A Prospective, Multicenter, Observational Study in Relapsed and/or Refractory Multiple Myeloma Patients Treated With Ixazomib Plus Lenalidomide and Dexamethasone
Conditions: Relapsed and/or Refractory Multiple Myeloma
Sponsor: Takeda

Title: A Prospective, Multicenter, Observational Study in Relapsed and/or Refractory 
Multiple Myeloma Patients Treated with Ixazomib plus Lenalidomide and 
Dexamethasone 
NCT Number: NCT03433001 
Protocol  Approve Date: 24-AUG-2021 
Certain information within this protocol has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable 
information 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. 

Ixazomib 
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CLINICAL STUDY PROTOCOL 
 
 
A Prospective, Multicenter, Observational Study in Relapsed and/or Refractory Multiple 
Myeloma Patients Treated with Ixazomib plus Lenalidomide and Dexamethasone 
 
 
Sponsor: 
Takeda Pharmaceutical Company Limited  
 
Study number: 
 
Study phase: 
C16042 
 
 
Medical Affairs, Post-Approval Company Sponsored (Observational) 
 
 
IND Number: 
Not Applicable  
EudraCT Number: 
Not Applicable 
Study Drug: 
Ixazomib  
Date: 
24 August 2021 
Amendment 
Number: 
Version 3 
 
 
 
 
. 
 
 
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1.0 
THE PRINCIPLES OF CLINICAL STUDIES AND ADMINISTRATIVE 
INFORMATION 
1.1 
Principles of Clinical Studies  
This study will be conducted with consideration for the individual participants in accordance 
with this clinical study protocol and the following: 
• The ethical principles based on the Declaration of Helsinki. 
• The Ethical Guidelines for Medical and Health Research Involving Human Subjects 
((Ministry of Education, Culture, Sports, Science and Technology, and Ministry of 
Health, Labor and Welfare). 
• All applicable laws and regulations, including data privacy laws, and guidelines and 
regulations on conflicts of interest). 
1.2 
Research Implementation Structure 
This clinical study will be conducted in accordance with the clinical study protocol planned and 
drafted by the sponsor according to the following implementation system: Other implementation 
systems are described in a separate document. 
Sponsor 
Takeda Pharmaceutical Company, Ltd. 
Japan Oncology Division 
Medical Affairs Department 
 
The sponsor is responsible for the planning, drafting, conducting, and managing this clinical 
study, obtaining results, and reporting. The method of supervision of subcontractors concerning 
this clinical study will be included in the supplementary documents to be prepared separately. 
The fees required for the administration of this clinical study are borne by the sponsor.* 
*In accordance with the service agreement, fees required for conducting this clinical study, 
including administration, monitoring, registration, statistical analysis, medical writing, clinical 
examinations, and data management will be paid by the sponsor to the subcontractor. Study sites 
will be paid agreed fees based on the ‘Study cost calculation Guidelines’ as specified separately. 
 
Study Steering Committee 
Study Steering Committee Chair:  
 
Study Steering Committee Members:  
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Director of Statistical Analysis: 
 
 
Clinical Genetics Specialists:  
 
 
 
1.3 
Contact for Inquiries Concerning Study Protocol 
Refer to Supplement 1 of Clinical Study Protocol 
1.4 
Contact for Inquiries Concerning Registration Procedures 
Refer to Supplement 1 of Clinical Study Protocol 
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TABLE OF CONTENTS 
1.0 
THE PRINCIPLES OF CLINICAL STUDIES AND ADMINISTRATIVE 
INFORMATION ............................................................................................................. 2 
1.1 
Principles of Clinical Studies ............................................................................. ... ... 2 
1.2 
Research Implementation Structure ............................................................... . . ........ 2 
1.3 
Contact for Inquiries Concerning Study Protocol ........................................ . ............ 3 
1.4 
Contact for Inquiries Concerning Registration Procedures .................... . .................. 3 
TABLE OF CONTENTS .................................................................................. ......................... 4 
2.0 
STUDY SUMMARY ...................................................................................................... 9 
3.0 
ABBREVIATIONS ...................................................................... ............................... 15 
4.0 
INTRODUCTION .............................................................. .... ..................................... 19 
4.1 
Background ............................................................ . . ........................................... 19 
4.2 
Rationale for the Proposed Study .......................... . ............................................... 21 
5.0 
STUDY OBJECTIVE .................................................................................................... 22 
5.1 
Objectives ................................................. .. ........................................................... 22 
5.2 
Outcomes............................................ . . ................................................................ 22 
5.2.1 
Primary Outcome ........................ ...................................................................... 22 
5.2.2 
Secondary Outcomes .............. .......................................................................... 22 
5.2.3 
.......................................................... 22 
6.0 
STUDY DESIGN ................ ... ..................................................................................... 23 
6.1 
Overall Study Design and Plan: Description............................................................. 23 
6.2 
Termination or Suspension of Study or Study Site ................................................... 23 
6.2.1 
Criteria for Premature Termination or Suspension of the Study .......................... 23 
6.2.2 
Criteria for Premature Termination or Suspension of Investigational Sites ......... 24 
6.2.3 
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s) ................................................................ 24 
6.3 
Procedures for Revision of Protocol ......................................................................... 24 
7.0 
STUDY SUBJECTS ...................................................................................................... 25 
7.1 
Inclusion Criteria ..................................................................................................... 25 
7 2 
Exclusion Criteria .................................................................................................... 25 
7.3 
Study Registration ................................................................................................... 25 
8.0 
TREATMENTS............................................................................................................. 27 
8.1 
IRd Therapy ............................................................................................................. 27 
8.1.1 
Definition of IRd Therapy .................................................................................. 27 
8.1.2 
Dosage and Administration Method in IRd Therapy ........................................... 27 
8.1.3 
Overdose of Ixazomib ........................................................................................ 27 
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8.2 
Excluded Concomitant Medications and Procedures ................................................ 27 
8.3 
Discontinuation of IRd Treatment ............................................................................ 28 
8.4 
Procedure for Discontinuation of Clinical Study by the Enrolled Patient .................. 29 
9.0 
STUDY PLAN ........................................................................................................ ... . 30 
9.1 
Study Procedures .......................................................................................... . . ...... 30 
9.1.1 
Informed Consent Procedure ................................................................. . .......... 30 
9.1.2 
Patient Demographics and Baseline Disease Characteristics ............ . ................ 30 
9.1.3 
Comorbidity ............................................................................... ....................... 32 
9.1.4 
Medical History ................................................................................................. 32 
9.1.5 
Physical Examination ........................................................ ............................... 32 
9.1.6 
Performance Status ................................................. .... ..................................... 32 
9.1.7 
Body Weight, Height ........................................ . . ........................................... 32 
9.1.8 
Status of IRd Therapy ..................................... . ............................................... 33 
9.1.9 
Clinical Laboratory Evaluations ......................................................................... 33 
9.1.10 Evaluation of QOL .............................. .. ........................................................... 34 
9.1.11 Quantification of M-protein .......... . . ................................................................ 34 
9.1.12 Response Assessment.................. ...................................................................... 34 
9.1.13 Bone Marrow Aspiration ..... .. .......................................................................... 34 
9.1.14 Biomarker Study ........... .................................................................................... 35 
9.1.15 Image Examination .. ... ..................................................................................... 35 
9.1.16 Supportive Therapy . .......................................................................................... 35 
9.1.17 Adverse Events ................................................................................................. 35 
9.1.18 Follow-up Assessments ...................................................................................... 35 
9.1.19 Next-line Treatment ........................................................................................... 36 
9.1.20 Pregnancy .......................................................................................................... 36 
9.1.21 Study Participation Discontinued Before Administration of Study Medication ... 36 
10.0 
BIOMARKER STUDY ................................................................................................. 38 
10.1 
Objective ................................................................................................................. 38 
10 2 
Planned Biomarker Study ........................................................................................ 38 
10.2.1 Relationship between outcomes and biomarkers ................................................. 38 
10.2.2 Other .................................................................................................................. 38 
10.3 
Rationale for selecting biomarkers ........................................................................... 39 
10.3.1 
........................................................................... 39 
10.3.2 
........................................................................... 39 
10.3.3 
........................................................................... 39 
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10.3.4 
................................................................................ 39 
10.3.5 
................................................................................ 40 
10.4 
Bone Marrow Aspiration ......................................................................................... 40 
10.4.1 Samples for Analysis ................................................................................... ... . 40 
10.4.2 Collection of Bone Marrow Aspirate ....................................................... . . ...... 40 
10.4.3 Delivery of Bone Marrow Aspirate ....................................................... . .......... 40 
10.5 
Blood samples ...................................................................................... . ................ 40 
10.5.1 Samples for analysis................................................................... ....................... 40 
10.5.2 Collection of Blood Samples .............................................................................. 40 
10.5.3 Submission of Blood Samples ........................................... ............................... 41 
10.6 
Analysis of Bone Marrow Aspirate and Blood Samples .... ..................................... 41 
10.7 
Storage and Disposal of Samples ............................ . . ........................................... 41 
10.7.1 Clinical Geneticist ........................................... . ............................................... 42 
10.7.2 Reporting of Analysis Results ............................................................................ 42 
11.0 
SAFETY REPORTING .................................. .. ........................................................... 43 
11.1 
Definitions .......................................... . . ................................................................ 43 
11.1.1 Adverse Event Definition ............ ...................................................................... 43 
11.1.2 Adverse Event Definition .... .. .......................................................................... 43 
11.1.3 Severity of AEs ............. .................................................................................... 46 
11.1.4 Clinically Important AEs (Intensively Investigated Events) ................................ 46 
11.1.5 Causal Relationship of Adverse Events .............................................................. 47 
11.1.6 Treatment Discontinuation due to AEs ............................................................... 47 
11.1.7 Outcome .. . ..................................................................................................... 47 
11.2 
Procedures for Recording and Reporting AEs and Serious AEs................................ 48 
11.2.1 Collection of  and Reporting of AEs and Product Quality Issues ........................ 48 
11.2.2 Collection and Reporting of Serious AEs ........................................................... 49 
11.3 
Follow-up of Serious AEs ........................................................................................ 49 
11.3.1 Reporting Serious AEs to the Ethical Review Committee and Regulatory 
Authorities ......................................................................................................... 49 
11.4 
Reporting of additional information on AEs ............................................................. 50 
12.0 
STUDY-SPECIFIC COMMITTEES ............................................................................. 51 
12.1 
Study Steering Committee ....................................................................................... 51 
13.0 
DATA HANDLING AND RECORDKEEPING ............................................................ 52 
13.1 
Case Report ............................................................................................................. 52 
13.2 
Electronic Case Report Input System Deadline ........................................................ 53 
13.3 
Record Retention ..................................................................................................... 53 
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14.0 
STATISTICAL ANALYSIS .......................................................................................... 54 
14.1 
Statistical Analysis Plan ........................................................................................... 54 
14.1.1 Analysis Sets...................................................................................................... 54 
14.1.2 Analysis of Demographics and Other Baseline Characteristics ..................... ... . 54 
14.1.3 Efficacy Analysis .................................................................................... . . ...... 54 
14.1.4 Analysis of Safety ................................................................................. . .......... 57 
14.2 
Interim Analysis and Criteria for Early Termination ............................. . ................ 57 
15.0 
QUALITY CONTROL AND QUALITY ASSURANCE....................... ....................... 60 
15.1 
Study-Site Monitoring Visits ................................................................................... 60 
15.2 
Deviations from Ethical Guidelines and Study Protocol Concerning Medical 
Research for People .......................................................... ...................................... 60 
15.3 
Quality Assurance Audits and Regulatory Agency Inspections ................................ 60 
16.0 
ETHICAL IMPLEMENTATION OF CLINICAL STUDY............................................ 61 
16.1 
IRB Approval .......................................................................................................... 61 
16.2 
Conflicts of Interest .................................... .. ......................................................... 61 
16.3 
Subject Information, Informed Consent, and Subject Authorization ......................... 62 
16.4 
Subject Confidentiality .................... . ..................................................................... 62 
16.5 
Consultation for Study Subjects or Stakeholders ...................................................... 63 
16.6 
Economic Burden or Reward for Research Patients.................................................. 63 
16.7 
Profit of Non-Profit for the Study Subject ................................................................ 63 
16.7.1 Profit of the Research Patient ............................................................................. 63 
16.7.2 Disadvantages for Research Patients .................................................................. 63 
16.8 
Attribution and Access Rights of Research Results .................................................. 64 
16.8.1 Attribution of Research Results .......................................................................... 64 
16.8.2 Data Access Rights ............................................................................................ 64 
16.9 
Publication, Disclosure, and Clinical Trial Registration Policy ................................. 64 
16.9.1 Publication ......................................................................................................... 64 
16.9 2 Clinical Trial Registration .................................................................................. 64 
16.9.3 Clinical Trial Results Disclosure ........................................................................ 64 
16.10 Insurance and Compensation for Injury .................................................................... 65 
17.0 
REFERENCES .............................................................................................................. 66 
............................................................ 70 
 ........................................................... 72 
........................................................... 73 
........................................................... 74 
........................................................... 75 
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.................................................... 76 
.................................................... 78 
.................................................... 80 
 ............................................. ... . 82 
 
