status report to IRB.  All IRB approvals 
and relevant documentation for these items must be provided to the sponsor or its designee. 
Subject incentives should not exert undue influence for participation.  Payments to subjects must 
be approved by the IRB and sponsor. 
15.2 
Subject Information, Informed Consent, and Subject Authorization 
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations.  The informed consent form describes the planned and permitted 
uses, transfers, and disclosures of the subject’s personal and personal health information for 
purposes of conducting the study.  The informed consent form further explains the nature of the 
study, its objectives, and potential risks and benefits, as well as the date that informed consent is 
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given.  The informed consent form will detail the requirements of the participant and the fact that 
he or she is free to withdraw at any time without giving a reason and without prejudice to his or her 
further medical care. 
The principal investigator is responsible for the preparation, content, and IRB approval of the 
informed consent form.  The informed consent form must be approved by both the IRB and the 
sponsor prior to use. 
The informed consent form must be written in a language fully comprehensible to the prospective 
subject.  It is the responsibility of the investigator to explain the detailed elements of the informed 
consent form to the subject.  Information should be given in both oral and written form whenever 
possible and in the manner deemed appropriate by the IRB. 
The subject must be given ample opportunity to:  (1) inquire about details of the study and (2) 
decide whether or not to participate in the study.  If the subject determines he or she will participate 
in the study, then the informed consent form must be signed and dated by the subject, at the time of 
consent and prior to the subject entering into the study.  The subject should be instructed to sign 
using their legal names, not nicknames, using blue or black ballpoint ink.  The investigator must 
also sign and date the informed consent form at the time of consent and prior to subject entering 
into the study. 
Once signed, the original informed consent form will be stored in the investigator’s site file.  The 
investigator must document the date the subject signs the informed consent in the subject’s 
medical record.  Copies of the signed informed consent form shall be given to the subject. 
All revised informed consent forms must be reviewed and signed by relevant subjects in the same 
manner as the original informed consent.  The date the revised consent was obtained should be 
recorded in the subject’s medical record, and the subject should receive a copy of the revised 
informed consent form. 
15.3 
Subject Confidentiality 
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy.  Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number.  As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth may be used to verify the subject and accuracy of the subject’s unique identification 
number. 
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, the FDA, MHRA,PMDA), the sponsor’s designated auditors, and the 
appropriate IRBs to review the subject’s original medical records (source data or documents), 
including, but not limited to, laboratory test result reports, electrocardiogram reports, admission 
and discharge summaries for hospital admissions occurring during a subject’s study participation, 
and autopsy reports.  Access to a subject’s original medical records requires the specific 
authorization of the subject as part of the informed consent process (see Section 15.2). 
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Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s eCRF). 
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy 
15.4.1 Publication 
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the study.  During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor. 
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. 
The investigator needs to obtain a prior written approval from the sponsor to publish any 
information from the study externally such as to a professional association. 
15.4.2 Clinical Trial Registration 
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum register 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov or other 
publicly accessible websites before start of study, as defined in Takeda Policy/Standard.  Takeda 
contact information, along with investigator’s city, country, and recruiting status will be registered 
