Clinical trial NCT03416374
Conditions: Relapsed and/or Refractory Multiple Myeloma
Sponsor: Takeda
Start date: 2018-02-18; Completion date: 2021-05-28
Enrollment: 45 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to investigate the efficacy and safety of long-term administration of the oral proteasome inhibitor ixazomib as part of ixazomib in combination with lenalidomide and dexamethasone (IRd) therapy in patients with relapsed and/or refractory multiple myeloma (RRMM) treated initially with an injectable proteasome inhibitor-based therapy.

Detailed description:
The drug being tested in this study is called Ixazomib. Ixazomib is being tested to treat people who have RRMM. This study will look at the effectiveness and safety of IRd in participants with RRMM previously receiving an injectable proteasome inhibitor-based therapy. This study consists of two treatment periods, Treatment Period I and Treatment Period II.

The study will enroll 47 patients. All participants will receive following treatment:

\- Combination therapy with Bortezomib + Lenalidomide + Dexamethasone (VRd) or combination therapy with Carfilzomib + Lenalidomide + Dexamethasone (KRd), standard recommended dose according to the package insert of each drug, as Treatment Period I, followed by Combination therapy with Ixazomib 4.0 mg + Lenalidomide 25 mg + Dexamethasone 40 mg (IRd) as Treatment Period II

At start of this study, combination therapy of VRd or KRd will be decided by investigator as Treatment Period I after the baseline evaluations. After the start of Treatment Period I, a participant's eligibility for Treatment Period II is then determined 3 cycles. Participants who meet these eligibility criteria II subsequently continue into Treatment Period II and receive IRd.

This multi-center trial will be conducted in Japan. It is anticipated that the treatment phase of this study will last up to 39 months, including 18 months for enrollment. Participants will make multiple visits to the clinic in treatment period, and follow-up period including a follow-up assessment after last dose of study drug.

Arms: arm 1: Bortezomib + Lenalidomide + Dexamethasone, or Carfilzomib + Lenalidomide + Dexamethasone, standard recommended dose according to the package insert of each drug (Treatment Period I), followed by Ixazomib (4.0 mg) on Days 1, 8 and 15, plus Lenalidomide (25 mg) on Days 1 to 21, and Dexamethasone (40 mg) on Days 1, 8, 15 and 22, of a 28-day cycle (Treatment Period II)
Interventions: intervention 1: Ixazomib intervention 2: Bortezomib intervention 3: Carfilzomib intervention 4: Lenalidomide intervention 5: Dexamethasone
Intervention descriptions: intervention 1: Ixazomib capsules intervention 2: Bortezomib injections intervention 3: Carfilzomib intravenous infusions intervention 4: Lenalidomide capsules intervention 5: Dexamethasone tablets

Protocol documents:
Prot_000.pdf: 
 
 
Title: An Open-label, Single-Arm, Multicenter Study to Evaluate the Efficacy and Safety 
of Ixazomib in Combination with Lenalidomide and Dexamethasone in Patients with 
Relapsed and/or Refractory Multiple Myeloma Initially Treated with an Injection of  
Proteasome Inhibitor-Based Therapy 
 
NCT Number: NCT03416374 
Protocol Approve Date: 30-MAY-2019 
 
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 
An Open-label, Single-Arm, Multicenter Study to Evaluate the Efficacy and Safety of 
Ixazomib in Combination with Lenalidomide and Dexamethasone in Patients with Relapsed 
and/or Refractory Multiple Myeloma Initially Treated with an Injection of  Proteasome 
Inhibitor-Based Therapy 
Secondary Sponsor: 
Takeda Pharmaceutical Company Limited 
Study number: 
C16043 
IND Number: 
Not Applicable 
EudraCT Number: 
Not Applicable 
Study Drug: 
Ixazomib 
Indication: 
Multiple Myeloma 
Phase: 
4 
Date: 
30 May 2019 
Amendment 
Number: 
Version 5 
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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 the highest respect for individual study participants, according 
to the requirements of this study protocol and the following. This study will also be conducted as 
a “specified clinical trial” according to the Clinical Research Act (Act No. 16 of 2017): 
x
The ethical principles based on the Declaration of Helsinki 
x
Clinical Research Act (Act No. 16 of 2017)
x
International Conference on Harmonisation of Technical Requirements for Registration 
of Pharmaceuticals for Human Use (ICH) Guideline E6
x
All applicable laws and regulations, including data privacy laws, and regulation and 
guidelines on conflicts of interest
1.2
Research Implementation Structure
This clinical study will be conducted according to the study protocol with the following 
implementation system. Other implementation systems are described on a separate sheet.
Research Steering Committee
Research Steering Committee Chair: 
Research Steering Committee: 
Representative investigator: 
Director of Statistical Analysis: 
1.3
Secondary Sponsor
Takeda Pharmaceutical Company Limited, 
Representative:
Takeda Pharmaceutical Company Limited (hereinafter referred to as “Takeda”) will take 
responsibility for drafting of the study and procurement of the study funds as well as all matters 
related to the conduct of this clinical study for which the representative investigator is 
responsible in collaboration with the representative investigator. The method of oversight by 
subcontractors concerning this clinical study is described in the procedure manual prepared 
separately.
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The fees* required for the administration of this clinical study are borne by Takeda. 
*In accordance with the service agreement, fees required for conducting this study, including 
administration, monitoring, registration, statistical analysis, audit, medical writing, clinical 
examinations, and data management will be paid by Takeda to the subcontractor. Study sites will 
be paid agreed fees based on the ‘Study cost calculation Guideline’ as specified separately. 
1.4 
Inquiries Concerning Study Protocol 
Refer to Supplement 1 of Study Protocol 
1.5 
Inquiries Concerning Registration Procedures 
Refer to Supplement 1 of 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 
Secondary Sponsor ..................................................................................... . ............ 2 
1.4 
Inquiries Concerning Study Protocol ..................................................... . .................. 3 
1.5 
Inquiries Concerning Registration Procedures .................................. ......................... 3 
TABLE OF CONTENTS ............................................................................................................ 4 
2.0 
STUDY SUMMARY ................................................................... ............................... 10 
3.0 
ABBREVIATIONS ............................................................ .... ..................................... 17 
4.0 
INTRODUCTION ........................................................ . . ........................................... 20 
4.1 
Background .......................................................... . ............................................... 20 
4.2 
Rationale for the Proposed Study ............................................................................. 22 
5.0 
STUDY OBJECTIVE ..................................... .. ........................................................... 23 
5.1 
Objectives ........................................... . . ................................................................ 23 
5.2 
Endpoints.......................................... ...................................................................... 23 
5.2.1 
Primary Endpoint ................ .. .......................................................................... 23 
5.2.2 
Secondary Endpoints ..... .................................................................................... 23 
6.0 
STUDY DESIGN ................ ... ..................................................................................... 24 
6.1 
Overall Study Design and Plan: Description............................................................. 24 
6.2 
Termination or Suspension of Study or Study Site ................................................... 24 
6.2.1 
Criteria for Premature Termination or Suspension of the Study .......................... 24 
6.2.2 
Criteria for Premature Termination or Suspension of Investigational Sites ......... 25 
6.2.3 
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s) ................................................................ 25 
6.3 
Procedures for Revision of Protocol ......................................................................... 25 
7.0 
STUDY SUBJECTS ...................................................................................................... 26 
7.1 
Inclusion Criteria ..................................................................................................... 26 
7 2 
Exclusion Criteria .................................................................................................... 26 
7.3 
Study Registration ................................................................................................... 28 
8.0 
STUDY DRUG ............................................................................................................. 29 
8.1 
Study Drugs ............................................................................................................. 29 
8.1.1 
Study Drugs for Treatment Period I .................................................................... 29 
8.1.2 
Study Drugs for Treatment Period II .................................................................. 29 
8.2 
Definition of Study Treatment ................................................................................. 29 
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8.3 
Dose and Regimen of Study Drugs in Treatment Period I ........................................ 30 
8.4 
Dose and Regimen of Study Drugs in Treatment Period II ....................................... 30 
8.4.1 
Administration Schedule of Study Drugs in Treatment Period II ........................ 30 
8.4.2 
Revised Guidelines for Administering Agents in Treatment Period II ........... ... . 31 
8.4.2.1 Dose Adjustments for Rash: Ixazomib and Lenalidomide .................. . . ...... 32 
8.4.2.2 Dose Adjustments for Hematologic Toxicity: Ixazomib and Lenalidomide ... 33 
8.4.2.3 Ixazomib Treatment Modification ............................................. . ................ 36 
8.4.2.4 Lenalidomide Treatment Modification ................................. ....................... 37 
8.4.2.5 Dexamethasone Treatment Modification ...................................................... 38 
8.4.3 
Criteria for Toxicity Recovery Before Beginning the Next Cycle of Treatment 
in Treatment Period II ................................................. ...................................... 39 
8.5 
Overdose ................................................................... ............................................. 39 
8.6 
Excluded Concomitant Medications and Procedures ................................................ 40 
8.7 
Discontinuation of Study Treatment per Patient ....................................................... 40 
8.8 
Procedure for Discontinuation of Clinical Study by the Enrolled Patient .................. 41 
9.0 
STUDY PLAN .............................................................................................................. 42 
9.1 
Study Procedures ............................. . ..................................................................... 42 
9.1.1 
Informed Consent Procedure . . ......................................................................... 42 
9.1.2 
Patient Demographics ....... ................................................................................ 42 
9.1.3 
Comorbidity .............. . . .................................................................................... 42 
9.1.4 
Medical History ... . .......................................................................................... 43 
9.1.5 
Physical Examination ......................................................................................... 43 
9.1.6 
Body Weight, Height ......................................................................................... 43 
9.1.7 
Vital signs .......................................................................................................... 43 
9.1.8 
Status of Study Treatment .................................................................................. 43 
9.1.9 
Performance Status ............................................................................................ 43 
9.1.10 Clinical Laboratory Examinations ...................................................................... 44 
9.1.11 Evaluation of QOL ............................................................................................. 44 
9.1.12 Determination of M-protein ............................................................................... 45 
9.1.13 Response Assessment......................................................................................... 45 
9.1.14 Bone Marrow Aspiration .................................................................................... 45 
9.1.15 Supportive Therapy ............................................................................................ 45 
9.1.16 Image Inspection ................................................................................................ 45 
9.1.17 Adverse Events .................................................................................................. 45 
9.1.18 Scheduled Outpatient Clinic and Hospitalization ................................................ 46 
9.1.19 Follow-up Assessments ...................................................................................... 46 
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9.1.20 Next-line Treatment ........................................................................................... 46 
9.1.21 Contraception and Pregnancy Avoidance Procedure ........................................... 46 
9.1.22 Pregnancy .......................................................................................................... 46 
9.1.23 Study Participation Discontinued Before Administration of Study Medication . . 47 
10.0 
ADVERSE EVENTS ......................................................................................... . . ...... 48 
10.1 
Definitions .................................................................................................. . .......... 48 
10.1.1 Adverse Event Definition ................................................................ . ................ 48 
10.1.2 Adverse Event Definition ........................................................... ....................... 48 
10.1.3 Serious Adverse Event Definition ...................................................................... 50 
10.1.4 Clinically Important AEs (Intensively Investigated Events) ............................... 51 
10.1.5 Severity of AEs ....................................................... .... ..................................... 51 
10.1.6 Causal Relationship of Adverse Events ............. . . ........................................... 52 
10.1.7 Date of onset ................................................... . ............................................... 52 
10.1.8 Date of resolution ............................................................................................... 53 
10.1.9 Treatment Regarding Study Medication . ........................................................... 53 
10.1.10 
Outcome.................................. . . ................................................................ 53 
10.2 
Procedures for Recording and Reporting AEs and Serious AEs................................ 54 
10.2.1 Collection and Reporting of AEs ........................................................................ 54 
10.2.1.1 
Collection Period of AEs ........................................................................ 54 
10.2.1.2 
Reporting AEs .. ..................................................................................... 54 
10.2.2 Collection and Reporting of Serious AEs ........................................................... 55 
10.3 
Follow-up of Serious AEs ........................................................................................ 56 
10.3.1 Reporting Serious AEs to Regulatory Authorities ............................................... 56 
10.4 
Reporting of additional information on AEs ............................................................. 57 
11.0 
STUDY-SPECIFIC COMMITTEES ............................................................................. 58 
11.1 
Study Steering Committee ....................................................................................... 58 
12.0 
DATA HANDLING AND RECORDKEEPING ............................................................ 59 
12.1 
Case Report ............................................................................................................. 59 
12 2 
Electronic Case Report Input System Deadline ........................................................ 60 
12.3 
Record Retention ..................................................................................................... 60 
13.0 
STATISTICAL METHODS .......................................................................................... 61 
13.1 
Statistics and Analysis Plan...................................................................................... 61 
13.1.1 Analysis Sets...................................................................................................... 61 
13.1.2 Analysis of Demographics and Other Baseline Characteristics ........................... 61 
13.1.3 Efficacy Analysis ............................................................................................... 61 
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13.1.4 Analysis of Safety.............................................................................................. 65
13.2
Interim Analysis and Criteria for Early Termination ................................................ 66
13.3
Determination of Sample Size.................................................................................. 66
14.0
QUALITY CONTROL AND QUALITY ASSURANCE......................................... ... . 67
14.1
Study-Site Monitoring Visits ........................................................................ . . ...... 67
14.2
Deviations from the Clinical Research Act and Study Protocol ................... . .......... 67
14.3
Quality Assurance Audits and Regulatory Agency Inspections ............. . ................ 67
15.0
ETHICAL IMPLEMENTATION OF CLINICAL STUDY.................... ....................... 69
15.1
Certified Review Board Approval............................................................................ 69
15.2
Conflicts of Interest ................................................................ ............................... 69
15.3
Subject Information, Informed Consent, and Subject Authorization ......................... 69
15.4
Subject Confidentiality ........................................... . . ........................................... 70
15.5
Consultation for Study Subjects or Stakeholders... . ............................................... 71
15.6
Economic Burden or Reward for Research Patients.................................................. 71
15.7
Profit of Non-Profit for the Study Subject. .. ........................................................... 71
15.7.1 Profit of the Research Patient........ . . ................................................................ 71
15.7.2 Disadvantages for Research Patients .................................................................. 71
15.8
Attribution and Access Rights of Research Results .................................................. 71
15.8.1 Attribution of Research Results.......................................................................... 71
15.8.2 Data Access Rights .. ... ..................................................................................... 71
15.9
Publication, Disclosure, and Clinical Trial Registration Policy................................. 71
15.9.1 Publication..... . ................................................................................................. 71
15.9.2 Clinical Trial Registration.................................................................................. 72
15.9.3 Clinical Trial Results Disclosure ........................................................................ 72
15.10 Insurance and Compensation for Injury.................................................................... 72
16.0
REFERENCES.............................................................................................................. 73
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LIST OF IN-TEXT TABLES 
Table 8.a 
Study Drug and Administration Method ............................................................. 30 
Table 8.b 
Estimated Starting Dose of Lenalidomide when Administered to Patients with 
Impaired Renal Function (Quoted from Revlimid® Suitability Guide [24]) ... ... . 30 
Table 8.c 
Dose Reduction Steps for Ixazomib ........................................................ . . ...... 31 
Table 8.d 
Dose Reduction Steps for Lenalidomide ................................................ . .......... 31 
Table 8.e 
Dose Reduction Steps for Dexamethasone ...................................... . ................ 32 
Table 8.f 
Dose Reduction Steps for Ixazomib and Lenalidomide for Rash . ....................... 33 
Table 8.g 
Dose Reduction Steps for Ixazomib and Lenalidomide for Thrombocytopenia ... 34 
Table 8.h 
Dose Reduction Steps for Ixazomib and Lenalidomide for Neutropenia ............. 35 
Table 8.i 
Ixazomib Treatment Modifications (Delays, Reductions, and 
Discontinuations) Due to AEs .............................. ............................................. 36 
Table 8.j 
Lenalidomide Treatment Modifications (Delays, Reductions, and 
Discontinuations) Due to Non-Hematologic AEs ............................................... 37 
Table 8.k 
Dexamethasone Treatment modifications (Delays, Reductions, and 
Discontinuations) Due to AEs ............. .............................................................. 38 
Table 9.a 
Laboratory tests............................. . .................................................................. 44 
Table 10.a 
Takeda Medically Significant AE List ................................................................ 51 
Table 10.b 
AE Grade Defined in CTCAE Japanese Version 4.03 ......................................... 51 
 
LIST OF IN-TEXT FIGURES 
Figure 6.a 
A Schematic Diagram of Clinical Study Design ................................................. 24 
Figure 8.a 
Administration Schedule of Ixazomib, Lenalidomide, and Dexamethasone ........ 30 
 
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Objective: 
To investigate the efficacy and safety of long-term administration of the oral proteasome inhibitor 
ixazomib as part of IRd therapy in patients with RRMM treated initially with an injectable 
proteasome inhibitor-based therapy. 
Subject population: RRMM patients who are able to treatment with an injectable and an oral 
proteasome inhibitor-based therapy 
Number of Subjects: 
Treatment Period I: 47 
(Treatment Period II: 39) 
Number of Sites:  
Approximately 30 
Dose Level(s): 
Treatment Period I: 
Standard dosing is recommended according to the 
package insert of each drug. 
Treatment Period II: 
Patients will receive ixazomib (4.0 mg) on Days 1, 
8 and 15, plus lenalidomide (25 mg) on Days 1 to 
21, and dexamethasone (40 mg) on Days 1, 8, 15 
and 22, of a 28-day cycle. 
Route of Administration:  
Treatment Period I: follow the package 
insert  
Treatment Period II: 
 Ixazomib: oral 
Lenalidomide: oral 
Dexamethasone: oral 
 
Duration of Treatment:  
Treatment in Treatment Period II is continued until 
either PD or an unacceptable AE is observed, 
whichever comes first.  
 
