Clinical trial NCT03275285
Conditions: Plasma Cell Myeloma
Keywords: Anti-CD38 monoclonal antibody
Sponsor: Sanofi
Start date: 2017-10-25; Completion date: 2025-01-03
Enrollment: 302 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study it to compare the efficacity of isatuximab when combined to carfilzomib and dexamethasone versus carfilzomib and dexamethasone in patients with multiple myeloma already treated with 1 to 3 prior lines of therapy.

Detailed description:
The duration of the study for a patient will include a period for screening of up to 3 weeks. Patients will be treated until disease progression, unacceptable AE, or patient decision to stop the study treatment. After study treatment discontinuation, patients will have follow-up visits until the analysis of overall survival.

Arms: arm 1: Isatuximab (intravenous) on day 1, 8, 15 and 22 of 1st cycle, then on day 1 and 15 of subsequent cycles in combination with carfilzomib (intravenous) on day 1, 2, 8, 9, 15 and 16 + dexamethasone (intravenous or by mouth \[po\]) on day 1, 2, 8, 9, 15, 16, 22 and 23 of a 28 day cycle. arm 2: Carfilzomib (intravenous) on day 1, 2, 8, 9, 15, 16 + dexamethasone (intravenous or po) on day 1, 2, 8, 9, 15, 16, 22 and 23 of a 28 day cycle.
Interventions: intervention 1: isatuximab SAR650984 intervention 2: carfilzomib intervention 3: dexamethasone
Intervention descriptions: intervention 1: Pharmaceutical form: solution for infusion

Route of administration: intravenous intervention 2: Pharmaceutical form: solution for infusion

Route of administration: intravenous intervention 3: Pharmaceutical form: tablets or solution for infusion

Route of administration: oral or intravenous

Protocol documents:
Prot_002.pdf: 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
According to template: QSD-002579 VERSION N°15.0 (22-MAR-2017)
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AMENDED CLINICAL TRIAL PROTOCOL 10 
COMPOUND: isatuximab/SAR650984 
Randomized, open label, multicenter study assessing the clinical benefit of 
isatuximab combined with carfilzomib (Kyprolis®) and dexamethasone versus 
carfilzomib with dexamethasone in patients with relapsed and/or refractory 
multiple myeloma previously treated with 1 to 3 prior lines 
STUDY NUMBER: EFC15246 
STUDY NAME: IKEMA 
VERSION DATE / STATUS: 24-Nov-2022 / Approved 
Version Number: 
1 
EudraCT  
2017-001940-37 
IND Number(s) 
103217 
WHO universal trial number 
U1111-1195-5957 
ClinicalTrials.gov identifier 
NCT03275285 
Date: 
24-Nov-2022
Total number of pages: 
180 
NCT03275285


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NAMES AND ADDRESSES OF 
COORDINATING 
INVESTIGATOR 
 
Name: 
Address: 
 
 
Tel: 
Fax: 
E-mail: 
 
 
MONITORING TEAM’S 
REPRESENTATIVE 
 
Name: 
Address: 
 
 
 
Tel: 
Fax: 
E-mail: 
 
 
SPONSOR 
 
Company: 
Address: 
 
 
 
 
Sanofi-Aventis Recherche & Développement 
1 avenue Pierre Brossolette  
91380 Chilly-Mazarin 
France 
 
OTHER EMERGENCY 
TELEPHONE NUMBERS 
 
 
 


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PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY  
 
Document 
Country/countries 
impacted by amendment 
Date, version 
Amended Clinical Trial Protocol 10 
All 
24 November 2022, version 1 (electronic 10.0) 
Amended Clinical Trial Protocol 09 
All 
14 September 2021, version 1 (electronic 9.0) 
Amended Clinical Trial Protocol 08 
Amended Clinical Trial Protocol 07 
All 
All 
11 March 2021, version 1 (electronic 8.0) 
10 August 2020, version 1 (electronic 7.0) 
Amended Clinical Trial Protocol 06 
All 
13 Nov 2019, version 1 (electronic 6.0) 
Amended Clinical Trial Protocol 05 
All 
11 Sep 2019, version 1 (electronic 5.0) 
Amended Clinical Trial Protocol 04 
All 
11 June 2019, version 1 (electronic 4.0) 
Amended Clinical Trial Protocol 03 
All 
02 July 2018, version 1 (electronic 3.0) 
Amended Clinical Trial Protocol 04 (GB) 
Great Britain only 
02 July 2018, version 1 (electronic 3.0) 
Protocol Amendment 04 
All 
02 July 2018, version 1 (electronic 1.0) 
Amended Clinical Trial Protocol 02 
All 
08 February 2018, version 1 (electronic 2.0) 
Amended Clinical Trial Protocol 03 (GB) 
Great Britain only 
08 February 2018, version 1 (electronic 2.0) 
Protocol Amendment 03 
All 
08 February 2018, version 1 (electronic 1.0) 
Amended Clinical Trial Protocol 02 (GB) 
Great Britain only 
30 August 2017, version 1 (electronic 1.0) 
Protocol Amendment 02 (GB) 
Great Britain only 
30 August 2017, version 1 (electronic 1.0) 
Amended Clinical Trial Protocol 01  
All 
21 August 2017, version 1 (electronic 1.0) 
Protocol Amendment 01 
All 
21 August 2017, version 1 (electronic 1.0) 
Original Protocol 
 
05 July 2017, version 1 (electronic 1.0) 
Amended protocol 10 (24-Nov-2022)   
This amended protocol 10 is considered to be substantial based on the criteria set forth in Article 
2(2)(13) of the Regulation No 536/2014 of the European Parliament and the Council of the 
European Union. 
OVERALL RATIONALE FOR THE AMENDMENT  
An overwhelming treatment effect of isatuximab carfilzomib dexamethasone (IKd) arm in 
comparison to carfilzomib dexamethasone (Kd) arm was observed at the time of the pre-specified 
interim analysis performed with a data cut-off date of 07 February 2020. However, the median 
progression free survival (PFS) was not reached for IKd arm while it was reached for Kd arm. It 
was anticipated that the median PFS could be not reached at the time of the pre-specified final 
analysis. Therefore, a descriptive additional PFS analysis was added in the amended protocol #08 
dated 11 March 2021 to increase the possibility of observing the median PFS time for the IKd arm 
when approximately 180 PFS events as per Independent Response Committee (IRC) are observed.  


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The final PFS analysis was performed with a data cut-off date of 14 January 2022 and median 
PFS was reached in the IKd arm at the time of this analysis. Therefore, the reason to perform 
additional descriptive analysis when approximately 180 PFS events are occurred is no longer 
necessary, and this amendment removes this analysis from the study protocol. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Title Page 
ClinicalTrials.gov identifier was added. 
To include the 
ClinicalTrials.gov identifier in 
the amended protocol. 
Protocol Amendment 
Summary of Changes 
“This amended protocol 09 is substantial based on the criteria 
set forth in Article 10(a) of Directive 2001/20/EC of the 
European Parliament and the Council of the European Union” 
was replaced by “This amended protocol 10 is considered to 
be substantial based on the criteria set forth in Article 2(2)(13) 
of the Regulation No 536/2014 of the European Parliament and 
the Council of the European Union” 
To reflect the current 
amendment number and for 
consistency with the protocol 
template released in 
September 2022. 
Clinical Trial Summary: 
Assessment Schedule 
Text related to additional descriptive PFS analysis was 
removed and the management of patients still on treatment or 
in the follow-up was updated accordingly. 
Median PFS was reached at 
the final PFS analysis; 
therefore, additional descriptive 
PFS analysis is no longer 
necessary. 
Clinical Trial Summary: 
Statistical Considerations, 
Primary analysis 
The following sentences were removed: “An additional PFS 
analysis will be performed when approximately 180 events 
assessed by the IRC have been observed to better 
characterize the distribution of PFS in the IKd arm in a 
descriptive way. This analysis will be performed at the latest 15 
months after the 159 PFS event analysis cut-off date in case of 
the approximately 180 PFS events are not observed at that 
time”. 
Median PFS was reached at 
the final PFS analysis; 
therefore, additional descriptive 
PFS analysis is no longer 
necessary. 
Clinical Trial Summary: 
Statistical Considerations, 
Interim analysis, Planned 
PFS and OS cut-off dates 
The following sentences were removed: “Efficacy results will be 
updated in a descriptive way (non-inferential analysis) at the 
time of the PFS additional analysis (approximately 180 
events)”. 
“The cut-off date for the additional PFS analysis will be the 
date when approximately 180 PFS events assessed by the IRC 
have occurred or 15 months after 159 PFS events analysis cut-
off date, whichever comes first”. 
Median PFS was reached at 
the final PFS analysis; 
therefore, additional descriptive 
PFS analysis is no longer 
necessary. 
Clinical Trial Summary: 
Duration of Study Period 
(per patient) 
All wordings related to additional PFS analysis was removed 
and the management of patients still on treatment or in the 
follow-up was updated accordingly. 
Median PFS was reached at 
the final PFS analysis; 
therefore, additional descriptive 
PFS analysis is no longer 
necessary. 
Section 6.2.1 Duration of 
study participation for 
each patient 
Text related to 180 additional PFS events was removed and 
management of patients still on treatment or in follow-up was 
updated accordingly. 
Median PFS was reached at 
the final PFS analysis; 
therefore, additional descriptive 
PFS analysis is no longer 
necessary. 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 6.2.2 
Determination of end of 
clinical trial (all patients) 
The following sentences were removed: “An additional PFS 
analysis will be performed at approximately 180 events. The 
additional analysis will be performed at the latest 15 months 
after the 159 PFS event analysis cut-off date in case of the 
approximately 180 PFS events are not observed at that time”. 
Median PFS was reached at 
the final PFS analysis; 
therefore, additional descriptive 
PFS analysis is no longer 
necessary. 
Section 6.4 Study 
Committees 
“No IRC review will be performed after the additional PFS 
analysis cut-off date” was replaced by “IRC will review disease 
assessments until the last time point with M protein assessed 
by central laboratory or overall survival cut-off date, whichever 
comes first”. 
To analyze all samples drawn 
before implementation of 
amended protocol #10. 
Section 10.1.6 After 
Implementation of 
Amended Protocol #10 
Previous heading “Post additional PFS analysis cut-off date 
(approximately 180 PFS events as per IRC)” and the 
applicable text in this section were replaced by “After 
implementation of amended protocol #10”. 
To reflect removal of the 
additional PFS analysis. 
Section 10.1.6 After 
Implementation of 
Amended Protocol #10 
Added that following additional information will be collected 
during the study treatment administration after the 
implementation of amended protocol #10: 
“Hematology and biochemistry, or any other laboratory results 
supporting the reported AEs.” 
“Other procedures supporting the reported AEs.” 
To include the additional 
information required to be 
collected after implementation 
of amended protocol #10. 
Section 10.1.6 After 
Implementation of 
Amended Protocol #10 
Updated that survival status and further anti-myeloma 
therapies will be collected twice a year if study treatment is 
stopped before the OS cut-off date. 
To correct inconsistency with 
Section 6.2.1.  
Section 10.1.7 Post OS 
analysis cut-off date 
Added that following additional information will be collected 
during the study treatment administration post OS analysis cut-
off date: 
“Hematology and biochemistry, or any other laboratory results 
supporting the reported AEs.” 
“Other procedures supporting the reported AEs.” 
“Death date and reason if occurred during study treatment.” 
To include the additional 
information required to be 
collected post OS analysis cut-
off date. 
Section 10.1.7 Post OS 
analysis cut-off date 
Added that following additional information will be collected 
after the discontinuation of study treatment: 
“Death date and reason if occurred in follow-up period due to 
related AE.” 
To include the additional 
information required to be 
collected post OS analysis cut-
off date. 
Section 11.4.2.1 Analysis 
of primary efficacy 
endpoint 
The following sentences were removed: “An additional PFS 
analysis (non-inferential analysis) will be performed when 
approximately 180 events assessed by the IRC have been 
observed to better characterize the distribution of PFS in the 
Ikd arm in a descriptive way. The additional analysis will be 
performed at the latest 15 months after the 159 PFS event 
analysis cut-off date in case of the approximately 180 PFS 
events are not observed at that time”. 
Median PFS was reached at 
the final PFS analysis; 
therefore, additional descriptive 
PFS analysis is no longer 
necessary. 
Section 11.4.2.3 
Multiplicity considerations 
The following sentence was removed: “Efficacy results will be 
updated at the time of the PFS additional analysis 
(approximately 180 events) but will be only descriptive (non-
inferential analysis)”. 
Median PFS was reached at 
the final PFS analysis; 
therefore, additional descriptive 
PFS analysis is no longer 
necessary. 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 11.5 Interim 
analysis 
The following sentences were removed: “Efficacy results will be 
updated at the time of the PFS additional analysis 
(approximately 180 events) but will be only descriptive (non-
inferential analysis). No α-spending or formal testing is planned 
for the PFS additional analysis”. 
Median PFS was reached at 
the final PFS analysis; 
therefore, additional descriptive 
PFS analysis is no longer 
necessary. 
Section 12.1 Ethical and 
Regulatory 
Considerations 
Additional details regarding ethical and regulatory standards 
included as per the updated protocol template. 
For consistency with the 
protocol template released in 
September 2022. 
Section 14.5 Data 
Protection 
Additional details regarding data protection methods included 
as per the updated protocol template. 
For consistency with the 
protocol template released in 
September 2022. 
Appendix O (Protocol 
amendment history) 
Changes related to amended protocol #09 were moved to 
Appendix O. 
History of amendment to this 
protocol added. 
 


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CLINICAL TRIAL SUMMARY 
COMPOUND: 
isatuximab/SAR650984 
STUDY No: EFC15246 
TITLE 
Randomized, open label, multicenter study assessing the clinical benefit of 
isatuximab combined with carfilzomib (Kyprolis®) and dexamethasone versus 
carfilzomib with dexamethasone in patients with relapsed and/or refractory 
multiple myeloma previously treated with 1 to 3 prior lines. 
INVESTIGATOR/TRIAL LOCATION 
Worldwide 
PHASE OF DEVELOPMENT 
Phase 3 
STUDY OBJECTIVES 
 
Primary objective: 
To demonstrate the benefit of isatuximab in combination with carfilzomib and 
dexamethasone in the prolongation of progression free survival (PFS) using 
International Myeloma Working Group (IMWG) criteria as compared to 
carfilzomib and dexamethasone in patients with relapsed and/or refractory 
multiple myeloma (MM) previously treated with 1 to 3 lines of therapy.  
Secondary objectives: 
Key efficacy objectives 
• To evaluate overall response rate (ORR). 
• To evaluate rate of very good partial response (VGPR) or better. 
• To evaluate rate of VGPR or better (IMWG criteria) with minimal residual 
disease (MRD) negativity in both arms. 
• To evaluate complete response (CR) rate in both arms (IMWG criteria). 
• To evaluate overall survival (OS) in both arms. 
Other secondary objectives 
• To evaluate safety in both arms. 
• To evaluate duration of response (DOR) in both arms. 
• To evaluate time to progression (TTP) in both arms. 
• To evaluate time from the date of randomization to the date of second 
PD or death from any cause, whichever happens first (PFS2) in 
both arms. 
• To evaluate time to first response in both arms 
• To evaluate time to best response in both arms 
• To determine the pharmacokinetic (PK) profile of isatuximab and 
carfilzomib when combined together. 
• To evaluate immunogenicity of isatuximab in isatuximab arm. 
• To evaluate generic and disease- and treatment-specific health-related 
quality of life (HRQL), and changes in HRQL, health state utility, and 
health status in both arms. 
Exploratory objectives: 
• To explore PK and pharmacodynamics relationship. 
• To explore the relationship between immune genetic determinants and 
efficacy endpoints. 
• To explore relationship between cytogenetics abnormalities not part of 
Revised International Staging System (R-ISS) including but not limited to 
del (1p) and gain (1q) and efficacy endpoints. 
• To explore the impact of M-protein measurement without isatuximab 
interference on best overall response assessment. 


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STUDY DESIGN 
This is a prospective multicenter, multinational, randomized, open label, parallel 
group, 2-arm study assessing the clinical benefit of isatuximab at 10 mg/kg 
weekly in the first cycle (4 weeks) and then combined with carfilzomib at 
56 mg/m² twice weekly 3 out of 4 weeks and dexamethasone (IKd arm) twice 
weekly versus carfilzomib at 56 mg/m² twice weekly 3 out of 4 weeks and 
dexamethasone  twice weekly (Kd arm), in terms of PFS in patients with 
relapsed and/or refractory MM previously treated with 1 to 3 prior lines. 
Patients will be treated until disease progression, unacceptable adverse event 
(AE), patient decision to stop the study treatment, or any other reasons. 
Isatuximab, carfilzomib, and dexamethasone are defined in this protocol as 
“study treatment”. 
Treatment allocation will be performed by an Interactive Response Technology 
(IRT). All eligible patients will be randomly assigned to the IKd (experimental) 
arm or Kd (control) arm in a 3:2 ratio.  
Randomization will be stratified by number of prior lines 1 vs. >1 and R-ISS I or 
II vs. III vs. not classified (inconclusive fluorescence in situ hybridization [FISH] 
unless stage can be determined on lactate dehydrogenase (LDH), albumin, and 
β2 microglobulin only) (see Appendix A). 
STUDY POPULATION  
Main selection criteria 
Inclusion criteria: 
I 01. Multiple myeloma. 
I 02. Measurable disease: 
Serum M protein ≥0.5 g/dL measured using serum protein 
immunoelectrophoresis; 
and/or 
Urine M protein ≥200 mg/24 hours measured using urine protein 
immunoelectrophoresis. 
I 03. Patient with relapsed and/or refractory MM with at least 1 prior line and 
no more than 3 prior lines. 
I 04. Patient has given voluntary written informed consent before performance 
of any study related procedures not part of normal medical care. 
Exclusion criteria: 
E 01. Less than 18 years (or country’s legal age of majority if the legal age 
is >18 years). 
E 02. Primary refractory MM defined as patients who have never achieved at 
least a minimal response with any treatment during the disease course. 
E 03. Patient with serum free light chain (FLC) measurable disease only. 
E 04. Patient with prior anti-CD38 monoclonal antibody (mAb) treatment with 
progression on or within 60 days after end of anti-CD38 mAb treatment 
or failure to achieve at least minimal response to treatment (ie, refractory 
to anti-CD38). 
E 05. Any anti-myeloma drug treatment within 14 days before randomization, 
including dexamethasone. 
E 06. Patient who has received any other investigational drugs or prohibited 
therapy for this study within 28 days prior to randomization  
(Section 8.8.2). 
E 07. Prior treatment with carfilzomib.  
E 08. Known history of allergy to Captisol (a cyclodextrin derivative used to 
solubilize carfilzomib), prior hypersensitivity to sucrose, histidine 
(as base and hydrochloride salt), polysorbate 80, or any of the 
components (active substance or excipient) of study treatment that are 