LIST OF IN-TEXT TABLES 
Table 9.a 
Criteria for determination of relapse ........................................... . . ................... 31 
Table 9.b 
Laboratory tests......................................................................... ........................ 33 
Table 10.a 
Method of Genetic Analysis ............................................ . ............................... 41 
Table 11.a 
Takeda Medically Significant AE List ........................ .. ................................... 45 
Table 11.b 
AE Grade Defined in CTCAE Japanese Version 4.03 ......................................... 46 
 
 
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2.0 
STUDY SUMMARY 
Sponsor: 
Takeda Pharmaceutical Co., Ltd. 
Title of Clinical Study:  
A Prospective, Multicenter, Observational Study in Relapsed and/or Refractory Multiple 
Myeloma Patients Treated with Ixazomib plus Lenalidomide and Dexamethasone 
Study Number: C16042 
Phase: 4 
Study Design: 
This clinical study is a non-interventional, domestic, multicenter, prospective, observational 
study in patients with relapsed and/or refractory multiple myeloma (RRMM). The patient 
population will consist of adult men and women who have a confirmed diagnosis of multiple 
myeloma (MM), who are scheduled to begin treatment with ixazomib, lenalidomide, and 
dexamethasone (IRd) due to relapsed and/or refractory disease, and who meet other eligibility 
criteria. Approximately 300 patients are planned for enrollment in this study. 
As this is a non-interventional study, the dosage and administration of ixazomib, 
lenalidomide, and dexamethasone will not be defined by the protocol but by the package 
insert of each drug. The IRd therapy administration period will be determined by the principal 
investigator or investigator(s), and patients are required to visit the hospital or contact the 
principal investigator or investigator(s) during the study (including the follow-up period).  
No restrictions will be placed on treatments received by, or management of, patients as part of 
routine medical care. However, study subjects will be asked to visit or contact the hospital 
periodically during the observational period (also including the follow-up period). 
The principal investigator or investigator(s) will conduct the clinical examinations and 
laboratory testing required for standard-of-care treatment, and conduct follow-up on the 
primary outcome of progression free survival (PFS) and secondary outcomes. Study subjects 
will be asked to complete the EORTC-QLQ-30 and MY-20 questionnaires at home or during 
hospital visits in order to assess their quality of life (QOL). 
After the patients start receiving IRd therapy, the principal investigator or investigator(s) will 
conduct follow-up investigations according to the clinical study schedule (Appendix A). The 
observation period for each patient will be from the start of IRd therapy until either 24 months 
after the enrollment date of the final patient to enrol, or until death or withdrawal of consent, 
whichever is earlier. The collection of safety data will begin at the start of IRd therapy and 
continue until 30 days after termination of IRd therapy or the start of the next treatment, 
whichever is earlier. 
Objective: 
To investigate the efficacy and safety of IRd therapy in patients with RRMM, under 
conditions of standard medical care. 
 
  
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Subjects:  
Patients with RRMM who are scheduled to begin IRd therapy 
Planned number of subjects: 
300 
Number of study sites: 
Approximately 100 
Dosage and administration: 
As this is a non-interventional study, the dosage 
and administration of ixazomib, lenalidomide, and 
dexamethasone will not be defined by the protocol 
but according to the package insert of each drug. 
Administration route: 
All of the drugs are taken orally. 
 
Duration of Treatment: 
At the discretion of the principal investigator or 
investigator(s). 
Period of Evaluation: 
Planned period for implementation of the 
clinical study (registration period and 
observation period): 36 months 
• Registration period: 12 months 
• Observation period: 24 months from 
the registration date of the 
last registered patient  
Inclusion criteria: 
Patients satisfying all of the following criteria are eligible to participate in this clinical study: 
1. Male or female patients 20 years of age or older at the time of enrollment 
2. Patients with RRMM 
3. Patients who are scheduled to start IRd therapy 
4. Patients who can provide written informed consent of their own free will before the start 
of study treatment 
5. Patients who are judged by the principal investigator or investigator(s) to have the faculty 
to understand and comply with the requirements of the study  
Exclusion criteria:  
Patients meeting any of the following criteria are not to be enrolled in this clinical study: 
1. Female patients who are nursing or pregnant 
2. Patients who have been treated with ixazomib 
3  Patients with hypersensitivity to any of the components of IRd therapy, their analogs or 
excipients 
4. Patients with another active malignancy, i.e. synchronous active malignancy or previous 
malignancy with a disease-free period of less than 5 years, except for patients with 
carcinoma in situ (intraepithelial carcinoma) or intramucosal carcinoma judged to be 
cured by topical treatment 
5. Patients who are not registered with, or comply with, the guidelines of the lenalidomide 
management program (RevMate®) 
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6. Patients who, in the judgment of the principal investigator or investigator(s), are 
considered to be unsuitable for enrollment into the study 
Criteria for Evaluation and Analyses: 
Primary outcome 
Progression-free survival (PFS) 
Secondary outcomes 
• PFS rate at 12 months and 24 months after the start of treatment 
• Overall survival (OS) 
• Best response 
• Time to next treatment (TTNT) 
• Duration of therapy (DOT) 
• Proportion of patients who continue to receive treatment at 12 months and 24 months 
after start of treatment 
• Overall response rate (ORR) 
• Complete response (CR) plus very good partial response (VGPR) rate (CR+VGPR 
rate) 
• Patient-reported outcomes: health-related quality of life (HRQoL), as evaluated by the 
EORTC QLQ-C30 and MY-20 instruments 
• Rate of minimal residual disease (MRD) negativity in bone marrow in patients who 
achieved CR 
• Relative dose intensity (RDI) for ixazomib, lenalidomide and dexamethasone 
• Bone evaluation 
• Adverse events (AEs) 
 
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Statistical methods: 
Population for Analyses:  
In this clinical study, the patient populations for analysis are classified as the ‘Full Analysis 
Set’, the ‘Effectiveness Analysis Set’, and the ‘Safety Analysis Set’.  
The ‘Full Analysis Set’ is defined as all patients who enroll into the study and who receive at 
least one dose of ixazomib. The ‘Efficacy Analysis Set’ are defined as all patients included in 
the FAS who have measurable lesions prior to the start of IRd therapy and who have at least 
one response evaluation after the start of IRd therapy. The ‘Safety Analysis Set  is defined as 
all patients who enroll into the study who receive at least one dose of any drug used in IRd 
therapy (i.e. ixazomib, lenalidomide, or dexamethasone). 
In addition to the analysis of all enrolled patients, analyses will be conducted in patient 
subgroups defined according to the following characteristics;  
• Frailty-adjusted subgroups 
• Cytogenetic risk subgroups 
• Renal function subgroups 
Analysis of effectiveness: 
Primary outcome  
PFS will be analyzed using disease progression data from the disease evaluations conducted 
by the principal investigator or investigator(s). 
PFS for the FAS will be estimated using the Kaplan-Meier method, and the quartiles and two-
sided 95% confidence intervals will be calculated. 
Secondary outcomes 
For the ‘Full analysis Set’and the ‘Efficacy Analysis Set’, exact two-sided 95% confidence 
intervals based on the ratio and binomial distribution, analysis by Kaplan-Meier method and 
summary statistics are calculated. 
Safety analysis 
For the ‘Safety Analysis Set’, data on the frequency of AEs will be collected. 
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Determination of sample size: 
The purpose of this clinical study is to investigate the efficacy and safety of IRd therapy in 
RRMM patients in Japan. 
Recent pivotal clinical trials in patients with RRMM, including ASPIRE, ELOQUENT-2, 
TOURMALINE-MM1, and POLLUX, were all designed with Rd therapy as a comparator; the 
values of median PFS with Rd in these studies were 17.6, 14.9, 14.7, and 18.4 months, 
respectively. The only report of a complete set of data on patients receiving Rd therapy in 
Japan is from a prospective observational study by KMF, with a reported median PFS of 17.0 
months. Although direct comparison between studies is difficult due to differences in patient 
populations and disease characteristics, the median PFS for patients receiving Rd therapy in 
Japan is estimated to be 15–18 months, based on currently available data. 
In TOURMALINE-MM1, a pivotal clinical trial investigating IRd triplet combination therapy, 
the hazard ratio for PFS in favor of the IRd therapy arm versus the control arm (placebo-Rd 
arm) was 0.74 (0.59–0.94). Based on the assumption that no differences exist in the relative 
efficacy of IRd and placebo-Rd between Japanese patients and the TOURMALINE-MM1 
study population, we used a conservative HR estimate of 0.80 for our calculations. Assuming 
a constant exponential survival distribution, and utilizing a median PFS of 15–18 months for 
Rd therapy and a HR in favor of IRd versus Rd of 0.74–0.80, the following table shows the 
expected median PFS values for IRd therapy: 
Median PFS of 
Rd therapy 
Estimated median PFS with IRd therapy 
HR=0.74 
HR=0.77 
HR=0.80 
15 months 
20.3 months 
19.5 months 
18.8 months 
16 months 
21.6 months 
20.8 months 
20.0 months 
17 months 
23.0 months 
22.1 months 
21.3 months 
18 months 
24.3 months 
23.4 months 
22.5 months 
 
The sample size for this study was determined using a precision-based method, based on the 
expected median PFS with IRd therapy, the primary outcome. The following equation based 
on the median PFS may be used for precision-based sample size calculation: 
 
 
 
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φ: cube root transformed hazard under the null hypothesis 
φ^: cube root transformed hazard under the alternative hypothesis 
    I: observed Fisher information 
r: expected number of events 
If the expected median PFS values with IRd therapy were as shown in the above table, then to 
estimate the two-sided 95% confidence interval with an accuracy of ± 3 months, the required 
sample sizes in the present study of IRd are shown in the corresponding locations in the table 
below (assuming a registration period of 12 months, and follow-up of 24 months from the 
time when the last patient enrolled into the study): 
Median PFS with 
Rd therapy 
Sample size required for study of IRd 
HR=0.74 
HR=0.77 
HR=0.80 
15 months 
224 
200 
180 
16 months 
266 
239 
214 
17 months 
317 
283 
256 
18 months 
370 
333 
298 
 
Based on the considerations above, the number of patients planned for enrollment in this study 
is 300. 
 
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3.0 
ABBREVIATIONS 
ADL 
activity of daily living 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BIRC2/3 
baculoviral IAP repeat containing gene2/3 
BRD 
Bromodomain 
CCI 
charlson comorbidity index 
Ccr 
creatinine clearance 
CCND 
cyclin D 
CD40 
cluster of differentiation 40 
Cdk 
cyclin-dependent kinase 
CI 
confidence interval 
CR 
complete response 
CRF 
case report form 
CRO 
contract research organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
CVA 
cerebrovascular attack 
CYLD 
Cylindromatosis 
DLT 
dose limiting toxity 
DNA 
deoxyribonucleic acid 
DOT 
duration of therapy 
ECOG 
Eastern Cooperative Oncology Group 
EDTA 
ethylenediaminetetraacetic acid 
eGFR 
estimated glomerular filtration rate 
EGFR 
epidermal growth factor receptor 
EORTC QLQ-C30 
European Organization for Research and Treatment of 
Cancer Quality of Life Questionnaire Core-30 module 
FGFR 
fibroblast growth factor receptor 
FLC 
free light chain 
G-CSF 
granulocyte-colony stimulating factor 
GM-CSF 
granulocyte macrophage colony stimulating factor 
GTP 
guanosine triphosphate 
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HIV 
human immunodeficiency virus 
HR 
hazard ratio 
HRQoL 
Health-related quality of life 
IADL 
instrumental activity of daily living 
IL 
Interleukin 
IMiDs 
immunomodulatory drugs 
IMWG 
International Myeloma Working Group 
IRd 
ixazomib plus lenalidomide and dexamethasone 
IRF 
interferon regulatory factor 
ISS 
International Staging System 
ITT 
intent-to-treat 
JCOG 
Japan Clinical Oncology Group 
KMF 
Kansai Myeloma Forum 
LDH 
lactate dehydrogenase 
LIF 
leukemia inhibitory factor 
MAPK 
mitogen-activated protein kinase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MM 
multiple myeloma 
MMSET 
multiple myeloma SET domain 
MR 
minimal response 
MRD 
minimal residual disease 
MRI 
magnetic resonance imaging 
NDMM 
newly diagnosed multiple myeloma 
NFκB 
nuclear factor-kappa B 
NIK 
NF-κB inducing kinase 
NGS 
next generation sequencing 
ORR 
overall response rate 
OS 
overall survival 
OSM 
oncostatin M 
PD 
progressive disease 
PFS 
progression-free survival 
PI 
proteasome inhibitor 
QOL 
quality of life 
RAS 
rat sarcoma oncogene 
RDI 
relative dose intensity 
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Rd 
lenalidomide and dexamethasone 
RRMM 
relapsed and/or refractory multiple myeloma 
SAE 
serious adverse event 
sCR 
stringent complete response 
SOC 
system organ class 
SPEP 
serum protein electrophoresis 
TEAE 
treatment-emergent adverse event 
TIA 
transient ischemic attack 
Tmax 
time to first occurrence of maximum concentration 
TRAF 
TNF receptor-associated factor 
TTNT 
time to next treatment 
UPEP 
urine protein electrophoresis 
VGPR 
very good partial response 
X-p 
x-ray photograph 
 
 
 
 
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In addition, the terms used in this clinical study protocol are defined as follows. 
Study site: 
Refers to corporations, administrative bodies, and sole proprietors who will conduct the 
clinical study. This excludes parties that are entrusted with only part of the tasks related 
to specimen and/or information storage, statistical analyses, and other study-related 
activities. 
Collaborative study sites: 
Refers to a study site where the study is conducted jointly based on the clinical study 
protocol. This includes institutions that acquire new samples and/or information from 
subjects for the study and supply it to other study sites. 
Investigator(s): 
Refers to the principal investigator and other relevant parties involved with the 
implementation of the study (including performing tasks at that site for the collection and 
distribution of samples and/or information). This excludes parties who only supply 
existing samples and/or information at locations other than the study sites, and parties 
involved with only a portion of the work associated with the study. 
Principal investigator: 
Refers to a person who is participating in the implementation of the study, and who 
oversees the tasks associated with the study at his or her affiliated study site. 
Director of study site: 
Refers to the representative of the corporation, the director of the administrative body, or 
the sole proprietor of the study site conducting the study. 
Study subject: 
Refers to persons, including those who are deceased, who fall under any of the following 
categories.  
1. Persons on whom the study is conducted, including persons who requested to 
participate in the study. 
2. Persons from whom existing samples and/or information were collected for use in 
the study. 
 