Period of Evaluation:  
Clinical research implementation 
scheduled period (enrollment period and 
study treatment period): 39 months 
Enrollment period: 18 months 
Inclusion Criteria: 
Patients satisfying all the following criteria are eligible to participate in this clinical study. 
Eligibility for Treatment Period I  
1. Men and women of age 20 years or older at the time of enrollment 
2. Patients with RRMM 
3. Patients who are planned to start combination therapy with bortezomib, lenalidomide, and 
dexamethasone (VRd), or combination therapy with carfilzomib, lenalidomide, and 
dexamethasone (KRd) as second, third or fourth line of treatment 
4. Patients with measurable disease defined by one or more of the following three 
measurements 
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• Serum M-protein: ≥0.5 g/dL (≥ 5 g/L) 
• Urine M-protein: ≥ 200 mg/24 hours 
• Serum free light chain assay: involved free light chain concentration ≥ 10 mg/dL (≥ 
100 mg/L) provided that the serum free light chain ratio is abnormal 
5. Patients with ECOG performance status (PS) 0–2; however, patients with ECOG PS 3 are 
eligible if they only have symptoms associated with bone lesions. 
6. Patients who are considered by the principal investigator or investigator not to be eligible 
for transplant; or, if considered eligible for transplant, patients who are planned not to 
undergo transplant for at least 12 months after the start of the study treatment 
7. Patients must be registered with, and comply with, the guidelines of the lenalidomide 
management program (RevMate®) 
8. Patients who, before implementing procedures related to clinical research (excluding 
standard medical practices), understand that they can withdraw consent at any time 
without suffering from disadvantages to future treatments, and can provide written 
informed consent 
Eligibility for Treatment Period II  
9. Patients must have received an injectable proteasome inhibitor (bortezomib or 
carfilzomib) in each treatment cycle of Treatment Period I 
Exclusion Criteria:  
Patients meeting any of the following exclusion criteria are not to be enrolled in this clinical 
study. 
Exclusion Criteria for Treatment Period I  
1. Women who are nursing or pregnant 
2. 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  
3. Patients with poorly controlled active thrombosis 
4. Patients who have participated in a clinical trial of ixazomib or have been treated with 
ixazomib 
5. Patients who were refractory to either treatment regimen based on lenalidomide and/or 
proteasome inhibitor(s) 
Note: Refractory MM is defined as PD on therapy or PD within 60 days after the last dose 
of a given therapy. Patients who have disease progressed 60 days after the last dose of a 
given therapy will be considered as relapsed in this study. 
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6. Patients with ongoing or active systemic infection, known hepatitis B virus infection, 
known hepatitis C virus infection, or known positivity to human immunodeficiency virus 
(HIV) 
7. Patients who underwent major surgery within 14 days prior to enrollment to Treatment 
Period I. Surgery for bone lesions is not considered as major surgery 
8. Patients who received radiation therapy within 14 days prior to enrollment to Treatment 
Period I. If the radiation field is small, 7 days is considered as a sufficient interval 
between radiation therapy and chemotherapy 
9. Patients who experience Grade 1 peripheral neuropathy accompanied by pain, or Grade 
≥2 peripheral neuropathy 
10. Evidence of current uncontrolled cardiovascular conditions, including uncontrolled 
hypertension, uncontrolled cardiac arrhythmia, symptomatic congestive heart failure, 
unstable angina, or myocardial infarction within the past 6 months before enrollment to 
Treatment Period I 
11. Infection requiring systemic antibiotic therapy or other serious infection within 14 days 
before enrollment into Treatment Period I 
12. Patients with central nervous system involvement 
13. Inability to swallow oral medications, inability or unwillingness to comply with the drug 
administration requirements, or gastrointestinal conditions that could interfere with the 
oral absorption or tolerance of treatment 
14. Psychiatric illness/social situation that would limit compliance with study requirements 
15. Comorbid systemic illnesses or other severe concurrent disease which, in the judgment of 
the investigator, would make the participant inappropriate for entry into this study or 
interfere significantly with the proper assessment of safety and toxicity of the prescribed 
regimens 
Exclusion Criteria for Treatment Period II  
16. Patients who do not achieve at least a minimal response (MR) to VRd or KRd in 
Treatment Period I per the International Myeloma Working Group (IMWG) response 
criteria, 2014 revision 
17. Patients who experience Grade 1 peripheral neuropathy accompanied by pain, or Grade 
≥2 peripheral neuropathy during Treatment Period I 
18. Patients with evidence of uncontrolled cardiovascular conditions, including uncontrolled 
hypertension, uncontrolled cardiac arrhythmia, symptomatic congestive heart failure, 
unstable angina, or myocardial infarction during Treatment Period I 
19. Patients using potent CYP3A4 inducing agents (rifampicin, rifapentine, rifabutin, 
carbamazepine, phenytoin, phenobarbital), or gingko biloba or St. John’s wort 
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20. Patients with hypersensitivity to any of the IRd study medications, their analogs, or 
excipients contained in IRd 
21. Comorbid systemic illnesses or other severe concurrent disease which, in the judgment of 
the investigator, would make the participant inappropriate for entry into this study or 
interfere significantly with the proper assessment of safety and toxicity of the prescribed 
regimens 
Criteria for Evaluation and Analyses:  
Primary endpoint 
Progression-free survival (PFS) rate at 12 months from the start of study treatment 
Secondary endpoints 
Overall survival (OS) from the start of study treatment 
PFS from the start of study treatment 
Proportion of patients who achieved very good partial response (VGPR) or better 
Rate of minimal residual disease (MRD) in bone marrow in patients who achieved complete 
response (CR)  
Best response 
Overall response rate (ORR) 
Proportion of patients continuing treatment with ixazomib at 12 months from the start of study 
treatment 
Duration of response (DOR) 
Patient-reported outcome: health-related quality of life (HRQoL), as evaluated by the EORTC-
QLQ-C30 and MY-20 instruments 
Evaluation of Quality-Adjusted Life-Years (QALYs) 
Healthcare resource utilization (HCRU) 
Relative Dose Intensity (RDI) 
Bone evaluation 
AEs 
Statistical methods: 
Population for Analyses:  
In this clinical study, the patient populations for analysis are classified as the ‘Full Analysis Set’,, 
the ‘Full Safety Analysis Set’, and the ‘Safety Analysis Set for Treatment Period II’.  
The ‘Full Analysis Set’ is defined as all patients who enroll in Treatment Period I and who 
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receive at least one dose of any therapy during the Treatment Period. The ‘Full Safety Analysis 
Set’ are defined as all patients who enroll in Treatment Period I and who receive at least one dose 
of any therapy during the Treatment Period. The ‘Safety Analysis Set for Treatment Period II’ is 
defined as all patients who enroll into Treatment Period II and who receive at least one dose of 
the study drug. 
Analysis of effectiveness: 
Primary endpoint  
For the analysis of the ‘Full Analysis Set’, a binomial test is conducted on the null hypothesis that 
PFS rate at 12 months after the start of study Treatment Period I is less than or equal to 36%. The 
one-sided significance level is 5%. The two-sided 90% confidence intervals based on exact 
binomial distribution will be calculated. 
Secondary endpoint 
For the ‘Full 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 ‘Full Safety Analysis Set’ and ‘Safety Analysis Set for Treatment Period II’, data on the 
frequency of AEs will be collected. 
Determination of sample size: 
The purpose of this clinical study is to investigate the efficacy and safety of long-term 
administration of PI-based therapy with IRd in RRMM patients who are unable to continue 
treatment with injectable PI-based therapy. The primary efficacy endpoint of this study is the 12-
month PFS rate. The sample size was estimated using the results of a preceding overseas (i.e. 
non-Japanese) clinical trial, and was set so the expected 12-month PFS rate exceeds the threshold 
12-month PFS rate. 
In a clinical trial of patients with RRMM treated with VRd therapy, the 12-month PFS rate was 
36%; this value was set as the threshold PFS rate. Assuming that the hazard rate follows a 
constant exponential distribution, the hazard rate was estimated to be 0.085. 
To calculate the expected PFS rate at 12 months, it is assumed that injectable PI-based therapy 
will be continued up to 3 cycles, and that the PFS rate 9 months after changing to IRd therapy can 
be based on the PFS distribution in the IRd arm of the C16010 study, an international, double-
blind, randomized, placebo-controlled phase 3 study conducted in patients with RRMM with 1-3 
prior therapies. In the C16010 study, the median PFS of the IRd group was 20.6 months; 
assuming that the hazard rate for PFS in the IRd group has a constant exponential distribution, the 
hazard rate with IRd was 0.034. For the present study, assuming that the hazard rate for the first 3 
months is 0.085, and assuming that from month 4 – after changing treatment to IRd therapy – the 
hazard rate is 0.034, the PFS rate at 9 months after switching to IRd therapy is estimated to be 
57%, and this is therefore the expected 12-month PFS rate. 
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With a threshold 12-month PFS rate of 36%, an expected 12-month PFS rate of 57%, a one-sided 
significance level of 5%, and 80% power, the number of study subjects required is 39. 
Based on the considerations above, the minimum number of patients required to be administered 
IRd in this clinical study is 39. However, estimating that approximately 20% of patients may not 
meet the inclusion criteria or may discontinue the trial, the number of patients enrolled in 
Treatment Period I will be 47. 
 
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3.0 
ABBREVIATIONS 
ADL 
activities of daily living 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
CCI 
Charlson comorbidity index 
Ccr 
creatinine clearance 
COI 
conflict of interest 
CR 
complete response 
CTCAE 
common terminology criteria for adverse events 
CVA 
cerebrovascular attack 
CYP 
cytochrome P450 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EORTC QLQ-C30 
European Organization for Research and Treatment of Cancer Quality of 
Life Questionnaire Core-30 Module 
FFPE 
formalin-fixed paraffin-embedded 
FLC 
free light chain 
GCP 
Good Clinical Practice 
HCRU 
Healthcare resource utilization 
HIV 
human immunodeficiency virus 
HR 
hazard ratio 
HRQoL 
health-related quality of life 
IMiDs 
immunomodulatory drugs 
ICH 
International Conference on Harmonisation 
IMWG 
International Myeloma Working Group 
IRd 
ixazomib plus lenalidomide and dexamethasone 
ISS 
International Staging System 
ITT 
intent-to-treat 
JAN 
Japan Accepted Name 
JCOG 
Japan Clinical Oncology Group 
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jRCT 
Japan Registry of Clinical Trials 
KRd 
carfilzomib plus lenalidomide and dexamethasone 
LDH 
lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MR 
minimal response 
MRD 
minimal residual disease 
MRI 
magnetic resonance imaging 
NDMM 
newly diagnosed multiple myeloma 
NGS 
next-generation sequencing 
ORR 
overall response rate 
OS 
overall survival 
PD 
progressive disease 
PFS 
progression-free survival 
PI 
proteasome inhibitor 
PR 
partial response 
QALY 
quality-adjusted life-year 
QOL 
quality of life 
RDI 
relative dose intensity 
RRMM 
relapsed and/or refractory multiple myeloma 
SAE 
serious adverse event 
SPEP 
serum protein electrophoresis 
sCR 
stringent complete response 
TEAE 
treatment-emergent adverse event 
TEN 
toxic epidermal necrolysis 
TIA 
transient ischemic attack 
UPEP 
urine protein electrophoresis 
VGPR 
very good partial response 
VRd 
bortezomib plus lenalidomide and dexamethasone 
 
 
 
 
 
 
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In addition, the terms used in this clinical study protocol are defined as follows. 
Study site: 
Institution where this clinical study will be conducted. 
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. 
Investigator(s): 
A physician taking some of the responsibilities for study-related activities under the 
direction of the investigator at the study site where this person is employed. 
Representative investigator: 
An investigator who acts as the representative of all the investigators at multiple study 
sites when a multicenter study is conducted. 
Director of study site: 
A person managing and supervising the investigator at the study site where the 
investigator is employed. 
Certified Review Board: 
A committee engaged in reviewing and giving opinions about the conduct of clinical 
studies established in compliance with the Clinical Research Act. 
Monitor: 
A person who are third party not engaged in this research, nominated by Takeda under 
responsible representative investigator. 
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]. MM is 
predominantly a disease of the elderly, and it is estimated that the median age at the time of 
diagnosis is 65 to 70 years [10]. MM is generally considered incurable with current therapy. 
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. Currently, 
three drug combinations 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 dexamethasone, are recommended [8,9].  
In recent years, the overall survival (OS) of patients with MM has been extended, associated 
with the introduction of novel therapeutic agents [11,12]. In a retrospective analysis by the 
Japanese Myeloma Society, 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 Myeloma Society and the European Myeloma 
Network showed that the use of new drugs was an independent prognostic factor improving OS 
for 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 Japan Society of Hematology. The number of treatment options using 
new therapeutic agents is increasing, and studies on prognostic factors are 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 the 20S proteasome which is activated in MM and other cancers. The 
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ubiquitin–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 feasible 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 (Rd), 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 health condition 
of 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 endpoint 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 for progression or death was 0.74 (p=0.01), representing a 35% 
improvement in PFS in the ixazomib group compared with the placebo group [18]. OS was a 
secondary endpoint; 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), and so the trial is 
continuing in a double-blind fashion to the next planned interim analysis for OS. 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% (15/361) in the ixazomib group and 6% (23/359) in the 
placebo group. The incidence of all adverse events (AEs) was 98% (355/361) and 99% (357/359) 
in the ixazomib and placebo groups, respectively, and the LQFLGHQFHRI*UDGH$(Vwas 74% 
(267/361) and 69% (247/359), respectively. AEs for which the incidence in the ixazomib group 
was 10 percentage points higher than in the placebo group were thrombocytopenia (31% and 
16%, respectively) and vomiting (23% and 12%, 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, double-blind, randomized, placebo-controlled phase 3 trial of ixazomib in 
patients with RRMM, 70% of the patients had prior treatment with a PI, and 69% had prior 
treatment with bortezomib. Furthermore, carfilzomib has been approved in Japan for use in 
patients with RRMM since August 2016. 
The 
primary endpoint of this study is PFS rate at 12 months from the start of study treatment. In order 
to investigate the influence on physical, social, and emotional functioning by the continued 
administration of oral PIs after treatment with injectable PIs, QOL will be evaluated in this study 
as secondary endpoint.
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5.0 
STUDY OBJECTIVE 
5.1 
Objectives 
To investigate the efficacy and safety of long-term administration of the oral proteasome 
inhibitor ixazomib as part of IRd therapy in patients with RRMM treated initially with an 
injectable proteasome inhibitor-based therapy. 
5.2 
Endpoints 
5.2.1 Primary Endpoint 
Progression-free survival (PFS) rate at 12 months from the start of study treatment 
5.2.2 Secondary Endpoints 
• Overall survival (OS) from the start of study treatment  
• PFS from the start of study treatment 
• Proportion of patients who achieved very good partial response (VGPR) or better 
• Rate of minimal residual disease (MRD) in bone marrow in patients who achieved 
complete response (CR)  
• Best response  
• Overall response rate (ORR) 
• Proportion of patients continuing treatment with ixiazomib at 12 months from the start of 
study treatment  
• Duration of response (DOR) 
• Patient-reported outcome: health-related quality of life (HRQoL), as evaluated by the 
EORTC-QLQ-C30 and MY-20 instruments  
• Evaluation of Quality-Adjusted Life-Years (QALYs) 
• Healthcare resource utilization (HCRU) 
• Relative Dose Intensity (RDI) 
• Bone evaluation 
• AEs 
 
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• A significant violation of the Clinical Research Act, or of ICH Good Clinical Practice 
(GCP), that compromises the safety of the study participants. 
• A regulatory authority decides to terminate the clinical study. 
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 Clinical Research Act, 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 representative investigator,Takeda, or the Certified Review Board elects to 
terminate or suspend the study or the participation of an study site, a study-specific procedure for 
early termination or suspension will be provided by the CRO; 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 representative investigator and Takeda 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.  
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 representative 
investigator and Takeda.  
Following notification regarding such a protocol revision, the principal investigator of each study 
site must obtain the approval from the director of the study site, 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 for 
Treatment Period I or Treatment Period II. 
7.1 
Inclusion Criteria 
Patients satisfying all the following criteria are eligible to participate in this clinical study. 
Eligibility for Treatment Period I  
1. Men and women aged 20 years or older at the time of enrollment 
2. Patients with RRMM 
3. Patients who are planned to start combination therapy VRd or KRd as second, third or 
fourth line of treatment 
4. Patients with measurable disease defined by one or more of the following three 
measurements 
• Serum M-protein: ≥0.5 g/dL (≥ 5 g/L) 
• Urine M-protein: ≥ 200 mg/24 hours 
• Serum free light chain assay: involved free light chain concentration ≥ 10 mg/dL (≥ 
100 mg/L) provided that the serum free light chain ratio is abnormal 
5. Patients with ECOG performance status (PS) 0–2; however, patients with ECOG PS 3 
are eligible if they only have symptoms associated with bone lesions 
6. Patients who are considered by the principal investigator or investigator not to be eligible 
for transplant; or, if considered eligible for transplant, patients who are planned not to 
undergo transplant for at least 12 months after the start of the study treatment 
7. Patients must be registered with, and comply with, the guidelines of the lenalidomide 
management program (RevMate®) 
8. Patients who, before implementing procedures related to clinical research (excluding 
standard medical practices), understand that they can withdraw consent at any time 
without suffering from disadvantages to future treatments, and can provide written 
informed consent 
Eligibility for Treatment Period II  
9. Patients must have received an injectable proteasome inhibitor (bortezomib or 
carfilzomib) in each treatment cycle of Treatment Period I 
7.2 
Exclusion Criteria 
Patients meeting any of the following exclusion criteria are not to be enrolled in this clinical 
study. 
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Eligibility for Treatment Period I  
1. Women who are nursing or pregnant 
2. 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  
3. Patients with poorly controlled active thrombosis 
4. Patients who have participated in a previous clinical trial of ixazomib or who have been 
previously treated with ixazomib 
5. Patients who were refractory to either treatment regimen based on lenalidomide and/or 
proteasome inhibitor(s) 
Note: Refractory MM is defined as PD on therapy or PD within 60 days after the last 
dose of a given therapy. Patients who have disease progressed 60 days after the last dose 
of a given therapy will be considered as relapsed in this study. 
6. Patients with ongoing or active systemic infection, known hepatitis B virus infection, 
known hepatitis C virus infection, or known positivity to human immunodeficiency virus 
(HIV) 
7. Patients who underwent major surgery within 14 days prior to enrollment to Treatment 
Period I. Surgery for bone lesions is not considered as major surgery 
8. Patients who received radiation therapy within 14 days prior to enrollment to Treatment 
Period I. If the radiation field is small, 7 days is considered as a sufficient interval 
between radiation therapy and chemotherapy 
9. Patients who experience Grade 1 peripheral neuropathy accompanied by pain, or Grade 
≥2 peripheral neuropathy 
10. Evidence of current uncontrolled cardiovascular conditions, including uncontrolled 
hypertension, uncontrolled cardiac arrhythmia, symptomatic congestive heart failure, 
unstable angina, or myocardial infarction within the past 6 months before enrollment to 
Treatment Period I 
11. Infection requiring systemic antibiotic therapy or other serious infection within 14 days 
before enrollment into Treatment Period I 
12. Patients with central nervous system involvement 
13. Inability to swallow oral medications, inability or unwillingness to comply with the drug 
administration requirements, or gastrointestinal conditions that could interfere with the 
oral absorption or tolerance of treatment 
14. Psychiatric illness/social situation that would limit compliance with study requirements 
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15. Comorbid systemic illnesses or other severe concurrent disease which, in the judgment of 
the principal investigator or  investigator, would make the participant inappropriate for 
entry into this study or interfere significantly with the proper assessment of safety and 
toxicity of the prescribed regimens 
Eligibility for Treatment Period II 
16. Patients who do not achieve at least a MR to VRd or KRd in Treatment Period I per the 
IMWG response criteria, 2014 revision 
17. Patients who experience Grade 1 peripheral neuropathy accompanied by pain, or Grade 
≥2 peripheral neuropathy during Treatment Period I 
18. Patients with evidence of uncontrolled cardiovascular conditions, including uncontrolled 
hypertension, uncontrolled cardiac arrhythmia, symptomatic congestive heart failure, 
unstable angina, or myocardial infarction during Treatment Period I 
19. Patients using potent CYP3A4 inducing agents (rifampicin, rifapentine, rifabutin, 
carbamazepine, phenytoin, phenobarbital), or gingko biloba or St. John’s wort 
20. Patients with hypersensitivity to any of the IRd study medications, their analogs, or 
excipients contained in IRd 
21. Comorbid systemic illnesses or other severe concurrent disease which, in the judgment of 
the principal investigator or investigator, would make the participant inappropriate for 
entry into this study or interfere significantly with the proper assessment of safety and 
toxicity of the prescribed regimens 
7.3 
Study Registration 
Patients are enrolled into the study after providing consent, and are registered on the web-based 
registration site at the start of treatment.  
All patients who provided consent are registered. Refer to Section 9.1.22 for procedures 
concerning the record of the study subject who discontinued before the start of the study 
treatment. 
For all patients who underwent treatment during Treatment Period I, the results of eligibility for 
Treatment Period II is recorded on the web-based registration site at the start of the treatment for 
Treatment Period II.  
 