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not amenable to premedication with steroids, or H2 blockers, that would 
prohibit further treatment with these agents. 
E 09. Patients with contraindication to dexamethasone. 
E 10. Prior allogenic hematopoietic stem cell transplant with active graft versus 
host disease (any grade and/or being under immunosuppressive 
treatment within 2 months before randomization). 
E 11. Known amyloidosis or concomitant plasma cell leukemia. 
E 12. Pleural effusions requiring thoracentesis or ascites requiring 
paracentesis or any major procedures within 14 days before 
randomization: eg, plasmapheresis, curative radiotherapy, major surgery 
(kyphoplasty is not considered a major procedure).  
E 13. Eastern Cooperative Oncology Group (ECOG) performance status 
(PS) >2. 
E 14. Platelets <50,000 cells/µ L if <50% of bone marrow (BM) nucleated cells 
are plasma cells and <30,000 cells/µL if ≥50% of BM nucleated cells are 
plasma cells. Platelet transfusion is not allowed within 3 days before the 
screening hematological test. 
E 15. Absolute neutrophil count (ANC) <1000 μ/L (1 x 109/L). The use of 
granulocyte colony stimulating factor is not allowed to reach this level. 
E 16. Creatinine clearance <15 mL/min/1.73 m² (Modification of Diet in Renal 
Disease [MDRD] Formula). 
E 17. Total bilirubin >1.5 x upper limit of normal (ULN), except for known 
Gilbert syndrome. 
E 18. Corrected serum calcium >14 mg/dL (>3.5 mmol/L). 
E 19. Aspartate aminotransferase (AST) and/or alanine aminotransferase 
(ALT) >3 x ULN. 
E 20. Ongoing toxicity (excluding alopecia and those listed in eligibility criteria) 
from any prior anti-myeloma therapy of Grade >1 (National Cancer 
Institute Common Toxicity Criteria for Adverse Events [NCI-CTCAE] 
v4.03). 
E 21. Prior malignancy. Adequately treated basal cell or squamous cell skin or 
superficial (pTis, pTa, and pT1) bladder cancer or low risk prostate 
cancer or any in situ malignancy after curative therapy are allowed, as 
well as any other cancer for which therapy has been completed ≥5 years 
prior to randomization and from which the patient has been disease-free 
for ≥5 years.  
E 22. Any of the following within 6 months prior to randomization: myocardial 
infarction, severe/unstable angina pectoris, coronary/peripheral artery 
bypass graft, New York Heart Association class III or IV congestive heart 
failure, Grade ≥3 arrhythmias, stroke, or transient ischemic attack. 
E 23. Left ventricular ejection fraction <40%. 
E 24. Known acquired immunodeficiency syndrome (AIDS) related illnesses or 
HIV disease requiring antiretroviral treatment, or to have active hepatitis 
A, B (defined as a known positive hepatitis B surface antigen (HBsAg) 
result), or C (defined as a known quantitative hepatitis C [HCV] 
ribonucleic  acid RNA  results greater than the lower limits of detection 
of the assay or positive HCV antigen) infection. 
E 25. Any of the following within 3 months prior to randomization: treatment 
resistant peptic ulcer disease, erosive esophagitis or gastritis, infectious 
or inflammatory bowel disease, diverticulitis, pulmonary embolism, or 
other uncontrolled thromboembolic event. 


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E 26. Any severe acute or chronic medical condition which could impair the 
ability of the patient to participate in the study or interfere with 
interpretation of the study results (eg, systemic infection unless 
anti-infective therapy is employed), or patient unable to comply with the 
study procedures. 
E 27. Female patients who are pregnant or lactating. 
E 28. Women of childbearing potential (WOCBP) not protected by  
highly-effective method of birth control and/or who are unwilling or 
unable to be tested for pregnancy (see Appendix C). 
E 29. Male participant with a female partner of childbearing potential not 
protected by highly effective method of birth control. 
Total expected number of patients 
Approximately 300 (180 patients in IKd arm and 120 patients in Kd arm) 
STUDY TREATMENTS 
 
Investigational medicinal product 
Isatuximab 
Formulation: 
The drug product is presented as a concentrate for solution for infusion in vials 
containing 20 mg/mL (500 mg/25 mL) of isatuximab in 20 mM histidine, 
10% (w/v) sucrose, 0.02% (w/v) polysorbate 80, and pH 6.0 buffer. It is packed 
in 30 mL glass vials fitted with elastomeric closure. Each vial contains a 
nominal content of 500 mg of isatuximab. The fill volume has been established 
to ensure removal of 25 mL. 
Route of administration: 
Intravenous (IV) 
Dose regimen: 
Isatuximab will be given at 10 mg/kg IV on Days 1, 8, 15, and 22 in Cycle 1 and 
then on Days 1 and 15 in subsequent cycles. The duration of each cycle is  
28 days. 
Premedication will include acetaminophen or paracetamol, ranitidine or 
equivalent, and diphenhydramine or equivalent, in addition to dexamethasone. 
Dose omission/delay will be applied in case of toxicity. 
Investigational medicinal product 
Formulation: 
 
Carfilzomib (Kyprolis® ) 
Carfilzomib for injection is presented as a lyophilized parenteral product in 
single-use vials. The lyophilized product is reconstituted with water for injection 
to a final carfilzomib concentration of 2.0 mg/mL prior to administration. 
Route of administration: 
IV 
Dose regimen: 
 
 
Carfilzomib (after appropriate hydration) will be given as a 30-minute infusion 
on Days 1, 2, 8, 9, 15, and 16 of 28 day cycles at the dose of 20 mg/m² on 
Day 1 and Day 2 in Cycle 1 and then escalated to 56 mg/m² on Days 8, 9, 15, 
and 16 of Cycle 1 and Days 1, 2, 8, 9, 15, and 16 for subsequent cycles. 
The carfilzomib infusion should follow the isatuximab infusion and should begin 
just after the end of the isatuximab infusion. 
Patients with a body surface area (BSA) >2.2 m² will use 2.2 m² for the 
determination of carfilzomib dose. 
Hydration is required for the first cycle and left to the Investigator’s judgment for 
further administrations. 
Premedication will include dexamethasone. 
Anti-viral prophylaxis will be done according to site’s/Investigator’s practice. 
Dose modifications will be applied in case of toxicity. 
Investigational medicinal product 
Formulation: 
Dexamethasone 
The drug product is presented as 4 mg tablets; and 3.3 mg/mL for IV injection 
(8.3 mg/mL in the United States). 


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Routes of administration: 
IV/orally (PO) 
Dose regimen: 
 
 
Dexamethasone will be given at 20 mg for patients on Days 1, 2, 8, 9, 15, 16, 
22, and 23 in a 28-day cycle. Patients will be asked to maintain a diary to 
record the doses of dexamethasone PO to document all oral administrations. 
Dexamethasone will be administered IV on the days of isatuximab and/or 
carfilzomib infusions, and PO on the other days. 
Dose modifications will be applied in case of toxicity. 
Dexamethasone will have also intent of premedication for infusion acute 
reaction related to both isatuximab and carfilzomib. 
Non-investigational medicinal 
products (premedication) 
 
Product: 
Acetaminophen or paracetamol 
Route of administration: 
PO 
Dose regimen: 
 
Acetaminophen or paracetamol will be given 650 to 1000 mg 15 to 30 minutes 
(but no longer than 60 minutes) before isatuximab infusion. 
Product: 
Ranitidine or equivalent (other approved H2 antagonists [eg, cimetidine] or 
oral proton pump inhibitors [eg, omeprazole, esomeprazole]). 
Route of administration: 
IV 
Dose regimen: 
Ranitidine or equivalent will be given 50 mg 15 to 30 minutes (but no longer 
than 60 minutes) before isatuximab infusion. 
Product: 
Diphenhydramine or equivalent (eg, cetirizine, promethazine, or 
dexchlorpheniramine, according to local approval and availability). Intravenous 
route is preferred for at least the first 4 infusions. 
Route of administration: 
IV 
Dose regimen: 
Diphenhydramine or equivalent will be given 25 to 50 mg 15 to 30 minutes (but 
no longer than 60 minutes) before isatuximab infusion. 
ENDPOINTS 
 
Primary endpoint: 
The primary endpoint is PFS, defined as the time from the date of 
randomization to the date of first documentation of progressive disease (PD) 
(as determined by the Independent Response Committee [IRC]) or the date of 
death from any cause, whichever comes first. Response will be determined 
according to IMWG criteria. Progression based on paraprotein will be confirmed 
based on 2 consecutive assessments. 
Secondary endpoints: 
The key secondary efficacy endpoints are:  
• 
ORR: Defined as the proportion of patients with stringent complete 
response (sCR), CR, VGPR, and partial response (PR) as best 
overall response assessed by IRC using the IMWG response criteria. 
• 
Rate of VGPR or better: Defined as the proportion of patients with 
sCR, CR, and VGPR. 
• 
Rate of VGPR or better with MRD negativity: Defined as the 
proportion of patients for whom MRD assessed by sequencing is 
negative at any time after first dose of study treatment. Minimal 
residual disease will be assessed centrally by next-generation 
sequencing in BM aspiration samples from patients who achieve 
VGPR or better, to determine the depth of response at the molecular 
level. Threshold for negativity will be at least 10-5. 
• 
CR rate: Defined as the proportion of patients with sCR and CR. 


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• 
OS: Defined as the time from the date of randomization to death from 
any cause. 
The other secondary efficacy endpoints are: 
• 
DOR: Defined as the time from the date of the first IRC determined 
response for patients achieving PR or better to the date of first 
documented PD determined by IRC or death, whichever happens 
first. 
• 
TTP: Defined as time from randomization to the date of first 
documentation of PD (as determined by the IRC). 
• 
PFS2: Defined as time from the date of randomization to the date of 
first documentation of PD (as assessed by investigator) after initiation 
of further anti-myeloma treatment or death from any cause, whichever 
happens first. 
• 
Time to first response: Defined as the time from randomization to 
the date of first IRC determined response (PR or better) that is 
subsequently confirmed. 
• 
Time to best response: Defined as the time from randomization to 
the date of first occurrence of IRC determined best overall response 
(PR or better) that is subsequently confirmed. 
Safety evaluation: 
The secondary safety endpoints are: 
• 
Treatment-emergent adverse events (TEAEs)/serious adverse events 
(SAEs). Treatment-emergent AEs are defined as AEs that develop, 
worsen (according to the Investigator opinion) or become serious 
during the treatment period. The treatment period is defined as the 
time from first dose of study treatment up to 30 days after last dose of 
study treatment. 
• 
Infusion associated reactions (IARs). 
• 
Laboratory parameters. 
• 
Vital signs and electrocardiogram (ECG). 
• 
Findings from physical examination. 
Adverse events and laboratory parameters will be graded using NCI-CTCAE 
v4.03. 
 
PK evaluation: 
The PK evaluation of isatuximab will be performed in all patients in the IKd arm. 
Among them, approximately 12 patients will be sampled for carfilzomib PK 
evaluation. 
Isatuximab:  
• 
Blood samples will be collected up to Cycle 10 from all patients 
treated with isatuximab using a sparse sampling strategy in order to 
assess the PK profile of isatuximab using population PK approach. 
This analysis will involve an estimation of inter-patient PK variability, 
the population PK parameters estimates, and the assessment of 
carfilzomib and pathophysiologic covariate effects on the main 
PK parameters. Empirical Bayesian estimation of individual 
parameters and of individual exposure will also be performed.  
Carfilzomib:  
• 
Blood samples will be collected at selected time points in a subset of 
12 patients in the IKd arm at Cycle 1 Day 15. 
The following PK parameters will be estimated by non-compartmental 
analysis:  
• 
Ceoi, Cmax, tmax, Clast, tlast, Ctrough, AUClast and AUC. 


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Anti-drug antibodies (ADA):  
• 
Presence of isatuximab ADA in the IKd arm will be assessed in all 
patients up to Cycle 10. If ADA positive or inconclusive at Cycle 10, 
one additional sampling time for ADA evaluation will be collected  
3 months later. No further ADA will be sampled, even if this 3-month 
sample is positive. 
HRQL:  
• 
Health-related quality of life will be assessed using the European 
Organisation for Research and Treatment of Cancer (EORTC) 
myeloma module with 20 items (QLQ-MY20) and EORTC quality of 
life questionnaire with 30 questions (QLQ-C30).  
• 
Health state utility and health status will be assessed using the 
European Quality of Life Group questionnaire with 5 dimensions and  
5 levels per dimension (EQ-5D-5L). 
Exploratory endpoints: 
• 
Pharmacokinetic estimates will be investigated as prognostic factors 
for clinical outcome including safety and efficacy endpoints if 
possible. 
• 
Blood sample will be collected and analyzed for immune genetic 
determinants such as Fcγ receptor polymorphism and correlated with 
efficacy endpoints, including ORR, DOR, PFS, and OS. 
• 
In addition to the cytogenetic abnormalities assessed by FISH at 
baseline to determine R-ISS, other cytogenetic abnormalities such as 
but not limited to del(1p) and gain(1q) will be assessed and correlated 
with parameters of clinical response. 
• 
M protein measurement without isatuximab interference and impact 
on BOR will be assessed. Blood sample will be collected up to 
Cycle 30 for all patients in isatuximab arm. After Cycle 30, blood 
sample will be collected until disease progression only for patients 
who reach at least VGPR at this cycle. 
ASSESSMENT SCHEDULE 
The following evaluations will be performed at Screening/Baseline only: 
• 
Demographic characteristics and medical/surgical history. 
• 
Prior MM history (diagnosis, stage at diagnosis and at study entry, 
and prior anti-MM therapies). 
• 
Cardiac ultrasonography (multigated acquisition (MUGA) scan or MRI 
are accepted). 
• 
Serum β2-microglobulin. 
• 
Molecular analysis on BM samples (FISH for high risk cytogenetics 
[central laboratory]). 
The following laboratory assessments will be performed before study treatment 
initiation: 
• 
Blood typing: Complete blood phenotyping if not already available 
and antibody screening (indirect Coombs test or indirect antiglobulin 
test) in the IKd arm only (local laboratory). Indirect Coombs test will 
be repeated once after study treatment initiation. 
• 
Immune genetic determinants, such as Fcγ receptor polymorphism, 
will be performed prior to study treatment administration (central 
laboratory). 


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Safety evaluation will be performed during the treatment period and will include 
the following: 
• 
Serum or urine pregnancy test at Screening/Baseline, before each 
cycle, at end of treatment (EOT), and monthly during follow-up up to 
the end of contraception period. 
• 
Vital signs and physical examination. 
• 
ECOG PS. 
• 
AE evaluation. Severity grade will be determined according to the 
NCI-CTCAE v4.03. 
• 
Concomitant medications. 
• 
Laboratory tests (including coagulation urine analysis at baseline and 
then if clinically indicated). 
• 
ECG. 
• 
Presence of ADA in the IKd arm will be assessed in all patients up to 
Cycle 10. If ADA positive or inconclusive at Cycle 10, one additional 
sampling time for ADA evaluation will be collected 3 months later. 
No further ADA will be sampled, even if this 3-month sample is 
positive. 
• 
Hepatitis B virus (HBV) serology in patients with unknown HBV 
status. 
The following disease assessment procedures will be performed at Screening (for 
eligibility) and again at Cycle 1 Day 1 prior to study treatment administration, Day 1 
of every cycle during treatment up to progression, and at EOT: 
• 
M protein quantification (serum and 24-hour urine, protein 
immunoelectrophoresis, and immunofixation [IF]) (central laboratory). 
An additional sample (serum) will be collected for patients in the IKd 
arm to evaluate the potential isatuximab interference with the M 
protein assessment in immunoelectrophoresis and IF assays. This 
additional sample will be collected at all time points at which 
M protein is collected up to Cycle 30. After Cycle 30, this sample will 
be collected only for patients who reach at least VGPR at this cycle 
until disease progression. In case of isatuximab is stopped before 
progression, sample interference assay will be collected up to  
3 months or when PD is observed, whichever comes first. 
• 
Free light chains quantification (central laboratory). 
• 
Quantitative immunoglobulins (central laboratory). 
• 
For patients who discontinue study treatment for reasons other than 
disease progression, serum M protein, urine M protein, and serum 
FLCs are to be performed every 4 weeks (central laboratory) during 
the follow-up period until progression even if further  
anti-myeloma therapy is started before PD is diagnosed. 
 
Other examinations for disease assessment include: 
• 
Bone marrow aspiration for plasma cell infiltration assessment (local 
laboratory) at baseline and then in case of VGPR and/or to confirm 
CR or as clinically indicated. 
In case of VGPR, plasma cell infiltration assessment is mandatory for 
patients in IKd arm with residual serum M protein of Ig G ≤0.5 g/dL 
and/or residual kappa IF positivity in urine, due to potential 
interference between isatuximab and M protein. 
In case of CR on M protein, plasma cell infiltration assessment is 
mandatory in IKd arm and in Kd arm, unless a previous assessment 
was made within 3 months and showed plasma cells ≤ 5%. 
Bone marrow biopsy can be done for stringent CR (sCR) assessment as 
per investigator decision.  


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• 
Bone marrow aspiration for MRD assessment at baseline and in case 
of VGPR or better (central laboratory). If the patient presents ≥VGPR 
but is determined MRD positive, another BM sample will be collected 
3 months (3 cycles) later, in order to identify late negativity. A third 
sample may be collected after another 3 months if the patient remains 
MRD positive and is still being treated. If a patient becomes CR after 
a third BM sample MRD positive performed during VGPR, up to 
3 additional BM samples will be collected after CR. Therefore, a 
maximum of 6 BMA could be performed by patient (no more than 
3 per category of response). However, because BMA is invasive 
procedure, the following guidance is given in the purpose to limit as 
much as possible the number of BMA 
For patients with CR without previous documentation of VGPR, 
first bone marrow for MRD assessment will be collected at time of 
confirmation of CR (ie, at the second time point showing CR). If 
patient is determined MRD positive, another BM sample will be 
collected 3 months (3 cycles) later, in order to identify late negativity. 
A third sample may be collected after another 3 months if the patient 
remains MRD positive and is still being treated. 
• 
For patients with VGPR: 
- First bone marrow will be collected when VGPR is confirmed at the 
second time point or at a later time point as per investigator 
judgement based on kinetic of M protein decrease and/or if a 
plateau phase is reached (plateau is defined as variation less than 
20% over 12 weeks). 
- If MRD is positive on first BMA, a second BMA will be collected 
3 months later (3 cycles) to identify late negativity. 
- In case of MRD is still positive on second BMA made while patient 
is in VGPR, the timing to perform the third BMA can be postponed 
until CR achievement.  
- In case of the patient becomes CR and patient was MRD positive 
on the last BMA performed during VGPR, a BMA will be done for 
MRD assessment at time of confirmation of CR.   
- After the first BMA during CR is done and in case patient was 
MRD positive on this BMA, the additional BMA planned by the 
protocol can be discussed with the patient. 
• 
Radiological disease assessment. 
• 
Skeletal survey or whole-body low-dose computed tomography 
(WBLDCT) scan at baseline, then once a year and anytime during the 
study if clinically indicated. 
• 
Plasmacytoma assessment. 
• 
If known extramedullary disease at baseline, CT scan or magnetic 
resonance imaging (MRI) is to be done at baseline, every  
12 weeks (± 1 week) until PD (even for patients who would initiate 
further anti-myeloma therapy without PD) and if clinically indicated. 
• 
If suspected extramedullary disease (plasmacytoma) at baseline, 
CT scan or MRI is to be done at baseline. In case of confirmation of 
existing plasmacytoma, CT or MRI will be repeated every  
12 weeks (± 1 week) until PD (even for patients who would initiate 
further anti-myeloma therapy without PD) and if clinically indicated. 
• 
CT scan or MRI to be done in case of suspicion of progression or if 
clinically indicated in a patient with no previous positive image for 
extramedullary disease. 