 
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4.0 
INTRODUCTION 
4.1 
Background 
Multiple myeloma (MM) is a clonal disease of plasma cells that is characterized by an increase 
in serum or urine monoclonal immunoglobulin (M-protein) [1]. MM may result in bone marrow 
failure, bone destruction, hypercalcemia, and renal failure. MM constitutes approximately 1% of 
all reported neoplasms and approximately 13% of hematologic cancers worldwide [2]. In the 
United States in 2017, an estimated 30,280 cases of MM were diagnosed and 12,590 deaths 
occurred due to the disease [3]. In Europe in 2012, an estimated 38,900 cases of MM were 
diagnosed and 24,300 deaths occurred due to the disease [4]. In Asian countries, the incidence 
rate of MM is approaching that seen in Western countries [5][6]. According to the National 
Cancer Center, the number of new cases of MM in Japan in 2015 was estimated to be 
approximately 8,600, with approximately 4,200 deaths due to the disease [7].  
Treatment of MM has undergone major changes in recent years due to the increased 
understanding of the pathology of disease and improvements in therapeutic strategy. Previously, 
conventional therapeutic approaches focused on the use of cytotoxic drugs (e.g. alkylating 
agents, anthracyclines, etc.) and corticosteroids, which showed efficacy as front-line and 
subsequent therapies. However, proteasome inhibitors (PIs) such as bortezomib and 
immunomodulatory drugs such as thalidomide and lenalidomide resulted in improved treatment 
outcomes. hree drug combination of a PI, an immunomodulatory drug and an antibody 
formulation are recommended as treatment options for MM. In addition, two drug combination 
regimens, mainly carfilzomib and dexamethazon, are recommended [8][9]. MM is 
predominantly a disease of the elderly, and it is estimated that the median age at the time of 
diagnosis is 72 years [10]. MM is generally considered incurable with current therapy.  
In recent years, the overall survival (OS) of patients with MM has been extended with the 
introduction of novel therapeutic agents [11] [12]. In a retrospective analysis by the Japanese 
Society of Myeloma, the median OS for patients diagnosed between 2001 and 2012 was 60.6 
months, compared with 38.9 months for patients diagnosed between 1990 and 2000 [13]. A 
separate retrospective study by the Japanese Society of Myeloma and the European Myeloma 
Network showed that the use of new drugs was an independent prognostic factor improving OS 
in both newly diagnosed and relapsed/refractory patients with MM [14]. Regarding the 
prognostic factors for Japanese patients with MM, retrospective studies suggest that long-term 
prognosis is poorer with increasing numbers of prior lines of therapy [15]. Currently, a large-
scale prospective observational study (JSH-MM-15) on the prognosis of myeloma-related 
diseases is being conducted by the Japanese Society of Hematology. The number of treatment 
options using new therapeutic agents is increasing, and research into prognostic factors is 
progressing. However, MM remains incurable; ultimately, almost all patients will relapse and 
require further treatment, and so additional novel treatment options are needed. 
Ixazomib is a boronic acid compound and the biologically active form of ixazomib citrate. 
Ixazomib is an oral, small molecule PI developed by Takeda Pharmaceutical Company that 
selectively targets proteasomes, which are activated in MM and other cancers. The ubiquitin–
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proteasome cascade is a major regulatory system for maintaining protein homeostasis and an 
important mechanism for degradation of proteins including those involved in proliferation 
regulation, cell cycle regulation, and apoptosis. Inhibition of the 20S proteasome system has 
been shown to be effective in the treatment of MM and mantle cell lymphoma. Ixazomib 
selectively binds to the β5 subunit of the 20S proteasome, preventing its chymotrypsin-like 
activity, and inhibits degradation of misfolded proteins [16]. In addition, at higher 
concentrations, ixazomib also inhibits the activity of the β1 and β2 subunits. Furthermore, 
ixazomib has a shorter dissociation half-life compared to bortezomib; it has been shown to be 
widely distributed in tumor tissue, with more sustained proteasome inhibition, and to exert 
greater anti-tumor effects in various tumor xenografts [17]. 
Results of two clinical trials of ixazomib in Japanese patients have been reported. One was a 
domestic phase 1 trial of patients with relapsed/refractory multiple myeloma (RRMM), which 
was conducted following the availability of data from non-Japanese phase 1 clinical trial in solid 
tumors and hematologic malignancies. The domestic phase 1 trial was an open-label, non-
comparative study of the safety and pharmacokinetics of ixazomib 4.0 mg, alone or in 
combination with lenalidomide and dexamethasone, administered orally once a day on days 1, 8, 
and 15 of a 28 day-cycle. Ixazomib was administered to 14 patients (7 patients each in the 
monotherapy and combination therapy arms). No deaths were observed in this study; in the first 
cycle, which was considered as the evaluation period for dose-limiting toxicity (DLT), DLT was 
observed in 1 of 6 patients in the monotherapy arm (diarrhea, nausea, hypokalemia, 
hyponatremia, and hypertension [all Grade 3], and Grade 4 thrombocytopenia), and 1 of 6 
patients in the combination therapy arm (thrombocytopenia and neutropenia, both Grade 4). 
Japanese patients were also treated with ixazomib in another clinical trial – the international, 
double-blind, randomized, placebo-controlled phase 3 TOURMALINE-MM1 trial (C16010 
study) in patients with RRMM. The study compared the efficacy and safety of ixazomib 
administered with Rd (IRd; ixazomib group) with placebo administered with Rd (placebo group). 
Ixazomib 4.0 mg or placebo was administered orally on days 1, 8, and 15 of a 28-day cycle. 
Lenalidomide 25 mg was administered orally on days 1 to 21, and dexamethasone 40 mg was 
administered orally on days 1, 8, 15, and 22. Treatment was continued until the patient met the 
discontinuation criteria. The intent-to-treat (ITT) population consisted of 722 randomized 
patients, which included 41 Japanese patients. At the first planned interim analysis, at which the 
median follow-up was approximately 15 months, IRd was associated with a significant benefit 
compared to placebo-Rd in the primary outcome of progression-free survival (PFS) by 
independent review committee assessment. Median PFS was 20.6 months in the ixazomib group 
and 14.7 months in the placebo group, a difference of approximately 6 months. The hazard ratio 
(HR) for progression or death was 0.74 (95% confidence interval [CI], 0.59–0.94, stratified log 
rank p=0.012), representing a statistically significant improvement in PFS in the ixazomib group 
compared with the placebo group [18]. OS was a secondary outcome; median OS was not 
reached in either group at a subsequent analysis (median follow-up of approximately 23 months 
with data cut-off on July 12, 2015), with a HR of 0.87 (95% CI, 0.64–1.18). The proportion of 
patients with very good partial response (VGPR) or better (i.e. sCR, CR, or VGPR) was 
significantly higher in the ixazomib group (48.1%) compared with the placebo group (39.0%).  
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Safety was analyzed in 720 patients. The mortality rate during treatment or within 30 days after 
the last dose of study drug was 4.2% (15/361) in the ixazomib group and 6.4% (23/359) in the 
placebo group. The incidence of all adverse events (AEs) was 98.3% (355/361) and 99.4% 
(357/359) in the ixazomib and placebo groups, respectively, and the incidence of Grade ≥3 AEs 
was 74.0% (267/361) and 68.8% (247/359), respectively. AEs for which the incidence in the 
ixazomib group was 10 percentage points higher than in the placebo group were 
thrombocytopenia (23.8% and 11.4%, respectively) and vomiting (23.3% and 11.7%, 
respectively). The QOL evaluation results were comparable in both groups. 
Ixazomib was approved in the United States in November 2015 and in Europe in November 
2016, in combination with Rd, for the treatment of MM patients who have received at least one 
prior treatment. In Japan, ixazomib was approved for the treatment of patients with RRMM in 
March 2017. 
4.2 
Rationale for the Proposed Study 
In the international phase 3 C16010 trial (TOURMALINE-MM1), a statistically significant and 
clinically significant PFS extension was observed in the ixazomib group compared to the placebo 
group, in the primary efficacy analysis of the ITT population. However, it was determined that 
further study in a Japanese population was required as TOURMALINE-MM1 included only 41 
Japanese RRMM patients (20 in the ixazomib group and 21 in the placebo group). The C16010 
trial is ongoing in a double-blinded fashion, per protocol, to follow up for OS. Additionally, a 
domestic phase 2 trial of IRd – the C16028 trial – has started. The C16010 and C16028 trials are 
ongoing as post-marketing trials. In both trials, patients who were refractory to PI-based or 
lenalidomide treatment were excluded, and eligible patients were restricted to 1 to 3 prior 
therapies; in the C16010 trial, 90% of patients had 1 or 2 prior treatments [18]. Furthermore, 
lenalidomide was administered at a dose of 25 mg in C16010 and C16028, whereas the median 
dose of lenalidomide in a Japanese, post-marketing, all-case surveillance study was 15 mg [19]. 
Considering the restricted RRMM patient population for C16010 and C16028, the real-world 
dosing reported with lenalidomide, and the need to manage side effects with the IRd regimen, it 
was determined that investigation of IRd was required in a patient population that more closely 
reflected the real-world RRMM patient population in Japan.  
Therefore, this prospective, observational clinical study was planned to investigate the efficacy 
and safety of IRd therapy in Japanese patients with RRMM receiving standard medical care. As 
part of the study, subgroup analysis for identification of prognostic and predictive factors, 
investigation into risk-related factors, and evaluation of new patient stratification factors using an 
exploratory analysis are also planned. Furthermore, assessment of patients’ QOL during IRd 
treatment will be conducted to investigate the influence on physical, social, and emotional 
functioning by the continued administration of IRd under the daily medical practice. 
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5.0 
STUDY OBJECTIVE 
5.1 
Objectives 
To examine the efficacy and safety of ixazomib in combination with lenalidomide and 
dexamethasone in Japanese patients with RRMM receiving standard medical care. 
 