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8.0 
STUDY DRUG 
This section describes the treatment used in this clinical study. All treatments employed in this 
study were prescription medicines and were administered or monitored from investigational sites. 
For details and handling of medications, refer to the latest package insert. 
8.1 
Study Drugs 
8.1.1 Study Drugs for Treatment Period I 
Either of the following regimens are used as therapy in Treatment Period I. 
1. VRd  
Combination of bortezomib, lenalidomide and dexamethasone 
2. KRd  
Combination of carfilzomib, lenalidomide and dexamethasone 
8.1.2 Study Drugs for Treatment Period II 
Ixazomib was administered as part of a combination regimen with lenalidomide and 
dexamethasone (i.e. IRd therapy), in Treatment Period II. 
Study drug (Ixazomib) 
Common name:  Ixazomib citrate (JAN)  
Chemical name: 2,2’-{2-[(1R)-1-({[(2,5-Dichlorobenzoyl)amino]acetyl}amino)-3-methylbutyl]-
5-oxo-1,3,2-dioxaborolane-4,4-diyl}diacetic acid 
Lenalidomide 
Common name: lenalidomide hydrate (JAN) 
Dexamethasone 
Common name: dexamethasone 
8.2 
Definition of Study Treatment 
The study treatment period is defined as the period from the start of the treatment in Treatment 
Period I to the end of the treatment in Treatment Period II. The principal investigator or 
investigator administers the therapeutic agent (therapeutic agents for Treatment Period I and 
therapeutic agents for Treatment Period II) according to the clinical research schedule (Appendix 
A). 
In Treatment Period I, the study treatment is discontinued when the PI is not used in each cycle. 
The cycle start date is the earliest administration start date of any of the three drugs. 
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with Impaired Renal Function (Quoted from Revlimid® Suitability Guide 
[24])  
Renal function (Ccr) 
Recommended administration method 
Moderate renal dysfunction: 30 < Ccr 
<60 mL/min 
Start with 10 mg of lenalidomide once 
daily and increase to 15 mg if tolerable 
after 2 cycles 
Severe renal dysfunction (no dialysis 
required): Ccr <30 mL/min 
Lenalidomide 15 mg administered once 
every 2 days 
Severe kidney function disorder 
(dialysis necessary): Ccr <30 mL/min 
Lenalidomide 5 mg once daily (on 
dialysis day after dialysis) 
 
8.4.2 Revised Guidelines for Administering Agents in Treatment Period II  
(for reference) 
AEs are evaluated according to CTCAE (JCOG Japanese translation version v 4.03). For dosing 
changes within a treatment cycle, refer to 8.4.2.1–8.4.2.5; to determine the start of the next 
treatment refer to Section 8.4.3. 
Where more than one AE is observed, dose adjustment and/or delay are carried out according to 
the criteria of the most severe AE. 
In order to ensure the safety of the patient while maximizing the exposure of the study drug, 
another dose modification may be recommended. 
The dose reduction steps for ixazomib, lenalidomide, or dexamethasone are shown in Table 8.c, 
Table 8.d, and Table 8.e, respectively. 
 
Table 8.c 
Dose Reduction Steps for Ixazomib 
Starting dose 
First dose reduction 
Second dose 
reduction 
Third dose 
reduction 
4 0 mg 
3.0 mg 
2.3 mg 
Discontinue 
 
Table 8.d 
Dose Reduction Steps for Lenalidomide 
Starting dose 
First dose reduction 
Second dose 
reduction 
Third dose 
reduction 
25 mg 
15 mg 
10 mg 
Discontinue 
* Patients with moderate renal dysfunction (30 < Ccr < 60 mL/min) will receive lenalidomide from the starting dose of 10mg, 
first dose reduction of 5 mg, and discontinued at the second dose reduction. In the C16028 study, there were no reports of 
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lenalidomide treatment in patients with severe renal dysfunction (Ccr < 30 mL/min). Considering the recommendations for dose 
adjustments for patients with MDS, the patients with severe renal dysfunction may receive lenalidomide from the starting dose of 
5 mg, first dose reduction of 2.5 mg twice a week, but careful administration is recommended. 
 
Table 8.e 
Dose Reduction Steps for Dexamethasone 
Starting dose 
First dose reduction 
Second dose 
reduction 
Third dose 
reduction 
40 mg 
20 mg 
8 mg 
Discontinue 
 
8.4.2.1 Dose Adjustments for Rash: Ixazomib and Lenalidomide 
Ixazomib or lenalidomide dose adjustments for rash will be implemented as follows: 
• Occurrence of Grade 2 rash 
Supportive care and prophylaxis are recommended 
o Occurrence or recurrence of Grade 2 rash manageable by supportive care 
 Continue ixazomib and lenalidomide at the same dose with supportive 
care including prophylaxis 
 If it becomes unmanageable, see below. 
o Occurrence of Grade 2 rash which is not manageable by supportive care 
 Withhold ixazomib and lenalidomide until rash recovers to ≤ Grade 1. 
Following recovery within the same cycle (including potential delay for 
next cycle), resume ixazomib and lenalidomide at the same dose. In 
recurrence, reduce the drug according to Table 8.f 
• Occurrence or recurrence of Grade 3 rash 
o Supportive care and prophylaxis are recommended. Reduce the drug according to 
Table 8.f. 
In this study, ‘events manageable by supportive care’ is defined as events for which symptomatic 
treatment allows for continued study treatment without dose interruptions or reductions, while 
‘events not manageable by supportive care’ is defined as events that cannot be managed only by 
supportive care, and require dose interruptions or reductions. 
In severe situations, alternative dose modification may be made as needed. Angioedema and 
Grade 4 rash have been reported after the use of lenalidomide, and in such cases, lenalidomide 
should be discontinued [24]. Refer to Table 8.f for dose modification of lenalidomide if 
angioedema, Stevens-Johnson syndrome, or toxic epidermal necrolysis (TEN) is observed. 
 
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Table 8.f 
Dose Reduction Steps for Ixazomib and Lenalidomide for Rash 
Reduction 
Actions on Ixazomib and Lenalidomide 
Example of Dose Reduction 
Dose of Ixazomib 
Dose of 
Lenalidomidea 
1st reduction 
Withhold ixazomib and lenalidomide until 
rash recovers to ≤ Grade 1. When recovery 
within the same cycle, resume ixazomib at 
the next lower dose and lenalidomide at the 
same dose. 
3.0 mg 
25 mg (10 mg) 
 
2nd reduction 
Withhold ixazomib and lenalidomide until 
rash recovers to ≤ Grade 1. When recovery 
within the same cycle, resume ixazomib at 
the same dose and lenalidomide at the next 
lower dose. 
3.0 mg 
15 mg (5 mg) 
 
3rd reduction 
Withhold ixazomib and lenalidomide until 
rash recovers to ≤ Grade 1. When recovery 
within the same cycle, resume ixazomib at 
the next lower dose and lenalidomide at the 
same dose. 
2.3 mg 
15 mg (5 mg) 
 
4th reduction 
Withhold ixazomib and lenalidomide until 
rash recovers to ≤ Grade 1. When recovery 
within the same cycle, resume ixazomib at 
the same dose and lenalidomide at the next 
lower dose 
2.3 mg 
10 mg 
(Discontinue) 
aDose of lenalidomide in a parenthesis is for patients with renal dysfunction (creatinine clearance < 60 mL/min) 
 
8.4.2.2 Dose Adjustments for Hematologic Toxicity: Ixazomib and Lenalidomide 
A decision regarding which study treatment requires dose reduction will be dependent upon the 
toxicity, its onset, and time course. Ixazomib or lenalidomide will be adjusted according to each 
criterion on the occurrence of: thrombocytopenia (refer to Table 8.g), or neutropenia (refer to 
Table 8.h). When dose reduction is required, the reduction steps for ixazomib and lenalidomide 
are described in Table 8.c and Table 8.d, respectively. 
 
 
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Table 8.g 
Dose Reduction Steps for Ixazomib and Lenalidomide for Thrombocytopenia 
Platelet Count 
Action on Ixazomib 
Action on 
Lenalidomide 
Action 
First reduction to 
<30,000/mm3 
Interrupt treatment  
Interrupt treatment  
Follow complete blood count 
(CBC) weekly 
Return to ≥30,000/mm3 
within the same cycle 
Resume and maintain 
dose level 
Resume at next lower 
dose level 
Eg, if lenalidomide dose was 
25 mg, reduce to 15 mg 
Second reduction to 
<30,000/mm3 
Interrupt treatment  
Interrupt treatment  
Follow CBC weekly 
Return to ≥30,000/mm3 
within the same cycle 
Resume at next lower 
dose level 
Resume at maintain 
dose level 
Eg, if ixazomib dose was 4 
mg, reduce to 3 mg 
Third reduction to 
<30,000/mm3 
Interrupt treatment  
Interrupt treatment  
Follow CBC weekly 
Return to ≥30,000/mm3 
within the same cycle 
Resume and maintain 
dose level 
Resume at next lower 
dose level 
Eg, if lenalidomide dose was 
15 mg, reduce to 10 mg 
Fourth reduction to 
<30,000/mm3 
Interrupt treatment  
Interrupt treatment  
Follow CBC weekly 
Return to ≥30,000/mm3 
within the same cycle 
Resume at next lower 
dose level 
Resume and maintain 
dose level 
Eg, if ixazomib dose was 3 
mg, reduce to 2.3 mg 
Do not reduce below 2.3 mg 
Fifth reduction to 
<30,000/mm3 
Interrupt treatment  
Interrupt treatment  
Follow CBC weekly 
Return to ≥30,000/mm3 
within the same cycle 
Resume and maintain 
dose level 
Resume at next lower 
dose level 
Eg, if lenalidomide dose was 
10 mg, reduce to 5 mg 
Do not reduce below 5 mg 
 
 
 
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Table 8.h 
Dose Reduction Steps for Ixazomib and Lenalidomide for Neutropenia 
Platelet Count 
Action on Ixazomib 
Action on 
Lenalidomide 
Action 
First reduction to 
<500/mm3 
Interrupt treatment  
Interrupt treatment  
Follow complete blood count 
(CBC) weekly 
Return to ≥500/mm3 
within the same cycle 
Resume and maintain 
dose level 
Resume at next lower 
dose level 
Eg, if lenalidomide dose was 
25 mg, reduce to 15 mg 
Second reduction to 
<500/mm3 
Interrupt treatment  
Interrupt treatment  
Follow CBC weekly 
Return to ≥500/mm3 
within the same cycle 
Resume at next lower 
dose level 
Resume at maintain 
dose level 
Eg, if ixazomib dose was 4 
mg, reduce to 3 mg 
Third reduction to 
<500/mm3 
Interrupt treatment  
Interrupt treatment  
Follow CBC weekly 
Return to ≥500/mm3 
within the same cycle 
Resume and maintain 
dose level 
Resume at next lower 
dose level 
Eg, if lenalidomide dose was 
15 mg, reduce to 10 mg 
Fourth reduction to 
<500/mm3 
Interrupt treatment  
Interrupt treatment  
Follow CBC weekly 
Return to ≥500/mm3 
within the same cycle 
Resume at next lower 
dose level 
Resume and maintain 
dose level 
Eg, if ixazomib dose was 3 
mg, reduce to 2.3 mg 
Do not reduce below 2.3 mg 
Fifth reduction to 
<500/mm3 
Interrupt treatment  
Interrupt treatment  
Follow CBC weekly 
Return to ≥500/mm3 
within the same cycle 
Resume and maintain 
dose level 
Resume at next lower 
dose level 
Eg, if lenalidomide dose was 
10 mg, reduce to 5 mg 
Do not reduce below 5 mg 
 
 
 
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8.4.2.3 Ixazomib Treatment Modification 
Dose modification of ixazomib is allowed based on clinical and laboratory findings. Treatment 
modifications due to ixazomib-related AEs are outlined in Table 8.i. Sequential dose reductions 
of ixazomib from the starting dose of 4.0 mg per dose are recommended depending on toxicity as 
indicated in Table 8.c. 
Table 8.i 
Ixazomib Treatment Modifications (Delays, Reductions, and 
Discontinuations) Due to AEs 
AEs (Severity)  
Action on Ixazomib 
Further Considerations 
Grade 1 peripheral neuropathy 
No action 
Grade 1 signs and symptoms: 
asymptomatic, without pain or 
loss of function, clinical or 
diagnostic observations only 
Grade 1 peripheral neuropathy 
with pain or Grade 2 
Hold ixazomib until resolution to 
Grade ≤ 1 or baseline  
After resolution, resume 
ixazomib and maintain dose level 
Grade 2 signs and symptoms: 
moderate symptoms, limiting 
instrumental activities of daily 
living (ADL) 
Grade 2 peripheral neuropathy 
with pain or Grade 3 
Hold ixazomib until resolution to 
Grade ≤ 1 or baseline 
Reduce ixazomib to next lower 
dose upon recovery 
Grade 3 signs and symptoms: 
severe symptoms, limiting self 
care ADL, assistive device 
indicated 
Grade 4 peripheral neuropathy 
Discontinue ixazomib 
 
Grade 3 nonhematologic toxicity 
judged to be related to ixazomib 
If severity does not recover to 
≤ Grade 1 or baseline within 
4 weeks (including 
recurrence) 
Hold ixazomib until resolution to 
Grade ≤ 1 or baseline 
Reduce ixazomib to next lower 
dose upon return to ≤ Grade 1 or 
baseline 
Monitor closely (especially at the 
time of recurrence), take 
appropriate medical precautions, 
and provide appropriate 
symptomatic care 
Grade 4 nonhematologic 
toxicities judged to be related to 
ixazomib 
Consider permanently 
discontinuing ixazomib 
Exception where the principal 
investigator or investigator 
determines the patient is 
receiving a clinical benefit and 
has discussed the case with 
Takeda clinician 
 
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8.4.2.4 Lenalidomide Treatment Modification 
Dose modification of lenalidomide is allowed based on clinical and laboratory findings. 
Treatment modifications due to lenalidomide-related AEs are outlined in Table 8.j. Sequential 
dose reductions of lenalidomide from the starting dose of 25 mg daily (10 mg daily for patients 
with renal dysfunction) are recommended depending on toxicity as indicated in Table 8.d. 
Table 8.j 
Lenalidomide Treatment Modifications (Delays, Reductions, and 
Discontinuations) Due to Non-Hematologic AEs 
AEs (Severity)  
Action on Lenalidomide 
Further Considerations 
Grade 3/4 toxicities judged to be 
related to lenalidomide 
Hold lenalidomide treatment, and 
restart at the next lower dose 
level when toxicity has resolved 
to ≤ Grade 2 
Do not reduce below 5 mg daily 
Renal dysfunction  
 
Dose reduce per lenalidomide 
package insert for impaired renal 
function 
Care should be taken in dose 
selection/modification in the 
elderly as they are more likely to 
have decreased renal function. 
Monitor renal function regularly 
≥ Grade 2 thrombosis/embolism 
 
Hold lenalidomide and start 
anticoagulation therapy; restart at 
the principal investigator or  
investigator discretion after 
adequate anticoagulation; 
maintain dose level 
Monitor closely and take 
appropriate medical precautions  
Angioedema, Stevens-Johnson 
Syndrome, and Toxic Epidermal 
Necrolysis (TEN) 
Permanently discontinue 
lenalidomide as per package 
insert 
 
Grade 4 exfoliative or bullous 
rash 
Permanently discontinue 
lenalidomide as per package 
insert 
 
Tumor lysis syndrome 
Dose modify as per lenalidomide 
package insert 
Monitor closely and take 
appropriate medical precautions 
 
 
 
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8.4.2.5 Dexamethasone Treatment Modification 
Dose modification of dexamethasone is allowed based on clinical and laboratory findings. 
Treatment modifications due to dexamethasone-related AEs are outlined in Table 8.k. 
Sequential dose reductions of dexamethasone from the starting dose of 40 mg per dose are 
recommended depending on toxicity as indicated in Table 8.e. 
Table 8.k 
Dexamethasone Treatment modifications (Delays, Reductions, and 
Discontinuations) Due to AEs 
AEs (Severity)  
 
Action on Dexamethasone [24] 
Gastrointestinal 
disorder 
Dyspepsia, gastric, or duodenal 
ulcer, gastritis Grade 1-2 
(requiring medical management) 
Treat with histamine-2 blockers, 
sucralfate, or omeprazole. If 
symptoms persist despite these 
measures, decrease 
dexamethasone by 1 dose level. 
 
Dyspepsia, gastric, or duodenal 
ulcer, gastritis ≥ Grade 3 
(requiring hospitalization or 
surgery) 
Hold dexamethasone until 
symptoms are adequately 
controlled. Restart and decrease 1 
dose level of current dose along 
with concurrent therapy with 
histamine-2 blockers, sucralfate, 
or omeprazole. If symptoms 
persist despite these measures, 
discontinue dexamethasone and 
do not resume. 
 
Acute pancreatitis 
Discontinue dexamethasone and 
do not resume. 
Cardiovascular disorder 
 
Edema ≥ Grade 3 (limiting 
function and unresponsive to 
therapy, or anasarca) 
 
Diuretics as needed and decrease 
dexamethasone by 1 dose level. 
If edema persists despite these 
measures, decrease dose another 
level. Discontinue   
dexamethasone and do not 
resume if symptoms persist 
despite second reduction. 
Neurological disorder 
Confusion or mood alteration ≥ 
Grade 3 
Hold dexamethasone until 
symptoms resolve. After the 
symptoms resolved, restart with 1 
dose level reduction. If symptoms 
persist despite these measures, 
discontinue dexamethasone and 
do not resume. 
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Musculoskeletal 
disorder 
Muscle weakness ≥ Grade 3 
(interfering with function ± 
interfering with ADL) 
Decrease dexamethasone dose by 
1 dose level. If weakness persists 
despite these measures, decrease 
dose by 1 dose level. Discontinue 
dexamethasone and do not 
resume if symptoms persist 
despite second reduction. 
Metabolic disorder 
Hyperglycemia ≥ Grade 3 
Treatment with insulin or oral 
hypoglycemic as needed. If 
uncontrolled despite these 
measures, decrease 
dexamethasone dose by 1 dose 
level until levels are satisfactory. 
 