and available for public viewing.  
15.4.3 Clinical Trial Results Disclosure 
Takeda will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites (including the Takeda corporate site) and registries, as required by Takeda 
Policy/Standard, applicable laws and/or regulations. 
15.5 
Insurance and Compensation for Injury 
Each subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject is participating.  If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to clinical study subjects.  
Refer to the Clinical Study Site Agreement regarding the sponsor’s policy on subject 
compensation and treatment for injury.  If the investigator has questions regarding this policy, he 
or she should contact the sponsor or sponsor’s designee. 
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16.0 
REFERENCES 
1. Palumbo A, Anderson K. Multiple myeloma. N Engl J Med 2011;364(11):1046-60. 
2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin 2015;65(1):5-29. 
3. Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, Rosso S, Coebergh JW, Comber H, et al. 
Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J 
Cancer 2013;49(6):1374-403. 
4. Huang SY, Yao M, Tang JL, Lee WC, Tsay W, Cheng AL, et al. Epidemiology of multiple 
myeloma in Taiwan: increasing incidence for the past 25 years and higher prevalence of 
extramedullary myeloma in patients younger than 55 years. Cancer 2007;110(4):896-905. 
5. Qiu L, Wang Y, Qi P, Zou D, Zhao Y, Qi J. Clinical Epidemiological Study on Multiple 
Myeloma in China: A 18-Year Retrospective Study in a Representative Center. Blood (ASH 
Annual Meeting Abstracts) 2008;112(11):abstr 2723. 
6. Cancer Registry and Statistics. Cancer Information Service, National Cancer Center, Japan. 
Accessed on 15 June 2015. http://ganjoho.jp/reg_stat/statistics/stat/short_pred.html 
7. Barlogie B, Mitchell A, van Rhee F, Epstein J, Morgan GJ, Crowley J. Curing myeloma at last: 
defining criteria and providing the evidence. Blood 2014;124(20):3043-51. 
8. Dimopoulos MA, Richardson PG, Moreau P, Anderson KC. Current treatment landscape for 
relapsed and/or refractory multiple myeloma. Nat Rev Clin Oncol 2015;12(1):42-54. 
9. Facon T, Mary JY, Hulin C, Benboubker L, Attal M, Pegourie B, et al. Melphalan and 
prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity 
autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a 
randomised trial. Lancet 2007;370(9594):1209-18. 
10. San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, et al. 
Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J 
Med 2008;359(9):906-17. 
11. Dimopoulos M, Spencer A, Attal M, Prince HM, Harousseau JL, Dmoszynska A, et al. 
Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med 
2007;357(21):2123-32. 
12. Weber DM, Chen C, Niesvizky R, Wang M, Belch A, Stadtmauer EA, et al. Lenalidomide plus 
dexamethasone for relapsed multiple myeloma in North America. N Engl J Med 
2007;357(21):2133-42. 
13. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: 
Multiple Myeloma, Version 3. 2016.  
14. Japanese society of myeloma. Guidelines for the diagnosis and management of multiple 
myeloma Version 3. Bunkodo. 2012. 
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CONFIDENTIAL 
15. Moreau P, Masszi T, Grzasko N, Bahlis NJ, Hansson M, Pour L, et al. Oral Ixazomib, 
Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med 
2016;374(17):1621-34. 
16. Rajkumar SV, Harousseau JL, Durie B, Anderson KC, Dimopoulos M, Kyle R, et al. 
Consensus recommendations for the uniform reporting of clinical trials: report of the 
International Myeloma Workshop Consensus Panel 1. Blood 2011;117(18):4691-5. 
17. Common Terminology Criteria for Adverse Events (CTCAE). National Cancer Institute, 
National Institutes of Health, U.S. Department of Health and Human Services  Series v4.03. 
June 14, 2010. Publication No. 09-5410. 
18. Revlimid capsule (2.5 mg, 5 mg) Japanese proper use guide, February 2016 
19. LenaDex tablet (4 mg) Japanese proper use guide, July 2010 
20. Revlimid capsule (2.5 mg, 5 mg) Japanese package insert, January 2016 
21. Palumbo A, Rajkumar SV, Dimopoulos MA, Richardson PG, San Miguel J, Barlogie B, et al. 
Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia 
2008;22(2):414-23. 
22. Sviggum HP, Davis MD, Rajkumar SV, Dispenzieri A. Dermatologic adverse effects of 
lenalidomide therapy for amyloidosis and multiple myeloma. Arch Dermatol 
2006;142(10):1298-302. 
23. Castaneda CP, Brandenburg NA, Bwire R, Burton GH, Zeldis JB. Erythema 
multiforme/Stevens-Johnson syndrome/toxic epidermal necrolysis in lenalidomide-treated 
patients. J Clin Oncol 2009;27(1):156-7. 
 