 
5.2 
Outcomes 
5.2.1 Primary Outcome 
• Progression-free survival (PFS) 
5.2.2 Secondary Outcomes 
• PFS rate at 12 months and 24 months 
• Overall survival (OS) 
• Best response 
• Time to next treatment (TTNT) 
• Duration of therapy (DOT) 
• 
Proportion of patients who continue to receive treatment at 12 months and 24 months 
after start of treatment 
• Overall response rate (ORR) 
• Complete response (CR) plus very good partial response (VGPR) rate (CR+VGPR rate) 
• Patient-reported outcomes: health-related quality of life (HRQoL), as evaluated by the 
EORTC QLQ-C30 and MY-20 instruments 
• Rate of minimal residual disease (MRD) negativity in the bone marrow of patients who 
achieve CR 
• Relative dose intensity (RDI) for ixazomib, lenalidomide and dexamethasone 
• Bone evaluation 
• AEs 
5.2.3 
 
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6.0 
STUDY DESIGN 
6.1 
Overall Study Design and Plan: Description 
This clinical study is a non-interventional, domestic, multicenter, prospective, observational 
study in patients with RRMM. Adult men and women who have a confirmed diagnosis of MM, 
who are scheduled to begin IRd therapy due to relapsed and/or refractory disease, and who meet 
other eligibility criteria, will be enrolled. Approximately 300 patients will be enrolled in the 
study. 
As this is a non-interventional study, the dosage and administration of the ixazomib, 
lenalidomide, and dexamethasone will not be defined by the protocol but by the package insert of 
each drug. The IRd therapy administration period will be determined by the principal 
investigator or investigator(s), and patients are required to visit the hospital or contact the 
principal investigator or investigator(s) during the study (including the follow-up period). 
Assuming a registration period of 12 months, and follow-up of 24 months from the time when 
the last patient enrolled into the study. 
No restrictions will be placed on treatments received by, or management of, patients as part of 
routine medical care. However, study subjects will be asked to visit or contact the hospital 
periodically during the observational period (also including the follow-up period). 
The principal investigator or investigator(s) will conduct the clinical examinations and laboratory 
testing required for standard-or-care treatment, and conduct follow-up on the primary outcome of 
PFS and secondary outcomes. Study subjects will be asked to complete the EORTC QLQ-30 and 
MY-20 questionnaires at home or during hospital visits in order to assess their QOL. 
After the patients start IRd therapy, the principal investigator or investigator(s) will conduct 
follow-up investigations according to the clinical study schedule (Appendix A). The observation 
period for each patient will be from the start of IRd therapy until either 24 months after the 
enrollment date of the final patient to enroll, or until death or withdrawal of consent, whichever 
is earlier. The collection of safety data will begin at the start of IRd therapy and continue until 30 
days after termination of IRd therapy or the start of the next treatment, whichever is earlier. 
For the testing  observation, and follow-up schedule, refer to Appendix A. 
6.2 
Termination or Suspension of Study or Study Site 
6.2.1 Criteria for Premature Termination or Suspension of the Study 
The study will be completed as planned unless one or more of the following criteria are satisfied 
that require temporary suspension or early termination of the study: 
• New information or other evaluation regarding the safety or efficacy of ixazomib that 
indicates a change in the known risk/benefit profile of the compound is obtained, such 
that the risk/benefit profile is no longer acceptable for patients participating in the study. 
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• A significant violation of Ethical Guidelines for Medical and Health Research Involving 
Human Subjects that compromises the safety of the study participants. 
6.2.2 Criteria for Premature Termination or Suspension of Investigational Sites 
A study site may be terminated prematurely or suspended if the study site (including the 
investigator) is found in significant violation of the Ethical Guidelines for Medical and Health 
Research Involving Human Subjects, clinical protocol, or contractual agreement, is unable to 
ensure adequate performance of the study, or as otherwise agreed by the contractual agreement. 
6.2.3 Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s) 
In the event that the sponsor, an institutional review board (IRB), or regulatory authority elects to 
terminate or suspend the study or the participation of a study site, a study-specific procedure for 
early termination or suspension will be provided by the sponsor; the applicable study site will 
follow procedure during the course of termination or study suspension. 
6.3 
Procedures for Revision of Protocol  
If the protocol needs to be revised, the sponsor shall consider and decide whether the revision is 
possible or not. The principal investigator of each site shall be informed of the details of each 
protocol revision. In addition, principal investigators shall confirm the content of the revision of 
the protocol and submit a letter of agreement to the sponsor as evidence of agreement with the 
protocol revision. 
Revising clinical study implementation plan 
1. Change or addition of objective(s) 
2. Change or addition of evaluation method for efficacy or safety 
3. Additional procedures (including frequency) for which the burden on the study 
participant increases  
4. Significant change to, or addition of, inclusion or exclusion criteria 
5. Change in the number of planned participants 
6. Change in the plan or description, due to the occurrence of serious AEs 
7. A change determined to be serious as a result of consultation between the sponsor and the 
research steering committee chairperson.  
Following notification regarding such a protocol revision, the principal investigator of each study 
site must obtain the approval from the head of the study site after undergoing review by the site’s 
internal ethics committee as necessary, according to the regulations of each study site. 
 
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7.0 
STUDY SUBJECTS 
All entry criteria, including test results, need to be confirmed prior to start of treatment. 
7.1 
Inclusion Criteria 
Patients satisfying all the following criteria are eligible to participate in this clinical study: 
1. Men and women aged 20 years or older at the time of enrollment 
2. Patients with RRMM 
3. Patients who are scheduled to start IRd therapy 
4. Patients who can provide written informed consent of their own free will before the start 
of study treatment 
5. Patients who are judged by the principal investigator or investigator(s) to have the faculty 
to understand and comply with the requirements of the study 
7.2 
Exclusion Criteria 
Patients meeting any of the following exclusion criteria are not to be enrolled in this clinical 
study. 
1. Female patients who are nursing or pregnant 
2. Patients who have been treated with ixazomib 
3. Patients with hypersensitivity to any of the components of IRd therapy, their analogs or 
excipients 
4. Patients with another active malignancy, i.e. synchronous active malignancy or previous 
malignancy with a disease-free period of less than 5 years, except for patients with 
carcinoma in situ (intraepithelial carcinoma) or intramucosal carcinoma judged to be 
cured by topical treatment 
5. Patients who are not registered with, or comply with, the guidelines of the lenalidomide 
management program (RevMate®) 
6. Patients who, in the judgement of the principal investigator or investigator(s), are 
considered to be unsuitable for enrolment into the study 
7.3 
Study Registration 
Patients are to be enrolled into the study after providing consent and all patients who provide 
consent are to be registered on the web-based registration site at the start of treatment.  
For procedures to document study subjects who withdraw before the start of IRd therapy, refer to 
section 9.1.21. 
Subjects should be included in the study only once.  
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Data erroneously collected from subjects for which written consent is not available, will not be 
included in or will be deleted from the database. 
 
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8.0 
TREATMENTS  
Non-interventional/observational – no treatments/pharmacotherapy are instructed by the study 
protocol. 
All treatments employed in this study are prescription medicines and will be administered or 
monitored from study sites. For details and handling of medications, refer to the latest package 
inserts. 
8.1 
IRd Therapy 
8.1.1 Definition of IRd Therapy 
IRd therapy used in this clinical study is a combination of three drugs: ixazomib, lenalidomide, 
and dexamethasone. IRd therapy will be considered to be ongoing even during periods in which 
any of the three drugs are not administered due to e.g. AEs. 
The start date of a cycle of IRd therapy will be defined as the earliest date of the three start dates 
for ixazomib, lenalidomide, and dexamethasone. One cycle is defined as 28 days. 
8.1.2 Dosage and Administration Method in IRd Therapy 
As this clinical study is a non-interventional study, the dosage and administration of ixazomib, 
lenalidomide, and dexamethasone will not be defined by the protocol but by the latest package 
insert of each drug. 
8.1.3 Overdose of Ixazomib 
An overdose is defined as a known, deliberate, or accidental administration of ixazomib, to or by 
a patient, at a dose above that which is specified in the package insert. 
All cases of overdose of ixazomib should be documented in the appropriate section in the case 
report form (CRF), in order to record any data on ixazomib overdose into a database. Any AEs 
due to overdose of ixazomib are to be documented according to section 11.0. 
Any serious adverse events (SAEs) associated with overdose of ixazomib are to be reported 
according to section 11.2.2. 
8.2 
Excluded Concomitant Medications and Procedures  
As this is a non-interventional observational study, there will be no provisions on excluded 
concomitant medications, or procedures; however, the precautions for concomitant medications 
for each drug must be followed as described in the latest package insert. 
If any drugs or procedures other than IRd therapy are administered during the clinical study for 
the treatment of MM, information on these drugs or treatments will be gathered as described in 
the protocol. 
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8.3 
Discontinuation of IRd Treatment  
The number of cycles of IRd therapy is not prespecified and is determined according to the 
judgement of the principal investigator or investigator(s) until a patient wishes to stop 
participating in the clinical study or dies. The principal investigator or investigator(s) must 
record the main reason for discontinuation of study treatment in the CRF, according to the 
following classifications. For cases in which the patient discontinues before commencing IRd 
therapy, see section 9.1.21. 
1. Lack of efficacy (or exacerbation of disease) 
Defined as PD according to IMWG criteria (Appendix F). 
2. Adverse event 
If an AE requiring an early discontinuation, or if the patient does not wish to continue 
with the study due to AE, the patient will be discontinued to avoid unacceptable risk to 
the health of the patient. In case the patient dies during the study treatment, it is classified 
as death during study treatment 
3. Voluntary withdrawal by patient 
Defined as when a patient wishes to stop participating in study treatment. If the reason for 
discontinuation is known, the investigator is to record the reason(s) in the CRF 
Investigators should attempt to make the reasons for voluntary discontinuation as clear as 
possible 
4. Significant deviation from study protocol 
Defined as occurring if, after the start of IRd therapy, it becomes known that the patient 
did not meet the inclusion criteria of the study protocol; or, there is a possibility that 
continued clinical study may result in an unacceptable risk to the patient’s health because 
the patient or investigators did not comply with the study protocol 
5. Lost to follow-up 
Defined as if a patient does not visit the hospital and the investigator can not contact the 
patient. In this case, the investigator should record that an attempt has been made to 
contact the patient in the source document. 
6. Termination of study 
For example, if the sponsor, ethics review committee, or regulatory authority decide to 
terminate the clinical study. See section 6.2.1 for details. 
7. Patient Death during study treatment 
Defined as if a patient dies before a decision is reached to discontinue IRd therapy. The 
investigator to record the date of death in the CRF. 
8. Pregnancy 
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When a female patient’s pregnancy becomes known. 
9. Other 
If the principal investigator or investigator(s) decide that it is necessary to discontinue 
treatment for any other reasons, the investigator will describe the details in the CRF. 
8.4 
Procedure for Discontinuation of Clinical Study by the Enrolled Patient 
A patient may discontinue their participation in the study at any time without explanation. 
If a patient discontinues from the study, the principal investigator or investigator(s) will record 
the main reason in the CRF. 
 
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9.0 
STUDY PLAN 
9.1 
Study Procedures  
The following section describes the study procedures and data to be collected by the principal 
investigator or investigator(s). For each procedure, the same principal investigator or 
investigator(s) will perform the testing, observation, and follow-up of the subjects whenever 
possible. For the study schedule, refer to Appendix A. 
9.1.1 Informed Consent Procedure 
The protocol for obtaining informed consent is described in Section 16.3. Each patient must 
provide written informed consent before any study-related procedures are conducted, including 
collection of any study data (but excluding data collected as part of standard clinical care).  
A unique patient identifier (subject ID) will be assigned to each patient at the time that informed 
consent is obtained; this subject ID will be used throughout the study and will remain unchanged. 
A separate informed consent will be requested from the patient for the exploratory biomarker 
study. 
9.1.2 Patient Demographics and Baseline Disease Characteristics 
Demographic information and disease characteristics at baseline to be obtained will include: 
• Date of birth (if not provided, age at registration will be used) 
• Sex 
• Initial diagnosis of MM: initial date of diagnosis of MM 
• M-protein isotype: 
IgG κ or λ, IgA κ or λ, IgD κ or λ, IgE κ or λ, IgM κ or λ, Bence Jones type κ or λ, non-
secretory type, other 
• 
Clonal bone marrow plasma cell percentage:  
Clonal bone marrow plasma cell percentage will be collected if it is measured just before 
starting of IRd therapy. 
• 
Immunophenotyping: CD20, CD56 (positive, negative, not conducted) 
• Clinical stage according to ISS (Appendix C) 
• Cytogenetic abnormalities at initial diagnosis: t(4;14), t(14;16), t (11;14), del(17p), 1q 
gain 
• Frailty score: 
Patients will be investigated the frailty score according to the IMWG frailty scale 
(Appendix E) [21]. Patients will record the activities of daily living (ADL) and the 
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instrumental activities of daily living (IADL) and investigators will record the charlson 
comrbidity index (CCI) as described in Section 9.1.3 at the start of IRd therapy.  
• Evaluation of bone lesions and extramedullary masses: 
If imaging is conducted at the start of the IRd therapy, it will be assessed for the presence 
of bone lesions and extramedullary masses (bone-delivered, or soft tissue-delivered or 
others). Alternatively, the most recent imaging assessments from prior to obtaining 
consent may instead be used. 
• Determination of prior treatment efficacy: 
The clinical efficacy of prior treatment received immediately before commencing IRd 
therapy will be determined based on the IMWG criteria (2014 version) (Appendix 
F ,Table 9.a) [9].  
The treatment effect is determined by comparing the best response of prior treatment with 
the laboratory result at relapse. 
 