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Note: For bone lesion or extramedullary disease assessment, the same 
modality should be used throughout the study for each individual 
patient. All imaging must be sent for central review. 
Carfizomib PK will be assessed on D15 cycle 1 in approximately 12 patients.  
Further anti-myeloma therapies, best overall response and date of progression 
on further anti myeloma therapies according to Investigator’s assessment and 
survival status will be collected at every 3 months follow-up visit. In case of 
initiation of first further anti-myeloma therapy without PD, disease assessment 
will continue to be performed monthly as done during study treatment up to PD 
and then follow-up done as described just above.  
HRQL will be assessed electronically on Day 1 prior to first study treatment 
administration, on Day 1 of each cycle throughout the study treatment period, at 
EOT 30 ± 5 days after last study treatment administration (or before further 
anti myeloma therapy whichever comes first), and 90 days after last study 
treatment administration (first or second FU visit in case of study treatment due 
discontinuation due to PD or without PD, respectively). 
The PK samples will be collected from all patients receiving isatuximab using a 
sparse sampling strategy (central laboratory) up to Cycle 10 (stopped at  
Cycle 11). 
For all alive patients at the implementation of amended protocol #10, survival 
status will be collected approximately twice a year, until death, or OS analysis 
cut-off date, whichever comes first. 
Patients still on treatment at the implementation of amended protocol #10 or 
OS analysis cut-off date and benefitting from the study treatment can continue 
the study treatment until disease progression, unacceptable AEs, patient wish 
to discontinue further study treatment, or any other reasons. For cycles 
completed after the cut-off dates, all SAEs (related or not) and all related non-
serious AEs ongoing at the cut-off date, and then all new related AEs (serious 
or not) occurred post cut-off date, IP administration, and reason of end of 
treatment (EOT) will continue to be collected. If last ADA before cut-off date is 
positive or inconclusive, one additional sampling time for ADA evaluation 
should be collected 3 months later. No further ADA will be sampled, even if this 
3-month sample is positive. 
STATISTICAL CONSIDERATIONS 
 
Sample size determination: 
A total of 159 PFS events will be needed to detect a hazard ratio of 0.59 using 
a log rank test at the 1-sided level of 0.025 and a 90% power. Assuming 
proportional hazards and based on an anticipated median PFS time of 
19-months in the Kd arm; this is expected to correspond to a median PFS of 
32-months in the IKd arm. 
In addition, with a total of 300 patients (180 patients in IKd arm and 120 
patients in Kd arm) and assuming a uniform accrual rate of 19 patients per 
month, the cut-off date for the final analysis of PFS is expected to be 
approximately 36 months after first patient in. 
Main analysis populations: 
Intent-to-treat (ITT) population: This population will include all patients who 
have given their informed consent and for whom there is a confirmation of 
successful allocation of a randomization number by the IRT. This population is 
the primary population for all efficacy parameters. All analyses using this 
population will be based on the treatment assigned at randomization. 


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Primary analysis: 
Primary analysis will consist of PFS comparison between the IKd arm versus 
the Kd arm through a log-rank test procedure stratified by stratification factors 
as entered in the IRT. The significance levels at the interim and final analyses 
will be determined using alpha-spending function (see below).  
The analysis of PFS will be based on the following censoring rules: 
• 
If progression and death are not observed before the analysis cut-off 
date or the date of initiation of further anti-myeloma treatment, PFS 
will be censored at the date of the last valid disease assessment not 
showing disease progression performed prior to initiation of a further 
anti-myeloma treatment (if any) or the analysis cut-off date, whichever 
comes first. 
• 
A patient without an event (death or disease progression) and without 
any valid post-baseline disease assessments will be censored at the 
day of randomization (Day 1). 
The cut-off date for the final analysis of PFS will be the date when the 
159th PFS event assessed by the IRC has been observed. 
The estimates of the hazard ratio and corresponding (1-2α)% (α being the 
one-sided  nominal significance level: α=0.023 at final analysis and 0.005 at 
PFS interim analysis) confidence intervals (CI) will be provided using the Cox 
proportional hazard model stratified by stratification factors as entered in the 
IRT. The median PFS and probabilities of being progression free at different 
time points calculated using the Kaplan-Meier methods as well as 
corresponding CI will be presented by treatment arm. The Kaplan-Meier PFS 
curves will also be presented. 
Sensitivity analyses of PFS will be performed (eg, different censoring rules and 
PFS assessed by the Investigator). Subgroup analyses of PFS (eg, by high risk 
status, number of prior lines of treatment) will also be conducted. 
 
Analysis of key secondary efficacy endpoints: 
Key secondary endpoints other than OS will be analyzed at the time of the 
primary and/or the final analysis of PFS. The CR rate will only be tested for 
comparison when the antibody-capture interference assay will be available. 
Key secondary endpoints other than OS will be summarized with descriptive 
statistics per treatment arm. They will be compared between treatment arms 
using Cochran Mantel Haenszel stratified method. The (1-2α) % 2-sided CI will 
be also computed for these endpoints using the Clopper-Pearson method. 
The OS analysis will be similar to what is described for PFS and will be 
performed approximately 3 years after the primary PFS analysis cut-off date. It 
will be based on the following censoring rules: patients without death prior to 
the OS analysis cut-off date will be censored at the last date the patient was 
known to be alive or the OS analysis cut-off date, whichever comes first. 
Analysis of other secondary efficacy endpoints: 
Other secondary endpoints will be analyzed at the time of the primary and/or 
the final analysis of PFS. 
The analyses of TTP, PFS2, DOR, time to first response and time to best 
response will be similar to what is described for PFS and will be based on the 
following censoring rules:  
• 
TTP: If progression is not observed before the PFS analysis cut-off 
date or the date of initiation of further anti-myeloma treatment, TTP 
will be censored at the date of the last valid disease assessment not 
showing disease progression performed prior to initiation of a further 
anti-myeloma treatment (if any) or the analysis cut-off date, whichever 
comes first. 


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• 
PFS2: For patients alive without a progression after initiation of 
further anti-myeloma treatment before the PFS analysis cut-off date, 
PFS2 will be censored at the date of the last follow-up visit not 
showing disease progression after initiation of further anti-myeloma 
treatment or the analysis cut-off date, whichever comes first. 
• 
DOR: In the absence of the confirmation of subsequent disease 
progression or death before the analysis cut-off date, the DOR will be 
censored at the date of the last valid disease assessment not 
showing disease progression performed prior to initiation of a further 
anti-myeloma treatment or the analysis cut-off date, whichever is 
earlier. 
• 
Time to first response: in the absence of response, patients will be 
censored at the earliest of the date of the last valid disease 
assessment before disease progression or death, the date of the last 
valid disease assessment before initiation of a further anti-myeloma 
treatment (if any) or the analysis cut-off date, whichever comes first. 
• 
Time to best response: The same censoring rules as time to first 
response will be used. 
Multiplicity issues: Hypothesis testing of the key secondary efficacy endpoints 
will be performed using a closed test procedure. The hierarchical procedure will 
follow the order of the list of key secondary objectives. 
 
Analysis of safety endpoints: 
Number (%) of patients experiencing TEAEs by primary system organ class 
and preferred term will be summarized by NCI-CTCAE v4.03 grade (all grades 
and Grade ≥3) for the safety population. The same summaries will be prepared 
for treatment-related TEAEs, TEAEs leading to premature/definitive 
discontinuation, TEAEs leading to dose modification, serious TEAEs, and 
TEAEs with fatal outcome. For patients with multiple occurrences of the same 
AE within treatment period, the worst grade will be used. 
Hematology and biochemistry results will be graded according to NCI-CTCAE 
v4.03, when applicable. Number (%) of patients with laboratory abnormalities 
(ie, all grades and by grade) using the worst grade during the treatment period 
will be provided for the safety population. 
Analysis of HRQL endpoints: 
Compliance rates (%) for completion of the EORTC QLQ-C30, QLQ-MY20, and 
EQ-5D-5L at each time point will be calculated via number of received 
assessments divided by number of expected assessments. 
Changes in health state utility (EQ-5D-5L) values and health status between 
treatment arms will be assessed by analyzing change scores from Day 1 of 
each cycle to EOT and 90 days after last study treatment administration. 
Interim analysis: 
An interim analysis for efficacy assessment of PFS is planned when 65% of the 
159 PFS events have been observed. An O’Brien and Fleming α-spending 
function will be used to obtain the nominal significance levels for the interim and 
final analyses of survival. The 1-sided nominal significance level to terminate 
the study for efficacy at 65% information fraction (103 PFS events) is 0.005 
(corresponding to a hazard ratio [HR] of 0.6). The 1-sided nominal significance 
level to declare superiority of IKd at the final analysis (159 events) is 
0.023 (corresponding to a HR of 0.725). For key secondary efficacy endpoints, 
the significance levels for the interim and final analyses will be determined 
using alpha-spending function specific to each endpoint except if the 
information fraction is 100% at the interim analysis of PFS (ie, information on 
secondary endpoints available for every patient).  


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Planned PFS and OS cut-off dates: 
Estimated cut-off dates will be approximately 24 months and 36 months after 
first patient in (FPI) for the interim PFS analysis and for the final PFS analysis, 
respectively. The cut-off date for analysis of OS will be 3 years after the primary 
PFS analysis cut-off date. The primary PFS analysis corresponds either to the 
positive interim PFS analysis or the final PFS analysis. 
DURATION OF STUDY PERIOD 
(per patient)  
The duration of the study for a patient will include a period for screening of up to 
3 weeks. The cycle duration is 28 days. 
Patients will be treated until disease progression, unacceptable AE, or patient 
decision to stop the study treatment. 
After study treatment discontinuation, patients will return to the study site 30 
days after the last dose of study treatment or before further anti myeloma 
therapy whichever comes first for EOT assessments, and 90 days after the last 
dose of study treatment for HRQL questionnaires.  
Patients who discontinue the study treatment due to PD will be followed every 
3 months (12 weeks) for HRQL at first FU visit (90 days after last study 
treatment), further anti-myeloma therapies, second primary malignancies, PFS2 
and survival until death or the implementation of amended protocol #10, 
whichever comes first. Patients who discontinue the study treatment prior to 
documentation of PD will be followed-up every 4 weeks until disease 
progression (even for patients who would initiate further anti-myeloma therapy 
without PD) and HRQL 90 days after last study treatment, and then after 
confirmation of disease progression, every 3 months (12 weeks) for further anti-
myeloma therapies, second primary malignancies, PFS2 and survival, until 
death or the implementation of amended protocol #10, whichever comes first. 
For all alive patients in follow-up at the implementation of amended protocol 
#10, survival status will be collected twice a year until death, or OS analysis 
cut-off date, whichever comes first.  
If a patient is still on treatment at the implementation of amended protocol #10 
or OS analysis cut-off date and benefitting from the study treatment, the patient 
can continue the study treatment until disease progression, unacceptable AEs, 
patient wish to discontinue further study treatment, or any other reason. 
 


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1 
FLOW CHARTS  
The sponsor collects only those data that are strictly relevant and necessary in view of the objectives of the research. 
1.1 
GRAPHICAL STUDY DESIGN  
 


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1.2 
STUDY FLOW CHART  
 
Evaluationa 
Screening/ 
Baseline 
Cycle 1c 
Subsequent Cyclesc 
End of Treatment 
(EOT) 
 Follow-up Period 
Day -21  
to 1 
D1, 
D2 
D8, 
D9 
D15, 
D16 
D22, 
D23 
D1, 
D2 
D8, 
D9 
D15, 
D16 
D22, 
D23 
30 days after last 
study treatment 
administrationcc 
Every 3 months after 
last study treatment 
administrationdd 
Informed Consenta, Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
Randomizationb 
X 
 
 
 
 
 
 
 
 
 
 
Demography, Medical/Surgical Historyd 
X 
 
 
 
 
 
 
 
 
 
 
Prior anti-myeloma treatment and Myeloma 
historye 
X 
 
 
 
 
 
 
 
 
 
 
Physical examinationf 
X 
X 
X 
X 
X 
X 
 
 
 
X 
 
Vital signsg 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Cardiac Ultrasonographyh 
X 
 
 
 
 
 
 
 
 
 
 
12-Lead ECGh 
X 
Xh 
 
 
 
X 
 
 
 
X 
 
ECOG PS 
X 
X 
 
 
 
X 
 
 
 
X 
 
LOCAL LAB 
Assessments 
 
Pregnancy testi 
X 
Xi 
 
 
 
X  
 
 
 
X 
Xi 
Hematologyj 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
Blood chemistryk 
X 
Xk 
Xk 
Xk 
Xk 
Xk 
Xk 
Xk 
 
X 
 
Complete blood phenotyping 
(IKd  arm only)l 
X 
 
 
 
 
Xl 
 
 
 
 
 
Coagulationm 
X 
As clinically indicated 
As clinically indicated 
 
Urinalysisn 
X 
As clinically indicated 
As clinically indicated 
 
Serum β2-microglobulino 
X 
 
 
 
 
 
 
 
 
 
 
Hepatitis B virus serology 
 
Once at any time if HBV status unknown before treatment 
started and to be repeated if clinically indicated  
(see Section 8.2.7) 
 
 


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Evaluationa 
Screening/ 
Baseline 
Cycle 1c 
Subsequent Cyclesc 
End of Treatment 
(EOT) 
 Follow-up Period 
Day -21  
to 1 
D1, 
D2 
D8, 
D9 
D15, 
D16 
D22, 
D23 
D1, 
D2 
D8, 
D9 
D15, 
D16 
D22, 
D23 
30 days after last 
study treatment 
administrationcc 
Every 3 months after 
last study treatment 
administrationdd 
CENTRAL LAB  
Assessmentsp 
 
IKd arm only: 
 PKq 
 
See PK flow chart Section 1.3 
 
 
ADAr 
 
X 
 
 
 
X 
 
 
 
 
 
Exploratory (both arms): 
Immune genetic 
determinants (blood)t 
 
X 
 
 
 
 
 
 
 
 
 
Disease assessment labs:  
Serum M proteinu 
Immunoelectrophoresis and 
Immunofixation (IF) 
X 
X 
 
 
 
X 
 
 
 
X 
If EOT without PD disease 
assessment as during study 
treatment up to PDdd 
Urine M protein (24-hour 
urine)u 
Immunoelectrophoresis and 
IF  
X 
X 
 
 
 
X 
 
 
 
X 
If EOT without PD disease 
assessment as during study 
treatment up to PDdd 
Serum Free light chainsu 
X 
X 
 
 
 
X 
 
 
 
X 
If EOT without PD disease 
assessment as during study 
treatment up to PDdd 
Immunoglobulins: IgG, IgA, 
IgM, IgD, IgEu 
X 
X 
 
 
 
X 
 
 
 
X 
If EOT without PD disease 
assessment as during study 
treatment up to PDdd 
 


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Evaluationa 
Screening/ 
Baseline 
Cycle 1c 
Subsequent Cyclesc 
End of Treatment 
(EOT) 
 Follow-up Period 
Day -21  
to 1 
D1, 
D2 
D8, 
D9 
D15, 
D16 
D22, 
D23 
D1, 
D2 
D8, 
D9 
D15, 
D16 
D22, 
D23 
30 days after last 
study treatment 
administrationcc 
Every 3 months after 
last study treatment 
administrationdd 
Other Disease assessments  
Bone Marrow for disease assessments:  
FISH (aspirate)s  
X 
 
 
 
MRD assessment (aspirate)s 
X 
In case of VGPR or better 
As clinically indicated 
 
Bone disease involvement (plasma cell infiltration) 
X 
In case of VGPR or better and as clinically indicated 
As clinically indicated 
 
Radiological disease assessment: 
Skeletal surveyv 
X 
Once a year and if clinically indicated 
As clinically indicated 
 
Extramedullary disease (plasmacytoma) (CT scan 
or MRI)v 
X 
 If present at baseline every 12 weeks, and if clinically 
indicatedv 
As clinically indicated  
If EOT without PD disease 
assessment as during study 
treatment up to PDdd 
Electronic 
HRQLw  
QLQ-C30 
 
X 
 
 
 
X 
 
 
 
X 
X (90 days only) 
QLQ-MY20 
 
X 
 
 
 
X 
 
 
 
X 
X (90 days only) 
EQ-5D-5L 
 
X 
 
 
 
X 
 
 
 
X 
X (90 days only) 
Study Treatmentsx: 
 
 
 
 
 
 
 
 
 
 
 
Isatuximab (IKd arm only)  
 
D1, D8, D15, D22 
D1, D15 
 
 
Carfilzomib  
 
D1, D2, D8, D9, D15, D16 
 
 
Dexamethasone (IV/PO)y 
 
D1, D2, D8, D9, D15, D16, D22, D23 
 
 
AE Assessmentz 
X 
Continuously throughout study period 
X 
X (related AEs, all SAEs) 
Prior/Concomitant Medicationaa 
X 
Continuously throughout study period 
X 
 
Further anti-myeloma therapybb 
 
 
 
 
 
 
 
 
 