8.4.3 Criteria for Toxicity Recovery Before Beginning the Next Cycle of Treatment in 
Treatment Period II  
The criteria for toxicity recovery before the patient can begin the next cycle of treatment are as 
follows: 
• ANC ≥1,000/mm3 
• Platelet count ≥75,000/mm3 
• Other clinically significant non-hematologic toxicities ≤ Grade 1 or to the patient’s 
baseline condition. 
If the beginning the next cycle of treatment are delayed by more than 4 weeks, discontinue 
administration (exclude when the principal investigator or investigator judge it clinically 
beneficial).  
If the patient does not recover completely from the treatment-related toxicity, see Section 
8.4.2.1–8.4.2.5 for recommended dose reduction. 
8.5 
Overdose 
An overdose is defined as a known deliberate or accidental administration of investigational drug, 
to or by a study patient, at a dose above that which is assigned to that individual patient 
according to the study protocol.  
All overdose should be recorded in the case report using the appropriate forms, by the principal 
investigator or investigator, in order to record any data on study drug overdose into a database. 
Any AEs due to overdose of treatment should be recorded according to section 10.0. 
Furthermore, any serious AEs due to overdose of treatment should be recorded according to 
section 10.2.2. 
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If overdose occurs, consider close observation for hemodynamics and supportive care under 
hospitalization in study site. 
8.6 
Excluded Concomitant Medications and Procedures  
The following medications are prohibited during the study. 
• Any antineoplastic therapy effective against MM other than the study medication 
• Radiation therapy (note that, in general, the requirement for local radiation therapy 
indicates PD) 
Participants are advised by the principal investigator or investigators not to take any medications, 
including marketed drugs, other than the drugs as instructed without prior consultation. 
8.7 
Discontinuation of Study Treatment per Patient 
In any of the following study treatment discontinuation criteria, the study treatment is 
discontinued.  The principal investigators or investigators must record the main reason for 
discontinuation of clinical study in the case report form, according to the following 
classifications. For cases where the patient discontinued before treatment medication was 
administered, see section 9.1.23. 
1. Lack of efficacy (or exacerbation of disease), defined as PD according to IMWG criteria 
(Appendix E). 
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. 
Furthermore, if the AE caused a delay of a treatment cycle of more than 4 weeks during 
the Treatment Period II.  
3. If the patient does not meet the inclusion criteria for Treatment Period II, or meets the 
exclusion criteria. The investigator to record the corresponding criteria(s) in the case 
report. 
4. Voluntary withdrawal by patient 
When the patient wish to stop participating in the clinical study. If the reason for 
discontinuation is known, the investigator to record the reason(s) in the case report. 
Investigators should attempt to make the reasons for voluntary discontinuation as clear as 
possible; note that discontinue due to AEs or lack of efficacy is not classified as 
voluntary discontinuation. 
5. Death during study treatment 
If the patient dies before the decision of discontinuation of the study treatment, the 
investigator to record the date of death in the case report. 
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6. Significant deviation from study protocol 
After start of treatment, if it becomes known that the patient did not meet the inclusion 
criteria of the study protocol; or, if 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. 
7. Lost to follow-up 
Defined as if the patient did not visit the hospital and the investigator could not contact 
the patient. In this case, investigator should record that an attempt had been made to 
contact the patient in the original document. 
8. Termination of study 
See section 6.2.1 for details. 
9. Pregnancy 
When a female patient’s pregnancy becomes known. 
Note: If a female patient's pregnancy is known, the patient must immediately discontinue 
participating in the clinical study. For the discontinuation protocol, see section 9.1.22. 
10. Other 
For other reasons, if the principal investigator or investigator judges that it is necessary to 
stop the study treatment, the investigator will describe the details in the case report. 
 
8.8 
Procedure for Discontinuation of Clinical Study by the Enrolled Patient 
The principal investigator or investigator will discontinue the trial if the patient violates the 
criteria described in Section 8.7. 
In addition, the patient may discontinue participating in the study at any time without 
explanation. 
If the patient discontinues the study, the principal investigator or investigator will record the 
main reason in the case report. The investigator must perform all inspections, observations and 
evaluations that should be performed at the time of discontinuation. 
 
 
 
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9.0 
STUDY PLAN 
9.1 
Study Procedures  
The following section describe the study procedures and data to be collected by the principal 
investigator or investigator. For each procedure, patients are to be tested/observed/assessed by 
the same principal investigator or investigator whenever possible. The Schedule of Study 
Procedures is located in Appendix A. 
9.1.1 Informed Consent Procedure 
The protocol for obtaining informed consent is described in Section 15.3. Each patient must 
provide written informed consent before any study-related procedures are conducted.  
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. 
9.1.2 Patient Demographics  
Demographic information to be obtained will include. 
• Date of birth (if it is not provided, use the age at registration) 
• Sex 
• Initial diagnosis of MM: Initial date of diagnosis NDMM 
• M-protein isotype (IgG κ･λ, IgA κ･λ, IgD κ･λ, IgE κ･λ, IgM κ･λ, Bence Jones type κ･λ,  
non-secretory type, unknown, others) 
• Clinical stage according to ISS (Appendix C) 
• Chromosome abnormality at the initial diagnosis: t (4;14), t (14;16), t (11;14), del17p, 1q 
gain 
• Chromosomal abnormalities at disease recurrence: del17p, 1q gain 
• Evaluation of bone lesions and extramedullary disease 
(If imaging test is performed at the start of the study treatment, the investigator evaluates 
the presence or absence of bone lesions or extramedullary disease (bone-delivered, or soft 
tissue-delivered or others). In addition, the investigator evaluates the longest diameter 
and shortest diameter of the largest extramedullary plasmacytoma of all observed 
extramedullary disease. As a substitute, the most recent image evaluation until the 
consent acquisition may be used 
 
9.1.3 Comorbidity 
Investigators must investigate patient comorbidities at the beginning of the clinical study using 
the Charlson comorbidity index (CCI) [26] (Appendix B). 
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In addition, investigators evaluate the presence or absence, and Grade, of peripheral neuropathy 
and rash for the patients at the start of study. 
9.1.4 Medical History 
The investigator will record prior radiation therapy, antineoplastic therapy, or hematopoietic 
stem cell transplantation for therapy of MM. 
• Prior antineoplastic therapies: drug name, reason for termination (i.e. PD or ‘other’) 
• Prior radiation therapy  
• Prior hematopoietic stem cell transplantation  
9.1.5 Physical Examination 
Physical examination based on symptoms, and evaluation (by the investigator) of the organ 
system related to those symptoms. 
Regarding the results of the examination after the start of study treatment, the investigator 
evaluates the presence or absence of abnormality which is clinically considered to be a problem 
compared with the examination result before the start of the examination treatment. 
9.1.6 Body Weight, Height 
Weight and height are measured at each site  
Height is measured in centimeters with only integers and weight is measured in kilograms up to 
the first decimal place. 
E.g.: Height = 176 cm, weight = 79.2 kg 
9.1.7 Vital signs 
Blood pressure and pulse rate are measured as vital signs.  
9.1.8 Status of Study Treatment 
The principal investigator or investigator records the following information related to the study 
drug in the case report 
• Dosing of each drug used for study treatment (start date of a treatment cycle, number of 
cycle days of Treatment Period I, date and dose administered of each PI, start dose 
administered of lenalidomide and dexamethasone, frequency administered of 
lenalidomide and dexamethasone) 
Note: The start date of a treatment cycle is defined as the earliest date of the 3 drug start 
dates within Treatment Period I and within Treatment Period II. 
9.1.9 Performance Status 
Performance Status determined according to ECOG PS according to Appendix D. 
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9.1.10 Clinical Laboratory Examinations 
Laboratory tests are conducted at each study site. For parameters measured, see Table 9.a. 
 
Table 9.a 
Laboratory tests 
Hematologic  
Blood biochemistry 
WBC count  
Hemoglobin 
Platelet count 
Neutrophil count 
 
albumin  
total bilirubin  
AST  
ALT  
ALP  
LDH  
Creatinine 
Ccr (measured value) *if available in clinical 
records 
calcium 
β2-microglobulin 
 
Ccr (estimated value) is calculated by using the formula below; the Cockcroft-Gault equation 
using serum creatinine value may also be used. 
 
   For men: 
Ccr = 
(140 −age [years]) × weight [kg]
72 × serum creatinine [mg/dL]  
   For women: 
Ccr = 0.85 (140 −age [years]) × weight [kg]
72 × serum creatinine [mg/dL]
 
 
9.1.11  Evaluation of QOL 
Patients’ QOL will be evaluated by the investigators using EORTC-QLQ-C30  (Appendix F)[27] 
and MY-20 (Appendix G)[28]. 
Evaluation of QOL shall be conducted before study drug is administered. During Treatment 
Period II, QOL will be evaluated every 3 cycles (i.e. Cycles 1, 4, 7, 10 etc.). Patients ineligible 
for Treatment Period II (i.e. those who did not meet Eligibility for Treatment Period II) are 
required to have a QOL evaluation once prior to the start of next treatment. 
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9.1.12 Determination of M-protein
M-protein in blood samples and urine samples will be measured at each study site. If it is not 
possible to measure serum and urine M-protein, it can be substituted with serum FLC (free light 
chain) level. 
9.1.13 Response Assessment
The principal investigator or investigators will determine the clinical response of the patient 
according to the IMWG criteria (2014 version), based on serum M-protein, urine M-protein, and 
serum FLC, plus other parameters as required (Appendix E).
9.1.14 Bone Marrow Aspiration
Investigators will perform bone marrow aspiration. If a patient is suspected to have achieved CR, 
the investigator will collect specimens for evaluation of the presence of minimal residual disease 
(MRD). Re-assessment is possible from 6 months after bone marrow aspiration until completion 
of this clinical study. Bone marrow aspiration must take place on Monday through Friday, and 
must not take place on Saturday, Sunday or the holiday. The collected sample of bone marrow 
aspirate will be used to measure MRD.
x
MRD measurement:
MRD was measured by the 
flow method using bone marrow aspiration at the time of 
CR assessment, and it was measured by the NGS method using both FFPE samples of 
preserved bone marrow aspiration at the study sites and bone marrow aspiration at the time 
of CR assessment.
9.1.15 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 the study treatment to the discontinuation of the study treatment.  
9.1.16  Image Inspection
When the investigator performs either a CT scan or MRI on the patient, the presence or absence 
of new extramedullary plasmacytomas will be evaluated, and the longest diameter and the short 
diameter of the largest extramedullary plasmacytoma measured.
9.1.17 Adverse Events
AEs (serious and non-serious) will be monitored throughout the study period. For details of 
defining, recording and reporting of AEs and serious AEs, see section 10.0. 
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9.1.18  Scheduled Outpatient Clinic and Hospitalization 
If the patient visits the clinic as an outpatient or is hospitalized during the clinical study, the 
investigator will record the date of outpatient visit and hospitalization (admission date and 
discharge date). Duration of Treatment Period I and II are defined as; 
 Treatment Period I: from the start date of study drug administration for Treatment Period I to 
the day before the start date of study drug administration for Treatment Period II. For patients 
who discontinued after Treatment Period I, from the cycle start date to the decision date of 
discontinuation of the study treatment. 
    Treatment Period II: from the start date of study drug administration for Treatment Period II to 
the decision date of discontinuation of the study treatment.  
9.1.19  Follow-up Assessments 
Patients who discontinue administration of study treatment before disease progression in 
Treatment Period II are subject to follow-up surveillance to determine PFS. Follow-up is 
conducted every 3 months by hospital visits, until death or the patient is lost to follow-up.  
All patients who discontinue administration of study treatment in Treatment Period II are subject 
to follow-up surveillance to determine OS. Follow-up is conducted every 6 months until death or 
the patient is lost to follow-up. Follow-up for OS is conducted by way of telephone, e-mail, mail, 
etc.; a hospital visit may not be necessary. Investigators will record the following information 
• Date of follow-up 
• Date of death or final known survival date. 
9.1.20  Next-line Treatment 
If the patients received treatment after discontinuing IRd in Treatment Period II, for the first 
therapy after discontinuation the investigator collects the following contents. 
• Names of regimens used 
• Start date 
9.1.21 Contraception and Pregnancy Avoidance Procedure  
From signing of informed consent to the end of the study, female patients of childbearing 
potential (i.e., nonsterilized, premenopausal female patients) who are sexually active must 
comply with RevMate® and use appropriate methods of contraception.  
9.1.22  Pregnancy  
If any female patient is found to be pregnant during the study period 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 investigator or sub-investigator should notify the primary care physician that the 
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patient was participating in a clinical study at the time she became pregnant and provide details 
of treatment the patient received.  
For all reported pregnancies, the outcome until the delivery, including premature birth, will be 
followed up and reported to the representative investigator and Takeda using the pregnancy form 
under the agreement from the patient. Evaluations after the birth of the child will also be 
conducted. 
For male patients, if a patient’s female partner becomes pregnant during study treatment or 
within 90 days of termination of study, the outcome until the delivery, including premature birth, 
will be followed up and reported to the representative investigator and Takeda using the 
pregnancy form under the agreement from the patient. Evaluations after the birth of the child will 
also be conducted. 
9.1.23  Study Participation Discontinued Before Administration of Study Medication  
In the event that a patient signs a consent form and the investigator prepares a case report form, 
for those patients who then discontinue before the administration of the study medication, the 
case report will contain the following items: 
• Date of consent acquisition 
• Date of birth (If a date cannot be provided, then the age at registration) 
• Sex 
• Eligibility 
• Reason for cancellation  
Investigators to collect the main reasons for the patients who discontinued before starting 
treatment medication administration in the following categories: 
o Does not meet selection criteria or violates 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 use the identification code of the patient who discontinued before the 
start of study drug administration. 
 
 
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10.0 
ADVERSE EVENTS 
10.1 
Definitions 
10.1.1 Adverse Event Definition 
AE is defined as any untoward medical occurrence in a patient or subject administered a 
pharmaceutical product (including the study drug); the untoward medical occurrence does not 
necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product whether or 
not it is related to the medicinal product. This includes any newly occurring event, or a previous 
condition that has increased in severity or frequency since the administration of study drug. 
Adverse event is a disease or the like in the clinical research method  
10.1.2 Adverse Event Definition 
Generally, undesirable AEs include: 
• Newly diagnosed disease or deterioration of an existing condition   
(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 study drug or dose change 
• AEs that the principal investigators or investigators regarded as undesirable 
Diagnosis name and signs/symptoms: 
• AEs are recorded by diagnosis name. Any accompanying signs (including abnormal 
laboratory test values or abnormal ECG) or symptoms are not considered AEs. In case of 
an AE without a diagnosis, signs and symptoms are considered AEs. 
Laboratory test values and ECG findings: 
• For clinical laboratory test values or ECG, it is considered as an AE only when the 
responsible the principal investigator or investigator determines that there is a clinical 
problem from the transition (i.e., when a treatment or medical treatment is required, or if 
the principal investigator or the investigator deems a change 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 to be 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 is 
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 study drug administration are 
recognized as complications and are not recognized as AEs. If the complication worsens, 
the deterioration is recognized as an AE, and the principal investigator or investigator 
records the name of AE name as a worsening of complications (e.g. ‘worsening 
hypertension’) in the case report 
• If the patient has a temporary existing disease (e.g., asthma, epilepsy), if the frequency of 
its symptoms increases, or an increase in severity or advancement of disease is observed, 
the existing disease is recorded as an AE. If the patient has a chronic disease (e.g. cataract, 
rheumatoid arthritis), the chronic disease is recorded as an AE if the symptoms worsen 
more than expected. The principal investigator or investigator 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. 
• Deterioration of AE: 
If the AE worsens after a change in the study medication, or if secondary signs and 
symptoms of the adverse event are observed, these secondary changes are regarded as 
new AEs, and recorded in the case report  The principal investigator or investigator 
should record the reported AE name to clearly show that the symptom change (e.g. 
worsening of …). 
Changes in the severity of AE: 
• If there is a change in the severity of the AE, the principal investigator or investigator 
records only the instance when the maximum severity is observed. 
Pre-planned surgery or treatment: 
• The surgery or treatment planned before the start of study drug administration is not 
considered an AE. However, if the patient's existing symptoms deteriorate markedly and 
surgery or treatment needs to be performed urgently, that condition or event is considered 
an AE. Complications due to pre-planned surgical procedures are recorded as AEs. 
Surgery or treatment requiring no urgency: 
• Surgery or treatment which does not suddenly affect the patient’s symptoms, such as 
cosmetic surgery, is not considered an AE. However, the investigator records this case in 
the case report. Complications due to surgery that require no urgency are reported as AEs. 
Progressive disease: 
• PD is not regarded as an AE as it is a result of lack of efficacy of pharmaceuticals. Also, 
symptoms that are merely for PD need not be considered serious AEs. However, if the 
progress of existing cancers (including the development of new metastases) is confirmed 
clinically or by examination, and if the degree of progression of the cancer falls under the 
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serious criterion of as per section 10.1.3, progression of the cancer is considered a serious 
AE. 
Overdose of study drug: 
• Overdose of drugs without any event expression is not considered an AE. However, 
investigators record overdose in the case report. When an event occurs due to overdose of 
the drug, the investigator records the symptom as an AE in the case report. 
10.1.3 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 in which the patient was at risk of death at the time of 
the event. It does not refer to an event which hypothetically might have caused death if it 
were more severe). 
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, require 
medical or surgical intervention to prevent one of the outcomes listed above, or involves 
suspected transmission via a medicinal product of an infectious agent. 
Examples of such medical events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse; any organism, virus, or 
infectious particle (e.g., prion protein transmitting Transmissible Spongiform Encephalopathy), 
pathogenic or nonpathogenic, is considered an infectious agent. Any terms included in the 
Takeda Medically Significant AE List (Table 10.a) are defined as a Serious AE. 
 
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Table 10.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 suspect thereof 
 
10.1.4 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 representative investigator and Takeda when they request 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 investigator to the representative 
investigator and Takeda, see Section 10.4. 
10.1.5 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 10.b) 
 
Table 10.b 
AE Grade Defined in CTCAE Japanese Version 4.03 
Grade 
Definition 
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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. 
 
10.1.6 Causal Relationship of Adverse Events 
Causal relationship between test medication (study drug at Treatment Period I, study drug at 
Treatment Period II) and AE, and causal relationship with study drug (only in case of ‘related’) 
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 study drug or study treatment. 
Not related 
There is no clear temporal correlation with study drugs or treatments. Or an AE that is 
considered to be related to other factors such as original disease, complications, 
concomitant medications, concomitant treatment or the like 
10.1.7 Date of onset 
Judge the date of onset of adverse event according to the following criteria: 
Adverse event 
Date of onset 
Signs, symptoms, 
diseases (diagnosis 
name) 
Record the date when the subject or the principal investigator or investigator noticed 
the first signs and symptoms of adverse event. 
Asymptomatic 
disease 
Record the date of obtaining a definite diagnosis after conducting a test for diagnosis.  
Record the date of obtaining a definite diagnosis even when the test findings show old 
findings or suggest approximate timing of onset. 
Aggravation of 
complications 
Record the date when the subject or the principal investigator or investigator noticed 
the signs and symptoms of adverse event for the first time. 
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Abnormal 
laboratory findings 
after initiation of 
protocol treatment 
Record the date of test where abnormal laboratory values considered clinically 
problematic were observed. 
Abnormality was 
observed on the test 
at initiation of 
protocol treatment, 
and aggravation 
was shown on 
subsequent tests. 
Record the date of tests when values were medically judged to be obviously increased 
and decreased based on the changes in test values. 
 