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Appendix A Schedule of Events 
SCHEDULE OF EVENTS 
Study Procedures 
Screening 
Treatment Period 
End of 
Treatmenta 
Follow-up 
28-Day Cycles 
PFS 
OS 
Cycle 
C1 
C2 
C3 
C4 and 
beyond 
Every 
4 weeks 
Every 
12 weeks 
Days 
-28 to -1 
1 
7 
14 
21 
1 
7 
14 
21 
1 
14 
1 
Window 
 
± 2 daysb 
+1 wk 
± 1 wk 
± 1 wk 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteriac 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Symptom-Directed 
Physical Exam 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
ECOG performance status 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
X 
X 
 
Vital Signs 
X 
X 
 
 
 
X 
 
 
 
X 
 
X 
X 
X 
 
Height (cm) & Weight (kg) 
Xd 
Xd 
 
 
 
Xd 
 
 
 
Xd 
 
Xd 
Xd 
 
 
Pregnancy Teste 
X 
X 
X 
X 
X 
X 
 
 
 
X 
 
X 
X 
 
 
Hematology Laboratoryf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Chemistry Laboratoryf 
X 
X 
 
 
 
X 
 
 
 
X 
 
X 
X 
 
 
Thyroid testing 
X 
 
 
 
 
 
 
 
 
 
 
Xg 
X 
 
 
Skeletal Surveyh 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
Radiographic Disease 
Assessmenti 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
 
β2-microglobulin 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Study Procedures 
Screening 
Treatment Period 
End of 
Treatmenta 
Follow-up 
28-Day Cycles 
PFS 
OS 
Cycle 
C1 
C2 
C3 
C4 and 
beyond 
Every 
4 weeks 
Every 
12 weeks 
Days 
-28 to -1 
1 
7 
14 
21 
1 
7 
14 
21 
1 
14 
1 
Window 
 
± 2 daysb 
+1 wk 
± 1 wk 
± 1 wk 
M-protein Measurements 
(SPEP) 
X 
Xj 
 
 
 
X 
 
 
 
X 
 
X 
X 
X 
 
M-protein Measurements 
(UPEP [24hr Urine 
collection]) 
X 
Xj 
 
 
 
X 
 
 
 
X 
 
X 
X 
X 
 
Serum Free Light Chain 
Assay 
X 
Xj 
 
 
 
X 
 
 
 
X 
 
X 
X 
X 
 
Immunofixation - serum 
and urine 
X 
Xj 
 
 
 
X 
 
 
 
X 
 
X 
X 
X 
 
Bone Marrow Aspiration 
 
- Disease Assessment 
Xk 
 
 
 
 
Xk 
 
 
 
Xk 
 
Xk 
Xk 
Xk 
 
- Cytogenetic assessment 
Xl 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Event Reportingm 
 
Recorded from the first dose of study treatment through 30 days after last dose of study treatment, or 
the start of  subsequent antineoplastic therapy, whichever occurs first 
 
 
Serious adverse events and serious pretreatment events will be collected from signing of the informed consent 
through 30 days after administration of the last dose of study treatment, or the start of  subsequent antineoplastic 
therapy, whichever occurs first 
 
 
Concomitant 
Medications/Proceduresn 
 
Recorded from the first dose of study treatment through 30 days after administration of the last dose 
of study treatment, or the start of subsequent antineoplastic therapy, whichever occurs first 
 
 
Skeletal-related Events 
 
Continuous from the start of study treatment administration until death or termination of the study by the sponsor 
New Primary Malignancy 
Assessment 
 
Continuous from the start of study treatment administration until death or termination of the study by the sponsor 
Survival 
 
 
 
 
X 
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Study Procedures 
Screening 
Treatment Period 
End of 
Treatmenta 
Follow-up 
28-Day Cycles 
PFS 
OS 
Cycle 
C1 
C2 
C3 
C4 and 
beyond 
Every 
4 weeks 
Every 
12 weeks 
Days 
-28 to -1 
1 
7 
14 
21 
1 
7 
14 
21 
1 
14 
1 
Window 
 
± 2 daysb 
+1 wk 
± 1 wk 
± 1 wk 
Study Treatment Administration 
Ixazomib 
 
Days 1, 8 and 15 of each cycle 
 
 
 
Lenalidomide 
 
Daily Days 1 through 21 of each cycle 
 
 
 