 
X 
Survival status 
 
 
X 


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a Evaluation: Assessments to be performed prior to study treatment administration and prior to any premedication arm unless otherwise indicated. Inform consent should be signed before any study specific 
procedures. It can be signed more than 21 days prior to randomization. Screening time indicates in which time frame exams used to support eligibility have to be done prior to randomization. 
b Randomization: To take place once the consented patient has completed all the necessary screening procedures and is deemed eligible (based on myeloma-specific results from the central laboratory [see 
footnote u]) and hematology/biochemistry local laboratory results) for study entry by the Investigator or designee. All eligible patients must be randomized using Interactive Response Technology (IRT). Every effort 
should be made to start treatment within 3 working days of randomization. 
c Cycle: A cycle duration is 28 days. Day 1 of Cycle 1 refers to the day the patient receives the first study treatment administration. Day 1 of each subsequent cycle corresponds to Day 29 of the previous cycle. The 
time window for Days 8, 9, 15, 16, 22, and 23 is ± 1 day; any delay above this time window or any omission due to AEs will be documented in the electronic case report form (eCRF).  
d Demography: Includes age, gender, and race. Medical/Surgical History, other than MM, includes relevant history of previous/associated pathologies including respiratory function history (smoking status will be 
collected). 
e Prior anti-myeloma treatment and myeloma history: Includes date of initial diagnosis of symptomatic MM, stage of the disease at diagnosis and at study entry, type of disease at diagnosis and at study entry 
(heavy and light chain component), and previous anti-myeloma therapy (transplant if any, drug name, start and stop dates, intent, date of progression, best response, and reason for discontinuation). 
f 
Physical Examination: To be performed at screening (<7 days prior to randomization), prior to study treatment administration on Days 1, 8, 15, and 22 of Cycle 1, and then on Day 1 of each subsequent cycle, 
and at the EOT visit. Consists of examination of major body systems including neurological, digestive, respiratory (signs and symptoms, respiratory rate), hepatic and spleen span, and lymph node examinations, 
plus weight and height (height at baseline only). Only the main diagnoses will be reported in the eCRF as AEs or medical history. Signs and symptoms related to MM ongoing at baseline will be recorded in the 
patient’s medical history and will be reported in the AE page in case they worsen or become serious during study treatment. Laboratory abnormalities at baseline will be recorded in the laboratory pages. 
g Vital Signs: Blood pressure, heart rate, temperature, and respiration rate will be recorded at screening, on Days 1, 2, 8, 9, 15, and 16 of Cycle 1 in both arms, and on Day 22 of Cycle 1 in IKd arm. For each 
subsequent cycle, vital signs are to be measured on Days 1, 2, 8, 9, 15, and 16 in both arms. In addition, in the IKd arm, vital signs are to be taken just before starting infusion, 1 hour after starting infusion, and at 
EOI on Days 1, 8, 15, and 22 of Cycle 1, Days 1 and 15 of each subsequent cycle up to Cycle 4, and as clinically indicated. The final measurements will be performed at the EOT visit in both arms. 
h Cardiac ultrasonography and 12-Lead ECG: Cardiac ultrasonography (MUGA scan or MRI are accepted) to be performed at screening; 12-Lead ECG to be performed at screening and repeated within 1 day 
prior to Cycle 1 Day 1 if screening test >7 days of Day 1 Cycle 1, within 1 day prior each cycle administration, at EOT, and as clinically indicated. 
i 
Pregnancy tests (serum or urine) for WOCBP to be performed prior to randomization (should be within 7 days prior to first study treatment administration), within 1 day before each cycle initiation, at EOT visit, 
and monthly during follow-up (up to 3 months in the Kd arm and up to 5 months in the Ikd arm). It can be performed at home during the follow-up period.. 
j 
Hematology: To be performed at screening and repeated within 1 day prior to Cycle 1 Day 1 if screening test >7 days of Day 1 Cycle 1, on Days 8, 15, and 22 of Cycle 1, on Days 1 and 15 of every subsequent 
cycle, at the EOT visit, and as clinically indicated. Hematology includes hemoglobin, hematocrit, red blood cells (RBC), white blood cells (WBC) with differential and platelet count. In the event of Grade 4 
neutropenia, ANC is assessed every 2 to 3 days until ANC ≥0.5 x 109/L and at least weekly thereafter until ANC ≥1.0 x 109/L (test to be done prior to study treatment administration). Hematological abnormalities 
will be recorded as AEs only if they are serious or lead to study treatment modification or discontinuation. 
k Blood Chemistry: Full blood biochemistry (see below) to be performed at screening and repeated within 1 day prior to Cycle 1 Day 1 if screening test >7 days of Day 1 Cycle 1. Full biochemistry will be performed 
prior to study treatment administration on Days 1, 8, 15, and 22 at Cycle 1, and on Day 1 for subsequent cycles. Restricted biochemistry (see below) will be performed on Days 2, 9, and 16 at Cycle 1, and then on 
Days 8 and 15 at Cycle 2, and then on Day 15 for subsequent cycles. Full biochemistry will be performed at the EOT visit and as clinically indicated throughout the study treatment.  
Full biochemistry/blood chemistry includes AST, ALT, bilirubin (total and direct), alkaline phosphatase, LDH, sodium, potassium, chloride, bicarbonate or carbon dioxide (venous) (if bicarbonate or carbon dioxide 
are assessed only on arterial blood at site level, to be done only if clinically indicated), calcium, corrected serum calcium, magnesium, phosphate, uric acid, serum creatinine and estimated creatinine clearance 
(MDRD Formula), urea or blood urea nitrogen (BUN), fasting glucose (according to site guidelines), albumin, and total protein. Biochemistry abnormalities will be recorded as AEs only if they are serious or lead to 
study treatment modification or discontinuation. Restricted biochemistry includes sodium, potassium, chloride, bicarbonate/carbon dioxide, urea or BUN, serum creatinine, and estimated creatinine clearance 
(MDRD Formula). 
l 
Blood typing (A, B, O, and Rh), complete blood phenotyping (C,c; E,e; Kell. Kidd; Duffy; S,s is recommended, if not available follow site’s standard), and antibody screening (Indirect Coombs Test, Indirect 
Antiglobulin Test) in IKd arm only to be drawn after randomization and prior first study treatment administration if not already available. The blood type card will be kept by the patient with the study card. 
Blood transfusions are to be recorded in the eCRF. The blood bank needs to be informed that the patient is receiving a treatment with an anti-CD38 and a potential interference with the Coombs test is possible. 
Indirect Coombs test will be repeated once after study treatment initiation (on Day 1 at Cycle 2 or on Day 1 of a later cycle if not done at Cycle 2). 
m Coagulation: To be performed at screening and then as clinically indicated. Coagulation includes prothrombin time or international normalized ratio, and activated partial thromboplastin time. 
n Urinalysis: To be performed at screening and as clinically indicated. Quantitative or semi quantitative (according to site practice and if semi-quantitative method can provide with an absolute numeric value of the 
parameters) urinalysis (ie, RBCs, protein, glucose, pH, ketones, bilirubin, and leucocytes) at baseline and qualitative (dipstick; ie, blood, protein, glucose, pH, ketones, bilirubin, and leucocytes). 
o Serum β2-microglobulin: To be performed at screening. 


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p Central Labs: Refer to laboratory manual for sample collection and shipping information. 
q Pharmacokinetics (PK): Refer to Pharmacokinetics/Pharmacodynamics Flow Chart in Section 1.3. 
r 
ADA (IKd arm only): To be performed on Day 1 of every cycle prior to each isatuximab administration up to Cycle 10. If the test is positive or inconclusive at Cycle 10, additional ADA samples will be done 
3 months later. If isatuximab is stopped prior to carfilzomib and dexamethasone administration, ADA will be tested 3 months later. 
s Bone marrow aspirate:  
• 
At screening: Bone marrow aspirate (BMA) will be collected for FISH (including, but may not be limited to, del(17p), t(4:14), t(14:16)), and MRD analyses in central laboratory. Central laboratory samples for FISH 
will be collected and analyzed for all patients, R-ISS used as stratification factor will be assessed with FISH central laboratory results. Central laboratory samples for MRD will be collected for all patients but will 
be analyzed only for patients who will reach VGPR or better. Bone marrow aspirate or core biopsy (as clinically indicated) will be collected for bone marrow involvement assessment (local laboratory). 
In case of randomization would be delayed due to unplanned event after BMA was done, BMA will not need to be done again if BMA remains within 8 weeks prior to randomization,  
• 
During study treatment:  
For plasma cell infiltration assessment (local laboratory) in case of VGPR and/or to confirm CR or as clinically indicated. In case of VGPR, plasma cell infiltration assessment is mandatory for patients in IKd arm 
with residual serum M protein of Ig G ≤0.5 g/dL and/or residual kappa IF positivity in urine, due to potential interference between isatuximab and M protein. In case of CR on M protein, plasma cell infiltration 
assessment is mandatory in IKd arm and in Kd arm, unless a previous assessment was made within 3 months and showed plasma cells ≤5 %.  
Bone marrow biopsy can be done for stringent CR (sCR) assessment as per investigator decision. 
For MRD assessment in case of VGPR or better (central laboratory), and if MRD positive to be repeated 3 months later for late negativity (one additional sample can be collected if patient remains MRD positive 
at the second assessment). No more than 3 post-baseline samples are to be obtained unless a patient becomes CR after a third BM sample MRD positive performed during VGPR. In this case no more than 3 
additional BM samples will be collected. Therefore a maximum of 6 BMA could be performed by patient (no more than 3 per category of response). However, because BMA is invasive procedure, the following 
guidance is given in the purpose to limit as much as possible the number of BMA. 
For patients with CR without previous documentation of VGPR, first bone marrow for MRD assessment will be collected at time of confirmation of CR (ie, at the second time point showing CR) If patient is 
determined MRD positive, another BM sample will be collected 3 months (3 cycles) later, in order to identify late negativity. A third sample may be collected after another 3 months if the patient remains MRD 
positive and is still being treated. 
For patients with VGPR:  
- 
First bone marrow will be collected when VGPR is confirmed at the second time point or at a later time point as per investigator judgement based on kinetic of M protein decrease and/or if a plateau 
phase is reached (plateau is defined as variation less than 20% over 12 weeks).  
- 
If MRD is positive on first BMA, a second BMA will be collected 3 months later (3 cycles) to identify late negativity.  
- 
In case of MRD is still positive on second BMA made while patient is in VGPR, the timing to perform the third BMA can be postponed until CR achievement.  
- 
In case of the patient becomes CR and patient was MRD positive on the last BMA performed during VGPR, a BMA will be done for MRD assessment at time of confirmation of CR.   
- 
After the first BMA during CR is done and in case patient was MRD positive on this BMA, the additional BMA planned by the protocol can be discussed with the patient.  
t 
Blood sample for immune genetic determinants (such as Fcγ receptor polymorphism): To be performed on Cycle 1 Day 1 prior to study treatment administration (central laboratory).  
u Laboratory evaluation of disease assessment (central laboratory for each planned and any unplanned time point): At screening, all laboratory assessments are to be performed within 21 days prior to 
randomization. Eligibility will be assessed based on central laboratory results. Results for central M protein must be available before the patient may be randomized.  
All laboratory assessments to be performed again prior to first study treatment administration on Cycle 1 Day 1 and response evaluation will be calculated compared to Cycle 1 Day 1 assessments. In the IKd arm 
only, an additional blood sample will be collected at all time-points to evaluate the potential interference of isatuximab in the M protein assessment (central laboratory) up to Cycle 30. After Cycle 30, this sample 
will be collected only for patients who reach at least VGPR at this cycle until disease progression. In case of isatuximab is stopped before progression, sample interference assay will be collected up to 3 months or 
PD, whichever comes first. 
Laboratory findings on Day 1 of every cycle will be used for response assessment, to confirm response, and to confirm disease progression. Efficacy analyses will be performed according to IRC assessment, 
which will use central laboratory data. 
• 
Serum-Protein immunoelectrophoresis (SPEP) and IF: To be performed at screening and again at Cycle 1 Day 1 (-1 day) prior to study treatment administration, then at Day 1 (-1 day) of every subsequent cycle 
prior to study treatment administration, and at the EOT visit.  


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• 
Urine M protein (24-hour urine) immunoelectrophoresis (UPEP) and IF: To be performed at screening, Cycle 1 Day 1, Day 1 of every subsequent cycle prior to study treatment administration, and at the EOT 
visit. If urine M protein is negative at baseline and Cycle 1 Day 1, this assessment is to be repeated every 3 cycles only (Cycle 4, Cycle 7, Cycle 10, etc) to confirm CR on blood labs.  
After Cycle 1 Day 1, IF to be done if UPEP is negative in patients whose disease is evaluable in urine. The 24-hour urine collection should be completed prior new cycle initiation. 
• 
Serum FLCs (quantification and ratio): To be performed at screening, Cycle 1 Day 1, Day 1 of every subsequent cycle, and at EOT. 
• 
Immunoglobulins (IgG, IgA, IgM, IgD, and IgE): To be performed at screening, Cycle 1 Day 1, Day 1 of every subsequent cycle prior to study treatment administration, and at EOT (IgD or E only if the heavy 
chain component of the disease is known to be E or D). 
For patients who discontinue study treatment for reasons other than disease progression, serum M protein, urine M protein, and serum FLCs to be performed monthly (central laboratory) during the follow-up period 
until progression (even for patients who would initiate further anti-myeloma therapy without PD). 
In case of PD diagnosis made on laboratory criteria, this must be confirmed by 2 consecutive measures before to treatment discontinuation. Treatment should continue until confirmation of the PD. 
v Radiological assessment:  
Bone lytic disease assessment: Skeletal survey (including skull, spine, all long bones, pelvis, and chest) or low dose whole body CT scan (see Appendix M) at baseline (within 21 days prior to randomization), once 
a year, and anytime during the study if clinically indicated. 
Extramedullary disease (plasmacytoma) assessment (including bone plasmacytoma):  
• 
If known extramedullary disease at baseline, CT scan or MRI is to be done at baseline, repeated every 12 weeks (± 1 week) until PD (even for patients who would initiate further anti-myeloma therapy without PD), 
and if clinically indicated. 
• 
If suspected extramedullary disease (plasmacytoma) at baseline, CT or MRI is to be done at baseline and if plasmacytoma confirmed on the exam to be repeated every 12 weeks (± 1 week) until PD (even for 
patients who would initiate further anti-myeloma therapy without PD) and if clinically indicated. 
• 
To be done in case of suspicion of progression or if clinically indicated in a patient with no previous positive image for extramedullary disease. 
• 
Note: For bone lesion assessment and extramedullary disease, the same modality (skeletal survey or low-dose whole body CT scan; CT scan or MRI) should be used throughout the study for each individual 
patient when radiological follow-up is needed. All imaging will be sent for central review. Intravenous contrast is recommended if not medically contra-indicated. Patients who have contra-indication to CT scan 
with IV contrast may have MRI exams performed instead. 
w ePRO (EORTC QLQ-C30, QLQ-MY20, and EQ-5D-5L): To be completed by the patient at the center prior to discussing their health/disease status, prior to study treatment administration or other study-related 
procedures on Day 1 of every cycle, at the EOT visit, and 90 days (± 5 days) after last study treatment administration. The time estimated to complete the EORTC QLQ-C30 is approximately 10 to 15 minutes. The 
time estimated to complete the QLQ-MY20 and EQ-5D-5L is approximately 5 to 10 minutes. 
x Study treatments: In both arms, carfilzomib will be given as a 30-minute infusion at a dose of 20 mg/m² Day 1 and Day 2 on Cycle 1 and then escalated to 56 mg/m² on Days 8, 9, 15, and 16 of Cycle 1 and 
Days 1, 2, 8, 9, 15, and 16 for subsequent cycles. The carfilzomib infusion should follow the isatuximab infusion and should begin just after the end of the isatuximab infusion. Dexamethasone will be given at 
20 mg for patients on Days 1, 2, 8, 9, 15, 16, 22, and 23. Patients will be asked to maintain a diary to record the doses of dexamethasone PO to document all oral administration. In addition, in the IKd arm, 
isatuximab will be given at a dose of 10 mg/kg IV on Days 1, 8, 15, and 22 in the first cycle, then Days 1 and 15 in subsequent cycles (premedication will include acetaminophen or paracetamol, ranitidine or 
equivalent, and diphenhydramine or equivalent, in addition to dexamethasone). 
y Dexamethasone: Oral dexamethasone will be recorded in patient diaries when not taken at the site level. 
z AE/SAE assessment: All AEs, including AEs of new onset as well as worsening of baseline signs and symptoms are to be reported from the signing of the informed consent to 30 days following the last 
administration of study treatment. When diagnosis can be done, only main diagnosis (without its signs and symptoms) will be recorded as AE. After the 30-day follow-up, all ongoing related AEs, all ongoing SAEs 
whatever relationship with study treatment, all new related AEs whatever seriousness, and second primary malignancy are to be reported and followed up until resolution or stabilization. Severity will be graded 
according to NCI-CTCAE v4.03. 
aa Prior medications (which are not prior anti-myeloma therapy) administered within 21 days prior to randomization will be collected. Concomitant medications to be collected from randomization to EOT. 
bb Further anti-myeloma treatments will be collected: drug name, start and stop date, best overall response and date of PD.  
cc EOT: EOT visit will be done 30 days after last study treatment administration or before further anti myeloma therapy initiation whichever comes first. 


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dd Follow-up: 
Patients who discontinue study treatment due to PD: Follow-up visit will be done every 3 months from the date of last study treatment administration until death: AEs according to footnote z, ePROs (at EOT and 
90 days [± 5 days] after last study treatment administration), further anti-myeloma therapies (up to OS cut-off date), and survival status will be collected. Every effort will be made to follow all patients. If survival 
follow-up is missed and is not obtained at the time of the scheduled interval, it should be retrieved immediately. For subsequent survival follow-up, the patient follow-up visit should be scheduled at the original 
scheduled survival follow-up interval. If the patient is unable to visit the clinical center, the follow-up may be done via phone from the Investigator or designee to the patient or the patient's caregiver or a family 
member, but this should be exception and any effort should be done to schedule follow-up visit at clinical center. 
Patients who discontinue the study treatment without PD will be followed every month for laboratory disease assessment (central laboratory) and radiological assessment every 12 weeks (± 1 week) in case of 
extramedullary disease (plasmacytoma) at baseline and once a year and as clinically indicated for bone lytic disease assessment (skeletal survey or whole body CT-scan) until confirmation of PD (even for patients 
who would initiate further anti-myeloma therapy without PD), BMA for plasma cell involvement and MRD assessment if appropriate, AEs according to footnote z, further anti-myeloma therapy if any. In addition, 
ePROs will be assessed at EOT and 90 days [± 5 days] after last study treatment administration. After PD, patients will be followed every 3 months as described above. 