10.1.8 Date of resolution 
The date when the adverse event resolved (or resolved with sequelae). Date of death when a 
subject died of the concerned adverse event. When recovery cannot be confirmed at study 
completion, it is considered ongoing. 
10.1.9 Treatment Regarding Study Medication 
As a treatment for the AE, the time at which the study treatment is discontinued is defined as 
‘discontinuation of administration’. 
10.1.10Outcome 
The outcomes of AEs are 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 AEs 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 was worse than at the time of observation 
• 
Irreversible congenital anomalies 
• 
In cases of death, if the adverse event is not a direct cause of death and the AE 
remains unrecovered 
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Recovered but with 
sequelae 
Dysfunction that interferes with daily living occurred 
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 
10.2 
Procedures for Recording and Reporting AEs and Serious AEs 
All AEs spontaneously reported by the patient and/or in response to an open question from study 
personnel or revealed by observation, physical examination, or other diagnostic procedures will 
be recorded on the appropriate page of the eCRF. Any clinically relevant deterioration in 
laboratory assessments or other clinical finding is considered an AE. When possible, signs and 
symptoms indicating a common underlying pathology should be noted as 1 comprehensive event. 
10.2.1 Collection and Reporting of AEs 
10.2.1.1 Collection Period of AEs 
Investigators will start collection of AEs from the start of the study Treatment Period I, and 
continue until discontinuation of the Treatment Period I, or 30 days after the discontinuation of 
Treatment Period II, or until the start of the next treatment, whichever comes first. 
In addition, new primary malignancies that occur during the follow-up periods after the 
discontinuation of the Treatment Period II must be reported, irrespective of causality to study 
regimen, to the representative investigator and Takeda for a minimum of 3 years after the 
discontinuation of study treatment through death or termination of the study by them. 
10.2.1.2 Reporting AEs 
When the patient visits, the principal investigator or investigator confirms the presence or 
absence of symptoms of AEs with patients. The investigator inquires with the patient, e.g. ‘How 
is your physical condition since the last visit?’ to the patient, and listens to the patient’s 
description AEs that occurred during the study. 
Regarding AEs, irrespective of the symptoms of the patients being related to the study drug, the 
principal investigator or investigator examines the symptoms of the patient until the symptoms 
disappear. The investigator examines the symptoms of the patient until the abnormality of the 
clinically relevant laboratory test value recovers to the value at the start of the test treatment. The 
investigator tracks all the patients to be studied until a sufficient explanation can be given about 
the change in the patient’s symptoms. Regardless of the patient's symptoms being related to the 
study treatment medicine, the principal investigator or investigator records all AEs on the AE 
page of the case report. Each event is described as follows. 
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1. Event name 
2. Expression date and date of disappearance 
3. Severity 
4. Causality relationship with study drug 
5. Clinical treatment for study drug 
6. Outcome 
7. Severity 
The principal investigator or investigators 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 recognizes the patient’s symptoms are likely due to AEs, 
the principal investigator or investigator may follow-up and investigate the patient's symptoms. 
The principal investigator or investigator then performs a medical evaluation on the symptoms of 
the patient. As a result of the follow-up study, if the symptom of the patient is judged to be an 
AE not previously reported, the investigator will report according to the usual reporting 
procedure. 
10.2.2 Collection and Reporting of Serious AEs 
The principal investigator or investigator immediately reports to the director of study site when 
the principal investigator or investigator judges that a serious adverse event has occurred. And 
the principal investigator or investigator should also report to the CRO within 24 hours of 
recognition of the onset of an event. In addition, the principal investigator will submit a serious 
AE report detailed in 10 calendar days to Takeda through the CRO. The principal investigator 
shall describe all information as much as possible, and the description of the following contents 
is mandatory. 
• Name of the adverse event (including known/unknown events*) 
• Brief description of the event and reasons for judging it to be serious 
• Research patient identification code 
• Name of the principal investigator or investigator  
• Name of study medication 
• Determination of causality 
*: The principal investigator or the investigator will determine whether adverse events are known 
or unknown according to the latest package insert of the drug used in the protocol treatment. 
The representative investigator receiving a report from the CRO will hear the opinions of the 
Certified Review Board, and also provide information to the principal investigator at each study 
site through the CRO according to the Clinical Research Act. The principal investigator will 
report to the director of the study site as necessary.  
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After the AE collection period, the principal investigator or investigator must report to the 
representative investigator and Takeda about any AEs voluntarily reported by the patient and 
may be due to the patient participation in the clinical study. 
10.3 
Follow-up of Serious AEs 
If the principal investigator or investigator obtained at a later date any information that was not 
initially reported, the principal investigator or investigator shall fill out a report of serious AEs 
for follow-up or create another document and promptly report it to Takeda through the CRO. If 
requested, the investigator copies relevant data (e.g. electrocardiogram, clinical laboratory value, 
summary of discharge report, necropsy outcome and so on) from the medical record of the study 
site and reports it to the representative investigator and Takeda. The principal investigator or 
investigator will track the patient's symptoms until the event disappears or the final outcome is 
confirmed. The deadline and procedure concerning the report of the follow-up survey are done in 
the same way as the initial report. 
10.3.1 Reporting Serious AEs to Regulatory Authorities 
Takeda should report according to regulations, unexpected serious adverse drug reactions and 
other serious adverse events that are subject to emergency reporting to regulatory authorities. 
From the time point of first acknowledging the event or receiving additional information, Takeda 
or CRO should comply with regulatory required time frame for reporting, and make emergency 
report concerning unexpected serious adverse drug reactions and expected serious adverse drug 
reactions to regulatory authorities. Also, Takeda should in the same way make an emergency 
report of other critical safety information that may have a major effect on the study drug risk-
benefit, continuation of study drug administration, and continuation of this clinical study . 
A report to CRB in the event that an adverse event suspected to be attributable to this study is 
reported comply with the following report deadline. 
Severity 
Predictability 
deadline 
death 
Does not matter 
Within 15 days 
Hospitalization or extension of 
hospitalization 
Handicap 
Fear of death or handicap 
Serious adverse events similar to 
the above 
Congenital disease in the later 
generations 
cannot predict 
Predictable but there are concerns 
about expansion 
Within 15 days 
predictable 
Within 30 days 
Adverse events due to infection 
cannot predict 
 
Within 15 days 
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Death from infectious diseases 
Hospitalization or extension of 
hospitalization 
Handicap 
Fear of death or failure 
Serious adverse events similar to 
the above 
Congenital disease in the later 
generations 
Does not matter 
Within 15 days 
 
10.4 
Reporting of additional information on AEs 
When the representative investigator and Takeda request the principal investigator or 
investigator to provide additional information on an AE, the principal investigator or investigator 
must enter it in the eCRF system or submit a written report. 
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11.0 
STUDY-SPECIFIC COMMITTEES  
No data safety monitoring committee or central assessment committee will be used in this study. 
 
11.1 
Study Steering Committee 
The study steering committee consists of medical professionals involved in this clinical study, 
Takeda, and independent statistical experts. The study steering committee and the representative 
investigator oversee 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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12.0 
DATA HANDLING AND RECORDKEEPING 
The full details of procedures for data handling will be documented in the Data Management 
Plan. If selected for coding, AEs will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA). Drugs will be coded using the database of medical drug name. 
12.1 
Case Report 
The principal investigator or investigator prepares a case report for all patients who have given 
consent. 
Takeda or its designee provides the study site with access rights to the electronic case report 
form (eCRF). Takeda or its designee provides training for site managers, investigators and 
research collaborators when using the eCRF. The case report will be used to report the 
information gathered during clinical research implementation to Takeda. The case report is 
prepared in Japanese. The principal investigator or investigator inputs the data directly when 
preparing the case report. 
Any change of, modification of, or addition to the data in the case report 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 case report. The principal investigator is fully responsible for 
the accuracy and authenticity of all data entered in the case report. 
The following are data recorded directly in the case report. 
• The severity and seriousness of AEs, causal relationships with study drugs and study 
drugs, outcome 
• Reason for  discontinuation before administration of study medication  
• Reason for discontinuation of clinical study end status 
In cases where the principal investigator or investigator changes or corrects the data inputs in the 
case report 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 case report is described accurately and completely, then signs or stamps 
and record the date. 
Takeda or its designee confirms that the case report is properly prepared according to the 
procedure prescribed for each study. The representative investigator or its designee will view 
medical records and hospital records of patients participating in the study as necessary to ensure 
the accuracy of the case report. The completed case reports are the sole property of Takeda 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 
Takeda. 
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12.2 
Electronic Case Report Input System Deadline 
Takeda 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 case 
report, the principal investigator or investigator must input the electronic case report system 
within 14 days as a general rule. 
12.3 
Record Retention 
The principal investigator or the director 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 the representative investigator 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 case report forms of changes 
and modifications record, and the like. In addition, the principal investigator and the director 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 representative investigator and Takeda request a longer period for retention, the 
director of the study site should discuss how long and hot retain those documents with them. 
  
 
 
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13.0 
STATISTICAL METHODS 
Statistical analysis will be undertaken by persons who are appointed by the statistical analysis 
manager and statistical analysis supervisor (analysts who belong to the contract research 
organization [CRO] independent from Takeda). 
13.1 
Statistics and 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 definition of analysis variables and analysis methodology to 
address all study objectives. 
13.1.1 Analysis Sets 
In this clinical study, the following two analysis sets are defined: 
• Full Analysis Set (FAS): all patients who enroll in Treatment Period I and who receive at 
least one dose of any therapy during the Treatment Period  
• Safety Analysis Set for Treatment Period II: all patients who enroll into Treatment Period 
II and who receive at least one dose of the study drug 
13.1.2 Analysis of Demographics and Other Baseline Characteristics 
The key demographics and other baseline characteristics will be summarized for the FAS. 
13.1.3 Efficacy Analysis 
(1) Primary Endpoint and Analytical Methods 
[Primary endpoint] 
PFS rate at 12 months from the start of study Treatment Period I. 
The primary endpoint of PFS rate at 12 months from the start of study Treatment Period I is 
defined as the proportion of patients who are alive and have not had disease progression at 12 
months after the start date. The start date is defined as the date of first dose of treatment in 
Treatment Period I. Patients without 12-month imaging data for determining PD, or patients lost 
to follow-up, are included in the denominator; however, they are not treated as patients who have 
not had disease progression. 
[Primary analysis] 
For the primary endpoint analysis, the null hypothesis will be that the proportion of patients in 
the FAS who are alive and progression-free at 12 months after the start of Treatment Period I is 
≤36%.The one-sided significance level will be 5%. Two-sided 90% confidence intervals will be 
calculated via exact binomial distribution. 
(2) Secondary Endpoints and Analytical Methods 
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[Secondary Endpoints] 
• OS from the start of study Treatment Period I  
OS is defined as the period from the first dose of treatment in Treatment Period I to the time 
when death (regardless of the cause of death) is confirmed. Patients who are still alive will be 
censored at the last confirmed date of survival or the date of data cut-off, whichever is earlier. 
[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 using the double logarithmic transformation 
method of Brookmeyer and Crowley [29]. 
• PFS from the start of study Treatment Period I 
PFS is defined as the period from the first dose of treatment in Treatment Period I to the time of 
confirmed PD or confirmed death (regardless of the cause of death), whichever is earlier. 
Patients who are still alive and progression-free will be censored at the last confirmed date at 
which they are progression-free. 
[Analysis Method] 
PFS for the FAS will be estimated using similar methodology to that used for analysis of OS. 
• Very Good Partial Response (VGPR) or more 
This secondary endpoint is defined as the proportion of patients achieving a VGPR or better, 
according to the IMWG criteria (2014 version) (Appendix E), after the start of the study. 
[Analysis Method] 
The percentage of patients achieving VGPR or better and 95% confidence intervals on both sides 
will be calculated for the FAS  Confidence intervals will be accurately calculated based on a 
binomial distribution. 
• Proportion of patients with CR who achieve minimal residual disease (MRD) negativity 
in bone marrow 
This secondary endpoint is defined as the proportion of patients achieving CR who are MRD-
negative. If a patient is MRD-positive at their first evaluation and MRD-negative after re-
examination, the patient will be considered to be MRD-negative. 
[Analysis Method] 
For patients in the FAS who enrolled in Treatment Period II and also achieved VGPR or above 
as best response in Treatment Period II,, the proportion of patients who are MRD-negative and 
two-sided 95% confidence intervals will be calculated. Confidence intervals will be accurately 
calculated based on a binomial distribution. 
• Best Response 
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The secondary endpoint 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 
E), after each cycle of treatment. 
[Analysis Method] 
A histogram (or similar) showing the numbers of patients in the FAS achieving different levels 
of best response will be created after each cycle of treatment. 
• Overall Response Rate (ORR) 
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 E) after the start of the study 
treatment. 
[Analysis Method] 
The ORR and 2-sided 95% confidence intervals will be calculated in the FAS. Confidence 
intervals will be accurately calculated based on a binomial distribution. 
• Proportion of patients continuing treatment with ixazomib at 12 months from the start of 
study Treatment Period I. 
[Analysis Method] 
For the FAS, the proportion of patients who are continuing to receive study drug at 12 months 
after the start of Treatment Period I, and the two-sided 95% confidence intervals, will be 
calculated. The confidence intervals will be calculated via exact binomial distribution. 
• Duration of Response (DOR) 
DOR is defined as the time from the date of first documentation of response ≥PR according to 
the IMWG criteria (2014 version) (Appendix E) to the date of first documentation of PD or death 
due to any cause. 
[Analysis Method] 
DOR for patients in the FAS who achieve PR or better at any time during the study will be 
estimated using the Kaplan-Meier method, and the quartiles and 95% confidence intervals will 
be calculated by the double logarithmic transformation method of Brookmeyer and Crowley [29]. 
Patients who achieve PR or better and have not experienced PD will be censored from the date 
when their response was confirmed as not being worse than PR. 
• Patient-reported outcome: HRQoL, determined using EORTC-QLQ-C30 and MY-20 
EORTC-QLQ-C30 comparises five functional scales (physical, role, emotional, cognitive, 
social), a global health/quality of life scale, three symptom scales (tiredness, nausea and 
vomiting, pain) and six single items (dyspnea, insomnia, anorexia, constipation, diarrhea, 
economic difficulty). 
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MY-20 consists of four independent subscales, two functional subscales (body image, future 
perspective) and two symptom subscales (multiple myeloma symptoms, treatment adverse 
effects).  
 [Analysis Method] 
Scores will be calculated for each subscale according to the EORTC Scoring Manual, and 
summary statistics (number of cases, average value, median, standard deviation, minimum value, 
maximum value, quartile value) and 2-sided 95% confidence intervals will be determined for 
each treatment cycle, and mean values will be calculated and presented graphically as plots over 
time. Summary statistics for change from cycle 1, Treatment Period I, plus the mean and 95% 
confidence intervals, will be calculated. For patients in the FAS who enroll in Treatment Period 
II, summary statistics for change from cycle 1, Treatment Period II, plus the mean and 95% 
confidence intervals, will also be calculated. Changes over time for each subscale will be 
evaluated in an exploratory fashion by utilizing a statistical model such as a linear mixture model. 
In addition, data from patients enrolled in Treatment Period I will be used for exploratory 
analyses of the trends in subscale scores over time. 
• Quality-Adjusted Life Years (QALY) 
The global health/quality of life scale score from the EORTC-QLQ-C30 instrument will be 
converted into a utility value ranging from 0 to 1, and used to adjust the value of survival years; 
this value is defined as the modified QALY. 
[Analysis Method] 
Summary statistics regarding modified QALYs will be calculated for the FAS. 
• Healthcare Resource Utilization 
[Analysis Method] 
For the FAS, the exposure-adjusted rate of hospitalization events (per patient-months) and the 
duration of hospitalization among patients in Treatment Period I and Treatment Period II will be 
calculated. 
• Relative Dose Intensity (RDI) 
[Analysis Method] 
Summary statistics for RDI for ixazomib, lenalidomide and dexamethasone, will be calculated 
for the FAS. Also, the time plot is outputted. 
• Bone Evaluation 
[Analysis Method] 
For the FAS, the proportion of patients with bone lesions and the two-sided 95% confidence 
intervals will be calculated. The confidence interval will be calculated via exact binomial 
distribution. 
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13.1.4 Analysis of Safety 
Treatment-emergent Adverse Events 
A treatment-emergent adverse event (TEAE) is defined as either: 
• For patients who discontinued after Treatment Period I, an AE that occurred from the 
start of study until the end of Treatment Period I  
• For patients who enrolled into Treatment Period II, an AE that occurred from the start of 
treatment in Treatment Period I until 30 days after the end of Treatment Period II or the 
start of next treatment, whichever occurs first 
 
TEAE will be coded using MedDRA and will be summarized by Preferred Term (PT) and 
System Organ Class (SOC). 
In Treatment Period II, TEAEs will be regarded as any AEs that occur after the first dose of 
study drug. 
The following data will be collected in the Full Safety Analysis Set. 
• Frequency of all TEAEs 
• Frequency of Grade 3 or higher TEAEs 
• Frequency by Grade for all TEAEs 
• Frequency of serious TEAEs 
• Frequency of TEAEs that result in death 
In addition, the following data reported during Treatment Period II will be analyzed in the Safety 
Analysis Set: 
• Frequency of all TEAEs observed during Treatment Period II 
• Frequency of study drug-related TEAEs observed during Treatment Period II 
• Frequency of Grade 3 or higher TEAEs observed during Treatment Period II 
• Frequency of Grade 3 or higher, drug-related TEAEs observed during Treatment Period 
II 
• Frequency by Grade of all TEAEs observed during Treatment Period II 
• Frequency by Grade of study drug-related TEAEs observed during Treatment Period II 
• Frequency of TEAEs resulting in discontinuation of treatment* during Treatment Period 
II  
• Frequency of TEAEs resulting in dose delay* during Treatment Period II  
• Frequency of TEAEs resulting in dose reduction* during Treatment Period II  
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• Frequency of serious TEAEs observed during Treatment Period II 
• Frequency of TEAEs resulting in death, observed during Treatment Period II  
* One or more of the following: study drug, lenalidomide, dexamethasone 
13.2 
Interim Analysis and Criteria for Early Termination 
An interim analysis is not planned. 
13.3 
Determination of Sample Size 
The purpose of this clinical study is to investigate the efficacy and safety of long-term 
administration of PI-based therapy with IRd in RRMM patients who are unable to continue 
treatment with injectable PI-based therapy. The primary efficacy endpoint of this study is the 12-
month PFS rate. The sample size was estimated using the results of a preceding overseas (i.e. 
non-Japanese) clinical trial, and was set so the expected 12-month PFS rate exceeds the threshold 
12-month PFS rate. 
In a clinical trial of patients with RRMM treated with VRd therapy, the 12-month PFS rate was 
36%; this value was set as the threshold PFS rate. Assuming that the hazard rate follows a 
constant exponential distribution, the hazard rate was estimated to be 0.085[30]. 
To calculate the expected PFS rate at 12 months, it is assumed that injectable PI-based therapy 
will be continued up to 3 cycles, and that the PFS rate 9 months after switching to IRd therapy 
can be based on the PFS distribution in the IRd arm of the C16010 study, an international, 
double-blind, randomized, placebo-controlled phase 3 study conducted in patients with RRMM 
with 1-3 prior therapies. In the C16010 study, the median PFS of the IRd group was 20.6 
months; assuming that the hazard rate for PFS in the IRd group has a constant exponential 
distribution, the hazard rate with IRd was 0.034. For the present study, assuming that the hazard 
rate for the first 3 months is 0.085, and assuming that from month 4 – after switching treatment 
to IRd therapy – the hazard rate is 0.034, the PFS rate at 9 months after switching to IRd therapy 
is estimated to be 57%, and this is therefore the expected 12-month PFS rate. 
With a threshold 12-month PFS rate of 36%, an expected 12-month PFS rate of 57%, a one-sided 
significance level of 5%, and 80% power, the number of study subjects required is 39. 
Based on the considerations above, the minimum number of patients required to be administered 
IRd in this clinical study is 39. However, estimating that approximately 20% of patients may not 
meet the inclusion criteria or may discontinue the trial, the number of patients enrolled in 
Treatment Period I will be 47. 
 