Table 9.a 
Criteria for determination of relapse 
Clinical relapse 
• Development of new soft tissue plasmacytomas or 
bone lesions on skeletal survey, magnetic resonance 
imaging, or other imaging 
• Definite increase in the size of existing 
plasmacytomas or bone lesions, defined as a 50% 
(and at least 1 cm) increase as measured serially by 
the sum of the products of the cross-diameters of the 
measurable lesion  
• Hypercalcemia (serum calcium > 0.25mmol/L of 
ULN; pH-corrected serum calcium > 11.5 mg/dL) 
• Decrease in hemoglobin of more than 2 g/dL 
(1.25mM) or to less than 10 g/dL 
• Rise in serum creatinine by more than or equal to  
2 mg/dL 
• Hyperviscosity requiring treatment 
Paraprotein relapse 
In patients who do not have clinical relapse, a significant 
paraprotein relapse is defined as patients fulfilling at least one 
of the below criteria for two consecutive measurements 
separated by ≤ 2 months 
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• Doubling or more of serum M-protein when M-
protein is ≥ 0.5 g/dL 
• Increase in the absolute level of serum M-protein by  
≥ 1 g/dL 
• Increase in urine M-protein by ≥ 500 mg/24h 
• Increase in the FLC level by ≥ 200 mg/L 
 
 
9.1.3 Comorbidity 
Investigators will record patient comorbidities at the start of IRd treatment using the Charlson 
comorbidity index (CCI) [20] (Appendix B). 
In addition, investigators will evaluate the presence or absence, and Grade, of peripheral 
neuropathy and rash at the start of IRd treatment. 
9.1.4 Medical History 
The investigator will record whether a patient has received antineoplastic therapy, prior radiation 
therapy, or hematopoietic stem cell transplantation for the treatment of MM. 
• Prior antineoplastic therapies: drug name, date of start of treatment, date of termination of 
treatment, reason for termination (i.e. PD, reason other than PD), best response 
• Prior radiation therapy 
• Prior hematopoietic stem cell transplant; if yes, the date of start of treatment.  
9.1.5 Physical Examination 
A complete physical examination and symptom-directed physical exam of relevant organ 
systems will be undertaken by the investigator prior to the start of IRd treatment. 
Regarding physical examinations after the start of IRd treatment, the investigator will evaluate 
the presence or absence of clinically significant differences compared with the examination 
undertaken prior to start of IRd treatment. 
9.1.6 Performance Status 
Performance Status will be assessed according to the ECOG PS (Appendix D). 
9.1.7 Body Weight, Height 
Weight and height will be measured at the study site prior to the start of IRd treatment. 
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Height will be recorded in centimeters to the nearest whole number, and weight will be measured 
in kilograms to one decimal place. 
E.g.: Height = 176 cm, weight = 79.2 kg 
9.1.8 Status of IRd Therapy 
The principal investigator or investigator(s) will record the following information related to IRd 
therapy in the CRF: 
• Dosing of each drug used in IRd therapy, including the start date of a treatment cycle, and 
the dose administered of each drug. 
Note: the start date of a treatment cycle is defined as the earliest of the three start dates of 
the drugs used in IRd therapy. One cycle is defined as 28 days. 
9.1.9 Clinical Laboratory Evaluations 
Clinical laboratory evaluations will be performed at each study site. For clinical chemistry and 
hematology parameters measured, see Table 9.b. 
 
Table 9.b 
Laboratory tests 
Hematology 
Serum biochemistry 
White blood cell count 
Hemoglobin 
Platelet count 
Neutrophil count 
Albumin 
Total bilirubin 
AST 
ALT 
ALP 
LDH (only at the start of IRd therapy) 
Creatinine 
Ccr (measured value) 
Calcium 
β2-microglobulin (only at the start of IRd 
therapy) 
 
Creatinine clearance (Ccr) (estimated value) and the glomerular filtration rate (eGFR) will be 
estimated using the serum creatinine value and, for Ccr, the Cockcroft-Gault equation. 
 
Calculation for the estimation of eGFR, published by the Japanese Society of Nephrology 
(2008): 
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For men: 
eGFR (mL/min/1.73 m2) = 194 * serum creatinine [mg/dL]-1 094 * age [years] -0 287 
For Women: 
eGFR (mL/min/1.73 m2) = 194 * serum creatinine [mg/dL]-1 094 * age [years]-0 287×0.789 
 
Cockcroft-Gault equation for the estimation of Ccr: 
For men: 
Ccr = 
(140 −age [years]) × weight [kg]
72 × serum creatinine [mg/dL]  
For women: 
Ccr = 
(140 −age [years]) × weight [kg]
72 × serum creatinine [mg/dL] × 0.85 
 
9.1.10  Evaluation of QOL 
Patient-reported outcomes (QOL) will be collected by the investigators using the EORTC-QLQ-
C30 (Appendix G) [22] and MY-20 (Appendix H) [23] instruments. 
Patient-reported outcomes will be collected before administration of IRd therapy. During 
treatment with IRd, patient-reported outcomes will be collected every 6 cycles (i.e. before 
administration of therapy in cycle 1, before administration of therapy in cycle 7, etc.). 
9.1.11  Quantification of M-protein 
M-protein levels in blood samples and urine samples will be measured at the study sites. If it is 
not possible to measure serum and urine M-protein levels, the serum FLC level may be measured 
instead. The reference value of FLC will be taken from the standards used in the FREELITE® 
assay, developed by Binding Site. 
9.1.12  Response Assessment 
The principal investigator or investigator(s) will determine the clinical response of the patient 
according to the IMWG criteria (2014 version) (Appendix F) using data on serum M-protein, 
urine M-protein, and serum FLC.  
9.1.13 Bone Marrow Aspiration 
Bone marrow samples will be collected at the start of IRd therapy and at suspected CR (response 
better than VGPR). Bone marrow aspiration must take place on Monday through Friday, and 
must not take place on Saturday, Sunday or the holiday. The samples collected at the start of IRd 
therapy will be used for cytogenetic testing, measurement of MRD, and biomarker research (see 
section 9.1.14). The samples collected at initial assessment of CR will be used for MRD 
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measurement; re-assessment for MRD is possible on one occasion, from 6 months after bone 
marrow aspiration for evaluation of MRD until completion of this clinical study. For patients 
from whom bone marrow samples were collected at discontinuation of IRd therapy (i.e. sample 
taken between the date of discontinuation of IRd and the date of initiation of next treatment), if 
possible, these samples should also be submitted for biomarker research. Clinically unnecessary 
intervention (i.e. bone marrow aspiration) to collect a sample at discontinuation of IRd therapy is 
prohibited. The time and date of sample collection will be noted on the analysis request form. 
• Cytogenetic testing 
Cytogenetic testing will be conducted using the bone marrow aspirate sample collected at the 
start of IRd therapy. After isolation of CD138-positive cells, the proportion of cells positive 
for t(4;14), t(11;14), t(14;16), 1q gain, and del(17p) will be measured   
• MRD measurement: 
MRD evaluation will be conducted by the NGS method using the bone marrow aspirate 
samples from the start of the IRd treatment, and MRD measurement will be conducted by 
both the NGS method and 
-flow method using bone marrow aspirate samples from CR 
assessment.  
9.1.14 Biomarker Study 
Samples of bone marrow aspirate (see section 9.1.13) and blood will be collected from patients 
who provide additional consent for participation in the biomarker study and evaluated for a range 
of biomarkers. See section 10.0 for more information on the biomarker study. 
9.1.15  Image Examination 
When the investigator(s) performs an imaging test on the patient, the presence or absence of new 
bone lesions and extramedullary plasmacytomas (bone-delivered, or soft tissue-delivered or 
others) will be evaluated. 
9.1.16  Supportive Therapy 
Investigators will record the use and timing (name of drugs, start date and discontinuation date) of 
supportive therapies for varicella zoster and P. jirovecii infection (e.g. ST combination drug) in 
the patient from the start of IRd therapy until discontinuation of IRd therapy. 
9.1.17  Adverse Events 
AEs (serious and non-serious) will be monitored throughout the study period. For details 
regarding defining, recording, and reporting of AEs and serious AEs, see section 11.0. 
9.1.18  Follow-up Assessments 
Patients who discontinue administration of IRd therapy before disease progression will be 
subject to follow-up surveillance to determine PFS. Follow-up assessment for PFS will be 
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conducted by hospital visits every 3 months until confirmed PD or death, or until the patient is 
lost to follow-up.  
All patients who discontinue IRd therapy will be subject to follow-up surveillance to determine 
OS. Follow-up assessment for OS will be conducted every 6 months until death or until the 
patient is lost to follow-up.  OS follow-up will be done by methods including telephone calls, e-
mails, or mail, and a hospital visit may not be necessary. Investigators will collect the following 
information 
• Survival date 
• Date of death or last known survival date 
9.1.19  Next-line Treatment 
If a patient receives treatment after discontinuing IRd therapy, the investigator will collect the 
following information for the subsequent therapy after discontinuation. 
• Name of drugs 
• Start date 
9.1.20 Pregnancy  
If any female patient is found to be pregnant during treatment with IRd therapy or within 90 days 
after the end of the study, the pregnancy should be reported immediately.  
If the patient agrees to the primary care physician (obstetrics and gynecology specialist) being 
informed, the principal investigator or investigator(s) should notify the primary care physician 
that the patient was participating in a clinical study at the time she became pregnant and provide 
details of the treatment the patient received.  
For all reported pregnancies, the outcome until the delivery, including premature birth, will be 
followed up and reported to the sponsor using the pregnancy form, with the patient’s consent. 
Evaluations after birth will also be conducted. 
For male patients, if a patient’s female partner becomes pregnant during treatment with IRd 
therapy or within 90 days of termination of study, the outcome until the delivery, including 
premature birth, will be followed up and reported to the sponsor using the pregnancy form, with 
the patient’s consent. Evaluations after birth will also be conducted. 
9.1.21  Study Participation Discontinued Before Administration of Study Medication  
In the event that a patient signs a consent form and the investigator prepares a CRF, but the 
patient then discontinues before the administration of the study medication, the CRF will contain 
the following items: 
• Date of consent acquisition 
• Consent to biomarker study 
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• Date of birth (If a date cannot be provided, then the age at registration) 
• Sex 
• Eligibility 
• Reason for cancellation  
Investigators will collect the main reasons for discontinuation before administration of 
IRd therapy medication according to the following categories: 
o Did not meet selection criteria or violated exclusion criteria 
o Critical deviation from study protocol 
o Unable to follow-up 
o Voluntary discontinuation; describe the reason 
o Cancellation of the clinical study as a whole 
o Other; describe the reason 
The investigator must not reuse the identification code of the patient who discontinued 
before administration of IRd therapy, for another patient in the study. 
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 relevant to IRd therapy. For biomarkers in this study, the 
appropriate myeloma-associated genes will be selected by the time of evaluation. The study 
protocol will be revised prior to evaluation to define the selected myeloma-associated genes. 
10.3 
Rationale for selecting biomarkers 
The following section describes the rationale for selecting each biomarker. With regards to 
genomic biomarker and measurement technology, new biomarkers may be added as new 
findings are obtained every day. Additional criteria using new measurement methods may be 
included. 
10.3.1 
 
10.3.2 
 
10.3.3 
 
10.3.4 
 
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10.3.5 
 
10.4 
Bone Marrow Aspiration 
10.4.1 Samples for Analysis 
For patients who provide consent at initiation of IRd therapy, bone marrow aspirate collected at 
initiation of IRd therapy will be used (see section 9.1.13). 
10.4.2 Collection of Bone Marrow Aspirate 
The principal investigator or investigator(s) will collect bone marrow aspirate samples according 
to section 9.1.13. 
10.4.3 Delivery of Bone Marrow Aspirate 
The principal investigator or investigator(s) will send the sample to 
 using materials 
prepared by 
. In advance of the study starting, 
 will send the necessary materials for 
transporting bone marrow aspirate samples to all participating study sites. 
10.5 
Blood samples 
10.5.1 Samples for analysis 
For patients who provide consent at initiation of IRd therapy, blood will be drawn at two 
timepoints: at initiation of IRd therapy and at termination of IRd therapy (i.e. between 4 weeks 
from the day of termination of IRd therapy and the start of next treatment). 
For cases in which consent is obtained after initiation of IRd therapy, a blood sample will be 
collected at termination of IRd therapy. 
10.5.2 Collection of Blood Samples 
The principal investigator or investigator(s) will send the samples to 
 using the materials 
prepared by 
. Two EDTA tubes (8 ml) of blood will be collected at each sample collection. 
The blood sample may be collected at any time after the patient has provided consent and until 
immediately before the initiation of IRd therapy. On termination of IRd therapy, a blood sample 
should be collected at 4 weeks from the date of treatment termination or before the start of the 
next treatment. 
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The collected blood sample will be centrifuged and the plasma stored in a ≤ -20°C freezer until 
 collects the sample. 
The date of blood collection should be noted on the analysis request form. 
10.5.3 Submission of Blood Samples 
 must send in advance any materials necessary for collecting and submitting blood samples 
to the registered study sites. 
The principal investigator or investigator(s) must request 
 to collect the sample before 
drawing blood. 
Details concerning the collection and submission of blood or plasma samples are described in the 
supplementary documents to be prepared separately. 
10.6 
Analysis of Bone Marrow Aspirate and Blood Samples 
Genetic material extracted from bone marrow aspirates and plasma samples will be analyzed for 
genetic mutations. 
The method of analysis is described, and details of the analytical laboratory are shown in 
Supplement 1 of the study protocol.  
Table 10.a 
Method of Genetic Analysis 
Sample type 
Measurement Method 
 
 
 
 
 
10.7 
Storage and Disposal of Samples 
The collected samples shall be stored by 
 and the gene analysis laboratory as described in 
Supplement 1 of the study protocol. Bone marrow aspirate samples and plasma samples, prior to 
DNA extraction, and extracted genomic samples, will be stored in a -80°C deep freezer. 
Submitted bone marrow aspirate and plasma samples, as well as extracted genomic samples, may 
be used in future for a secondary study of biomarkers. In this clinical study, therefore, the study 
subjects shall be asked to consent to the use of samples for secondary studies. The use of samples 
from consenting study subjects will not be limited to the current exploratory biomarker study. As 
these valuable samples may benefit future medical research, samples shall be kept for a 
maximum of 20 years after the completion of this clinical study. When these specimens are 
determined to not be used for further study, or when the preservation period expires, the subject 
ID shall be deleted, the specimens appropriately discarded as medical waste, and discard records 
shall be noted. In addition, if the study subjects withdraw consent, when the subject ID cannot be 
recognized e.g. due to label or computer abnormality, or when the principal investigator or 
investigator(s) determines that disposal is necessary, samples may be discarded. If the samples to 
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be discarded e.g. due to withdrawal of consent, are stored at the study site, the principal 
investigator or investigator(s) will discard them at the study site. If the stored sample is to be 
used for secondary medical research in the future, a new research plan will be prepared and 
approval obtained from the ethics review committee as necessary. 
10.7.1 Clinical Geneticist 
The main purpose of the clinical geneticist is to advise on the analytical results, and to consider 
the results obtained. Details of the role of the clinical geneticist are specified in a separate 
procedures manual. 
For the clinical geneticist, refer to section 1.2. 
10.7.2 Reporting of Analysis Results 
The analysis results shall be disclosed if there is a request from the study subject. However, 
when disclosing the analysis results to study subjects, it must be considered that the study of 
biomarkers in this clinical study is exploratory, and the results obtained need to be proved by 
further studies. The accuracy and precision of the analytical methods used may be immature and 
there may be uncertainties in analysis results. However, even if these considerations are taken 
into account, if it is considered to be better to disclose secondary findings to the study subject 
from an ethical point of view, the ethics review committee will deliberate on the issue as 
necessary. 
 