Dexamethasone 
 
Days 1, 8, 15 and 22 of each cycle 
 
 
 
a Review by Takeda clinician required prior to discontinuing patient from treatment. 
b Tests and procedures should be performed on schedule, but occasional changes may be allowed (± 2 days) for holidays and other administrative reasons.  If the 
study schedule is shifted, assessments must be shifted to ensure that collection of assessments is completed prior to dosing.  If extenuating circumstances prevent 
a patient from beginning treatment or completing a scheduled procedure or assessment within this time, the patient may continue the study only with the 
permission of the Takeda clinician. 
c Confirmation of patient eligibility by Takeda clinician is required prior to enrollment. 
d Height assessed at screening only. 
e Pregnancy tests (Refer to Section 9.4.8): 
• Screening: Female patients of childbearing potential (FCBP) must have 2 negative pregnancy tests prior to starting study treatment. The first pregnancy test 
must be performed within 10 to 14 days prior to the start of study treatment and the second pregnancy test must be performed within 24 hours prior to the start 
of study treatment of Cycle 1. 
• On-Treatment:  Pregnancy tests for FCBP to be collected weekly for the first 28 days and then every 28 days while on treatment.  If menstrual cycles are 
irregular, the pregnancy testing must occur weekly for the first 28 days and then every 14 days while on treatment. 
• End of Treatment:  Pregnancy tests for FCBP to be collected at treatment discontinuation and at Day 28 following therapy.  If menstrual cycles are irregular, 
the pregnancy testing must occur at drug discontinuation and at Days 14 and 28 following drug discontinuation. 
f Clinical laboratory evaluations will be performed by the central laboratory.  Central laboratory results should be used for confirmation of patient eligibility.  For 
dosing decisions, local hematology and chemistry laboratory results may be used; however, samples must still be sent to the central laboratory as well. 
Hematology and chemistry panels may be collected within 3 days before Day 1 dosing of each cycle and within 24 hours before Days 8, 15 and 22 dosing, where 
required. Local laboratory evaluations may be done more frequently at the investigators discretion, ie, for acute management of adverse events. (Refer to Section 
9.4.17) 
g Thyroid testing required every 4 cycles on treatment. 
h Skeletal survey will be performed at screening (within 8 weeks prior to enrollment) and, at a minimum, annually for all patients. More frequent assessments can 
be done at the discretion of the investigator (ie, for symptoms or signs that indicate increased or new bone lesions). (Refer to Section 9.4.9) 
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i Patients with documented extramedullary disease must have radiographic disease assessments (CT/PET-CT/MRI) performed at screening (within 8 weeks prior 
to enrollment), every other cycle during treatment, and every 8 weeks during the PFS follow-up period, until disease progression. (Refer to Section 9.4.18) 
j If the screening test was performed more than 14 days prior to the first dose, the test will be repeated at baseline. 
k The bone marrow disease assessment will be made at baseline. This assessment will be made again only if resolution of serum and urine M-protein consistent 
with CR is suspected or to investigate suspected PD by principal investigator /subinvestigator, if applicable. (Refer to Section 9.4.13) 
l Bone marrow aspirate (first or second pull preferred) for cytogenetics are required to be sent to the central laboratory at baseline.  Of note, cytogenetics may also 
be done locally if the site has the capability to perform analysis and sufficient specimen is available. Assessment of the following: +1q21, translocations t(4;14) 
and t(14;16), del(17), del(13). (Refer to Section 9.4.13) 
m All AEs should be followed until they either resolve or  become a chronic condition. This will not necessarily be done, however, if the investigator considers it is 
clinically appropriate to discontinue the follow-up or if the subject is lost to follow-up. (Refer to Section 10.3)  
n If an AE is still on follow-up, the concomitant medications and therapy will be recorded during the follow-up period. 
 