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14.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
14.1 
Study-Site Monitoring Visits 
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded in the case reports. The principal investigator and the director of study site guarantee 
access to the source documents by the monitor. 
All aspects of the study and its documentation will be subject to review by the monitor, including 
the patient identification code list, patient medical records, original informed consent 
documentation which includes the signature and date. Then, the monitor confirms that study is 
carried out in compliance with the study protocol. In addition, the monitor confirms the 
consistency between the case report and the relevant source material. The principal investigator 
or investigator and others involved in clinical research will make efforts to respond by allocating 
sufficient time for each worker to proceed with the work when making a visit to a research 
institution for monitoring. 
For details on the frequency of monitoring to research institutes and the procedure, follow the 
procedure written separately. 
14.2 
Deviations from the Clinical Research Act and Study Protocol 
The principal investigator or investigator should record all deviations from the Clinical Research 
Act and protocol. 
When acknowledging that the Clinical Research Act, ICH-GCP and protocol are not met 
(hereinafter referred to as “non-compliance”), the principal investigator or investigator should 
immediately report it to the director at the study site and notify the principal investigator through 
the CRO. They should provide information on non-compliance to principal investigator and 
director at each study site through the CRO. 
The representative investigator receiving a report from the CRO will hear the opinions of the 
Certified Review Board according to the Clinical Research Act when he/she determines it to be 
serious non-compliance. 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections 
The study site also may be subject to quality assurance inspections by the auditor and the 
Certified Review Board. In this circumstance, the representative investigator and Takeda 
designated auditor will contact the site in advance to arrange an inspecting 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 representative investigator and Takeda 
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should be notified immediately. The principal investigator and the director of the study site 
guarantee access for quality assurance auditors to all study documents.  
 
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15.0 
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 Clinical Research Act. Each principal 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 H and 
‘Responsibilities of the representative investigator and Investigator’ that are listed in Appendix I.  
15.1 
Certified Review Board Approval 
Through the conduct of this clinical study, approval by the Certified Review Board and 
permission for the conduct of the study by the director of study site should be obtained for the 
conduct of the study according to the clinical study protocol. 
. 
15.2 
Conflicts of Interest 
This clinical trial is conducted with support of Takeda. 
Prior to conduct of the study, the principal investigator should appropriately manage according to 
the Clinical Research Act, that this study has no conflict of interests (hereinafter referred to as 
COI) in companies involved in protocol treatment[31] [32]. 
The study site shall comply with all requirements prescribed by the Certified Review Board. This 
includes self-declaration of COI, study protocol, consent form and any explanatory documents. 
15.3 
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 Clinical Research Act and 
will be in accordance with all applicable laws and regulations. The informed consent form 
describes the approval by the Certified Review Board and the director of study site, the 
implementation plan has been submitted to the Minister of Health, Labor and Welfare, how to 
disclose the study information, the compensation for health damage related to the study and what 
they consist, content of examination by the Certified Review Board, 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 representative investigator is responsible for the preparation of the informed consent form, 
content, and Certified Review Board approval.  
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The informed consent form must be written in a language fully comprehensible to the 
prospective subject. It is the responsibility of the principal investigator or 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. 
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 
principal investigator or 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 
principal investigator or investigator must document the date the subject signs the informed 
consent in the subject’s medical record. Copies of the signed informed consent form shall be 
given to the subject.  
All revised informed consent forms must be reviewed and signed by relevant subjects in the 
same manner as the original informed consent. The date the revised consent was obtained should 
be recorded in the subject’s medical record, and the subject should receive a copy of the revised 
informed consent form. 
15.4 
Subject Confidentiality 
The person engaged in this clinical study or the person who has been engaged in this clinical 
study 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 Takeda’s clinical 
study database or documentation via a unique identification number. As permitted by all 
applicable laws and regulations, limited subject attributes, such as sex, age, or date of birth may 
be used to verify the subject and accuracy of the subject’s unique identification number. 
To comply with  the Clinical Research Act and to verify compliance with this protocol, the 
principal investigator to permit its monitor, representatives from any regulatory authority (eg, the 
FDA, MHRA,PMDA), the auditors, and the appropriate Certified Review Board 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 15.3) 
Copies of any subject source documents that are provided to the representative investigator and 
Takeda must have certain personally identifiable information removed (ie, subject name, address, 
and other identifier fields not collected on the subject’s case report form). 
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15.5
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.
15.6
Economic Burden or Reward for Research Patients
Of the expenses related to this clinical study, Takeda will provide finance which is not covered 
by national insurance. 
15.7
Profit of Non-Profit for the Study Subject
15.7.1 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. 
15.7.2 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.
15.8
Attribution and Access Rights of Research Results
15.8.1 Attribution of Research Results
All data and information obtained through this clinical study are attributed to Takeda. 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.
15.8.2 Data Access Rights
Access rights to all data and information obtained from this clinical study will be given to the 
person(s) approved by Takeda. 
15.9
Publication, Disclosure, and Clinical Trial Registration Policy
15.9.1 Publication
The principal investigator is obliged report a summary of results to the director of the study site, 
and to provide the representative investigator and Takeda with complete test results and all data 
derived by the principal investigator from the study. During and after the study, only 
representative investigator and/or  its designee may make study information available to other 
study investigators or to regulatory agencies, except as required by law or regulation. 
Property of Takeda: For non-commercial use only and subject to t
able Terms of Use
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During and after the study, the representative investigator  and/or its designee must summarize 
the data and publish in a medical journal and/or present at e.g. a meeting of a professional 
association. The representative investigator and/or its designee may publish any data and 
information from the study (including data and information generated by the principal 
investigator) with the consent of the principal investigator. 
The principal investigator or investigator needs to obtain a prior written approval from Takeda to 
publish any information from the study externally such as to a professional association  
When the final publication is completed, Takeda should notify the head of study site. 
15.9.2 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 representative investigator and 
Takeda will, at a minimum register interventional clinical trials Takeda conducted anywhere in 
the world on ClinicalTrials.gov or other publicly accessible websites before start of study. 
Takeda’s contact information, along with investigator’s institution name, city, country, and 
recruiting status will be registered and available for public viewing. 
The representative investigator will perform registration in the database established by the 
Ministry of Health, Labour and Welfare (jRCT: Japan Registry of Clinical Trials) according to 
the Clinical Research Act after approval by the Certified Review Board. 
15.9.3 Clinical Trial Results Disclosure 
Takeda 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. 
The representative investigator will post the results of clinical trials on the database established 
by the Ministry of Health, Labour and Welfare (jRCT: Japan Registry of Clinical Trials) 
according to the Clinical Research Act after reporting to the Certified Review Board. The 
representative investigator and/or its designee will report director of the study site that the final 
post of this clinical study was done. 
15.10 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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16.0 
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Palumbo A, Anderson K. Multiple myeloma. N.Engl J Med 2011; 364(11): 1046-60 
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日本骨髄腫学会（編）. 多発性骨髄腫の診療指針 第3 版. 文光堂. 2012. 
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Fujisawa M, Suehara Y, Fukumoto K, Takeuchi M, Matsue K. Changes in survival 
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Kobayashi T, Kuroda J, Fuchida S, Kaneko H, Yagi H, Shibayama H, et al. Impact of 
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Kupperman E, Lee EC, Cao Y, Bannerman B, Fitzgerald M, Berger A, et al. 
Evaluation of the proteasome inhibitor MLN9708 in preclinical models of human 
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Moreau P, Masszi T, Grzasko N, Bahlis NJ, Hansson M, Pour L, et al. Oral Ixazomib, 
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Cardiotoxicity Associated with Carfilzomib Use in Patients with Multiple Myeloma. 
Blood (ASH Annual Meeting Abstracts) 2016; 128(22): abstr 2126. 
24. 
レブラミド®カプセル2.5 mg、同5 mg 適正使用ガイド 2016 年2 月改訂 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Ixazomib 
 
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Revlimid capsule (2.5 mg, 5 mg) Japanese proper use guide, February 2016 
25. 
レナデックス®錠4 mg 適正使用ガイド 2010 年7 月作成 
LenaDex tablet (4 mg) Japanese proper use guide, July 2010 
26. 
Charlson ME, Pompei P, Ales KL, Mackenzie CR. A new method of classifying 
prognostic comorbidity in longitudinal studies: Development and validation. J 
Chronic Dis 1987; 40(5): 373-83. 
27. 
Basch E, Abernethy AP, Mullin CD, Reeve BB, Smith ML, Coon SJ, et al. 
Recommendations for incorporating patient-reported outcomes into clinical 
comparative effectiveness re-search in adult oncology. J Clin 
Oncol.2012;30(34):4249-55. 
28. 
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 
assessment for patients with multiple myeloma. European Organization for Research 
and Treatment of Cancer Study Group on Quality of Life. Br J Haematol.1999; 
104(3): 605-11 
29. 
Brookmeyer R, Crowley J. A Confidence Interval for the Median Survival Time. 
Biometrics 1982; 38; 29-41. 
30. 
Richardson PG1, Xie W, Jagannath S, Jakubowiak A, Lonial S, Raje NS, et al. A 
phase 2 trial of lenalidomide, bortezomib, and dexamethasone in patients with 
relapsed and relapsed/refractory myeloma.Blood. 2014 ;123(10):1461-9. 
31. 
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) 
32. 
臨床研究法における臨床研究の利益相反管理について（厚生労働省医政局研
究開発振興課長通知0302 第1 号 平成30 年3 月2 日） Management of 
Conflict of Interest in Clinical Trials in the Clinical Research Act (Notification by 
Director of Research and Development Division, Health, Labour and Welfare, 
Ministry of Health, Labour and Welfare No. 0302-1 dated March 2, 2018) 
 
 
 
 
 
 
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SAP_001.pdf: 
 
 
Title: An Open-label, Single-Arm, Multicenter Study to Evaluate the Efficacy and Safety 
of Ixazomib in Combination with Lenalidomide and Dexamethasone in Patients with 
Relapsed and/or Refractory Multiple Myeloma Initially Treated with an Injection of  
Proteasome Inhibitor-Based Therapy 
 
NCT Number: NCT03416374 
Statistical analysis plan Approve Date: 01-NOV-2021 
 
Certain information within this statistical analysis plan has been redacted (ie, specific 
content is masked irreversibly from view with a black/blue bar) to protect either 
personally identifiable information or company confidential information. 
 
This may include, but is not limited to, redaction of the following: 
 
Named persons or organizations associated with the study. 
 
Patient identifiers within the text, tables, or figures or in by-patient data listings. 
 
Proprietary information, such as scales or coding systems, which are considered 
confidential information under prior agreements with license holder. 
 
Other information as needed to protect confidentiality of Takeda or partners, 
personal information, or to otherwise protect the integrity of the clinical study. 
 
If needed, certain appendices that contain a large volume of personally identifiable 
information or company confidential information may be removed in their entirety if it 
is considered that they do not add substantially to the interpretation of the data (eg, 
appendix of investigator’s curriculum vitae). 
 
Note; This document was translated into English as the language on original version 
was Japanese. 


An Open-label, Single-Arm, Multicenter Study to Evaluate the Efficacy and Safety 
of Ixazomib in Combination with Lenalidomide and Dexamethasone in Patients with 
Relapsed and/or Refractory Multiple Myeloma Initially Treated with an Injection of 
Proteasome Inhibitor-Based Therapy 
（Study number: C16043） 
Statistical Analysis Plan 
（Ver.4.0; NOV 01, 2021） 
Secondary Sponsor: Takeda Pharmaceutical Company Limited 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


 
1 
TERMS and Abbreviations.................................................................................... 4 
2 
Analysis sets ......................................................................................................... 4 
3 
Considerations for analysis .................................................................................... 4 
4 
other data handling ................................................................................................ 5 
5 
PATIENTS, DEMOGRAPHICS AND OTHER BASELINE 
CHARACTERISTICS ................................................................................................ 12 
5.1 
Disposition of Patients ................................................................................... 12 
5.1.1 
Study Information ................................................................................... 12 
5.1.2 
Eligibility of Patients .............................................................................. 12 
5.1.3 
Exit Status of Patients ............................................................................. 12 
5.1.4 
Protocol Deviations and Analysis Datasets ............................................. 13 
5.2 
Patients Characteristics .................................................................................. 14 
5.2.1 
Demographics and Other Baseline Characteristics .................................. 14 
5.2.2 
Comorbidity ........................................................................................... 14 
5.2.3 
Prior Therapy .......................................................................................... 15 
5.2.4 
Supportive Therapy ................................................................................ 16 
5.2.5 
Next-line Treatment ................................................................................ 16 
5.2.6 
Follow-up Period .................................................................................... 17 
6 
Eficacy Analysis ................................................................................................. 18 
6.1 
Primary Endpoint and Analytical Methods .................................................... 18 
6.1.1 
PFS rate at 12 Months from the Start of Study Treatment Period I .......... 18 
6.1.2 
Supplemental Analysis for Primary Endpoint .......................................... 18 
6.2 
Secondary Endpoints and Analytical Methods ............................................... 18 
6.2.1 
OS from the Start of Study Treatment Period I ........................................ 18 
6.2.2 
PFS from the Start of Study Treatment Period I ...................................... 19 
6.2.3 
Very Good Partial Response (VGPR) or More ........................................ 20 
6.2.4 
Proportion of Patients with CR who Achieve Minimal Residual Disease 
(MRD) Negativity in Bone Marrow ..................................................................... 20 
6.2.5 
Best Response......................................................................................... 21 
6.2.6 
Overall Response Rate（ORR） ............................................................ 21 
6.2.7 
Proportion of Patients Continuing Treatment with Ixazomib at 12 Months 
from the Start of Study Treatment Period I .......................................................... 22 
6.2.8 
Duration of Response（DOR） .............................................................. 22 
6.2.9 
Time to Next Treatment（TTNT） ........................................................ 23 
6.2.10 Duration of Therapy（DOT） ................................................................ 23 
6.2.11 Patient Reported Outcome Health-related Quality of Life（HRQol）: 
EORTC-QLQ-C30/MY-20 .................................................................................. 24 
6.2.12 Quality Adjusted Life Years: QALY ....................................................... 24 
6.2.13 Health Care Resource Utilization: HCRU ............................................... 25 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


6.2.14 Relative Dose Intensity（RDI） ............................................................. 25 
6.2.15 Bone Evaluation ..................................................................................... 25 
6.2.16 M-protein ............................................................................................... 26 
7 
Safety analysis .................................................................................................... 27 
7.1 
Frequency of Treatment-Emergent Adverse Event ......................................... 27 
7.1.1 
Overview of Treatment-Emergent Adverse Event ................................... 27 
7.1.2 
Overview of Treatment-Emergent Adverse Event after the First Dose of 
Study Drug .......................................................................................................... 27 
7.1.3 
Output of Treatment-Emergent Adverse Event........................................ 28 
7.1.4 
Output of Treatment-Emergent Adverse Event after the First Dose of 
Study Drug .......................................................................................................... 29 
7.2 
Laboratory Results ........................................................................................ 30 
8 
Listings ............................................................................................................... 30 
9 
Considerations on Statistical Analysis ................................................................. 30 
9.1 
Covariate ....................................................................................................... 30 
9.2 
Handling of Dropouts or Missing Data .......................................................... 30 
9.3 
Criteria for Interim Analysis and Early Discontinuation ................................. 30 
9.4 
Multicenter Studies ........................................................................................ 30 
9.5 
Multiple Comparisons/Multiplicity ................................................................ 30 
9.6 
Consideration of Subgroups ........................................................................... 30 
10 Revision history .................................................................................................. 30 
 
 
 
 
 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


1 
TERMS AND ABBREVIATIONS 
Summary Statistics: number, mean, standard deviation, minimum/maximum value, quartiles 
VRd: bortezomib plus lenalidomide and dexamethasone 
KRd: carfilzomib plus lenalidomide and dexamethasone 
IRd: ixazomib plus lenalidomide and dexamethasone 
CCI: charlson comorbility index 
 
2 
ANALYSIS SETS 
Full Analysis Set (FAS): all patients who enroll in Treatment Period I and who receive at least one 
dose of any therapy during the Treatment Period 
Evaluable Analysis Set: FAS excluding patients who did not assessed a single response assessment 
Safety Analysis Set: all patients who enroll in Treatment Period I and who receive at least one dose 
of any therapy during the Treatment Period (Same as FAS) 
Safety Analysis Set for Treatment Period II: all patients who enroll into Treatment Period II and who 
receive at least one dose of the study drug 
 
3 
CONSIDERATIONS FOR ANALYSIS 
・ Significance level 
5% (one-sided test) 
・ Confidence coefficient 
For only primary analysis, 90% (two-sided estimation) 
Otherwise, 95% (two-sided estimation) 
・ Number of display digits 
- 
Mean/Quartiles/Confidence interval 
Round off two digits below the effective digit of the data and display up to one digit 
below. 
- 
Standard deviation 
Round off the third digit below the effective digit of the data and display up to the 
second digit below. 
- 
Minimum/Maximum value 
Display up to the significant digit of data. 
- 
Proportion/Percentage 
Round off the second decimal place and display to the first decimal place. 
- 
P value 
Round off the 5 decimal places and display up to 4 decimal places. 
However, when p value is less than 0.0001, it represents as "p <0.0001." 
 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


4 
OTHER DATA HANDLING 
 
Duration 
• Duration (day) 
Target Date – Start Date + 1 
 
 
TEAE 
• TEAE (treatment-emergent adverse event) 
• 
For patients who discontinued during Treatment Period I, an AE that occurred from the 
start of study until the end of Treatment Period I 
• 
For patients who enrolled into Treatment Period II, an AE that occurred from the start of 
treatment in Treatment Period I until 30 days after the end of Treatment Period II or the start of 
next treatment, whichever occurs first 
• TEAE after the First Dose of Study Drug 
In Treatment Period II, TEAEs will be regarded as any AEs that occur after the first dose of 
study drug. 
• non serious TEAE 
TEAE that excludes serious TEAE (refer to Study protocol 10.1.3), and the incidence rate 
exceeds 5 %. 
 
 
 
Quality-Adjusted Life-Years (QALYs) 
• modified QALY 
The global health/quality of life scale score from the EORTC-QLQ-C30 instrument will be 
converted into a utility value ranging from 0 to 1, and used to adjust the value of survival years; 
this value is defined as the modified QALY. 
 
 
modified QALY = ෍൫𝑢𝑢𝑗𝑗+ 𝑢𝑢𝑗𝑗−1൯
2
𝐽𝐽𝑖𝑖
𝑗𝑗=2
× 𝑡𝑡+
൫𝑢𝑢𝐽𝐽𝑖𝑖+ 𝑢𝑢𝐶𝐶൯
2
× ൫𝑡𝑡𝐶𝐶−𝑡𝑡𝐽𝐽𝑖𝑖൯ 
𝐽𝐽𝑖𝑖 : The number assessment before the minimum follow-up time (𝑡𝑡𝐶𝐶) 
𝑢𝑢𝑖𝑖 : The utility value at any time point j 
 
For limited follow-up, 𝑢𝑢𝑐𝑐 can be estimated as utility at 𝑡𝑡𝐶𝐶 using a trapezoidal estimate for the 
partial follow-up time. 
𝑢𝑢𝐶𝐶= 𝑢𝑢𝐽𝐽𝑖𝑖+
൫𝑢𝑢𝐽𝐽𝑖𝑖+1 −𝑢𝑢𝐽𝐽𝑖𝑖൯
൫𝑡𝑡𝐽𝐽𝑖𝑖+1 −𝑡𝑡𝐽𝐽𝑖𝑖൯× ൫𝑡𝑡𝐶𝐶−𝑡𝑡𝐽𝐽𝑖𝑖൯ 
 
 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


 
Relative dose intensity (RDI) 
• RDI 
RDI(%) =
(Actual dose) (Actual number of cycle days)
⁄
(Scheduled dose) (Scheduled number of cycle days)
⁄
× 100 
 
The actual number of cycle days shall be (next cycle start date) - (relevant cycle start date) if there is 
a next course, or the number of scheduled cycle days if there is no next course. The number of 
scheduled cycle days and dose for each drug should be set as following table. For VRd, the 
scheduled dose should be defined according to the number of scheduled cycle days selected in the 
CRF. 
 