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11.0 
SAFETY REPORTING 
11.1 
Definitions 
11.1.1 Adverse Event Definition 
An AE is defined as any untoward medical occurrence in a study subject administered a 
pharmaceutical product (including IRd therapy); the untoward medical occurrence does not 
necessarily have a causal relationship with the treatment (including IRd therapy.) 
An AE can therefore be any unfavorable and unintended sign (including a clinically significant 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medical product (including IRd therapy), whether or not it is related to the medical product 
(including IRd therapy). 
11.1.2 Adverse Event Definition 
Generally, undesirable AEs include: 
• Newly diagnosed disease or deterioration of an existing condition   
o (Intermittent events of existing disease are not considered as AEs) 
• Any event requiring treatment or medical treatment 
• AEs requiring invasive diagnostic procedures 
• AEs requiring discontinuation of IRd therapy or dose change 
• AEs that the principal investigator or investigator(s) regarded as undesirable 
Diagnosis name and signs/symptoms: 
• AEs will be recorded by diagnosis name. Any accompanying signs (including abnormal 
laboratory test values or abnormal ECG) or symptoms will not be considered AEs. In 
case of an AE without a diagnosis, signs and symptoms will be considered AEs. 
Laboratory test values and ECG findings: 
• Changes in clinical laboratory test values or ECGs will be considered as AEs only when 
the responsible principal investigator or investigator(s) determines that there is a clinical 
problem arising from the changes (i.e., when a treatment or medical treatment is required, 
or if the principal investigator or the investigator(s) regards the change as beyond the 
normal physiological variation range for the patient). Reexamination and/or ongoing 
monitoring of abnormal values are not considered as medical treatment. In addition, 
repeated or additional noninvasive examination for verification, evaluation, or monitoring 
is not considered a medical treatment. 
However, if the clinical laboratory test value or ECG is accompanied by a diagnosis of an 
AE (e.g. creatinine increase due to impaired renal function), its diagnosis name will be 
regarded as an AE. 
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Existing diseases (diseases and symptoms existing before the start of study drug administration): 
• Diseases and symptoms existing before the start of administration of IRd therapy will be 
recognized as complications and not as AEs. If the complication worsens, the 
deterioration will be recognized as an AE, and the principal investigator or investigator(s) 
will record the name of AE name as a worsening of complications (e.g. ‘worsening 
hypertension’) in the CRF 
• If a patient has a temporary existing disease (e.g., asthma, epilepsy), if the frequency of 
its symptoms increases, or if an increase in severity or advancement of disease is 
observed, the existing disease will be recorded as an AE. If a patient has a chronic disease 
(e.g. cataract, rheumatoid arthritis), the chronic disease will be recorded as an AE if the 
symptoms worsen more than expected. The principal investigator or investigator(s) 
should record the reported AE name as a change in existing chronic disease symptoms 
(e.g. worsening of...) from the start of the study treatment  
Changes in the severity of AE: 
• If there is a change in the severity of the AE, the investigator will record only the instance 
when the maximum severity is observed. 
Pre-planned surgery or treatment: 
• Surgery or treatment planned before the start of administration of IRd therapy will not be 
considered an AE. However, if a patient's existing symptoms deteriorate markedly and 
surgery or treatment needs to be performed urgently, that condition or event will be 
considered an AE. Complications due to pre-planned surgical procedures will be recorded 
as AEs. 
Surgery or treatment requiring no urgency: 
• Surgery or treatment that does not suddenly affect the patient’s symptoms, such as 
cosmetic surgery, will not be considered an AE. However, the investigator will record 
this in the CRF. Complications due to surgery that require no urgency will be reported as 
AEs. 
Progressive disease: 
• PD will not be regarded as an AE as it is a result of lack of efficacy of pharmaceuticals. 
Also, symptoms that corresponds to a diagnosis of PD do not need to be considered as a 
serious AE. However, if the progression of an existing cancer (including the development 
of new metastases) is confirmed clinically or by examination, and if the degree of 
progression of the cancer falls under the serious criterion of as per section 11.1.3, 
progression of the cancer will be considered a serious AE. 
Overdose of ixazomib: 
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Overdose of ixazomib without any event will not be considered an AE. However, investigators 
shall record the overdose in the CRF. When an event occurs due to overdose of the drug, the 
investigator will record the symptom as an AE in the CRF. 
• Serious Adverse Event Definition 
Serious AE means any untoward medical occurrence that at any dose: 
1. Results in death. 
2. Is life-threatening (refers to an AE from which the patient was at risk of death at the time 
of the event. It does not refer to an event that hypothetically might have caused death if it 
were more severe). 
3. Requires inpatient hospitalization or prolongation of an existing hospitalization (see 
below on hospitalizations that are not considered serious AEs). 
a. Planned hospital admissions or surgical procedures for an illness or disease that 
existed before the patient was enrolled in the study 
b. Hospital admissions or surgical procedures for an illness or disease that are not 
related to AEs. 
4. 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.) 
5. Results in a congenital anomaly/birth defect. 
6. Is a medically serious 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, or require 
medical or surgical intervention to prevent one of the outcomes listed above. Any terms 
included in the Takeda Medically Significant AE List (Table 11.a) are defined as a 
Serious AE. 
 
Table 11.a 
Takeda Medically Significant AE List 
Acute respiratory failure, or acute respiratory 
distress syndrome (ARDS) 
Torsarde de pointes, ventricular fibrillation, or 
ventricular tachycardia 
Malignant hypertension 
Convulsive seizures (including convulsions, 
epilepsy) 
Agranulocytosis 
Aplastic anemia 
Toxic epidermal necrolysis, or Stevens-Johnson 
syndrome 
Hepatic necrosis 
Acute liver failure 
Anaphylactic shock 
Acute renal failure 
Pulmonary hypertension 
Pulmonary fibrosis (including interstitial 
pneumonia) 
Malignant syndrome or malignant hyperthermia 
Spontaneous abortion, stillbirth or fetal death 
Transmission or suspected transmission of drug-
mediated infection 
Endotoxin shock or suspicion thereof 
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11.1.3 Severity of AEs 
Severity (toxicity grade) for each AE, including any laboratory abnormality, will be determined 
using the NCI CTCAE Japanese Version 4.03, and defined as below (Table 11.b) 
 
Table 11.b 
AE Grade Defined in CTCAE Japanese Version 4.03 
Grade 
Definition 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL* 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL** 
Grade 4 
Life-threatening consequences; urgent intervention indicated 
Grade 5 
Death related to AE 
A semi-colon indicates ‘or’ within the description of the grade. 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc. 
**Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden. 
11.1.4 Clinically Important AEs (Intensively Investigated Events) 
Among the important identified risks, the important potential risks or the related events described 
in the drug risk management plan of the study drugs, the following events are intensively 
investigated events. 
The principal investigator or the investigator continuously monitors these events and promptly 
notifies the sponsor when the sponsor requests the information. 
• Thrombocytopenia 
• Severe gastrointestinal disorders 
• Skin disorders 
• Peripheral neuropathy 
• Infection 
These events may require further investigation to establish an evaluation. For the reporting 
method and the reporting time from the principal investigator or the investigator to the sponsor, 
see Section 11.4. 
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11.1.5 Causal Relationship of Adverse Events 
A causal relationship between IRd therapy and an AE, and a causal relationship with ixazomib 
(only in the case of AEs deemed ‘related’ to IRd therapy) is classified and defined as follows 
Related 
There is an obvious temporal correlation (including the course of symptoms after 
discontinuation of administration). Or, other factors such as original disease, 
complications, concomitant medications, and combined treatment, may be responsible 
for the AE, but it may also be caused by IRd therapy or ixazomib. 
Not related 
There is no clear temporal correlation with IRd therapy or ixazomib. Or an AE that is 
considered to be related to other factors such as original disease, complications, 
concomitant medications, concomitant treatment or the like 
11.1.6 Treatment Discontinuation due to AEs 
Discontinuation of IRd therapy due to an AE will be defined as ‘discontinuation of 
administration’. Treatment is not regarded as discontinued if administration of any of the three 
drugs is continued.  
11.1.7 Outcome 
The outcome of AEs will be classified as follows  
Classification 
Evaluation 
Recovered 
• 
Disappearance of symptoms and findings, or recovery 
• 
Normalization of laboratory values, or recovery to baseline 
Lightly recovered 
• 
Severity reduced by ≥1 Grade 
• 
Disappearance of symptoms and findings 
• 
Improvement of laboratory values, but not recovered to baseline 
• 
In cases of death, the AE was not a direct cause of death, and the AE had lightly 
recovered before death 
Unresolved 
• 
No change in symptoms, findings, and laboratory values 
• 
Symptoms, findings, and laboratory values on the last day of the observable 
period were worse than at the time of observation 
• 
Irreversible congenital anomalies 
• 
In cases of death, if the AE is not a direct cause of death and the AE remains 
unresolved 
Recovered but with 
sequelae 
• 
Dysfunction that interferes with daily living occurred 
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Died 
• 
There was a direct association between death and the AE; ‘direct relevance was 
recognized’ is defined as the AE causing the death or the AE contributed to the 
death 
• 
Any AEs that were judged or estimated not to be the direct cause of death, shall 
not be recorded as death due to AE 
Unknown 
• 
Not able to follow-up after the date of observation as described in the study 
protocol due to e.g. hospital transfer or patient relocation 
11.2 
Procedures for Recording and Reporting AEs and Serious AEs 
11.2.1 Collection of  and Reporting of AEs and Product Quality Issues 
11.2.1.1 Collection Period of AEs 
The collection of safety data will begin at the start of IRd therapy and continue until 30 days 
after termination of IRd therapy or the start of the next treatment, whichever is earlier. 
In addition, new primary malignancies that occur during the follow-up periods must be reported, 
irrespective of causality to study regimen, to the sponsor for a minimum of 3 years after the 
discontinuation of IRd therapy through death or termination of the study by the sponsor. 
 