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Appendix B Responsibilities of the Investigator 
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. 
The investigator agrees to assume the following responsibilities. 
1. Conduct the appropriate study in accordance with the protocol and GCP considering the rights, 
safety and wellbeing of human subjects. 
2. When a part of the important activities related to the study are delegated to the sub-investigator 
or the study collaborator, prepare the lists of activities to be delegated and responsible 
personnel, submit the lists to the head of the study in advance to get them accepted. 
3. Prepare a written informed consent form and other written information, and update as 
appropriate. 
4. Confirm the contents of the clinical study agreement. 
5. Provide necessary information on the protocol, medications and responsibilities of individual 
personnel to the investigator and study collaborator, and provide guidance and supervision. 
6. Screen subjects who meet the requirements of the protocol, provide the explanation of the 
study in writing and obtain the written consent. 
7. Assume responsibility for all the medical judgement related to the study. 
8. Ensure in collaboration with the head of the study that sufficient medical care on all clinically 
significant adverse events related to the study are provided to subjects throughout and beyond 
the period when subjects participate in the study. 
9. If a subject consults other medical institution or other department, notify the physician of the 
medical institution or department of the subject’s participation in the study upon obtaining the 
consent of the subject, as well as the end and termination of the study in writing, and document 
such records. 
10. In case of urgent report of a SAE, immediately notify the head of the study and the sponsor in 
writing. 
11. Prepare correct and complete (e)CRFs, and submit them to the sponsor with electronic 
signature. 
12. Check and confirm the contents of (e)CRFs prepared by the sub-investigator or transcribed 
from the source data by the study collaborator, and submit them to the sponsor with electronic 
signature. 
13. Discuss any proposal from the sponsor including update of the protocol. 
14. Notify the director of the site of the end of the study in writing. 
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Appendix C Investigator Consent to Use of Personal Information 
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information.  In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, United States, and Japan), including the following: 
• Takeda, its affiliates, and licensing partners. 
• Business partners assisting Takeda, its affiliates, and licensing partners. 
• Regulatory agencies and other health authorities. 
• IRBs. 
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following: 
• Assessment of the suitability of investigator for the study and/or other clinical studies. 
• Management, monitoring, inspection, and audit of the study. 
• Analysis, review, and verification of the study results. 
• Safety reporting and pharmacovigilance relating to the study. 
• Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study. 
• Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study medication. 
• Inspections and investigations by regulatory authorities relating to the study. 
• Self-inspection and internal audit within Takeda, its affiliates, and licensing partners. 
• Archiving and audit of study records. 
• Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites. 
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s own 
country. 
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above. 
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Appendix D Eastern Cooperative Oncology Group (ECOG) Scale for Performance Status 
Grade 
Description 
0 
Normal activity.  Fully active, able to carry on all predisease performance without restriction. 
1 
Symptoms but ambulatory.  Restricted in physically strenuous activity, but ambulatory and able to 
carry out work of a light or sedentary nature (eg, light housework, office work). 
2 
In bed < 50% of the time.  Ambulatory and capable of all self-care, but unable to carry out any work 
activities. Up and about more than 50% of waking hours. 
3 
In bed > 50% of the time.  Capable of only limited self-care, confined to bed or chair more than 50% 
of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or 
chair. 
5 
Dead 
Source:  Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al.  Toxicity and response criteria 
of the Eastern Cooperative Oncology Group.  American Journal of Clinical Oncology 1982;5(6):649-55. 
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Appendix E Multiple Myeloma Diagnostic Criteria 
IMWG Criteria for the Diagnosis of Myeloma 
Diagnosis 
Diagnostic Criteria: All Three Required 
Symptomatic multiple myelomaa 
• Monoclonal plasma cells in the bone marrow ≥ 10% and/or 
presence of a biopsy-proven plasmacytoma 
• Monoclonal protein present in the serum and/or urineb 
• Myeloma-related organ dysfunction (≥1)c 
[C] Calcium elevation in the blood (serum calcium 
> 10.5 mg/dL or upper limit of normal) 
[R] Renal insufficiency (serum creatinine > 2 mg per 100 ml) 
[A] Anemia (hemoglobin < 10 g per 100 ml or 2 g <normal) 
[B] Lytic bone lesions or osteoporosisd 
Source:  International Myeloma Foundation, myeloma.org. Accessed 16 January 2012. 
a These criteria identify Stage IB and Stages II and III A/B myeloma by Durie/Salmon stage.  Stage IA becomes 
smoldering or indolent myeloma. 
b If no monoclonal protein is detected (non-secretory disease), then ≥ 30% monoclonal bone marrow plasma cells 
and/or a biopsy-proven plasmacytoma required. 
c A variety of other types of end-organ dysfunctions can occasionally occur and lead to a need for therapy. Such 
dysfunction is sufficient to support classification as myeloma if proven to be myeloma related. 
d If a solitary (biopsy-proven) plasmacytoma or osteoporosis alone (without fractures) is the sole defining criteria, 
then ≥ 30% plasma cells are required in the bone marrow. 
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Appendix F Cockcroft-Gault Equation 
For males:   
Creatinine
Clearance = 72 × (serum creatinine[mg/dL])
(140-age[years]) × weight [kg]  OR 0.81 × (serum creatinine[µmol/L])
(140-age[years]) × weight [kg]  
 