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1.3 
PHARMACOKINETIC/PHARMACODYNAMIC FLOW CHART  
1.3.1 Cycle 1: IKd arm only (approximately 12 patients)  
 
  
Cycle 1 
Day within the cycle 
Day 1 
Day 8 
Day 15 
Day 18 
Day 22 
Time relative to isatuximab 
(decimal hours) 
SOI 
EOI 
1h  
post 
EOI 
SOI 
SOI 
EOI 
 
 
 
 
 
 
4.5h  
post EOI 
72h  
post 
EOI 
SOI 
Time windowa 
-10min 
± 10min 
± 10min 
-10min 
 
 
 
 
 
 
 
 
 
± 5h 
-
10min 
Time relative to carfilzomib 
(decimal hours) 
 
 
 
 
 
SOI 
EOI 
5 mins 
post EOI 
15 mins 
post 
EOI 
30 mins 
post 
EOI 
1h  
post EOI 
2 h  
post EOI 
4h  
post EOI 
 
 
Indicative clock time  
8:00 
AM 
12:00 
PM 
1:00 
PM 
8:00 
AM 
8:00 
AM 
12:00 
PM 
12:30 
PM 
12:35 
PM 
12:45 
PM 
1:00 
PM 
1:30 
PM 
2:30 
PM 
4:30 
PM 
12:00 
PM 
8:00 
AM 
Treatment 
Isatuximab (IV infusion)  
X 
 
X 
X 
 
 
 
 
 
 
 
 
X 
Carfilzomib (IV infusion) 
X 
 
X 
 
Pharmacokineticb  
Isatuximab 
RNT (hour) 
0 
4 
5 
0 
0 
4 
8.5 
76 
0 
Sample ID 
P00c 
P01d 
P02e 
P03c 
P04c 
P05d 
P06 
P07 
P08c 
Carfilzomib 
RNT (min/ 
hour) 
 
0 
30 min 
35 min 
45 min 
60 min 
1h 30 
min 
2h 30 
min 
4h 30 
min 
 
Sample ID 
 
P00c 
P01d 
P02 
P03 
P04 
P05 
P06 
P07 
 
Immunogenicity 
 
ADA (anti-drug antibody)f 
AB00c 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a Time window permitted for PK/PDy and immunogenicity sampling. No time window are allowed on Cycle 1 Day 15 for the 12 patients with carfilzomib PK sampling. 
b Refer to laboratory manual for sample collection, processing and shipping. 
c Sample collected just (within 10 mins) and strictly before the start of isatuximab infusion (ie, after administration of the isatuximab premedications). 
d Sample collected just before actual EOI. 
e Sample collected 1 hour after the actual end of infusion. 
f 
The sampling times for ADA detection can be modified based on the updated knowledge of isatuximab on immunogenicity. 


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1.3.2 Subsequent cycles: IKd arm only (approximately 12 patients) up to Cycle 10  
 
 
Cycle 2 
Cycle 3 
Cycle 4 
Up to Cycle 10 
3 months later 
Day within the cycle 
Day 1 
Day 1 
Day 1 
Day 1 
±5 days after last ADA 
positive at cycle 10  
Time relative to isatuximab 
(decimal hours) 
SOI 
EOI 
SOI 
SOI 
SOI 
Time windowa 
-10 mins 
± 10 mins 
-10 mins 
-10 mins 
-10 mins 
 
Indicative clock time 
8:00 AM 
12:00 PM 
8:00 AM 
8:00 AM 
8:00 AM 
8:00 AM 
Treatment 
Isatuximab (IV infusion) 
X 
X 
X 
X 
Carfilzomib (IV infusion) 
X 
Pharmacokineticb 
Isatuximab 
RNT (hour) 
0 
4 
0 
0 
0 
sample ID 
P00c 
P01d 
P00c 
P00c 
P00c 
 
Immunogenicity 
ADA (anti-drug antibody)e 
AB00c 
AB00c 
AB00c, f 
AB00c 
AB F00f 
a Time window permitted for PK/PDy and immunogenicity sampling. 
b Refer to laboratory manual for sample collection, processing and shipping. 
c Sample collected just (within 10 mins) and strictly before the start of isatuximab infusion (ie, after administration of the isatuximab premedications). 
d Sample collected just before actual EOI. 
e The sampling times for ADA detection can be modified based on the updated knowledge of isatuximab on immunogenicity. 
f 
At Cycle 10, if patient is positive or inconclusive for ADA, additional ADA will be collected 3 months later. No further ADA will be sampled, even if this 3-month sample is positive. If isatuximab is stopped prior to 
carfilzomib and dexamethasone, before Cycle 10 and last ADA is positive or inconclusive, ADA will be sampled 3 months later. No further ADA will be sampled, even if this 3-month sample is positive. For patients 
with less than 10 cycles at the cut-off date, both PK and ADA samples collection will be stopped from the cut-off date. If last ADA before cut-off date is positive, one additional sampling time for ADA evaluation 
should be collected 3 months later. No further ADA will be sampled, even if this 3-month sample is positive. 


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1.3.3 All cycles: IKd arm only (approximately 168 patients) up to Cycle 10  
 
Study Phase 
Treatment Phase 
3 months later 
 
Cycle 1 
Cycle 2 
Cycle 
3 
Cycle 4 
Subsequent 
Cycles up to 
10 cycles 
±5 days after last ADA 
positive at cycle 10 
Day 
Day 1 
Day 8 Day 15 Day 22 
Day 1 
Day 1 
Day 1 
Day 1 
Time (decimal hours) 
SOI 
EOI 
EOI + 1h 
SOI 
SOI 
SOI 
SOI 
EOI 
SOI 
SOI 
SOI 
 
Time windowa 
-10min 
± 10min 
± 10min 
-10min 
-10min 
-10min 
-10min 
± 10min 
-10min 
-10min 
-10min 
 
Indicative clock time 
8:00 
AM 
12:00 
PM 
1:00 
PM 
8:00 
AM 
8:00 
AM 
8:00 
AM 
8:00 
AM 
12:00 
AM 
8:00 
AM 
8:00 
AM 
8:00 
AM 
8:00 
AM 
Treatment 
isatuximab (IV infusion) 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Pharmacokineticsb 
isatuximab 
RNT (hour) 
0 
4 
5 
0 
0 
0 
0 
4 
0 
0 
0 
 
Sample ID 
P00c 
P01d 
P02e 
P03c 
P04c 
P05c 
P00c 
P01d 
P00c 
P00c 
P00c 
 
Immunogenicity 
ADA (anti-drug antibody)f 
AB00c 
 
 
 
 
 
AB00c 
 
AB00c 
AB00c 
AB00g 
ABF00h 
a Time window permitted for PK/PDy and immunogenicity sampling. 
b Refer to laboratory manual for sample collection, processing and shipping. 
c Sample collected just (within 10 mins) and strictly before the start of isatuximab infusion (ie, after administration of the isatuximab premedications). 
d Sample collected just before actual EOI. 
e Sample collected 1 hour after the actual end of infusion.  
f 
The sampling times for ADA detection can be modified based on the updated knowledge of isatuximab on immunogenicity. 
g At Cycle 10, if patient is positive or inconclusive for ADA, additional ADA will be sampled 3 months later. 
h At Cycle 10, if patient is positive or inconclusive for ADA, additional ADA will be sampled 3 months later. No further ADA will be sampled, even if this 3-month sample is positive. If isatuximab is stopped prior to 
carfilzomib and dexamethasone before Cycle 10 and last ADA was positive or inconclusive, additional ADA will be sampled 3 months later. No further ADA will be sampled, even if this 3-month sample is positive. 
For patients with less than 10 cycles at the cut-off date, both PK and ADA samples collection will be stopped from the cut-off date. If last ADA before cut-off date is positive, one additional sampling time for ADA 
evaluation should be collected 3 months later. No further ADA will be sampled, even if this 3-month sample is positive. 
  


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2 
TABLE OF CONTENTS  
AMENDED CLINICAL TRIAL PROTOCOL 10 .............................................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 3 
1 
FLOW CHARTS ............................................................................................................................. 20 
1.1 
GRAPHICAL STUDY DESIGN ...................................................................................................... 20 
1.2 
STUDY FLOW CHART .................................................................................................................. 21 
1.3 
PHARMACOKINETIC/PHARMACODYNAMIC FLOW CHART .................................................... 28 
1.3.1 
Cycle 1: IKd arm only (approximately 12 patients) ........................................................................ 28 
1.3.2 
Subsequent cycles: IKd arm only (approximately 12 patients) up to Cycle 10 .............................. 29 
1.3.3 
All cycles: IKd arm only (approximately 168 patients) up to Cycle 10 ........................................... 30 
2 
TABLE OF CONTENTS ................................................................................................................ 31 
2.1 
LIST OF TABLES ........................................................................................................................... 38 
2.2 
LIST OF FIGURES ......................................................................................................................... 38 
3 
LIST OF ABBREVIATIONS .......................................................................................................... 39 
4 
INTRODUCTION AND RATIONALE ............................................................................................. 42 
4.1 
ISATUXIMAB ................................................................................................................................. 42 
4.1.1 
Isatuximab description ................................................................................................................... 42 
4.1.2 
Isatuximab non-clinical and clinical data ........................................................................................ 42 
4.2 
CARFILZOMIB ............................................................................................................................... 43 
4.2.1 
Carfilzomib description ................................................................................................................... 43 
4.2.2 
Carfilzomib clinical data ................................................................................................................. 43 
4.3 
ISATUXIMAB IN COMBINATION WITH CARFILZOMIB ............................................................... 44 
4.4 
STUDY DESIGN RATIONALE ....................................................................................................... 45 
4.4.1 
Choice of standard arm .................................................................................................................. 45 
4.4.2 
Isatuximab dose and regimen ........................................................................................................ 45 
4.5 
BENEFIT RISK ASSESSMENT ..................................................................................................... 46 
4.5.1 
Efficacy ........................................................................................................................................... 46 
4.5.2 
Safety ............................................................................................................................................. 46 
5 
STUDY OBJECTIVES ................................................................................................................... 48 


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5.1 
PRIMARY ....................................................................................................................................... 48 
5.2 
SECONDARY ................................................................................................................................ 48 
5.3 
EXPLORATORY ............................................................................................................................ 48 
6 
STUDY DESIGN ............................................................................................................................ 49 
6.1 
DESCRIPTION OF THE STUDY ................................................................................................... 49 
6.2 
DURATION OF STUDY PARTICIPATION .................................................................................... 50 
6.2.1 
Duration of study participation for each patient ............................................................................. 50 
6.2.2 
Determination of end of clinical trial (all patients) .......................................................................... 51 
6.3 
INTERIM ANALYSIS ...................................................................................................................... 51 
6.4 
STUDY COMMITTEES .................................................................................................................. 51 
7 
SELECTION OF PATIENTS .......................................................................................................... 53 
7.1 
INCLUSION CRITERIA .................................................................................................................. 53 
7.2 
EXCLUSION CRITERIA ................................................................................................................ 53 
8 
STUDY TREATMENTS ................................................................................................................. 56 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCTS ............................................................................. 56 
8.1.1 
Isatuximab ...................................................................................................................................... 56 
8.1.1.1 
Pharmaceutical form ...................................................................................................................... 56 
8.1.1.2 
Dilution method .............................................................................................................................. 56 
8.1.2 
Carfilzomib ..................................................................................................................................... 57 
8.1.2.1 
Dilution method .............................................................................................................................. 57 
8.1.3 
Dexamethasone IV/PO .................................................................................................................. 57 
8.2 
DOSAGE AND SCHEDULE .......................................................................................................... 57 
8.2.1 
Study treatments (IMP) .................................................................................................................. 57 
8.2.2 
Premedication (NIMP): prevention of infusion associated reactions ............................................. 59 
8.2.2.1 
Ranitidine or equivalent ................................................................................................................. 60 
8.2.2.2 
Diphenhydramine or equivalent ..................................................................................................... 60 
8.2.2.3 
Acetaminophen or equivalent ........................................................................................................ 60 
8.2.3 
Carfilzomib hydration ..................................................................................................................... 61 
8.2.4 
Dose modifications ......................................................................................................................... 61 
8.2.4.1 
General rules .................................................................................................................................. 61 
8.2.4.2 
Modification of isatuximab/carfilzomib/dexamethasone dose levels in case of dose 
reduction ........................................................................................................................................ 63 
8.2.4.3 
Dose adjustments in IKd arm ......................................................................................................... 64 
8.2.4.4 
Dose adjustments in Kd arm .......................................................................................................... 69 
8.2.5 
Infusion reactions ........................................................................................................................... 73 


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8.2.6 
Posterior reversible encephalopathy syndrome and progressive multifocal 
leukoencephalopathy ..................................................................................................................... 74 
8.2.7 
Hepatitis B virus infection ............................................................................................................... 75 
8.2.8 
Cardiac failure ................................................................................................................................ 75 
8.2.9 
Tumor Lysis syndrome ................................................................................................................... 76 
8.2.10 
Other adverse drug reactions ........................................................................................................ 76 
8.3 
BLINDING PROCEDURES ............................................................................................................ 77 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP .............................................. 77 
8.5 
INVESTIGATIONAL MEDICINAL PRODUCT PACKAGING AND LABELING ............................. 77 
8.5.1 
Isatuximab ...................................................................................................................................... 77 
8.5.2 
Carfilzomib ..................................................................................................................................... 78 
8.5.3 
Dexamethasone IV/PO .................................................................................................................. 78 
8.6 
STORAGE CONDITIONS AND SHELF LIFE ................................................................................ 78 
8.6.1 
Isatuximab ...................................................................................................................................... 78 
8.6.2 
Carfilzomib ..................................................................................................................................... 78 
8.6.3 
Dexamethasone IV/PO .................................................................................................................. 78 
8.7 
RESPONSIBILITIES ...................................................................................................................... 78 
8.7.1 
Treatment accountability and compliance...................................................................................... 79 
8.7.2 
Return and/or destruction of treatments ........................................................................................ 79 
8.8 
CONCOMITANT MEDICATION ..................................................................................................... 80 
8.8.1 
G-CSF prophylaxis ......................................................................................................................... 80 
8.8.2 
Prohibited concomitant therapy ..................................................................................................... 80 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT .............................................. 81 
9.1 
PRIMARY ENDPOINT ................................................................................................................... 81 
9.2 
SECONDARY ENDPOINTS .......................................................................................................... 82 
9.2.1 
Key secondary efficacy endpoints ................................................................................................. 82 
9.2.2 
Other secondary efficacy endpoints ............................................................................................... 84 
9.2.3 
Safety endpoints ............................................................................................................................ 84 
9.2.4 
Patient-reported outcomes (HRQL/health economic variables/other endpoints) .......................... 84 
9.2.4.1 
EORTC QLQ-C30 .......................................................................................................................... 85 
9.2.4.2 
EORTC QLQ-MY20 ....................................................................................................................... 86 
9.2.4.3 
EQ-5D-5L ....................................................................................................................................... 86 
9.2.5 
Pharmacokinetics ........................................................................................................................... 87 
9.2.5.1 
Sampling time ................................................................................................................................ 87 
9.2.5.2 
Pharmacokinetics handling procedure ........................................................................................... 87 


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9.2.5.3 
Bioanalytical method ...................................................................................................................... 87 
9.2.5.4 
Pharmacokinetics parameters ....................................................................................................... 88 
9.2.6 
Immunogenicity .............................................................................................................................. 88 
9.3 
EXPLORATORY ENDPOINTS ...................................................................................................... 90 
9.3.1 
Exploratory biomarker analysis ...................................................................................................... 90 
9.4 
FUTURE USE OF SAMPLES ........................................................................................................ 91 
9.5 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 91 
10 
STUDY PROCEDURES ................................................................................................................ 92 
10.1 
VISIT SCHEDULE .......................................................................................................................... 92 
10.1.1 
Screening/baseline......................................................................................................................... 92 
10.1.2 
Randomization ............................................................................................................................... 94 
10.1.3 
Treatment period ............................................................................................................................ 94 
10.1.3.1 Cycle 1 (Days 1-2, Days 8-9, Days 15-16, and Days 22-23) ......................................................... 94 
10.1.3.2 Subsequent cycles (Days 1-2, Days 8-9, Days 15-16, and Days 22-23) ...................................... 96 
10.1.4 
End of treatment ............................................................................................................................. 99 
10.1.5 
Post study treatment follow-up ..................................................................................................... 101 
10.1.6 
After Implementation of Amended Protocol #10 .......................................................................... 104 
10.1.7 
Post OS analysis cut-off date ....................................................................................................... 104 
10.2 
DEFINITION OF SOURCE DATA ................................................................................................ 105 
10.3 
HANDLING OF PATIENT PERMANENT TREATMENT DISCONTINUATION AND OF 
PATIENT STUDY DISCONTINUATION ...................................................................................... 105 
10.3.1 
Permanent treatment discontinuation with investigational medicinal product(s) ......................... 105 
10.3.2 
List of criteria for permanent treatment discontinuation ............................................................... 106 
10.3.3 
Handling of patients after permanent treatment discontinuation ................................................. 106 
10.3.4 
Procedure and consequence for patient withdrawal from study .................................................. 107 
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING ........................ 108 
10.4.1 
Definitions of adverse events ....................................................................................................... 108 
10.4.1.1 Adverse event .............................................................................................................................. 108 
10.4.1.2 Serious adverse event ................................................................................................................. 108 
10.4.1.3 Adverse event of special interest ................................................................................................. 109 
10.4.1.4 Pregnancy .................................................................................................................................... 109 
10.4.1.5 Overdose ...................................................................................................................................... 109 
10.4.2 
General guidelines for reporting adverse events ......................................................................... 110 
10.4.3 
Instructions for reporting serious adverse events ........................................................................ 110 
10.4.4 
Guidelines for reporting adverse events of special interest ......................................................... 111 
10.4.5 
Guidelines for reporting product complaints ................................................................................ 111 


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10.5 
OBLIGATIONS OF THE SPONSOR ........................................................................................... 112 
10.6 
SAFETY INSTRUCTIONS ........................................................................................................... 112 
10.6.1 
Guidelines for the management of potential infusion associated reactions................................. 112 
10.6.2 
Guidelines for the management of tumor lysis syndrome ........................................................... 112 
10.7 
ADVERSE EVENTS MONITORING ............................................................................................ 112 
11 
STATISTICAL CONSIDERATIONS ............................................................................................ 113 
11.1 
DETERMINATION OF SAMPLE SIZE ......................................................................................... 113 
11.2 
DISPOSITION OF PATIENTS ..................................................................................................... 113 
11.3 
ANALYSIS POPULATIONS ......................................................................................................... 114 
11.3.1 
Efficacy populations ..................................................................................................................... 114 
11.3.1.1 Intent-to-treat population .............................................................................................................. 114 
11.3.2 
Safety population ......................................................................................................................... 114 
11.3.3 
Pharmacokinetic population ......................................................................................................... 114 
11.3.4 
ADA population ............................................................................................................................ 114 
11.4 
STATISTICAL METHODS ........................................................................................................... 114 
11.4.1 
Extent of study treatment exposure and compliance ................................................................... 115 
11.4.2 
Analyses of efficacy endpoints ..................................................................................................... 116 
11.4.2.1 Analysis of primary efficacy endpoint........................................................................................... 116 
11.4.2.2 Analyses of secondary efficacy endpoints ................................................................................... 117 
11.4.2.3 Multiplicity considerations ............................................................................................................ 118 
11.4.3 
Analyses of safety data ................................................................................................................ 119 
11.4.3.1 Adverse events ............................................................................................................................ 119 
11.4.3.2 Treatment-emergent adverse events ........................................................................................... 120 
11.4.3.3 Deaths .......................................................................................................................................... 121 
11.4.3.4 Other safety evaluation ................................................................................................................ 121 
11.4.4 
Analyses of pharmacokinetic and pharmacodynamic variables .................................................. 122 
11.4.4.1 Analysis of pharmacokinetic variables ......................................................................................... 122 
11.4.5 
Analysis of immunogenicity variables .......................................................................................... 123 
11.4.6 
Analyses of biomarker variables .................................................................................................. 123 
11.4.7 
Analyses of PRO (health-related quality of life/health economics variables) .............................. 123 
11.5 
INTERIM ANALYSIS .................................................................................................................... 124 
12 
ETHICAL AND REGULATORY CONSIDERATIONS ................................................................. 125 
12.1 
ETHICAL AND REGULATORY STANDARDS ............................................................................ 125 
12.2 
INFORMED CONSENT ............................................................................................................... 126 