11.2.1.2 Reporting AEs 
When a study subject visits the site, the principal investigator or investigator(s) will confirm the 
presence or absence of symptoms of AEs with patients. At each study visit, the principal 
investigator or investigator(s) will interview the subject to determine whether any AEs had 
occurred. A neutral question, such as, ‘How have you been feeling since your last visit?’ will be 
asked to capture any AEs occurring between the visits. 
All subjects experiencing AEs, whether considered associated with the use of the study drug or 
not, will be followed until the symptoms resolve, or any clinically significant abnormal 
laboratory values return to baseline (screening values), or there was a satisfactory explanation for 
the change (for permanent or irreversible AEs). 
Regardless of the patient's symptoms being related to IRd therapy, the principal investigator or 
investigator(s) will record all AEs on the appropriate pages of the CRF. Each event will be 
described as follows: 
1. AE term 
2. Date of onset and resolution 
3. Severity 
4. Causal relationship with IRd therapy or ixazomib 
5. Action taken for the IRd therapy 
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6. Outcome of event 
7. Seriousness 
The principal investigator or investigator(s) should not use QOL questionnaires as the main 
method for collecting AEs. However, if, during the collection of QOL questionnaires the 
principal investigator or investigator(s) recognizes that the patient’s symptoms are likely due to 
AEs, the principal investigator or investigator(s) may follow-up and clinically evaluate the 
patient’s symptoms. If, as a result of the follow-up study, the symptom of the patient is 
determined to be an AE not previously reported, the investigator shall report according to the 
usual reporting procedure. 
11.2.2 Collection and Reporting of Serious AEs 
Any SAEs that developed during the period of AE collection will be reported by the principal 
investigator to the chief executive of the study site immediately, and to the Takeda PV Drug 
Safety immediately (within 24 hours) after obtaining knowledge of the event. The principal 
investigator is required to submit an official report to the sponsor detailing the event within 10 
calendar days. 
The following details will be included in the report, along with as much other information as 
possible. 
• Brief description of the AE and why it was deemed to be serious 
• Subject ID code 
• Name of principal investigator or investigator(s) 
• Name of study drug 
• Determined causal relationship 
The principal investigator or investigator(s) are required to spontaneously reported SAEs 
collected even after the AE collection period to the sponsor. 
11.3 
Follow-up of Serious AEs 
The principal investigator or investigator(s) will follow up all SAEs until they resolve, or the 
final outcome of the event determined. If information for a SAE was not included in the detailed 
report and was obtained later, the principal investigator or investigator(s) must provide an 
addendum or submit an updated report within 1 day of the onset. Relevant data collected at the 
research site (e.g., ECG charts, laboratory test values, discharge summary, postmortem results) 
will be sent to the sponsor or IEC upon request. 
11.3.1 Reporting Serious AEs to the Ethical Review Committee and Regulatory 
Authorities 
On receiving a report of a serious AE from the principal investigator, the head of study site will 
consult with the ethics review committee etc., and will notify the outcome to the clinical study 
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sites through the sponsor or the clinical research organization (CRO) commissioned by the 
sponsor. 
If the head of study site receives a report from the principal investigator or investigator(s) of an 
unexpected serious AE or a serious AE where the direct causal relationship with the study 
treatment (i.e. IRd therapy) cannot be determined, the head of study site will include additional 
information to the report from the principal investigator, and submit the report to the Minister of 
Health, Labor and Welfare, and notifies the other study sites. It is also possible to report to the 
Minister of Health, Labor and Welfare or to disseminate it to the study site through the sponsor. 
Additional information to be added are: 
• Actions taken for the serious AEs (e.g. discontinuation of new enrolment, revision of 
informed consent form and/or explanation document, re-consent obtained from other 
study subjects, etc.) 
• Date of review, summary of review, result, necessary action, etc. related to the Ethics 
Review Committee, etc. 
• Communication to collaborative study sites 
The sponsor is required to report unpredictable serious AEs or any serious AE which are a target 
of the emergency report, to the heads of regulating authorities, principal investigators and study 
sites. 
From the point of time when the sponsor or CRO commissioned by the sponsor initially learned 
of the event or of the additional information, the sponsor or CRO is required to make an 
emergency report containing unexpected serious AEs or predictable serious AEs, and must 
comply with the reporting deadline stipulated by the regulatory requirements. In addition, the 
sponsor will also urgently report on ixazomib’s risk-benefit, continued administration of 
ixazomib, and other serious safety information which may have a significant impact on the 
continuation of the clinical study. The study site must submit a copy of the emergency report 
document to the Ethics Review Committee. 
11.4 
Reporting of additional information on AEs 
When the sponsor requests the principal investigator or investigators to provide additional 
information on an AE, the principal investigator or investigators must enter it in the eCRF 
system or submit a written report. 
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12.0 
STUDY-SPECIFIC COMMITTEES 
No data safety monitoring committee or central assessment committee will be used in this study. 
12.1 
Study Steering Committee 
The study steering committee consists of medical professionals involved in this clinical study, 
sponsors, and independent statistical experts. The study steering committee oversees the 
implementation and reporting of the study, ensures highly specialized medical guidance, ensures 
a high level of scientific quality, and makes appropriate revision of the study protocol. The 
responsibilities of the committee are stipulated in the procedure manual of the clinical research 
steering committee. 
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13.0 
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 and concurrent conditions will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the database of 
medical drug name. 
13.1 
Case Report 
The principal investigator or investigator prepares a case report form (CRF) for all patients who 
have given consent. 
The sponsor or its designee provides the study site with access rights to the electronic case report 
form (eCRF). A sponsor or its designee provides training for site managers, investigators and 
research collaborators when using the eCRF. The CRF will be used to report the information 
gathered during clinical research implementation to the sponsor. The CRF is prepared in 
Japanese. The investigator or investigator inputs the data directly when preparing the CRF. 
Any change of, modification of, or addition to the data in the CRF are recorded.  These 
corrections are recoded as audit trails that capture the information before and after the change or 
modification, the personnel who made these change or correction, and the date of change or 
modification.  
The principal investigator must review the eCRF for completeness and accuracy and digitally 
sign the corresponding page of the CRF. The principal investigator is fully responsible for the 
accuracy and authenticity of all data entered in the CRF. 
The following are data recorded directly in the CRF. 
• The severity and seriousness of AEs, causal relationships with IRd therapy and ixazomib, 
outcome 
• Reason for  discontinuation before administration of IRd therapy  
• Reason for discontinuation of clinical study end status 
In cases where the principal investigator or investigator changes or corrects the data inputs in the 
CRF after the database is fixed, the principal investigator or investigator must obtain and use the 
Data Clarification From. The principal investigator must confirm that the change and correction 
record of the CRF is described accurately and completely, then signs or stamps and record the 
date. 
The sponsor or its designee confirms that the CRF is properly prepared according to the 
procedure prescribed for each study. A sponsor or its designee will view medical records and 
hospital records of patients participating in the study as necessary to ensure the accuracy of the 
CRF. The completed CRFs 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 the written permission of the sponsor 
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13.2 
Electronic Case Report Input System Deadline 
The sponsor and its designee must request the principal investigator or investigator to input the 
electronic case report system at an early stage in the period from the registration of the research 
patient to the end of the follow-up period. After obtaining the data to be recorded in the CRF, the 
investigator must input the CRF within 14 days as a general rule. 
13.3 
Record Retention 
The principal investigator or the head of study site shall keep the following documents, including 
records and study-specific documents as specified in section 12.1, for investigation or audit by 
regulatory authorities and sponsors and its designee. The documentation, research patient 
identification code list, medical records, signed and dated original informed consent form, 
including the audit trail, copies of CRFs of changes and modifications record, and the like. In 
addition, the principal investigator and the head of study site must retain these documents until 
the day 5 years after the early termination or completion of the study, or the day 3 years after 
which the study results are presented in public. 
However, if the sponsor requests a longer period for retention, the head of the study site should 
discuss how long and hot retain those documents with the sponsor. 
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14.0 
STATISTICAL ANALYSIS 
Statistical analysis will be undertaken by analysts who belong to the contract research 
organization [CRO] and who are independent from the sponsor; the analysts will be appointed by 
the statistical analysis manager and statistical analysis supervisor. The sponsor will not be 
involved in the statistical analysis. 
14.1 
Statistical Analysis Plan 
An initial version of the statistical analysis plan (SAP) will be prepared prior to acquisition of 
consent from the first patient. The SAP will be finalized prior to database lock  The SAP will 
provide further details regarding the definitions of analysis variables and the analysis 
methodologies to be used to address all study objectives. 
14.1.1 Analysis Sets 
In this clinical study, the following three analysis sets are defined: 
• Full Analysis Set (FAS): all patients who enroll into the study and who receive at least 
one dose of ixazomib  
• Effectiveness Analysis Set: all patients included in the FAS who have measurable lesions 
prior to the start of IRd therapy and who have at least one response evaluation after the 
start of IRd therapy  
• Safety Analysis Set: all patients who enroll into the study who receive at least one dose of 
any drug used in IRd therapy (i.e  ixazomib, lenalidomide, or dexamethasone) 
In addition to the analysis of all enrolled patients, analyses will be conducted in patient 
subgroups defined according to the following characteristics; additions or changes to these 
subgroups may be made at a later date. 
• Frailty-adjusted subgroups 
• Cytogenetic risk subgroups 
• Renal function subgroups 
14.1.2 Analysis of Demographics and Other Baseline Characteristics 
The key demographics and other baseline characteristics (e.g. number of previous treatments, 
duration of disease, etc.) will be summarized for the FAS. 
14.1.3 Efficacy Analysis 
(1) Primary Outcome and Analytical Methods 
[Primary outcome] 
• PFS 
 [Analysis Method] 
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PFS will be analyzed using disease progression data from the disease evaluations conducted by 
the principal investigator or investigator(s). 
PFS for the FAS will be estimated using the Kaplan-Meier method, and the quartiles and two-
sided 95% confidence intervals will be calculated. PFS is defined as the period from the first 
dose of treatment to the time of confirmed PD or confirmed death (regardless of the cause of 
death), whichever is earlier.  
(2) Secondary Outcomes and Analytical Methods 
[Secondary Outcomes] 
• PFS rate at 12 months and at 24 months from the start of study. 
[Analysis Method] 
The secondary outcomes of PFS rate at 12 months and at 24 months from the start of study will 
be analyzed for patients in the FAS. 
• OS  
 [Analysis Method] 
OS for the FAS will be estimated using the Kaplan-Meier method, and the quartiles and two-
sided 95% confidence intervals will be calculated. OS is defined as the period from the first dose 
of treatment to the time when death is confirmed (regardless of the cause of death).  
• Best Response 
The secondary outcome of best response is defined as the cumulative numbers of patients who 
achieve each level of best response, as defined by the IMWG criteria (2014 version) (Appendix 
F), after each cycle of treatment. 
[Analysis Method] 
A histogram (or similar) showing the numbers of patients in the FAS and the Efficacy Analysis 
Set achieving different levels of best response will be created after each cycle of treatment, from 
cycle 1 onwards. 
• Time to Next Treatment (TTNT) 
[Analysis Method] 
The secondary outcome of TTNT for the FAS will be estimated using the Kaplan-Meier method, 
and the quartiles and two-sided 95% confidence intervals will be calculated. TTNT is defined as 
the period from the first dose of treatment to the start of next treatment or time when death is 
confirmed (regardless of the cause of death), whichever is earlier.  
• Duration of Therapy (DOT) 
[Analysis Method] 
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Summary statistics for the secondary outcome of DOT in patients in the FAS will be collected, 
including the number of patients, mean, standard deviation, minimum value, maximum value, 
and the quartiles). DOT is defined as the treatment duration of IRd therapy. 
• Proportion of patients who continue to receive treatment at 12 months and 24 months 
after start of treatment  
[Analysis Method] 
The secondary outcome of proportion of patients in the FAS who continue to receive treatment at 
12 months and 24 months, and the two-sided 95% confidence intervals, will be calculated. 
Confidence intervals will be accurately calculated based on a binomial distribution. 
• Overall Response Rate (ORR) 
[Analysis Method] 
The ORR and 2-sided 95% confidence intervals will be calculated in the Efficacy Analysis Set. 
Confidence intervals will be accurately calculated based on a binomial distribution. The ORR is 
defined as the proportion of patients who achieve a best response of PR or better according to the 
IMWG criteria (2014 version) (Appendix F) after the start of IRd therapy. 
• Rate of Complete Response (CR) and Very Good Partial Response (VGPR) (Rate of CR 
+ VGPR) 
The rate of CR + VGPR and 2-sided 95% confidence intervals will be calculated in the Efficacy 
Analysis Set. Confidence intervals will be accurately calculated based on a binomial distribution. 
The rate of CR + VGPR is defined as the proportion of patients who achieve a best response of 
VGPR or better according to the IMWG criteria (2014 version) (Appendix F) after the start of 
the IRd therapy. 
• Patient-reported outcomes: HRQoL, determined using EORTC-QLQ-C30 and MY-20 
[Analysis Method] 
For patients in the FAS, summary scores for all functional domains, subscales, and symptom 
scales of the EORTC and MY-20 instruments will be determined, and longitudinal changes for 
each subscale will be evaluated. Particular focus will be given to the physical function scale, the 
global health/quality of life scale, and the individual scales of tiredness, nausea and vomiting, 
pain, dyspnea, anorexia, constipation, and diarrhea. Analyses of these scores will be conducted 
using repeated measures analyses across all timepoints. 
• Detection frequency of MRD in patients with CR 
 [Analysis Method] 
The proportion of patients who are MRD-negative, and 95% confidence intervals on both sides, 
will be calculated for the Efficacy Analysis Set. Confidence intervals will be accurately 
calculated based on a binomial distribution. Patients will be considered MRD-negative if a first 
test is MRD-positive but a subsequent test is MRD-negative. 
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• Relative Dose Intensity (RDI) 
[Analysis Method] 
Summary statistics for RDI of ixazomib, lenalidomide, and dexamethasone will be calculated for 
the Safety Analysis Set. The outputs will include a plot of change over time. 
14.1.4 Analysis of Safety 
The following analysis will be evaluated in the Safety Analysis Set. 
(1) Treatment-emergent Adverse Events (TEAEs) 
A TEAE is defined as an AE that occurs at any time between the start of IRd therapy and 30 days 
after the end of IRd therapy or the start of next treatment, whichever occurs first. TEAEs will be 
coded using MedDRA and will be summarized by Preferred Term (PT) and System Organ Class 
(SOC). 
The following data will be collected and analyzed: 
• Frequency of all TEAEs 
• Frequency of ixazomib-related TEAEs 
• Frequency of Grade 3 or higher TEAEs 
• Frequency of ixazomib-related Grade 3 or higher TEAEs 
• Frequency by Grade for all TEAEs 
• Frequency by Grade for ixazomib-related TEAEs 
• Frequency of TEAEs resulting in discontinuation of treatment 
• Frequency of serious TEAEs 
• Frequency by time to onset of all TEAEs 
• Frequency of TEAEs that result in death 
(2) Laboratory values 
Laboratory data values from before and after IRd therapy administration will be tabulated. 
14.2 
Interim Analysis and Criteria for Early Termination 
An interim analysis is planned at 12 months from enrollment of the last patient, using data 
collected until that time. This interim analysis will evaluate the PFS rate at 12 months, the 
proportion of patients still on study treatment, and safety. 
2.3 
Determination of Sample Size 
The purpose of this clinical study is to investigate the efficacy and safety of IRd therapy in 
RRMM patients in Japan. 
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Recent pivotal clinical trials in patients with RRMM, including ASPIRE, ELOQUENT-2, 
TOURMALINE-MM1, and POLLUX, were all designed with Rd therapy as a comparator; the 
values of median PFS with Rd in these studies were 17.6, 14.9, 14.7, and 18.4 months, 
respectively. The only report of a complete set of data on patients receiving Rd therapy in Japan 
is from a prospective observational study by KMF, with a reported median PFS of 17.0 months. 
Although direct comparison between studies is difficult due to differences in patient populations 
and disease characteristics, the median PFS for patients receiving Rd therapy in Japan is 
estimated to be 15–18 months, based on currently available data. 
In TOURMALINE-MM1, a pivotal clinical trial investigating IRd triplet combination therapy, 
the hazard ratio for PFS in favor of the IRd therapy arm versus the control arm (placebo-Rd arm) 
was 0.74 (0.59–0.94). Based on the assumption that no differences exist in the relative efficacy 
of IRd and placebo-Rd between Japanese patients and the TOURMALINE-MM1 study 
population, we used a conservative HR estimate of 0.80 for our calculations. Assuming a 
constant exponential survival distribution, and utilizing a median PFS of 15–18 months for Rd 
therapy and a HR in favor of IRd versus Rd of 0.74–0.80, the following table shows the expected 
median PFS values for IRd therapy: 
Median PFS of 
Rd therapy 
Estimated median PFS with IRd therapy 
HR=0.74 
HR=0.77 
HR=0.80 
15 months 
20.3 months 
19.5 months 
18.8 months 
16 months 
21.6 months 
20.8 months 
20.0 months 
17 months 
23.0 months 
22.1 months 
21.3 months 
18 months 
24.3 months 
23.4 months 
22.5 months 
 