For females:   
Creatinine
Clearance = 72 × (serum creatinine[mg/dL])
0.85 (140-age[years]) × weight [kg] OR 0.81 × (serum creatinine[µmol/L])
0.85 (140-age[years]) × weight [kg] 
 
Source:  Cockcroft DW, Gault MH.  Prediction of creatinine clearance from serum creatinine.  Nephron 
1976;16(1):31-41. 
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Appendix G International Staging System Staging Criteria and Durie-Salmon Criteria 
International Staging System 
Stage 
Criteria 
Stage I 
Serum β2-microglobulin < 3.5 mg/L 
Serum albumin ≥ 3.5 g/dL 
Stage II 
Neither Stage I or Stage IIIa 
Stage III 
Serum β2-microglobulin ≥ 5.5 mg/L 
Source:  Greipp PR, San Miguel J, Durie BG, Crowley JJ, Barlogie B, Bladé J et al. International staging system for 
multiple myeloma. J Clin Oncol. 2005;23(15):3412-20.  
a There are two categories for stage II:  serum β2-microglobulin < 3.5 mg/L but serum albumin < 3.5 g/dL; or serum 
β2-microglobulin 3.5 to < 5.5 mg/L irrespective of the serum albumin level. 
 
Durie-Salmon Criteria 
Stage 
Criteria 
I 
All of the following: 
• Hemoglobin value > 10 g/dL  
• Serum calcium value normal or ≤ 12 mg/dL  
• Bone x-ray, normal bone structure (scale 0) or solitary bone plasmacytoma only  
• Low M component production rate 
○ IgG value < 5 g/dL; IgA value < 3 g/dL 
○ Bence Jones protein < 4 g/24 h 
II 
Neither stage I nor stage III 
III 
1 or more of the following: 
• Hemoglobin value < 8.5 g/dL  
• Serum calcium value > 12 mg/dL  
• Advanced lytic bone lesions (scale 3)  
• High M component production rate 
○ IgG value > 7 g/dL; IgA value > 5 g/dL 
○ Bence Jones protein > 12 g/24 h 
Durie-Salmon sub classifications (either A or B) 
A:  Relatively normal renal function (serum creatinine value < 2.0 mg/dL) 
B:  Abnormal renal function (serum creatinine value ≥ 2.0 mg/dL) 
Source: Durie BG, Salmon SE. A clinical staging system for multiple myeloma. Correlation of measured myeloma 
cell mass with presenting clinical features, response to treatment, and survival. Cancer 1975;36(3):842-54. 
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Appendix H Response Criteria 
Patients will be assessed for disease response according to the IMWG criteria below, versions 
2011. 
 
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For VGPR:  Disappearance of any soft tissue plasmacytomas present at baseline and no new plasmacytomas. 
Source:  Rajkumar SV, Harousseau JL, Durie B, Anderson KC, Dimopoulos M, Kyle R, et al. Consensus 
recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop 
Consensus Panel 1. Blood 2011;117(18):4691-5. 
 
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Appendix I 
Changes in Procedures in Study Protocol after Shifting to the Post-marketing 
Clinical Study 
After a marketing approval of ixazomib was obtained in Japan, this study will be continued as a 
post-marketing clinical study in compliance with the GCP and the Good Post-marketing Study 
Practice. The changes in procedures in the study protocol after shifting to the post-marketing 
clinical study are described below. 
 
Entire Protocol 
In the protocol, the term "study" will be replaced by "post-marketing clinical study".  
 
8.0 Study Drug 
Even after a marketing approval of ixazomib was obtained, ixazomib capsules should be supplied 
by the sponsor as a drug used in this post-marketing clinical study, and handling procedures should 
not be changed. 
 
10.2 Procedures for Recording and Reporting Adverse Events and Serious 
Adverse Events 
The following actions will be added in Section 10.2. 
If any non-serious adverse events were observed after a marketing approval of ixazomib was 
obtained, the principal investigator/subinvestigator should report them to the sponsor. The 
investigator or subinvestigator should submit the report to the sponsor upon request within a 
period of time designated by the sponsor. 
 