 
Drug 
Length of cycle 
Dose 
Period I-KRd 
（Cycle 1） 
Carfilzomib 
28 
20mg/m2×2 
＋27mg/m2×4 
Lenalidomide 
25mg×21 
Dexamethasone 
40mg×4 
Period I-KRd 
（After Cycle 2） 
Carfilzomib 
28 
27mg/m2×6 
Lenalidomide 
25mg×21 
Dexamethasone 
40mg×4 
Period I-VRd(1) 
Bortezomib 
21 
1.3mg/m2×4 
Lenalidomide 
25mg×14 
Dexamethasone 
40mg×3 
Period I-VRd(2) 
Bortezomib 
28 
1.3mg/m2×4 
Lenalidomide 
15mg×18 
Dexamethasone 
40mg×4 
Period I-VRd(3) 
Bortezomib 
35 
1.3mg/m2×4 
Lenalidomide 
15mg×21 
Dexamethasone 
20mg×8 
Period II 
Ixazomib 
28 
4.0mg×3 
Lenalidomide 
25mg×21 
Dexamethasone 
40mg×4 
 
 
 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


 
Handling of values below or above the quantitative limit 
• Serum free light chain (FLC) 
If FLC κ or FLC λ is below the limit of quantification, the limit of quantification is imputed. κ/λ 
ratio is calculated using the imputed value. 
 
 
International Staging System (ISS) 
• Staging criteria (according to Study Protocol Appendix C) 
Stage I: (Serum β2-microglobulin <3.5 mg/L) and (Serum albumin ≥3.5 g/dL) 
Stage II: Neither Stage I or Stage III 
 
There are two definitions of Stage II:  
(serum β2-microglobulin <3.5 mg/dL) and (serum albumin <3.5 g/dL), or 
serum β2-microglobulin 3.5– <5.5 mg/dL (irrespective of serum albumin concentration) 
Stage III: Serum β2-microglobulin ≥5.5 mg/L 
* The clinical stage (ISS) at the recurrence (at the start of treatment period I) is calculated from the 
clinical laboratory values. If the patient does not fall into Stage III and any one of serum β2-
microglobulin and serum albumin is missing, the patient should not be classified. 
 
 
Time allowance 
• 
Time allowance for Month 12 after the start of treatment period I 
In the analysis of the event rate without using the Kaplan-Meier method, the allowable of diagnoses 
and tests for event determination at 12 months is 52 weeks ± 4 weeks, and the event rate is 
calculated as follows. 
<For analysis of PFS rate> 
(1) No assessment at 52 ± 4 weeks, or only “NE”/”Unknown” during that period;  
 
Included in denominator (Treated as PD) 
(2) If one of two consecutive PD assessments was performed by 52 + 4 weeks;  
 
PD 
(3) Otherwise;  
 
Progression Free Survival 
 
<For analysis of modified PFS rate> 
(1) No assessment at 52 ± 4 weeks, or only “NE”/”Unknown” during that period;  
 
Included in denominator (Treated as PD) 
(2) If one of two consecutive PD assessments was performed by 52 + 4 weeks;  
 
PD 
(3) If no results are available after a single PD assessment performed by 52 + 4 weeks;  
 
Included in denominator (Treated as PD) 
(4) Otherwise;  
 
Progression free survival 
 
 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


 
Censoring scheme 
• 
Overall survival (OS) 
 
Situation 
Date of event expression or 
censoring 
Outcome 
Death 
Date of death 
event 
Discontinuation of treatment period I 
Date of discontinuation 
- 
Discontinuation of treatment period II 
Date of discontinuation 
- 
Next antitumor treatment started* 
Date of start of next 
treatment 
censoring / - 
Alive 
Last confirmed date of 
survival 
censoring 
For the start of next antitumor treatment, analyze both the case of not censoring and the case of 
censoring. 
 
• 
Progression Free survival (PFS) 
 
Situation 
Date of event expression or 
censoring 
Outcome 
Incomplete or no baseline assessments 
Date of first treatment period 
I 
censoring 
Progression 
Assessment date of the first 
of two consecutive 
assessments 
event 
Death 
Date of death 
event 
Discontinuation of treatment period I 
Date of discontinuation 
- 
Discontinuation of treatment period II 
Date of discontinuation 
- 
Next antitumor treatment started 
Date of start of next 
treatment 
censoring 
No progression 
Last confirmed date at which 
patients are progression-free 
censoring 
 
 
• 
modified PFS 
 
Situation 
Date of event expression or 
censoring 
Outcome 
Incomplete or no baseline assessments 
Date of first treatment period 
I 
censoring 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Progression 
Assessment date of the first 
of two consecutive 
assessments 
event 
Two consecutive PD assessments have 
not been obtained, but the final 
assessment is PD 
Final assessment date 
event 
Death 
Date of death 
event 
Discontinuation of treatment period I 
Date of discontinuation 
- 
Discontinuation of treatment period II 
Date of discontinuation 
- 
Next antitumor treatment started 
Date of start of next 
treatment 
censoring 
No progression 
Last confirmed date at which 
patients are progression-free 
censoring 
 
• 
Duration of Response (DOR) 
DOR is defined for the patients assessed as ≥PR according to the IMWG criteria (2014 version) 
 
Situation 
Date of event expression or 
censoring 
Outcome 
Incomplete or no baseline assessments 
- 
NA 
Progression 
Assessment date of the first 
of two consecutive 
assessments 
event 
Death 
Date of death 
event 
Discontinuation of treatment period I 
Date of discontinuation 
- 
Discontinuation of treatment period II 
Date of discontinuation 
- 
Next antitumor treatment started 
Date of start of next 
treatment 
censoring 
No progression 
Last confirmed date as not 
less than PR 
censoring 
 
• 
modified DOR 
modified DOR is defined for the patients assessed as ≥PR according to the IMWG criteria (2014 
version) 
 
Situation 
Date of event expression or 
censoring 
Outcome 
Incomplete or no baseline assessments 
- 
NA 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Progression 
Assessment date of the first 
of two consecutive 
assessments 
event 
Two consecutive PD assessments have 
not been obtained, but the final 
assessment is PD 
Final assessment date 
event 
Death 
Date of death 
event 
Discontinuation of treatment period I 
Date of discontinuation 
- 
Discontinuation of treatment period II 
Date of discontinuation 
- 
Next antitumor treatment started 
Date of start of next 
treatment 
censoring 
No progression 
Last confirmed date as not 
less than PR 
censoring 
 
• 
Time to Next Treatment (TTNT) 
 
Situation 
Date of event expression or 
censoring 
Outcome 
Incomplete or no baseline assessments 
Date of first treatment period 
I 
censoring 
Progression 
Assessment date of the first 
of two consecutive 
assessments 
- 
Death 
Date of death 
event 
Next antitumor treatment started 
Date of start of next 
treatment 
event 
Continued study treatment  
Last observed date 
censoring 
Discontinued during treatment period I 
and no information of next treatment 
Start date of last cycle 
censoring 
Discontinued during treatment period 
II and no information of next treatment 
Last observed date 
censoring 
Last observed date; last date of the date of discontinuation, the date of last dose of study treatment or 
the date of final assessment 
 
 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


 
• 
Duration of Therapy (DOT) 
 
Situation 
Date of event expression or 
censoring 
Outcome 
Incomplete or no baseline assessments 
Date of first treatment period 
I 
censoring 
Progression 
Assessment date of the first 
of two consecutive 
assessments 
- 
Death 
Date of death 
- 
Discontinuation of treatment period I 
Date of discontinuation or 
date of last dose of 
proteasome inhibitor 
event 
Discontinuation of treatment period II 
Date of discontinuation or 
date of last dose of Ixazomib 
event 
Continued study treatment  
Last observed date 
censoring 
 
 
Other valuables to be derived 
• 
Body surface area (BSA) 
Body Surface Area (m2) = Weight (kg) 0.425 × Height (cm) 0.725 × 0.007184 
 
 
 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


5 
PATIENTS, DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS 
5.1 
Disposition of Patients 
5.1.1 
Study Information 
Analysis Set: 
All patients obtained informed consent 
 
Analysis Variables: 
The earliest date of informed consent 
The latest date of the last visits 
Version of MedDRA 
Version of SAS 
 
Analysis Methods: 
(1) 
Output above items. 
 
5.1.2 
Eligibility of Patients 
Analysis Set: 
All patients obtained informed consent 
 
Analysis Variables: 
Eligibility for Period I [yes, no (reasons)] 
Eligibility for Period II [yes, no (reasons)] 
 
Analysis Methods: 
(1) 
Frequency count 
 
5.1.3 
Exit Status of Patients 
Analysis Set: 
Full Analysis Set 
 
Analysis Variables: 
Exit status [complete, incomplete (reasons)] 
 
Analysis Methods: 
Analysis will be performed by period I treatment (VRd, KRd) and overall. 
(1) 
Frequency count 
(2) 
Cross table of the number of cycle and the reason for discontinuation 
The number of cycles in which any of the drugs VRd, KRd, or IRd is administered will be used. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


 
 
5.1.4 
Protocol Deviations and Analysis Datasets 
5.1.4.1 
Protocol Deviations 
Analysis Set: 
All patients obtained informed consent 
 
Analysis Variables: 
Protocol Deviations 
[Major GCP Violations, Deviations of Protocol Entry Criteria, Deviations of Discontinuation 
Criteria, Deviations Related to Treatment Procedure or Dose, Deviations Concerning Excluded 
Medication or Therapy, Deviations to Avoid Emergency Risk, Other Deviations] 
 
Analysis Methods: 
Analysis will be performed by period I treatment (VRd, KRd) and overall. 
(1) 
Summarize the number of patients who have deviated from the protocol, classify the 
deviations into above category, and show the breakdown of deviations. Patients applicable for 
multiple categories will be counted in each category. 
 
5.1.4.2 
Analysis Datasets 
Analysis Set: 
Eligible Patients Period I 
 
Analysis Variables: 
Protocol deviation related to analysis set [Inclusion, Exclusion] 
Inclusion or Exclusion for each analysis set 
 
Full Analysis Set 
 
Safety Analysis Set 
 
Safety Analysis Set for Treatment Period II 
 
Analysis Methods: 
Analysis will be performed by period I treatment (VRd, KRd) and overall. Patients applicable for 
multiple categories will be counted once in each category. 
(1) 
Frequency count about the determination of inclusion for each analysis set 
(2) 
Frequency count of the number of patient included for each analysis set 
 
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5.2 
Patients Characteristics 
5.2.1 
Demographics and Other Baseline Characteristics 
Analysis Set: 
Full Analysis Set, Safety Analysis Set, Safety Analysis Set for Treatment Period II 
 
Analysis Variables: 
Age（year）[Min<= - <=65、65< - <=75、75< - <=Max] 
Sex [Male、Female] 
Height（cm） 
Weight（kg） 
BMI（kg/m2） 
BSA（m2） 
M-protein isotype [IgG κ･λ, IgA κ･λ, IgD κ･λ, IgE κ･λ, IgM κ･λ, Bence Jones type 
κ･λ,  non-secretory type, unknown, others] 
Clinical stage according to ISS at initial diagnosis [Stage Ⅰ, II, III] 
Clinical stage according to ISS at disease recurrence (at first treatment period I) [Stage Ⅰ, II, III] 
Chromosome abnormality at the initial diagnosis [t (4;14), t (14;16), t (11;14), del17p, 1q gain] 
Chromosomal abnormalities at disease recurrence (at first treatment period I) [del17p, 1q gain] 
Whether imaging tests are performed [Conducted, Not conducted] 
Presence of Bone Lesion [yes, no] 
Presence of Extramedullary Masses [yes, no] 
Extramedullary Masses [Bone-delivered, Soft tissue-delivered or others] 
The longest diameter and shortest diameter of the largest extramedullary plasmacytoma (mm) 
Prior antineoplastic therapies [Conducted, Not conducted] 
Prior radiation therapy [Conducted, Not conducted] 
Prior hematopoietic stem cell transplantation [Conducted, Not conducted] 
M-protein in blood samples and urine samples 
Serum FLC (free light chain)（FLC κ, FLC λ, κ/λ ratio [Min<= - <0.26, 0.26=< - <=1.65, 1.65< - 
<=Max]）） 
ECOG performance status [0, 1, 2, 3, 4] 
 
Analysis Methods: 
Analysis will be performed by period I treatment (VRd, KRd) and overall. 
(1) 
Frequency count of categorical data and summary statistics of continuous data 
Note：For patients whose M-protein isotype: type of light chain is “κ”, FLC κ will be calculated. 
For patients whose M-protein isotype: type of light chain is “λ”, FLC λ will be calculated.  
 
5.2.2 
Comorbidity 
Analysis Set: 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Full Analysis Set 
 
Analysis Variables: 
Charlson comorbidity index（CCI）; 
Myocardial infarction (history, not ECG changes only) 
Congestive heart failure 
Peripheral disease (includes aortic aneurysm ≥ 6 cm) 
Cerebrovascular disease: CVA with mild or no residua or TIA 
Dementia 
Chronic pulmonary disease 
Peptic ulcer disease 
Liver disease [Mild (without portal hypertension, includes chronic hepatitis), Moderate or severe] 
Diabetes [Without end-organ damage (excludes diet-controlled alone),  
With end-organ damage (retinopathy, neuropathy, nephropathy, or brittle diabetes)] 
Hemiplegia 
Moderate to severe renal disease 
Tumor without metastasis (exclude if > 5years from diagnosis) 
Leukemia (acute or chronic) 
Lymphoma 
Metastatic solid tumor 
AIDS (not just HIV positive) 
 
Analysis Methods: 
Analysis will be performed by period I treatment (VRd, KRd) and overall. 
(1) 
Frequency count 
(2) 
Frequency count[Min<= - <=1、2<= - <=Max] and summary statistics of CCI score 
 
5.2.3 
Prior Therapy 
Analysis Set: 
Full Analysis Set 
 
Analysis Variables: 
Prior Antineoplastic Therapies [Bortezomib, Carfilzomib, Lenalidomide, Pomalidomide, 
Prednisolone, Dexamethasone, Melphalan, Adriamycin, Cyclophosphamide, Elotuzumab, 
Daratumumab, Panobinostat, Vincristine, Other] 
Number of collected prior regimen [1, 2, 3, 4……] 
Prior Regimen（Pattern of prior antineoplastic therapies） 
Reason for termination by prior regimen（Pattern of prior antineoplastic therapies） [PD or ‘other’] 
 
Analysis Methods: 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Analysis will be performed by period I treatment (VRd, KRd) and overall. For method (1) and (3), 
analysis will be performed by one previous drugs, two or more previous regimens and all previous 
regimens. 
(1) 
Frequency count of prior antineoplastic therapies 
Sorted by frequency. If the antineoplastic therapies is used more than once to the same patient, it will 
be counted as one case. 
 
(2) 
Summary of the number of prior regimens 
The number of collected antineoplastic therapy regimens will be calculated for each patient, and 
frequency count and summary statistics will be calculated. 
 
(3) 
Summary of prior regimens 
For high frequency regimens, the frequency of the regimen, the reason for termination and the 
response for each regimen will be tabulated. 
 
5.2.4 
Supportive Therapy 
Analysis Set: 
Full Analysis Set 
 
Analysis Variables: 
Supportive Therapy [varicella zoster, P. jirovecii infection (e.g. ST combination drug)] 
 
Analysis Methods: 
Analysis will be performed by period I treatment (VRd, KRd) and overall. 
(1) 
Frequency count 
Sorted by frequency. If the antineoplastic therapies is used more than once to the same patient, it will 
be counted as one case. 
 
5.2.5 
Next-line Treatment 
Analysis Set: 
Full Analysis Set 
 
Analysis Variables: 
Next-line Treatment 
 
Analysis Methods: 
Analysis will be performed by period I treatment (VRd, KRd) and overall. 
 (1) 
Frequency count 
 
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5.2.6 
Follow-up Period 
Analysis Set: 
Full Analysis Set 
 
Analysis Variables: 
Follow-up period 
 
Analysis Methods: 
Analysis will be performed by period I treatment (VRd, KRd) and overall. 
(1) 
reverse Kaplan-Meier method 
Analysis will be performed by using reverse indicator of 6.2.1 ”OS from the start of study treatment 
period I” in order to estimate median of follow-up period. 
(2) 
Analysis (1) will be repeated with patients dosed of study drug. 
 
 
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6 
EFICACY ANALYSIS 
6.1 
Primary Endpoint and Analytical Methods 
6.1.1 
PFS rate at 12 Months from the Start of Study Treatment Period I 
Analysis Set: 
Full Analysis Set 
 
Analysis Variables: 
PFS rate at 12 Months from the Start of Study Treatment Period I 
 
Analysis Methods: 
Analysis will be performed by period I treatment (VRd, KRd) and overall. Statistical test will be 
performed only for overall analysis. 
 (1) 
The primary endpoint of PFS rate at 12 months from the start of study Treatment Period I 
is defined as the proportion of patients who are alive and have not had disease progression at 12 
months after the start date. The start date is defined as the date of first dose of treatment in Treatment 
Period I. Patients without 12-month imaging data for determining PD, or patients lost to follow-up, 
are included in the denominator; however, they are not treated as patients who have not had disease 
progression. For the primary endpoint analysis, the null hypothesis will be that the proportion of 
patients in the FAS who are alive and progression-free at 12 months after the start of Treatment 
Period I is ≤36%.The one-sided significance level will be 5%. Exact two-sided 90% confidence 
intervals will be calculated via binomial distribution. The same analysis will be performed by 
defining a modified PFS rate to account for the possibility that a new treatment is administered 
before two consecutive assessments, even though PD has been determined at one time. The 
evaluation was conducted under the assumption that all the patients were confirmed to have PD 
again, and the patients was treated as PD once determined to have PD. 
6.1.2 
Supplemental Analysis for Primary Endpoint 
Analysis Set: 
Evaluable Analysis Set 
 
Analysis Variables: 
PFS rate at 12 Months from the Start of Study Treatment Period I 
 
Analysis Methods: 
6.1.1 Analysis will be repeated for Evaluable Analysis Set. 
 
6.2 
Secondary Endpoints and Analytical Methods 
6.2.1 
OS from the Start of Study Treatment Period I 
Analysis Set: 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Full Analysis Set 
 
Analysis Variables: 
OS from the start of study Treatment Period I 
 
Analysis Methods: 
Analysis will be performed by period I treatment (VRd, KRd) and overall. 
(1)  
OS is defined as the period from the first dose of treatment in Treatment Period I to the 
time when death (regardless of the cause of death) is confirmed. Patients who are still alive will be 
censored at the last confirmed date of survival or the date of data cut-off, whichever is earlier. OS for 
the FAS will be estimated using the Kaplan-Meier method, and the quartiles and two-sided 95% 
confidence intervals will be calculated using the double logarithmic transformation method of 
Brookmeyer and Crowley. 
 