The sample size for this study was determined using a precision-based method, based on the 
expected median PFS with IRd therapy, the primary outcome. The following equation based on 
the median PFS may be used for precision-based sample size calculation: 
 
 
φ: cube root transformed hazard under the null hypothesis 
φ^: cube root transformed hazard under the alternative hypothesis 
    I: observed Fisher information 
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r: expected number of events 
If the expected median PFS values with IRd therapy were as shown in the above table, then to 
estimate the two-sided 95% confidence interval with an accuracy of ± 3 months, the required 
sample sizes in the present study of IRd are shown in the corresponding locations in the table 
below (assuming a registration period of 12 months, and follow-up of 24 months from the time 
when the last patient enrolled into the study): 
Median PFS with 
Rd therapy 
Sample size required for study of IRd 
HR=0.74 
HR=0.77 
HR=0.80 
15 months 
224 
200 
180 
16 months 
266 
239 
214 
17 months 
317 
283 
256 
18 months 
370 
333 
298 
 
Based on the considerations above, the number of patients planned for enrollment in this study 
is 300. 
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15.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
15.1 
Study-Site Monitoring Visits 
The sponsor or its designee will conduct monitoring visits to the study sites periodically during 
the study to ensure that all aspects of the protocol are followed. Details on the frequency of 
monitoring to research institutes and the procedure, included in the supplementary documents to 
be prepared separately.  
The principal investigator and the head of study site guarantee access to the source documents to 
the sponsor or its designee and the IRB. 
15.2 
Deviations from Ethical Guidelines and Study Protocol Concerning Medical 
Research for People 
Principal investigator or investigator shall record all actions deviating from the ethical guidelines 
on medical research on human patients and the implementation plan of clinical trials. 
The principal investigator shall promptly notify the head of the study site and the sponsor when a 
serious departure is found. In addition, the principal investigator consults with and agrees with 
the sponsor about the revision of the implementation plan of the clinical trial as necessary. When 
revising, the principal investigator or investigator submits the draft as soon as possible to the 
head of the research institution and obtains approval from the ethics review committee etc. 
15.3 
Quality Assurance Audits and Regulatory Agency Inspections 
The study site also may be subject to quality assurance audits by the sponsor or its designees to 
ensure that study procedures comply with the protocol and standard operating procedures, and 
that collected data is correct and complete. 
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. 
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16.0 
ETHICAL IMPLEMENTATION OF CLINICAL STUDY 
This study will be conducted with the highest respect for the individual participants (ie, patients) 
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 
I. 
16.1 
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 and explanatory documentation) 
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. 
 
16.2 
Conflicts of Interest 
This clinical trial is conducted with support of the study sponsor. 
Prior to conducting this clinical study, the investigators involved in this clinical study should 
appropriately manage their conflicts of interest (COI) so investigators involved in this clinical 
study will not violate the COI of their institutions [36] [37] [38] [39] [40]. 
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The study site shall comply with all requirements prescribed by the IRB. This includes self-
declaration of COI, study protocol, consent form and any explanatory documents. 
16.3 
Subject Information, Informed Consent, and Subject Authorization 
Written consent documents and explanatory documentations 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, including to national or 
international third parties. 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 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. 
16.4 
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 
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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 (refer to Section 
16.3) 
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 CRF). 
16.5 
Consultation for Study Subjects or Stakeholders 
The principal investigator establishes a consultation desk to respond to consultations on this 
clinical trial from patients or stakeholders. Details about the consultation desk are described in 
the consent form and explanation document. 
16.6 
Economic Burden or Reward for Research Patients 
Of the expenses related to this clinical study, the sponsor will provide finance which are not 
covered by national insurance. For any expenses which may arise due to normal clinic visits may 
be paid for by the study subject.  
In addition, the sponsor will pay burden reduction costs to the study subjects in this clinical study 
for additional research (Frailty score survey, QOL survey) accompanying time extension of 
medical treatment performed. Details concerning the economic burden and rewards to the 
patients are described in the consent form and explanation document. 
16.7 
Profit of Non-Profit for the Study Subject 
16.7.1 Profit of the Research Patient 
As this clinical study is conducted within the scope of medical treatment, there will be no 
specific profit for patients in participating in this study. 
16.7.2 Disadvantages for Research Patients 
As this clinical study is conducted within the scope of medical treatment, there will be no 
specific disadvantages for patients in participating in this study. 
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16.8 
Attribution and Access Rights of Research Results 
16.8.1 Attribution of Research Results 
All data and information obtained through this clinical study are attributed to the sponsor. The 
data obtained in this study may be used for secondary analyses e.g. for meta-analysis, and such 
data will not be linked to personal identification information. 
16.8.2 Data Access Rights 
Access rights to all data and information obtained from this clinical study will be given to the 
person(s) approved by the sponsor. 
16.9 
Publication, Disclosure, and Clinical Trial Registration Policy 
16.9.1 Publication 
The investigator is obliged report a summary of results to the head of the study site, and 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. 
During and after the study, the sponsor and designee must summarize the data and publish in a 
medical journal and/or present at e.g  a meeting of a professional association. 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. 
When the final publication is completed, the sponsor should notify the head of study site. 
16.9.2 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, the sponsor 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. The sponsor’s contact information, along with 
investigator’s institution name, city, country, and recruiting status will be registered and 
available for public viewing. 
16.9.3 Clinical Trial Results Disclosure 
The sponsor will post the results of clinical trials on ClinicalTrials.gov or other publicly 
accessible websites and registries, as required by applicable laws and/or regulations. 
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16.10 Insurance and Compensation for Injury 
Regarding health damage caused by participating in this clinical study, the study subject is 
provided adequate treatment as insurance medical treatment according to the medical condition 
as well as ordinary medical treatment. At that time, the self-payment of medical expenses will be 
covered by the study subject and no compensation will be made with money. 
 
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17.0 
REFERENCES 
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Moreau P, Masszi T, Grzasko N, Baslis NJ, Hansson M, Pour L, et al. Oral Ixazomib, 
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Revlimid® capsule (5 mg) Special Drug Use-Results Survey(all-case surveillance); 
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2013) 
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21. 
Palumbo A, Bringhen S, Mateos MV, Larocca A, Facon T, Kumar SK, et al. Geriatric 
assessment predicts survival and toxicities in elderly myeloma: an International 
Myeloma Working Group report. Blood 2015;125:2068-2074 
22. 
Basch E, Abernethy AP, Mullin CD, Reeve BB, Smith ML, Coon SJ et al. 
Recommendations for incorporating patient-reported outcomes into clinical 
comparative effectiveness research in adult oncology. J Clin 
Oncol.2012;30(34):4249-55. 
23. 
Stead ML, Brown JM, Velikova G, Kaasa S, Wisloff F, Child JA et al. Development 
of an EORTC questionnaire module to be used in health-related quality-of-life 
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assessment for patients with multiple myeloma. European Organization for Research 
and Treatment of Cancer Study Group on Quality of Life. Br J Haematol.1999; 
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25. 
Lionetti M, Barbieri M, Todoerti K, Agnelli L, Marzorati S, et al. Molecular spectrum 
of BRAF, NRAS and KRAS gene mutations in plasma cell dyscrasias: implication for 
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26. 
Rustad EH, Dai HY, Hov H, Coward E, Beisvag V, et al. Clinical and Biological 
implications of BRAF V600E mutation in multiple myeloma. Blood 2014; 124(21): 
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Annunziata CM, Davis RE, Demchenko Y, Bellamy W, Gabrea A, et al. Frequent 
engagement of the classical and alternative NF-kappaB pathways by diverse genetic 
abnormalities in multiple myeloma. Cancer Cell. 2007; 12(2): 115-130. 
28. 
Demchenko YN and Kuehl WM, A critical role for the NFkB pathway in multiple 
myeloma. Oncotarget. 2010; 1(1): 59-68. 
29. 
Chatterjee M, Jain S, Stühmer T, Andrulis M, Ungethüm U, et al. STAT3 and MAPK 
signaling maintain overexpression of heat shock proteins 90 α and β in multiple 
myeloma cells, which critically contribute to tumor-cell survival. Blood 2007; 109 (2) 
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30. 
Lauta VM. A review of the cytokine network in multiple myeloma. Cancer 2003; 97 
(10): 2440-2452. 
31. 
Husang X, Di Liberto M, Jayabalan D, Liang J, Ely S, et al. Prolonged early G1 arrest 
by selective CDK4/CDK6 inhibition sensitizes myeloma cells to cytotoxic killing 
through cell cycle–coupled loss of IRF4. Blood 2012; 120 (2) 1095-1106. 
32. 
Kalff A, Spencer A. The t (4;14) translocation and FGFR3 overexpression in multiple 
myeloma: prognostic implications and current clinical strategies. Blood Cancer J. 
2012; 2(9), e89. 
33. 
Mirabella F, Wu P, Wardell CP, Kaiser MF, Walker BA, et al. MMSET is the key 
molecular target in t(4;14) myeloma. Blood Cancer 2013; 3(5): e114. 
34. 
Shaffer AL, Emre NCT, Lamy L, Ngo VN, Wright G, et al. IRF4 addiction in 
multiple myeloma. Nature 2008; 454 (7201): 226-231. 
35. 
Lovén J, Hoke HA, Lin CY, Lau A, Orlando DA, Vakoc CR, Bradner JE, Lee TI, 
Young RA. Selective inhibition of tumor oncogenes by disruption of super-enhancers. 
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36. 
利益相反ワーキング・グループ報告書（文部科学省 平成14 年11 月1 日） 
Report of the Working Group on Conflicts of Interest (Ministry of Education, 
Culture, Sports, Science and Technology Japan, 11 January 2002) 
37. 
臨床研究の利益相反ポリシー策定に関するガイドライン（臨床研究の倫理と
利益相反に関する検討班 平成18 年3 月）Guidelines concerning conflict of 
interest policies in clinical research (Study group on ethics and conflicts of interest in 
clinic research, March 2006) 
38. 
厚生労働科学研究における利益相反（Conflict of Interest:COI）の管理に関す
る指針（平成20 年3 月31 日）Guidelines for management of conflicts of interest 
(COI) in health and labour sciences research (31 March 2008) 
39. 
医学研究のCOI マネージメントに関するガイドライン（日本医学会 臨床部
会利益相反委員会 平成23 年2 月）Guidelines for COI management in medical 
research (Japan Association of Medical Science, Clinical COI committee, February 
2011) 
40. 
臨床研究の利益相反（COI）に関する共通指針（日本内科学会、日本肝臓学
会、日本循環器学会、日本内分泌学会、日本糖尿病学会、日本呼吸器学会、
日本血液学会、日本アレルギー学会、日本感染症学会 2011 年8 月）
Common guidelines for conflict of interest (COI) in clinical research (Japanese 
Society of Internal Medicine, Japan Society of Hepatology, The Japanese Circulation 
Society, The Japan Endocrine Society, The Japan Diabetes Society, The Japanese 
Respiratory Society, Japanese Society of Hematology, Japanese Society of 
Allergology, The Japanese Association for Infectious Diseases, August 2011) 
 
 
 
 
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