10.6 Safety Reporting to Investigators, IRBs and Regulatory Authorities 
The Section 10.6 will be changed as follows (underlined text was added). 
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to the regulatory authorities, investigators, IRBs or the 
head of each study site. Relative to the first awareness of the event by/or further provision to the 
sponsor or sponsor's designee, SUSARs will be submitted to the regulatory authorities as an 
expedited report within 7 days for fatal and life-threatening events and 15 days for other serious 
events, unless otherwise required by national regulations. All SUSARs and known SAEs will be 
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submitted to the regulatory authorities as an expedited report within the reporting deadlines 
specified in applicable regulatory requirements.  
 (The rest is omitted) 
 
12.2  Record Retention   
The section 12.2 will be changed as follows (Underlined texts were added). 
 
 (First part omitted) 
The investigator and the head of the study site must retain the essential documents until the 
following date of 1) or 2), whichever occurs later. After a marketing approval of ixazomib was 
obtained, the duration of record retention shall expire on the day when a re-examination of 
ixazomib is completed, instead of the following dates of 1) and 2). However, if the sponsor 
requests a longer time period for retention, the head of the study site should discuss how long and 
how to retain those documents with the sponsor. 
1) The day when a marketing approval of the study drug was obtained (or the day 3 years after the 
notification of early termination of the study). 
2) The day 3 years after the date of early termination or completion of the study. 
In addition, the investigator and the head of the study site should retain the essential relevant 
documents until the receipt of a sponsor-issued notification to state the retention is no longer 
required.  
(The rest omitted) 
 
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Appendix J 
Detailed Description of Amendments to Text 
The following is described based on the contents of Amendment 01. 
 
Page 1, Cover Page (Amendment History) 
Existing Text 
(No Text) 
Added Text 
Note:  This study will be continued as a post-marketing clinical study after a marketing 
approval of ixazomib was obtained in Japan. In the protocol, the term "study" will be 
replaced by "post-marketing clinical study" as appropriate, and the protocol is continuously 
used.  
Rationale for Amendment 
Actions taken after a marketing approval of ixazomib was obtained will be described. 
 
Page 9, Section 2.0 
Existing Text 
(No Text) 
Added Text 
Note: This study will be continued as a post-marketing clinical study after a marketing 
approval of ixazomib was obtained in Japan. In the protocol, the term "study" will be 
replaced by "post-marketing clinical study" as appropriate, and the protocol is continuously 
used. 
Rationale for Amendment 
Actions taken after a marketing approval of ixazomib was obtained will be described. 
 
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Page 14, Section 4.2 
Existing Text 
(No Text) 
Added Text 
This study will be continued as a post-marketing clinical study after a marketing approval of 
ixazomib was obtained in Japan. In the study protocol, the term "study" will be replaced by 
"post-marketing clinical study" as appropriate. The details of changes in study procedures to be 
made after shifting to the post-marketing clinical study are found in Appendix I. 
Rationale for Amendment 
Actions taken after a marketing approval of ixazomib was obtained will be described. 
 
Page 20, Section 7.2  
Existing Text 
12. Ongoing or active systemic infection, known human immunodeficiency virus (HIV)-RNA 
positive, known hepatitis B surface antigen seropositive or known hepatitis C virus (HCV)-RNA 
positive. 
Revised Text 
12. Ongoing or active systemic infection, known human immunodeficiency virus (HIV)- positive, 
known hepatitis B surface antigen seropositive or known hepatitis C virus (HCV)-RNA positive. 
Rationale for Amendment 
To correct typographical errors in the text. 
 
Page 32, Section 8.5  
Existing Text 
(No Text) 
Added Text 
Nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided with impaired renal 
function given reported NSAID-induced renal failure in patients with decreased renal 
function. 
Rationale for Amendment 
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To ensure the subjects’ safety. 
 