(2)  
OS rate at Month 3, 6, 9, 12, 15, 18, 21, 24, 27 and the two-sided 95% confidence interval 
will be estimated by Kaplan-Meier method. The confidence interval is constructed based on the 
variance calculated by Greenwood's formula for the double logarithmically transformed OS rate, and 
then calculated by exponential transformation. 
 
6.2.2 
PFS from the Start of Study Treatment Period I 
Analysis Set: 
Full Analysis Set 
 
Analysis Variables: 
PFS from the start of study Treatment Period I 
 
Strata:  
Clinical stage according to ISS at disease recurrence (at first treatment period I) [Stage Ⅰ, II, III] 
Best response [at least VGPR, PR or worse] 
Charlson comorbidity index（CCI） [Min<= - <=1、2<= - <=Max] 
 
The following items may fall under each category in duplicate. 
Chromosome abnormality at the initial diagnosis [t (4;14), t (14;16), t (11;14), del17p, 1q gain] 
Chromosomal abnormalities at disease recurrence (at first treatment period I) [del17p, 1q gain] 
Prior antineoplastic therapies* [Treated, Not treated] 
*Bortezomib, Carfilzomib, Lenalidomide, Pomalidomide, Elotuzumab, Daratumumab 
 
Analysis Methods: 
Analysis will be performed by period I treatment (VRd, KRd) and overall. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


 (1) 
PFS is defined as the period from the first dose of treatment in Treatment Period I to the 
time of confirmed PD or confirmed death (regardless of the cause of death), whichever is earlier. 
Patients who are still alive and progression-free will be censored at the last confirmed date at which 
they are progression-free. PFS for the FAS will be estimated using similar methodology to that used 
for analysis of OS. The same analysis will be performed by defining a modified PFS to account for 
the possibility that a new treatment is administered before two consecutive assessments, even though 
PD has been determined at one time. The evaluation was conducted under the assumption that all the 
patients were confirmed to have PD again, and the patients was treated as PD once determined to 
have PD. 
 
(2)  
PFS rate at Month 3, 6, 9, 12, 15, 18, 21, 24, 27 and the two-sided 95% confidence interval 
will be will be estimated using similar methodology to that used for analysis of OS. 
 
(3)  
Analysis (1) and (2) will be repeated for each strata.  
 
6.2.3 
Very Good Partial Response (VGPR) or More 
Analysis Set: 
Full Analysis Set 
 
Analysis Variables: 
Very Good Partial Response (VGPR) or more 
 
Analysis Methods: 
Analysis will be performed by period I treatment (VRd, KRd) and overall. 
 (1) 
The percentage of patients achieving a VGPR or better, according to the IMWG criteria 
(2014 version), after the start of the study, and 95% confidence interval will be calculated. Exact 
confidence intervals will be calculated based on a binomial distribution. 
 
6.2.4 
Proportion of Patients with CR who Achieve Minimal Residual Disease (MRD) 
Negativity in Bone Marrow 
Analysis Set: 
Full Analysis Set 
 
Analysis Variables: 
Percentage of MRD positive cells [=>10-4, 10-5<= - <10-4, 10-6<= - <10-5, 10-7<= - <10-6] 
Percentage of patients achieving MRD negativity [<10-4, <10-5, <10-6] 
 
Analysis Methods: 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Analysis will be performed by period I treatment (VRd, KRd) and overall. The same analysis will be 
performed for the SRL-flow method and the Adaptive. However, since the quantitative limit of the 
SRL-flow method is 10-6, the smallest category of positive cell rate is tabulated as "less than 10-6". 
 
(1) 
The percentage of corresponding each category will be calculated. 95% confidence 
interval of percentage of patients achieving MRD negativity will be calculated. Exact confidence 
intervals will be calculated based on a binomial distribution. If a patient is MRD-positive at their 
first evaluation and MRD-negative after re-examination, the patient will be considered to be MRD-
negative and corresponding percentage of MRD positive cells will be used for calculation of the 
percentage of MRD positive cells 
 
(2) 
If there are patients who achieved CR in the treatment period I, the same analysis will be 
conducted focusing on patients who achieved CR in the treatment period II. 
 
6.2.5 
Best Response 
Analysis Set: 
Full Analysis Set 
 
Analysis Variables: 
Best Response 
 
Analysis Methods: 
Analysis will be performed by period I treatment (VRd, KRd) and overall. 
 (1) 
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), after each cycle of treatment. A 
histogram (or similar) showing the numbers of patients achieving different levels of best response 
will be created after each cycle of treatment. 
 
(2) 
A shift table with the best response of Period I at the head of the table and the best 
response of Period II at the side will be created. Patients discontinued during period I will be 
tabulated as the best response of Period II “NA”. 
 
6.2.6 
Overall Response Rate（ORR） 
Analysis Set: 
Full Analysis Set 
 
Analysis Variables: 
ORR 
 
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Analysis Methods: 
Analysis will be performed by period I treatment (VRd, KRd) and overall. 
 (1) 
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) after the start of the study treatment. The ORR 
and 95% confidence interval will be calculated. Exact confidence intervals will be calculated based 
on a binomial distribution. 
 
 
6.2.7 
Proportion of Patients Continuing Treatment with Ixazomib at 12 Months from the 
Start of Study Treatment Period I 
Analysis Set: 
Full Analysis Set 
 
Analysis Variables: 
Proportion of patients continuing treatment with Ixazomib at 12 months from the start of study 
Treatment Period I 
 
Analysis Methods: 
Analysis will be performed by period I treatment (VRd, KRd) and overall. 
 (1) 
The proportion of patients who are continuing to receive study drug at 12 months after the 
start of treatment period I, and the two-sided 95% confidence intervals, will be calculated. Exact 
confidence intervals will be calculated based on a binomial distribution. 
 
6.2.8 
Duration of Response（DOR） 
Analysis Set: 
Full Analysis Set 
 
Analysis Variables: 
DOR 
 
Analysis Methods: 
Analysis will be performed by period I treatment (VRd, KRd) and overall. 
 (1) 
DOR is defined as the time from the date of first documentation of response ≥PR 
according to the IMWG criteria (2014 version) to the date of first documentation of PD or death due 
to any cause. DOR for patients in the FAS who achieve PR or better at any time during the study 
will be estimated using the Kaplan-Meier method, and the quartiles and 95% confidence intervals 
will be calculated by the double logarithmic transformation method of Brookmeyer and Crowley. 
Patients who achieve PR or better and have not experienced PD will be censored from the date when 
their response was confirmed as not being worse than SD. The same analysis will be performed by 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


defining a modified DOR to account for the possibility that a new treatment is administered before 
two consecutive assessments, even though PD has been determined at one time. The evaluation was 
conducted under the assumption that all the patients were confirmed to have PD again, and the 
patients was treated as PD once determined to have PD. 
 
 
(2)  
DOR rate at Month 3, 6, 9, 12, 15, 18, 21, 24, 27 and the two-sided 95% confidence 
interval will be will be estimated using similar methodology to that used for analysis of OS. 
 
6.2.9 
Time to Next Treatment（TTNT） 
Analysis Set: 
Full Analysis Set 
 
Analysis Variables: 
TTNT 
 
Analysis Methods: 
Analysis will be performed by period I treatment (VRd, KRd) and overall. 
 (1) 
TTNT is defined as the period from the first dose of treatment, which is based on 
proteasome inhibitor, in Treatment Period I to the time of next-line treatment or confirmed death 
(regardless of the cause of death), whichever is earlier. Patients who are still alive and no next-line 
treatment will be censored at the last confirmed date at last observed date. TTNT for the FAS will be 
estimated using similar methodology to that used for analysis of OS. 
(2)  
TTNT rate at Month 3, 6, 9, 12, 15, 18, 21, 24, 27 and the two-sided 95% confidence 
interval will be will be estimated using similar methodology to that used for analysis of OS. 
 
6.2.10 Duration of Therapy（DOT） 
Analysis Set: 
Full Analysis Set 
 
Analysis Variables: 
DOT 
 
Analysis Methods: 
Analysis will be performed by period I treatment (VRd, KRd) and overall. 
(1) 
DOT is defined as the period from the first dose of treatment, which is based on 
proteasome inhibitor, in Treatment Period I to the time of discontinuation of study treatment or last 
dose of proteasome inhibitor, whichever is later. Patients who continue study treatment will be 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


censored at the last confirmed date at last observed date. DOT for the FAS will be estimated using 
similar methodology to that used for analysis of OS. 
(2)  
DOT rate at Month 3, 6, 9, 12, 15, 18, 21, 24, 27 and the two-sided 95% confidence 
interval will be will be estimated using similar methodology to that used for analysis of OS. 
 
6.2.11 Patient Reported Outcome Health-related Quality of Life（HRQol）: EORTC-QLQ-
C30/MY-20 
Analysis Set: 
Full Analysis Set 
 
Analysis Variables: 
EORTC QLQ-C30 
• 
Five functional scales (physical, role, emotional, cognitive, social) 
• 
A global health/quality of life scale 
• 
Three symptom scales (tiredness, nausea and vomiting, pain)  
• 
Six single items (dyspnea, insomnia, anorexia, constipation, diarrhea, economic difficulty) 
EORTC QLQ-MY20 
• 
Four independent subscales 
• 
Two functional subscales (body image, future perspective) 
• 
Two symptom subscales (multiple myeloma symptoms, treatment adverse effects) 
 
Analysis Methods: 
Analysis will be performed by period I treatment (VRd, KRd) and overall. 
 (1) 
Scores will be calculated for each subscale according to the EORTC Scoring Manual, and 
summary statistics and 95% confidence intervals will be calculated for each treatment cycle.  
(2) 
Line plot (Mean±SD) will be presented graphically as plots over time. 
(3) 
Summary statistics for change from cycle 1, Treatment Period I, plus the mean and 95% 
confidence intervals, will be calculated. For patients enrolled in Treatment Period II, summary 
statistics for change from cycle 1, Treatment Period II, plus the 95% confidence intervals of mean, 
will also be calculated. 
 
6.2.12 Quality Adjusted Life Years: QALY  
Analysis Set: 
Full Analysis Set 
 
Analysis Variables: 
modified QALY 
 
Analysis Methods: 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Analysis will be performed by period I treatment (VRd, KRd) and overall. 
(1) 
Summary statistics regarding modified QALYs will be calculated at 12 months from the 
start of study Treatment Period I 
(2) 
Analysis (1) will be repeated without discontinued patients during treatment period I. 
 
6.2.13 Health Care Resource Utilization: HCRU 
Analysis Set: 
Full Analysis Set 
 
Analysis Variables: 
Hospitalization events 
Outpatient events 
 
Analysis Methods: 
Analysis will be performed by period I treatment (VRd, KRd) and overall. 
(1) 
The exposure-adjusted rate of hospitalization events (per patient-months) and the duration 
of hospitalization will be calculated by treatment period and overall. 
(2) 
The exposure-adjusted rate of outpatient events (per patient-months) will be calculated by 
treatment period and overall. 
 
6.2.14 Relative Dose Intensity（RDI） 
Analysis Set: 
Full Analysis Set 
 
Analysis Variables: 
RDI 
 
Analysis Methods: 
(1) 
Summary statistics for RDI for Ixazomib, Lenalidomide and Dexamethasone, will be 
calculated by cycle. 
(2) 
Time plot of Analysis (1) will be outputted. 
(3) 
Summary statistics for RDI for Ixazomib, Lenalidomide and Dexamethasone, will be 
calculated by treatment period and overall. For RDI of overall period, proteasome inhibitor 
(Bortezomib+Ixazomib, Carfilzomib+Ixazomib, Bortezomib/Carfilzomib+Ixazomib) will be 
combined. 
 
6.2.15 Bone Evaluation 
Analysis Set: 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Full Analysis Set 
 
Analysis Variables: 
Bone evaluation 
 
Analysis Methods: 
Analysis will be performed by period I treatment (VRd, KRd) and overall. 
(1) 
The percentage of patients with bone lesions and the two-sided 95% confidence intervals 
will be calculated. Exact confidence intervals will be calculated based on a binomial distribution. 
 
6.2.16 M-protein 
Analysis Set: 
Full Analysis Set 
 
Analysis Variables: 
M-protein measurement (SPEP/UPEP [24-hour urine collection], serum free light chain 
measurement) 
Best response of SPEP/UPEP percent change 
 
Analysis Methods: 
Analysis will be performed by period I treatment (VRd, KRd) and overall. 
(1) 
Summary statistics and 95% confidence interval of mean will be calculated. 
(2) 
Summary statistics for change from cycle 1, Treatment Period I, plus the 95% confidence 
interval of mean, will be calculated. For patients enrolled in Treatment Period II, summary statistics 
for change from cycle 1, Treatment Period II, plus the 95% confidence intervals of mean, will also 
be calculated. 
(3) 
The percent change of SPEP/UPEP is achieved when SPEP/UPEP is the lowest value by 
patients. Summary statistics for percent change from cycle 1, Treatment Period I, plus the 95% 
confidence interval of mean, will be calculated. For patients enrolled in Treatment Period II, 
summary statistics for percent change from cycle 1, Treatment Period II, plus the 95% confidence 
intervals of mean, will also be calculated. 
 
 
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7 
SAFETY ANALYSIS 
7.1 
Frequency of Treatment-Emergent Adverse Event 
7.1.1 
Overview of Treatment-Emergent Adverse Event 
Analysis Set: 
Safety Analysis Set 
 
Analysis Variables: 
TEAE 
 
Category： 
Grade [Grade1 – Grade5] 
 
Analysis will be performed by period I treatment (VRd, KRd) and overall. 
1) 
Frequency count of All TEAEs 
2) 
Frequency count of Grade 3 or higher TEAEs 
3) 
Frequency count of All TEAEs by grade 
4) 
Frequency count of Serious TEAEs 
5) 
Frequency count of TEAEs that Result in Death 
 
Note for calculation of incidence rate: 
・For tabulation by grade 
If a patient had two or more adverse events in the same category with different severities, then the 
event with the maximum severity was used for that patient. The denominator of incidence rate is the 
number of patients in analysis set. 
・Otherwise 
If a patient had two or more adverse events in the same category with different severities, then the 
event with the maximum severity was used for that patient. The denominator of incidence rate is the 
number of patients in analysis set. 
 
7.1.2 
Overview of Treatment-Emergent Adverse Event after the First Dose of Study Drug 
Analysis Set: 
Safety Analysis Set for Treatment Period II 
 
Analysis Variables: 
TEAEs after the first dose of study drug 
 
Categories： 
Relationship to study drug  [Related, Not related] 
Grade   
 
[Grade1 – Grade5] 
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Analysis will be performed by period I treatment (VRd, KRd) and overall. 
1) 
Frequency count of All TEAEs after the first dose of study drug 
2) 
Frequency count of study drug related TEAEs after the first dose of study drug 
3) 
Frequency count of grade 3 or higher TEAEs after the first dose of study drug 
4) 
Frequency count of study drug related grade 3 or higher TEAEs after the first dose of study 
drug 
5) 
Frequency count of All TEAEs after the first dose of study drug by grade 
6) 
Frequency count of study drug related TEAEs after the first dose of study drug by grade 
7) 
Frequency count of TEAEs resulting in discontinuation of treatment after the first dose of 
study drug 
8) 
Frequency count of serious TEAEs after the first dose of study drug 
10) 
Frequency count of TEAEs after the first dose of study drug that result in death 
 
Note for calculation of incidence rate: 
Same as 7.1.1 
 
7.1.3 
Output of Treatment-Emergent Adverse Event 
Analysis Set: 
Safety Analysis Set 
 
Analysis Variables: 
TEAE 
 
Category： 
Grade [Grade1 – Grade5] 
 
Analysis will be performed by period I treatment (VRd, KRd) and overall. 
TEAE will be coded using MedDRA and will be summarized by Preferred Term (PT) and System 
Organ Class (SOC). Analysis output will be sorted SOC alphabetically and PT frequency. 
 
1) 
Frequency count of All TEAEs by SOC and PT 
2) 
Frequency count of Grade 3 or higher TEAEs by SOC and PT 
3) 
Frequency count of TEAEs by SOC and PT by Grade 
4) 
Frequency count of Serious TEAEs by SOC and PT 
5) 
Frequency count of Non-serious TEAEs by SOC and PT 
6) 
Frequency count of TEAEs that Result in Death by SOC and PT 
 
Note for calculation of incidence rate: 
・For tabulation by grade 
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If a patient had two or more adverse events in the same SOC (or with the same PT) with different 
severities, then the event with the maximum severity was used for that patient. The denominator of 
incidence rate is the number of patients in analysis set. 
・Otherwise 
Patient with two or more AEs in the same SOC (or with the same PT) is counted only once for that 
SOC (or PT). The denominator of incidence rate is the number of patients in analysis set. 
 
7.1.4 
Output of Treatment-Emergent Adverse Event after the First Dose of Study Drug 
Analysis Set: 
Safety Analysis Set 
 
Analysis Variables: 
TEAE after the First Dose of Study Drug 
 
Categories： 
Relationship to study drug  [Related, Not related] 
Grade   
 
[Grade1 – Grade5] 
 
Analysis will be performed by period I treatment (VRd, KRd) and overall. 
TEAE after the First Dose of Study Drug will be coded using MedDRA and will be summarized by 
Preferred Term (PT) and System Organ Class (SOC). Analysis output will be sorted SOC 
alphabetically and PT frequency. 
1) 
Frequency count of TEAEs after the First Dose of Study Drug by SOC and PT 
2) 
Frequency count of Study Drug-related TEAEs after the First Dose of Study Drug by SOC 
and PT 
3) 
Frequency count of Grade 3 or higher TEAEs after the First Dose of Study Drug by SOC 
and PT 
4) 
Frequency count of Study Drug-related Grade 3 or higher TEAEs after the First Dose of 
Study Drug by SOC and PT 
5) 
Frequency count of TEAEs after the First Dose of Study Drug by SOC and PT by Grade 
6) 
Frequency count of Study Drug-related TEAEs after the First Dose of Study Drug by SOC 
and PT by Grade 
7) 
Frequency count of TEAEs Resulting in Discontinuation of Treatment after the First Dose 
of Study Drug by SOC and PT 
8) 
Frequency count of Serious TEAEs after the First Dose of Study Drug by SOC and PT 
9) 
Frequency count of Non-serious TEAEs after the First Dose of Study Drug by SOC and PT 
10) 
Frequency count of TEAEs that Result in Death after the First Dose of Study Drug by SOC 
and PT 
 
Note for calculation of incidence rate: 
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Same as 7.1.3 
 
7.2 
Laboratory Results 
Descriptive summary of laboratory data analyzed for safety analysis set. 
 
8 
LISTINGS 
Details will be specified in TFL Shells. 
 
9 
CONSIDERATIONS ON STATISTICAL ANALYSIS 
9.1 
Covariate 
Not applicable 
9.2 
Handling of Dropouts or Missing Data 
Missing values shall not be imputed unless otherwise noted. 
9.3 
Criteria for Interim Analysis and Early Discontinuation 
All planned analysis will be performed at 12 month after the last patient enrollment. 
9.4 
Multicenter Studies 
Analyses for consideration of medical institution will not be performed. 
9.5 
Multiple Comparisons/Multiplicity 
No adjustments for multiplicity are planned. 
9.6 
Consideration of Subgroups 
The subgroups is considered in 6.2.2. 
 
10 REVISION HISTORY 
This document is a translation of the 4th Japanese version. 
 
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