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12.3 
HEALTH AUTHORITIES AND INSTITUTIONAL REVIEW BOARD/INDEPENDENT 
ETHICS COMMITTEE (IRB/IEC) ................................................................................................. 126 
13 
STUDY MONITORING................................................................................................................. 128 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S) ..................................................................... 128 
13.2 
RESPONSIBILITIES OF THE SPONSOR ................................................................................... 128 
13.3 
SOURCE DOCUMENT REQUIREMENTS .................................................................................. 129 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST .................................................................................................................................... 129 
13.5 
USE OF COMPUTERIZED SYSTEMS ........................................................................................ 129 
14 
ADDITIONAL REQUIREMENTS ................................................................................................. 130 
14.1 
CURRICULUM VITAE.................................................................................................................. 130 
14.2 
RECORD RETENTION IN STUDY SITES .................................................................................. 130 
14.3 
CONFIDENTIALITY ..................................................................................................................... 130 
14.4 
PROPERTY RIGHTS ................................................................................................................... 131 
14.5 
DATA PROTECTION ................................................................................................................... 131 
14.6 
INSURANCE COMPENSATION .................................................................................................. 132 
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES ............................... 132 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE .......................................................................................................................................... 133 
14.8.1 
By the Sponsor ............................................................................................................................. 133 
14.8.2 
By the Investigator ....................................................................................................................... 133 
14.9 
CLINICAL TRIAL RESULTS ........................................................................................................ 133 
14.10 
PUBLICATIONS AND COMMUNICATIONS ............................................................................... 133 
15 
CLINICAL TRIAL PROTOCOL AMENDMENTS ........................................................................ 135 
16 
APPENDICES .............................................................................................................................. 136 
APPENDIX A 
REVISED INTERNATIONAL STAGING SYSTEM ............................................................ 136 
APPENDIX B 
MODIFICATION OF DIET IN RENAL DISEASE (MDRD) EQUATION ............................. 137 
APPENDIX C 
CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION ............................................................................................................................ 138 


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APPENDIX D 
EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE STATUS 
SCALE ......................................................................................................................................... 141 
APPENDIX E 
NATIONAL CANCER INSTITUTE COMMON TERMINOLOGY CRITERIA FOR 
ADVERSE EVENTS..................................................................................................................... 142 
APPENDIX F 
INTERNATIONAL MYELOMA WORKING GROUP RESPONSE CRITERIA ................... 143 
APPENDIX G 
GUIDELINES FOR THE DETERMINATION OF THE NUMBER OF PRIOR LINES 
OF THERAPY IN MULTIPLE MYELOMA .................................................................................... 147 
APPENDIX H 
DEFINITION OF RELAPSED AND REFRACTORY MYELOMA ...................................... 148 
APPENDIX I 
EORTC-QLQ-C30 SCALES, ITEMS, AND CLINICALLY IMPORTANT 
DIFFERENCES ............................................................................................................................ 149 
APPENDIX J 
QLQ-MY20 SCALES, ITEMS, AND CLINICALLY IMPORTANT DIFFERENCES ............. 152 
APPENDIX K 
EQ-5D-5L SCALES, ITEMS, AND CLINICALLY IMPORTANT DIFFERENCES .............. 155 
APPENDIX L 
CD38 BLOOD TEST INTERFERENCE GUIDELINE AABB2016 ...................................... 158 
APPENDIX M 
LOW DOSE WHOLE BODY CT SCAN ............................................................................ 162 
APPENDIX N 
CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL EMERGENCY 
THAT IS DECLARED BY A GOVERNMENTAL AGENCY .......................................................... 163 
APPENDIX O 
PROTOCOL AMENDMENT HISTORY ............................................................................. 165 
17 
BIBLIOGRAPHIC REFERENCES ............................................................................................... 178 
 


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2.1 
LIST OF TABLES  
Table 1 - Dose levels for carfilzomib dose reduction .................................................................................... 63 
Table 2 - Dose levels for dexamethasone dose reduction ............................................................................ 63 
Table 3 - Guidelines for dose adjustments for hematological toxicities - 
isatuximab/carfilzomib/dexamethasone combination .................................................................................... 64 
Table 4 - Guidelines for dose adjustments for non-hematologic adverse events –  
isatuximab/carfilzomib/dexamethasone combination .................................................................................... 65 
Table 5 - Guidelines for dose adjustments for hematologic toxicities –  carfilzomib/dexamethasone 
combination ................................................................................................................................................... 69 
Table 6 - Guidelines for dose adjustments for non-hematologic adverse events –  
carfilzomib/dexamethasone combination ...................................................................................................... 70 
Table 7 - Management of infusion associated reactions ............................................................................... 74 
Table 8 - Management of tumor lysis syndrome ........................................................................................... 76 
Table 9 - Bioanalytical methods for isatuximab and carfilzomib pharmacokinetic analysis .......................... 87 
Table 10 - List of pharmacokinetic parameters and definitions ..................................................................... 88 
Table 11 - Bioanalytical method for isatuximab immune response assessment .......................................... 89 
Table 12 - Summary of adverse event reporting instructions...................................................................... 111 
 
2.2 
LIST OF FIGURES  
Figure 1 - Study design ................................................................................................................................. 49 
 


 
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3 
LIST OF ABBREVIATIONS  
 
ADA: 
anti-drug antibody 
AEs: 
adverse event 
AESI: 
adverse event of special interest 
AIDS: 
acquired immunodeficiency syndrome 
ALT: 
alanine aminotransferase 
ANC: 
absolute neutrophil count 
anti-HBc: 
Hepatitis B core antibody 
anti-HBs: 
Hepatitis B surface antibody 
ASCT: 
autologous stem cell transplantation 
AST: 
aspartate aminotransferase 
BM: 
bone marrow 
BSA: 
body surface area 
BUN: 
blood urea nitrogen 
CHF: 
congestive heart failure 
CI: 
confidence interval(s) 
CID: 
clinically important difference 
CR: 
complete response 
CT: 
computed tomography 
CV: 
coefficient of variation 
DL: 
dose level(s) 
DMC: 
data monitoring committee 
DOR: 
duration of response 
DRF: 
discrepancy resolution form 
ECG: 
electrocardiogram 
ECOG: 
eastern cooperative oncology group 
eCRF: 
electronic case report form 
ELISA: 
enzyme-linked immunosorbent assay 
EOI: 
end of infusion 
EORTC: 
European Organisation for Research and Treatment of Cancer 
EOT: 
end of treatment 
ePROs: 
electronic patient-reported outcome(s) 
EQ-5D-5L: 
european quality of life group questionnaire with 5 dimensions and 5 levels per 
dimension 
FISH: 
fluorescence in situ hybridization 
FLC: 
free light chain 
FSH: 
follicle stimulating hormone 
GCP: 
good clinical practice 
G-CSF: 
granulocyte colony stimulating factor 
GHS: 
Global Health Status 
GMP: 
Good Manufacturing Practice 
HBsAg: 
Hepatitis B surface antigen 


 
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HBV: 
Hepatitis B Virus 
HCV: 
Hepatitis C 
HLGT: 
high-level group term 
HLT: 
high-level term 
HR: 
hazard ratio 
HRQL: 
health-related quality of life 
HRT: 
hormonal replacement therapy 
IAR: 
infusion associated reaction 
ICH: 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC: 
independent ethics committee 
IF: 
immunofixation  
IKd: 
isatuximab carfilzomib dexamethasone 
IMWG: 
International Myeloma Working Group 
IRB: 
institutional review board 
IRC: 
Independent Response Committee 
IRT: 
Interactive Response Technology 
ITT: 
intent-to-treat 
IUD: 
intrauterine device 
IUS: 
intrauterine hormone-releasing system 
IV: 
intravenous(ly) 
Kd: 
carfilzomib dexamethasone 
KRd: 
carfilzomib lenalidomide dexamethasone 
LC-MS/MS: 
liquid chromatography with tandem mass spectrometry 
LDH: 
lactate dehydrogenase 
mAb: 
monoclonal antibody 
max: 
maximum 
MDRD: 
modification of diet in renal disease 
min: 
minimum 
MM: 
multiple myeloma 
MR: 
minimal response 
MRD: 
minimal residual disease 
MRI: 
magnetic resonance imaging 
MUGA: 
multigated acquisition 
NCI-CTCAE: 
National Cancer Institute Common Terminology for Adverse Events 
ORR: 
overall response rate 
OS: 
overall survival 
PCSA: 
potentially clinically significant abnormalities 
PD: 
progressive disease 
PDy: 
pharmacodynamic(s) 
PFS: 
progression free survival 
PFS2: 
time from the date of randomization to the date of second PD or death from any 
cause, whichever happens first 
PK: 
pharmacokinetic(s) 
PML: 
progressive multifocal leukoencephalopathy 
PO: 
oral(ly) 


 
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PR: 
partial response 
PRES: 
posterior reversible encephalopathy syndrome 
PS: 
performance status 
PT: 
preferred term 
QLQ-C30: 
quality of life questionnaire with 30 questions 
QLQ-MY20: 
EORTC myeloma module with 20 items 
RBC: 
red blood cell(s) 
Rd: 
lenalidomide dexamethasone 
RDI: 
relative dose intensity 
R-ISS: 
Revised International Staging System 
RNA: 
ribonucleic  acid 
RNT: 
relative normal time 
RRMM: 
relapsed refractory multiple myeloma 
SAE: 
serious adverse event 
SAP: 
statistical analysis plan 
sCR: 
stringent complete response 
SCT: 
stem cell transplantation 
SD: 
stable disease 
SEM: 
standard error of the mean 
SOC: 
system organ class 
SOI: 
start of infusion 
SPD: 
sum of the products of the maximal perpendicular diameters of measured lesions 
SPEP: 
serum immunoelectrophoresis 
TBD: 
to be determined 
TEAEs: 
treatment-emergent adverse event 
TLS: 
tumor lysis syndrome 
TTP: 
time to progression 
ULN: 
upper limit of normal 
UPEP: 
urine immunoelectrophoresis 
US: 
United States 
VAS: 
visual analog scale 
Vd: 
bortezomib dexamethasone 
VGPR: 
very good partial response 
WBC: 
white blood cell(s) 
WOCBP: 
woman/women of childbearing potential 
 


 
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4 
INTRODUCTION AND RATIONALE  
Multiple myeloma (MM), with 114,251 new cases per year, is the third most frequent 
hematological malignancy worldwide, after leukemia and non-Hodgkin lymphoma (1). 
The treatment of MM has improved remarkably over the last 2 decades with the development and 
introduction of numerous novel agents leading to more effective treatments, including 
3 generations of immunomodulator agents (thalidomide, lenalidomide, pomalidomide), 
2 generations proteasome inhibitor (bortezomib, then carfilzomib and ixazomib), and the most 
recent one, the first anti-CD38 antibody (daratumumab). These novel agents improved 
significantly overall survival (OS) of MM patients with a median OS improving from 3 to 
6 years (2); however, MM remains a fatal disease in majority of cases and the development of 
new therapeutic strategies with this evolving armamentarium and new drugs are still needed. 
Front line strategy is well defined with treatment sequence including induction plus or minus 
maintenance (with/without consolidation), depending on response induced by each regimen. For 
younger and fit patients, autologous stem cell transplantation (ASCT) is part of the front line 
strategy. For patients who are not eligible for high-dose therapy and ASCT, conventional 
treatments with immunomodulator agents, proteasome inhibitors, and other agents will be utilized. 
However, and whatever the front line treatment, the vast majority of the patients will progress or 
relapse and will need further lines of therapies. Drugs used in front line include more and more 
often thalidomide, bortezomib, and/or lenalidomide and new therapeutic options are to be 
developed for further lines.  
4.1 
ISATUXIMAB  
4.1.1 Isatuximab description  
CD38 (see Appendix L) is the most strongly and uniformly expressed antigen identified on the 
malignant clonal populations of myeloma cells compared with its pattern of expression on normal 
cells. Therefore, this antigen may be a useful target for the in vivo depletion of tumor cells while 
sparing normal cells (3). 
Isatuximab (SAR650984) is a naked chimeric monoclonal antibody (mAb) that binds selectively 
to a unique epitope on the human surface antigen CD38. Isatuximab kills tumor cells via multiple 
biological mechanisms, antibody-dependent cellular-mediated cytotoxicity, 
complement-dependent cytotoxicity, direct induction of apoptosis (pro-apoptosis) without 
crosslinking, and inhibition of CD38 enzymatic activity. 
4.1.2 Isatuximab non-clinical and clinical data  
For preclinical and clinical data of isatuximab in single agent and in combination with proteasome 
inhibitors (bortezomib and carfilzomib), please refer to the Investigator’s Brochure. 


 
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4.2 
CARFILZOMIB  
4.2.1 Carfilzomib description  
Carfilzomib is a tetrapeptide epoxyketone proteasome inhibitor that irreversibly binds to the 
N-terminal threonine-containing active sites of the 20S proteasome, the proteolytic core particle 
within the 26S proteasome. Carfilzomib had antiproliferative and proapoptotic activities in vitro 
in solid and hematologic tumor cells. In animals, carfilzomib inhibited proteasome activity in 
blood and tissue and delayed tumor growth in models of MM, hematologic, and solid tumors. 
Carfilzomib is structurally and mechanistically different from bortezomib. It has improved 
specificity for the proteasome and has less off-target activity when measured against a broad panel 
of proteases including metallo, aspartyl, and serine proteases compared to bortezomib. Thus, the 
selectivity of carfilzomib may be responsible for the reductions in myelosuppression and 
neuropathy observed in preclinical studies comparing carfilzomib with bortezomib (4). In animal 
models, carfilzomib has been administered intravenously (IV) for 5 consecutive days with 
excellent tolerability and prolonged proteasome inhibition (5). In contrast, uninterrupted daily 
dosing of boronated proteasome inhibitors in animal models demonstrated substantial morbidity 
and mortality (6). In addition, following brief exposure, carfilzomib was more cytotoxic than 
bortezomib, regardless of cell type, in multiple tumor cell lines (5). Carfilzomib was able to 
overcome acquired drug resistance in human MM cell lines. 
4.2.2 Carfilzomib clinical data  
Carfilzomib was first approved in the United States (US) in 2012 based on response rate in 
monotherapy reported in a single-arm multicenter study conducted in patients with at least 2 prior 
lines, having responded to at least 1 prior line and being refractory to the most recent therapy (7). 
Patients received carfilzomib 20 mg/m2 at each dose in Cycle 1, and 27 mg/m2 in subsequent 
cycles. Dexamethasone 4 mg orally (PO) or IV was administered prior to carfilzomib doses in the 
first and second cycles. A total of 266 patients were enrolled. The overall response rate (ORR) as 
determined by the Independent Response Committee (IRC) assessment using International 
Myeloma Working Group (IMWG) criteria was 23.7% (95% confidence interval [CI]: 18.7 to 
29.4) (N = 257 evaluable patients). The median duration of response was 7.8 months  
(95% CI: 5.6 to 9.2). Common adverse events (AEs) were fatigue (49%), anemia (46%), 
nausea (45%), and thrombocytopenia (39%). Thirty-three patients (12.4%) experienced peripheral 
neuropathy, primarily Grades 1 or 2. Thirty-three patients (12.4%) withdrew because of an AE.  
Carfilzomib has been further approved in combination with lenalidomide and dexamethasone in 
relapsed refractory multiple myeloma (RRMM; see Appendix H) patients with 1 to 3 prior lines 
(see Appendix G), based on the result of a study in which 792 patients were randomized 1:1 to 
receive carfilzomib biweekly 20 mg/m2 on Days 1 and 2, and then 27 mg/m2/day plus 
lenalidomide (Revlimid®) 25 mg per day over 21 days and dexamethasone 40 mg on Days 1, 8, 
15, and 22 (KRd) or lenalidomide 25 mg per day over 21 days and dexamethasone 40 mg (Rd) 
(8). Patients were previously pretreated with 1 to 3 lines of therapy. Patients in the KRd arm 
demonstrated improved progression free survival (PFS) compared with those in the Rd arm 
(hazard ratio [HR] = 0.69, with 2-sided p-value = 0.0001) as determined using standard objective 


 
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IMWG/European Society for Blood and Marrow Transplantation response criteria by an IRC. 
The median PFS was 26.3 months (95% CI: 23.3 to 30.5 months) in the KRd arm versus 
17.6 months (95% CI: 15.0 to 20.6 months) in the Rd arm. The results of OS were not 
significantly different at the interim analysis. The most frequent AEs were diarrhea (42.3%), 
fatigue (32.9%), cough, pyrexia and upper respiratory tract infection (28.8% each), 
hypokalemia (27.6%), and muscle spasm (26.5%).  
Clinical data of isatuximab in combination with carfilzomib and dexamethasone (IKd) are detailed 
in next section.  
4.3 
ISATUXIMAB IN COMBINATION WITH CARFILZOMIB  
One Investigator-sponsored Phase Ib study (TCD12795) is currently ongoing in US in patients 
with RRMM (NCT02332850) with the objective to determine the maximum tolerated dose of 
isatuximab when combined with carfilzomib. Three dose levels (DL)/schedules of isatuximab are 
being assessed: 10 mg/kg Q2W (DL1), 10 mg/kg QW/Q2W (DL2), and 20 mg/kg QW/Q2W 
(DL3). Isatuximab is combined to a fixed dose of carfilzomib 20 mg/m2 on Day 1 and Day 2 and 
then 27 mg/m2 on Days 8, 9, 15, and 16 on Cycle 1; twice weekly, 3 weeks out of 4 from Cycle 2 
to 8 and twice every 2 weeks after Cycle 8. Dexamethasone 20 mg is given as premedication prior 
to first infusion of isatuximab, and then 10 to 20 mg prior to each infusion. In addition, 
dexamethasone 4 mg is given as premedication prior to each carfilzomib infusion at Cycle 1 and 
then is given at the Investigator discretion.  
Recruitment is ongoing and preliminary data of this ongoing study were presented at American 
Society of Hematology meeting in 2016 (9), on the first 11 treated patients: 3, 3, and 5 patients 
treated at DL1, DL2, and DL3, respectively. The median number of prior lines was 4.5 (2 to 8), all 
patients were previously treated with lenalidomide, and 10 patients previously received 
bortezomib. Ten patients were refractory to their previous therapy. The median number of cycles 
administered was 6 (minimum [min]-maximum [max]: 1 to 20). No dose-limiting toxicity was 
reported. Infusion associated reaction was reported in 6 (54%) patients (4 patients with Grade 1 
and 2 patients with Grade 2), and all infusions were completed. The other most frequent 
treatment-emergent adverse events (TEAEs) were dyspnea (45%), fatigue (45%), nausea (45%), 
pain (back, chest wall, and pelvis; 36%), peripheral neuropathy (36%), hypertension (27%), 
cough (27%), anorexia (27%), gastroesophageal reflux disease (18%), constipation (18%), 
diarrhea (18%), nasal congestion (18%), and hypokalemia (18%). Grade 3/4 non-hematological 
TEAEs were reported in fewer than 5% of patients. Hematological abnormalities were mild; 
9% Grade 3/4 anemia, 9% Grade 3/4 neutropenia, and 64% Grade 3/4 lymphopenia. The most 
frequent serious adverse event (SAE) was Grade 3 pneumonia (18%).  
Interesting preliminary efficacy results were reported in 10 patients evaluable for response: 
2 patients had very good partial response (VGPR), 6 patients had partial response (PR), 1 patient 
had minimal response (MR), and 1 patient had stable disease (SD). 
The pharmacokinetics (PK) of isatuximab analyzed in 10 patients are not modified by the 
co-administration of carfilzomib (unpublished data).  