Page 48, Section 10.2 
Existing Text 
Regardless of causality, SAEs and serious PTEs (as defined in Section 10.1) must be reported (see 
Section 10.3 for the period of observation) by the investigator to the Emergency Reception Center 
for Safety Information (contact information provided below).  This should be done by faxing the 
SAE Form within 24 hours after becoming aware of the event. 
(snip) 
SAE Reporting Contact Information (the Emergency Reception Center for Safety Information) 
Bell Medical Solutions, Inc. 
Revised Text 
Regardless of causality, SAEs and serious PTEs (as defined in Section 10.1) must be reported (see 
Section 10.3 for the period of observation) by the investigator to the Emergency Reception Center 
for Safety Information (contact information provided below).  This should be done by e-mailing 
or faxing the SAE Form within 24 hours after becoming aware of the event. 
(snip) 
SAE Reporting Contact Information (the Emergency Reception Center for Safety Information) 
Bell Medical Solutions, Inc. 
Rationale for Amendment 
Reporting by e-mail has become available. 
 
Page 49, Section 10.3  
Existing Text 
– 
Related and unrelated treatment-emergent SAEs will be reported to the Emergency 
Reception Center for Safety Information during the period from the first dose of study 
treatment through 30 days after administration of the last dose of study treatment, or the 
start of subsequent antineoplastic therapy, whichever occurs first, and recorded in the 
PPD
PPD
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eCRF. After this period, only related SAEs must be reported to the Emergency Reception 
Center for Safety Information. 
Revised Text 
– 
Related and unrelated treatment-emergent SAEs will be reported to the Emergency 
Reception Center for Safety Information during the period from the first dose of study 
treatment through 30 days after administration of the last dose of study treatment, or the 
start of subsequent antineoplastic therapy, whichever occurs first, and recorded in the 
eCRF. After this period, only related SAEs must be reported to the Emergency Reception 
Center for Safety Information. However, even after this period, the information on 
new primary malignancy must be reported to the Emergency Reception Center for 
Safety Information during the period from the first dose of study treatment through 
death or termination of the study by the sponsor, regardless of whether the 
malignancy is related to the study treatment 
Rationale for Amendment 
To clarify the reporting of information on new primary malignancy. 
 
Page 50, Section 10.5 
Existing Text 
Whereas overdoses constitute medication errors, doses missed inadvertently by a patient do not.   
Revised Text 
Whereas overdoses and underdoses constitute medication errors, doses missed inadvertently by a 
patient do not.  
Rationale for Amendment 
To follow the Study Protocol Template. 
 
Page 64, Appendix A 
Existing Text 
Study Procedure 
Screening 
Treatment Period 
End of 
Treatment 
(Omitt
ed) 
28-day Cycle 
Cycle 
C1 
C2 
C3 
C4 and 
beyond 
Days 
-28 to -1 
1 
7 
14 
21 
1 
7 
14 
21 
1 
14 
1 
Window 
 
±2 daysb 
+1 week 
(Omitted) 
Height (cm) & Body 
Weight (kg) 
○d 
 
 
 
 
 
 
 
 
 
 
 
○d 
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Revised Text 
Study Procedures 
Screening 
Treatment Period 
End of 
Treatment a 
(Omitt
ed) 
28-day Cycle 
Cycle 
C1 
C2 
C3 
C4 and 
beyond 
Days 
-28 to -1 
1 
7 
14 
21 
1 
7 
14 
21 
1 
14 
1 
Window 
 
±2 daysb 
+1 week 
(Omitted) 
Height (cm) & Body 
Weight (kg) 
○d 
○d 
 
 
 
○d 
 
 
 
○d 
 
○d 
○d 
Rationale for Amendment 
To correct typographical  errors in the text 
 
Page 67, Appendix A, Footnote k 
Existing Text 
Only to be repeated if resolution of serum and urine M-protein consistent with CR is suspected or 
to investigate suspected PD by principal investigator /subinvestigator, if applicable. (Refer to 
Section 9.4.13) 
Revised Text 
The disease assessment will be made at baseline. This assessment will be made again only if 
resolution of serum and urine M-protein consistent with CR is suspected or to investigate 
suspected PD by principal investigator /subinvestigator, if applicable. (Refer to Section 9.4.13) 
Rationale for Amendment 
To clarify the text.  
 
Page 76, Appendix I 
The changes in procedures to be made after shifting to the post-marketing clinical study are 
described. (The replacements and changes are not detailed here.) 
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