 
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4.4 
STUDY DESIGN RATIONALE  
4.4.1 Choice of standard arm  
Bortezomib in combination with dexamethasone (Vd) has been utilized as standard of treatment 
for RRMM for over 10 years globally. Recently, the results of a Phase 3 study 
(ENDEAVOR study) conducted in 929 patients with RRMM after 1 to 3 prior treatments showed 
superiority of carfilzomib in combination with dexamethasone (Kd) versus Vd leading to 
registration of the Kd combination in this patient population in 2016 (10). A pre-specified interim 
analysis was planned when 395 (75%) of the 526 required progression or death events occurred. 
At the time of the interim analysis (made with 414 events and all patient were already recruited), 
the experimental arm (carfilzomib 20/56 mg/m2) demonstrated significant advantage in PFS with 
a median of 18.7 vs 9.4 months (HR: 0.53, 95% CI: 0.44 to 0.65, p <0.0001) crossing the  
pre-specified O’Brien-Fleming stopping boundary for efficacy of 0.023, adding this combination 
to the available therapeutic armamentarium for RRMM. The objective response rate was also 
significantly better in favor of Kd (77% vs. 63%, p <0.0001). The AEs of any grade occurring in 
more than 15% of patients were diarrhea (27%), fatigue (24%), dyspnea (23%), pyrexia (26%), 
anemia and cough (25%), insomnia (24%), peripheral edema (21%), upper respiratory syndrome, 
nausea and muscle spasm (18% each), asthenia (17%), and hypertension and headache 
(16% each). Grade 3/4 AEs occurring in ≥5% of patients were hypertension (9%, no Grade 4), and 
fatigue and dyspnea (5% each, no Grade 4). Grade 4 was reported for pyrexia in 2 patients and 
back pain in 1 patient. 
At the time of the interim analysis for PFS, OS data were immature. Results of a planned OS 
interim analysis showed a significant increase in OS in favor of Kd vs. Vd, with a median OS of 
47.6 months for Kd versus 40.0 for Vd, (HR = 0.79, 95% CI, 0.65 to 0.96) (11). Adverse events 
observed in this updated analysis were consistent with those previously reported for 
ENDEAVOR. The most common AEs (≥20%) in patients receiving Kd were anemia, diarrhea, 
pyrexia, dyspnea, fatigue, hypertension, cough, insomnia, upper respiratory tract infection, 
peripheral edema, nausea, bronchitis, asthenia, back pain, thrombocytopenia, and headache. 
Consistent efficacy results on PFS and OS of the Kd combination clearly established this regimen 
as standard treatments for patients with RRMM and demonstrated Kd being a better treatment 
option than Vd. This support Kd as standard arm in this Phase 3 study. 
Comparison of the IKd combination to the standard treatment option Kd will allow clear 
assessment of the effect of the addition of isatuximab to the standard treatment.  
4.4.2 Isatuximab dose and regimen  
Isatuximab single agent has shown an efficacy dose effect between 3 and 10 mg/kg and above.  
The recommended dose of isatuximab when administered in combination has been determined 
based on the study TCD11863 (lenalidomide and dexamethasone combination), and was then 
used in expansion cohorts of Phase I combination studies TCD14079 (pomalidomide and 
dexamethasone combination) and TCD13983 (bortezomib, cyclophosphamide, and 
dexamethasone combination) as well as in new studies TCD14906 (REGN2801 combination) 


 
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and EFC14335 (pomalidomide and dexamethasone combination). In the dose escalation part of 
studies TCD14079, TCD13983, and TCD12795 (carfilzomib and dexamethasone combination), 
exposure of isatuximab when administered with these combinations was in the range of exposure 
reported in TCD11863 and in single agent, for all explored dose levels. 
No evident difference was seen for safety and tolerability across the different dose levels. 
Analogously, the available data in combination with lenalidomide and pomalidomide do not 
demonstrate major differences in efficacy between 10 and 20 mg/kg with comparable response 
rate in heavily pretreated patients. Pharmacokinetic/PDy analyses performed with TCD11863 
data, including trial simulations and simulations of serum M protein-profiles, showed higher 
predicted ORR and reduction in M protein at 8/12 weeks at doses ≥10 mg/kg. However, the 
benefit in terms of ORR increase or in terms of serum M protein reduction appeared limited when 
increasing the dose from 10 to 20 mg/kg QW x 4, Q2W. Therefore, based on clinical efficacy, 
safety, PK simulations, and PK/PDy analyses, the dose selected for further isatuximab 
combination studies is 10 mg/kg QW x 4 administrations followed by 10 mg/kg Q2W (refer to 
Investigator’s Brochure).  
Based on these data, the dose of isatuximab 10 mg/kg is the selected dose for combination 
therapies. 
4.5 
BENEFIT RISK ASSESSMENT  
4.5.1 Efficacy  
All patients randomized in the study will receive Kd combination, an established standard 
treatment option for patients with MM having received 1 to 3 prior lines of treatment, either alone 
or with addition of isatuximab, which means that all patients will receive effective treatment. 
As of 05 January 2017, 323 patients have received isatuximab across 5 ongoing or completed 
Phase I/II clinical studies conducted in patients with MM or other hematological malignancies 
(319 patients with MM). Isatuximab has been investigated either as a monotherapy or in 
combination with conventional treatment regimens in MM. Anti-tumor activity of isatuximab has 
been shown in heavily pre-treated MM patients across these clinical studies and preliminary 
efficacy results reported in the ongoing study assessing isatuximab in combination with 
carfilzomib support further evaluation of this combination. 
4.5.2 Safety  
Isatuximab used as monotherapy or in combination treatments was well tolerated with a 
manageable safety profile consistent across multiple studies. Infusion associated reaction is the 
main AE related to isatuximab and is adequately managed with steroid and antihistamine 
premedication. All grades and Grade ≥3 infusion associated reactions (IARs) were reported in 
49.5% and 2.2% of the patients treated with isatuximab single agent, respectively. With 
premedication, IAR were Grade 1 or 2 in more than 95% of the patients who experienced IARs. 
Infusion-associated reactions occurred once at the first infusion in more than 90% of the patients 
and led to treatment discontinuation in fewer than 5% of patients. 


 
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The safety profile of Kd combination is known and manageable. 
Beside the IARs, other adverse drug reactions known to be associated with both isatuximab and 
carfilzomib (including symptoms of IAR reported as AEs in previous isatuximab studies) are 
anemia, neutropenia, thrombocytopenia, diarrhea, nausea, vomiting, chills, fatigue, fever, 
pneumonia, headache, cough, dyspnea, and hypertension. In the ongoing study assessing 
isatuximab with carfilzomib twice weekly at 27 mg/m2, preliminary safety results showed a safety 
profile consistent with the known safety profile of each drug, supporting the feasibility of this 
combination for further assessment.  
Close monitoring of the safety is planned and an independent data monitoring committee (DMC) 
will regularly monitor the safety of the patients. The first safety review will be done after the 
first 15 patients will have completed 2 cycles in the isatuximab in combination with carfilzomib 
and low-dose dexamethasone (IKd) arm. 
Based on available data, the overall risk/benefit appears favorable and supports the evaluation of 
the combination of isatuximab with carfilzomib and dexamethasone in MM patients previously 
treated with 1 to 3 prior lines. 


 
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5 
STUDY OBJECTIVES  
5.1 
PRIMARY  
The primary objective of this study is to demonstrate the benefit of isatuximab in combination 
with carfilzomib and dexamethasone in the prolongation of PFS using IMWG criteria  
(see Appendix F) as compared to carfilzomib and dexamethasone in patients with relapsed and/or 
refractory MM previously treated with 1 to 3 lines of therapy. 
5.2 
SECONDARY  
The key efficacy objectives are as follows: 
• To evaluate ORR.  
• To evaluate rate of VGPR or better. 
• To evaluate rate of VGPR or better (IMWG criteria) with minimal residual disease (MRD) 
negativity in both arms. 
• To evaluate complete response (CR) rate in both arms (IMWG criteria). 
• To evaluate OS in both arms. 
Other secondary objectives are as follows: 
• To evaluate safety in both arms. 
• To evaluate duration of response (DOR) in both arms. 
• To evaluate time to progression (TTP) in both arms. 
• To evaluate PFS2 (see definition in Section 9.2.2) in both arms. 
• To evaluate time to first response in both arms 
• To evaluate time to best response in both arms 
• To determine the PK profile of isatuximab and carfilzomib when combined together. 
• To evaluate immunogenicity of isatuximab in isatuximab arm. 
• To evaluate generic and disease- and treatment-specific health-related quality of life 
(HRQL), and changes in HRQL, health state utility, and health status in both arms. 
5.3 
EXPLORATORY  
Exploratory objectives are as follows: 
• To explore PK and pharmacodynamics (PDy) relationship.  
• To explore the relationship between immune genetic determinants and efficacy endpoints. 
• To explore relationship between cytogenetics abnormalities not part of Revised 
International Staging System (R-ISS) including but not limited to del (1p) and gain (1q) 
and efficacy endpoints. 
• To explore the impact of M-protein measurement without isatuximab interference on best 
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6 
STUDY DESIGN  
6.1 
DESCRIPTION OF THE STUDY  
This is a prospective multicenter, multinational, randomized, open label, parallel group, 2-arm 
study assessing the clinical benefit of isatuximab at 10 mg/kg weekly in the first cycle (4 weeks) 
and then combined with carfilzomib at 56 mg/m2 twice weekly 3 out of 4 weeks and 
dexamethasone twice weekly (IKd arm) versus carfilzomib at 56 mg/m2 twice weekly 3 out of  
4 weeks and dexamethasone twice weekly (Kd arm), in terms of PFS in patients with relapsed 
and/or refractory MM previously treated with 1 to 3 prior lines. After confirmation of eligibility 
criteria, patients will be randomly assigned to 1 of the 2 arms using an Interactive Response 
Technology (IRT) system in a 3:2 ratio: 
• Isatuximab in combination with carfilzomib and low-dose dexamethasone  
(IKd [experimental] arm). 
• Carfilzomib and low-dose dexamethasone (Kd [control] arm). 
Isatuximab, carfilzomib, and dexamethasone are defined in this protocol as “study treatment”. 
Randomization will be stratified by number of prior lines 1 versus >1 and R-ISS (12) I or II 
versus III versus not classified (inconclusive fluoroscence in situ hybridization [FISH] unless 
stage can be determined on lactate dehydrogenase [LDH], albumin, and β2 microglobulin only)  
(See Appendix A). 
Patients will be treated until disease progression, unacceptable AE, or patient decision to stop the 
study treatment. 
Study design is summarized in Figure 1. 
Figure 1 - Study design  
 


 
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6.2 
DURATION OF STUDY PARTICIPATION  
6.2.1 Duration of study participation for each patient  
The patient will be considered in the study from informed consent signature until death, consent 
withdrawal, or the OS analysis cut-off date, whichever comes first.  
The duration of the study for a patient will include a period for screening of up to 3 weeks. 
A cycle duration is 28 days. Patients will continue study treatment until disease progression, 
unacceptable AEs, patient wish to discontinue further study treatment, or any other reasons  
(see Section 10.3). All AEs occurring after informed consent signature will be reported up to  
30 days after last study treatment administration. 
After study treatment discontinuation, patients will return to the study site 30 days after the last 
dose of study treatment for end of treatment or before further anti myeloma therapy initiation, 
whichever comes first (EOT) assessments, and 90 days after the last dose of study treatment for 
HRQL questionnaires. 
Related AEs and all SAEs regardless of relationship to the study treatment ongoing at the time of 
study treatment discontinuation will be followed during the follow-up period until resolution or 
stabilization. During the follow-up period, all (serious or non-serious) new AEs related to study 
treatment and any second primary malignancy will be collected and followed up until resolution 
or stabilization. 
Patients who discontinue the study treatment due to progressive disease (PD) will be followed up 
every 3 months (12 weeks) for HRQL at first FU visit (90 days after the last study treatment) and 
for further anti-myeloma therapies, second primary malignancies, PFS2, and survival until death 
or the implementation of amended protocol #10, whichever comes first. Patients who discontinue 
the study treatment prior to documentation of PD will be followed-up every 4 weeks until disease 
progression (even for patients who would initiate further anti-myeloma therapy without PD), 
HRQL 90 days after last study treatment, and then after confirmation of disease progression, 
every 3 months (12 weeks) for further anti-myeloma therapies, second primary malignancies, 
PFS2, and survival, until death or the implementation of amended protocol #10, whichever comes 
first. 
For all alive patients at the implementation of amended protocol #10, survival status will be 
collected approximately twice a year until death, or OS analysis cut-off date, whichever comes 
first.  
Patients still on treatment at the time of the implementation of amended protocol #10 or OS 
analysis cut-off date, and benefitting from the study treatment, can continue the study treatment 
until disease progression, unacceptable AEs, patient wish to discontinue further study treatment, 
or any other reasons. For cycles administered after the cut-off dates, all ongoing SAEs (related or 
not) and all ongoing related non serious AEs at this cut-off date, all new related AEs (serious or 
not), IP administration, and reason of EOT will continue to be collected. If a patient received less 
than 10 cycles at the final PFS analysis cut-off date, anti-drug antibodies (ADA)/PK samples will 
be stopped. In case of the last ADA is positive or inconclusive an additional ADA will be sampled  
3 months later. No further ADA will be sampled, even if this 3-month sample is positive. 


 
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6.2.2 Determination of end of clinical trial (all patients)  
The PFS analysis (primary endpoint analysis) is event driven and the final PFS analysis cut-off 
date will be the date when 159 PFS events (progression or death, whichever comes first) assessed 
by the IRC have occurred (around 36 months from first patient being randomized). 
It is assumed that OS will not be mature at the time of the PFS analysis. The OS analysis cut-off 
date will be approximately 3 years after the primary PFS analysis cut-off date. The primary 
analysis of PFS corresponds either to the positive interim analysis or the final PFS analysis. 
The end of the study is defined as the date of the last visit of the last participant in the study. 
6.3 
INTERIM ANALYSIS  
An interim analysis for efficacy assessment of PFS is planned when 65% of the 159 PFS events 
will be observed. The interim PFS cut-off date is expected approximately 24 months after the FPI. 
The procedure and criteria for undertaking an interim analysis are described in Section 11.5. 
6.4 
STUDY COMMITTEES  
The Steering Committee will include a Chairman, investigators, and sponsor’s representatives. 
The Steering Committee will be responsible for: 
• Supervising the progress of the trial towards its overall objectives. 
• Reviewing at regular intervals relevant information that may affect the study conduct. 
• Discussing the implementation of the recommendations of the independent DMC. 
An independent DMC, consisting of 3 external independent members (2 physicians with MM 
expertise and 1 statistician), not associated with the conduct of the study or other study 
committees will meet regularly to as specified in the DMC charter: 
• Review the progress of the trial. 
• Review the safety data. 
• Advise the sponsor on potential modifications or communications that may be necessary to 
ensure the patient safety or protect the scientific integrity of the trial. The sponsor will 
make the final decision(s). 
• Review the results of the planned PFS interim analysis by arm during the course of the 
study. 
The first meeting will be set up to review early safety results (eg, after approximately 15 patients 
have completed at least 2 cycles in IKd arm), and then periodically. Ad-hoc DMC meetings may 
also be held if a significant safety issue or issue deemed important for discussion arise on this or 
any other studies of isatuximab. After each meeting, the DMC will advise the Steering Committee 
and the sponsor’s representatives on recommendations regarding the continued safety of treating 
ongoing and future study patients, as well as the course of action regarding the conduct of the 
trial.  


 
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One PFS interim analysis is planned and, after review of the results by arm, the DMC will make 
recommendations on continuation of the study or not according to the stopping rules pre-specified 
in the protocol (see Section 11.5). 
The DMC procedures will be detailed in the DMC charter and approved by the DMC members. 
The charter will be finalized before the first patient enrolled.  
An IRC will determine disease response and progression according to efficacy MM laboratory 
data (central laboratory results), local bone marrow (BM) for plasma cell infiltration assessment 
as recorded in the eCRF, and imaging as per IMWG criteria and in line with the IRC charter up to 
additional analysis on PFS. IRC will review disease assessments until the last time point with M 
protein assessed by the central laboratory or overall survival cut-off date, whichever comes first.  


 
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7 
SELECTION OF PATIENTS  
7.1 
INCLUSION CRITERIA  
Patients will be considered for inclusion in this study if they meet all of the following criteria 
(all necessary baseline studies for determining eligibility must be obtained within 21 days prior to 
randomization): 
I 01. Multiple myeloma. 
I 02. Measurable disease: Serum M protein ≥0.5 g/dL measured using serum protein 
immunoelectrophoresis and/or urine M protein ≥200 mg/24 hours measured using urine 
protein immunoelectrophoresis. 
I 03. Patient with relapsed and/or refractory MM with at least 1 prior line and no more than 
3 prior lines. 
I 04. Patient has given voluntary written informed consent before performance of any study 
related procedures not part of normal medical care. 
7.2 
EXCLUSION CRITERIA  
Patients who have met all the inclusion criteria listed in Section 7.1 will be screened for the 
following exclusion criteria:  
 Less than 18 years (or country’s legal age of majority if the legal age is >18 years). 
 Primary refractory MM defined as patients who have never achieved at least a MR with 
any treatment during the disease course. 
 Patient with serum free light chain (FLC) measurable disease only. 
 Patient with prior anti-CD38 mAb treatment with progression on or within 60 days after 
end of anti-CD38 mAb treatment or failure to achieve at least MR to treatment 
(ie, refractory to anti-CD38). 
 Any anti-myeloma drug treatment within 14 days before randomization, including 
dexamethasone. 
 Patient who has received any other investigational drugs or prohibited therapy for this 
study within 28 days prior to randomization (Section 8.8.2). 
 Prior treatment with carfilzomib. 
 Known history of allergy to captisol (a cyclodextrin derivative used to solubilize 
carfilzomib), prior hypersensitivity to sucrose, histidine (as base and hydrochloride salt), 
polysorbate 80, or any of the components (active substance or excipient) of study treatment 
that are not amenable to premedication with steroids, or H2 blockers, that would prohibit 
further treatment with these agents. 


 
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 Patients with contraindication to dexamethasone. 
 Prior allogenic hematopoietic stem cell transplant with active graft versus host disease (any 
grade and/or being under immunosuppressive treatment within 2 months before 
randomization). 
 Known amyloidosis or concomitant plasma cell leukemia. 
 Pleural effusions requiring thoracentesis or ascites requiring paracentesis or any major 
procedures within 14 days before randomization: eg, plasmapheresis, curative 
radiotherapy, major surgery (kyphoplasty is not considered a major procedure). 
 Eastern Cooperative Oncology Group (ECOG) performance status (PS) >2  
(see Appendix D). 
 Platelets <50,000 cells/µL if <50% of BM nucleated cells are plasma cells and 
<30,000 cells/µL if ≥50% of BM nucleated cells are plasma cells. Platelet transfusion is 
not allowed within 3 days before the screening hematological test. 
 Absolute neutrophil count (ANC) <1000 μ/L (1 x 109/L). The use of granulocyte colony 
stimulating factor (G-CSF) is not allowed to reach this level. 
 Creatinine clearance <15 mL/min/1.73 m2 (Modification of Diet in Renal Disease 
[MDRD] Formula, see Appendix B). 
 Total bilirubin >1.5 x upper limit of normal (ULN), except for known Gilbert syndrome. 
 Corrected serum calcium >14 mg/dL (>3.5 mmol/L). 
 Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >3 x ULN. 
 Ongoing toxicity (excluding alopecia and those listed in eligibility criteria) from any prior 
anti-myeloma therapy of Grade >1 (National Cancer Institute Common Terminology for 
Adverse Events [NCI-CTCAE] v4.03; see Appendix E). 
 Prior malignancy. Adequately treated basal cell or squamous cell skin or superficial 
(pTis, pTa, and pT1) bladder cancer or low risk prostate cancer or any in situ malignancy 
after curative therapy are allowed, as well as any other cancer for which therapy has been 
completed ≥5 years prior to randomization and from which the patient has been 
disease-free for ≥5 years. 
 Any of the following within 6 months prior to randomization: myocardial infarction, 
severe/unstable angina pectoris, coronary/peripheral artery bypass graft, New York Heart 
Association class III or IV congestive heart failure (CHF), Grade ≥3 arrhythmias, stroke, 
or transient ischemic attack. 
 Left ventricular ejection fraction <40%. 
 Known acquired AIDS related illness or HIV disease requiring antiretroviral treatment, or 
to have active hepatitis A, B (defined as a known positive hepatitis B surface antigen 


 
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(HBsAg) result), or C (defined as known quantitative HCV RNA results greater than the 
lower limits of detection of the assay or positive HCV antigen) infection. 
 Any of the following within 3 months prior to randomization: treatment resistant peptic 
ulcer disease, erosive esophagitis or gastritis, infectious or inflammatory bowel disease, 
diverticulitis, pulmonary embolism, or other uncontrolled thromboembolic event. 
 Any severe acute or chronic medical condition which could impair the ability of the patient 
to participate in the study or interfere with interpretation of the study results (eg, systemic 
infection unless anti-infective therapy is employed), or patient unable to comply with the 
study procedures. 
 Female patients who are pregnant or lactating. 
 Women of childbearing potential (WOCBP) not protected by highly-effective method of 
birth control and/or who are unwilling or unable to be tested for pregnancy  
(see contraceptive guidance in Appendix C). 
 Male participant with a female partner of childbearing potential not protected by 
highly-effective method of birth control. 


 
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8 
STUDY TREATMENTS  
8.1 
INVESTIGATIONAL MEDICINAL PRODUCTS  
In case of a regional or national emergency declared by a governmental agency that results in 
travel restrictions, confinement, or restricted site access, the oral IMP may be supplied at the site 
or from the PI/site/Sponsor to the participant via a Sponsor-approved courier company where 
allowed by local regulations and agreed upon by the participant during the time the measures are 
applied. 
8.1.1 Isatuximab  
8.1.1.1 Pharmaceutical form  
The C1P2F2 drug product is presented as a concentrate for solution for infusion in vials 
containing 20 mg/mL (500 mg/25 mL) isatuximab in 20 mM histidine, 10% (w/v) sucrose, 
0.02% (w/v) polysorbate 80, and pH 6.0 buffer. 
It is supplied for parenteral administration as a sterile, nonpyrogenic, injectable, 20 mg/mL 
concentrate for solution for infusion essentially free of visible particulates and is packaged in  
30 mL glass vials fitted with elastomeric closure. Each vial contains a nominal content of 500 mg 
of isatuximab. The fill volume has been established to ensure removal of 25 mL. 
For administration to patients, the appropriate volume of isatuximab will be diluted in a 250-mL 
infusion bag of 0.9% sodium chloride or 5% dextrose solution.  
Please refer to the Pharmacy Manual for more information. 
8.1.1.2 Dilution method  
Isatuximab concentrate for solution for infusion will be diluted in an infusion bag with 
0.9% sodium chloride or 5% dextrose solution to achieve the appropriate drug concentration for 
infusion. 
Infusion via a central line is preferred, if available. In case of patients with local intolerance after 
peripheral IV infusion, the decision to use a central line is left to the Investigator’s decision. The 
final infusion volume corresponding to the dose of isatuximab will be administered by IV infusion 
for the period of time that will depend on total dose administered. 
Prior to dosing, each patient's dose will be individually prepared by the study pharmacist and 
labeled with protocol number, patient number, and treatment description. The total dose will be 
calculated based on the most recent weight available the day of the infusion preparation: the 
weight on the day of the infusion or the most recent weight assuming it was assessed in a 
reasonable time frame according to investigator assessment. If the infusion is prepared with the 
most recent weight assessed in a reasonable time frame, this will not prevent to assess the weight 
on D1 of each cycle, which has to be recorded in the eCRF.  


 
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Detail instructions for dilution of the isatuximab concentrate for solution for infusion is provided 
in a Pharmacy Manual. 
8.1.2 Carfilzomib  
Carfilzomib (Kyprolis®) from available commercial supplies will be used for this study where 
applicable; otherwise, it will be re-labeled by the sponsor according to Good Manufacturing 
Practice (GMP) guidelines before supplies are provided to the study sites. 
Please refer to package insert for further details as regards to formulation, storage, and handling 
procedures.  
8.1.2.1 Dilution method  
The lyophilized product is reconstituted with water for injection to a final carfilzomib 
concentration of 2 mg/mL prior to administration.  
8.1.3 Dexamethasone IV/PO  
Dexamethasone IV/PO from available commercial supplies will be used for this study where 
applicable; otherwise, it will be re-labeled by the sponsor according to GMP guidelines before 
supplies are provided to the study sites. 
Please refer to package insert for further details as regards to formulation and handling 
procedures. 
8.2 
DOSAGE AND SCHEDULE  
There is no limitation in the number of cycles to be administered in the absence of major toxicity, 
disease progression or any other discontinuation criteria as defined in Section 10.3. In case of 
PD diagnosis made on laboratory criteria, this needs to be confirmed by 2 consecutive measures 
before to treatment discontinuation, the treatment should continue until confirmation of the PD. 
Dose adjustment (dose delay, dose omission, and for carfilzomib and dexamethasone dose 
reduction) will be permitted for subsequent treatment cycles based on individual patient tolerance. 
No dose reductions are allowed for isatuximab infusion (see Section 8.2.4). 
8.2.1 Study treatments (IMP)  
Study treatment is defined as isatuximab/carfilzomib/dexamethasone in IKd experimental arm and 
carfilzomib/dexamethasone in Kd control arm. 
Both isatuximab and carfilzomib can induce IARs and premedication is required prior to their 
administration. 
Patients allocated to IKd arm should routinely receive premedications, which also includes 
dexamethasone, prior to isatuximab infusion to reduce the risk and severity of IARs commonly 
observed with mAbs and with carfilzomib. Dexamethasone should be administered prior to 
carfilzomib for patients allocated to the Kd arm, and for patients allocated to IKd arm, 


 
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dexamethasone should be administered prior to carfilzomib administration when there is no 
isatuximab infusion (on Days 2, 9, and 16 at Cycle 1 and on Days 2, 8, 9, and 16 at further 
cycles). 
Hydration is required prior to the 2 first carfilzomib administrations (on Day 1 and Day 2 
Cycle 1). Hydration should be started orally at least 48 h prior Day 1 Cycle 1. Hydration for 
further infusions within cycle 1 and further cycles is left to Investigator judgment. Details for 
hydration are given in Section 8.2.3.  
Patients with a BSA >2.2 m2 will use 2.2 m2 for the determination of carfilzomib dose. 
Detailed guidelines for the premedication are provided in Section 8.2.2 and details for 
management of IARs are provided in Section 10.6.1. 
IKd arm (experimental arm) 
Drug administration (after pre-medication as described Section 8.2.2) for patients treated with 
isatuximab, carfilzomib, and dexamethasone combination is as follows:  
• Dexamethasone 20 mg on Days 1, 2, 8, 9, 15, 16, 22, and 23 in a 28-day cycle, between 
15 to 30 minutes (but no longer than 60 minutes) prior to isatuximab or at least 30 minutes 
prior to carfilzomib on the days when there is no isatuximab administration. 
Dexamethasone will be administered IV on the days of isatuximab and/or carfilzomib 
administration and PO on the other days (see Section 8.2.2). 
• Isatuximab is to be administered IV at a dose of 10 mg/kg weekly for the first month, then 
Q2W thereafter. The rate of infusion for isatuximab should be initiated at 175 mg/hour.  
Patients still receiving isatuximab will switch to the registered infusion rate as described 
below. For those patients, premedication for the prevention of infusion reaction (IR) has to 
be given for the first isatuximab infusions. Patients who do not experience an IR upon 
4 consecutive administrations of isatuximab may have their need for subsequent 
premedication reconsidered, at the Investigator’s discretion.    
- 
First isatuximab infusions: initiate infusion at 25 mL/hour. In the absence of IRs after 
1 hour of infusion, increase infusion rate by 25 mL/hour increments every 30 minutes, 
to a maximum of 150 mL/hour. In case of grade 2 IR during first infusion, infusion 
could be restarted at one-half of the initial infusion rate (12.5 mL/hour) when the IR 
improves to Grade ≤1. If symptoms do not recur after 30 minutes, the infusion rate 
may be increased by 25 mL/hour increments every 30 minutes, until the total volume 
is infused to maximum rate of 150 mL/hr. 
- 
Second infusion: Initiate infusion at 50 mL/hour. In the absence of Grade 2 IR after 
30 minutes of infusion, increase rate to 100 mL/hour for 30 minutes, then, to 
200 mL/hour until the total volume is infused. 
- 
In case of Grade 2 IR during second infusion, infusion could be restarted at one-half of 
the initial infusion rate (25 mL/hour) when the IR improves to Grade ≤1. If symptoms 
do not recur after 30 minutes, the infusion rate may be increased by 50 mL/hour 
increments every 30 minutes, until the total volume is infused to maximum rate of 
200 mL/hr. 


 
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- 
Third and subsequent infusions: Initiate infusion at a fixed infusion rate of 
200 mL/hour, until the total volume is infused. In case of Grade 2 IR during third 
infusion, infusion could be restarted at one-half (100 mL/hour) of the infusion rate 
(100 mL/hour) when the IR improves to Grade ≤1. If symptoms do not recur after 
30 minutes, the infusion rate may be increased by 50 mL/hour increments every 
30 minutes, until the total volume is infused to maximum rate 200 mL/hr. 
- 
Guidelines for patients who develop IARs are provided in Section 10.6.1. 
• Carfilzomib (after appropriate hydration, see Section 8.2.3) is to be administered IV over 
30 minutes at a dose of 20 mg/m2 on Days 1 and 2, 56 mg/m2 on Days 8, 9, 15, and 16 of 
Cycle 1, and then 56 mg/m2 on Days 1, 2, 8, 9, 15, and 16 of all further cycles. The 
carfilzomib infusion should follow the isatuximab infusion and should begin just after the 
end of the isatuximab infusion. The dose will be escalated to 56 mg/m2 on Day 8 and for 
further administrations if the patient did not experience any toxicity Grade >2 (except non-
complicated hematological toxicity (toxicity meaning related to study treatment) or 
recovered tumor lysis syndrome (TLS)). 
Kd arm (control arm) 
Drug administration for patients treated with carfilzomib and dexamethasone combination is as 
follow: 
• Dexamethasone 20 mg on Days 1, 2, 8, 9, 15, 16, 22, and 23, at least 30 mins prior to 
carfilzomib on the days of carfilzomib administration. Dexamethasone will be 
administered IV on the days of carfilzomib administration and PO on the other days. 
• Carfilzomib (after appropriate hydration, see Section 8.2.3) is to be administered IV over 
30 mins at a dose of 20 mg/m2 on Days 1 and 2, 56 mg/m2 on Days 8, 9, 15, and 16 of 
Cycle 1, then 56 mg/m2 on Days 1, 2, 8, 9, 15, and 16 of all further cycles. The dose will 
be escalated to 56 mg/m2 on Day 8 and for further administrations if the patient did not 
experience any toxicity higher than Grade 2 (except non-complicated hematological 
toxicity (toxicity meaning related to study treatment) or recovered TLS). 
As per amended protocol 09, for patients still on treatment in IKd arm and patients in Kd 
arm, the omission of carfilzomib dosing on Days 8 and 9 while keeping or not dexamethasone 
dosing on Day 8, 9, 22, 23 is authorized if patient requests a more convenient schedule and if 
investigator judges that the maximum benefit has been reached with the weekly schedule. Same 
dose modification recommendations will be followed. If carfilzomib dose was decreased due to 
adverse event at the time the decision is taken, dose of carfilzomib cannot be re-increased while it 
could be possible for dexamethasone based on Investigator judgement.  
8.2.2 Premedication (NIMP): prevention of infusion associated reactions  
Patients allocated to the IKd arm should routinely receive premedication prior to isatuximab 
infusion to reduce the risk and severity of IARs commonly observed with mAbs. The 
recommended premedication agents are diphenhydramine 25 to 50 mg IV (or equivalent), 
dexamethasone IV/PO (dose defined below), ranitidine 50 mg IV (or equivalent), and 
acetaminophen 650 to 1000 mg PO 15 to 30 minutes (but no longer than 60 minutes) prior to 


 
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isatuximab infusion. Once the premedication regimen is completed, the isatuximab infusion must 
start immediately. 
The day of isatuximab administration, the following order is recommended:  
• Acetaminophen (paracetamol) 650 mg to 1000 mg PO. 
• Ranitidine 50 mg IV (or equivalent). The use of ranitidine or equivalent as IR 
premedication will be based on Investigators’ judgement. 
• Diphenhydramine 25 mg to 50 mg IV (or equivalent). 
• Dexamethasone 20 mg IV (which is also part of study treatment). 
In countries where there is no IV formulation of diphenhydramine or equivalent, per os 
formulation is allowed from the first isatuximab infusion. In this case, it should be taken one to 
two hours prior to isatuximab infusion start. 
When carfilzomib is administered without isatuximab (patients allocated to the Kd arm and on 
Days 2, 8, and 16 for patients allocated to the IKd arm), dexamethasone is to be administered at 
least 30 minutes prior to carfilzomib infusion. 
In case of dexamethasone being prematurely stopped and other study treatment being continued, 
steroid premedication can be considered with methylprednisolone 100 mg IV if IAR 
premedication is still needed for isatuximab and/or carfilzomib according to investigator 
judgment. 
For the patients who do not experience an IAR upon 4 consecutive administrations of isatuximab, 
the Investigator may reconsider the need of specific isatuximab premedication for IAR. 
General guidelines for the management of the IAR are provided in Section 10.6.1.  
8.2.2.1 Ranitidine or equivalent  
Ranitidine is presented as a solution for IV infusion. Commercial supplies of ranitidine or 
equivalent (other approved H2 antagonists, oral proton pump inhibitors) will be used for this 
study. Please refer to package insert for further details as regards to formulation, storage, and 
handling purposes. 
The use of ranitidine or equivalent as IR premedication will be based on Investigators’ judgement. 
8.2.2.2 Diphenhydramine or equivalent  
Diphenhydramine is presented as a solution for IV infusion. Commercial supplies of 
diphenhydramine or equivalent (cetirizine, promethazine) will be used for this study. Please refer 
to package insert for further details as regards to formulation, storage, and handling purposes. 
8.2.2.3 Acetaminophen or equivalent  
Commercial supplies of acetaminophen or equivalent will be used for this study. Please refer to 
package insert for further details as regards to formulation, storage, and handling purposes. 


 
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8.2.3 Carfilzomib hydration  
At least 48 hours before Cycle 1 Day 1, oral hydration should be given as follows: 30 mL/kg/day 
(approximately 6 to 8 cups of liquid per day) continuing up to the time of treatment. Patient 
compliance must be assessed before initiating treatment, which is to be delayed if oral hydration is 
not adequate. Oral hydration may be continued for infusions within Cycle 1 and in Cycle 2 and 
beyond at the Investigator’s discretion. In case of TLS occurred after prior study treatment 
administration, hydration for subsequent infusions will be done as needed as per investigator 
judgement. 
Patients with a history of cardiac disease (such as CHF and cardiomyopathy) or pulmonary edema 
should be monitored closely for signs of fluid overload. Patients with hypertension in medical 
history must have controlled blood pressure before treatment initiation. 
Intravenous hydration will be given immediately prior to carfilzomib on D1 and D2 during 
Cycle 1, and at the Investigator’s discretion after Cycle 1. This will consist of 500 mL normal 
saline or other appropriate IV fluid prior to carfilzomib infusion over 30 to 60 minutes. The goal 
of the hydration program is to maintain robust urine output (eg, ≥2 L/day). Patients should be 
monitored periodically during this period for evidence of fluid overload. 
The days where both isatuximab and carfilzomib are administered, the volume of isatuximab 
infusion should be considered in hydration required prior to carfilzomib infusion. If the volume of 
isatuximab infusion does not reach at least 500 mL, additional hydration should be administered 
to reach at least 500 mL. In this case, additional volume should be administered prior start of 
isatuximab infusion. Total volume of hydration can be less than 500 mL (no less than 250 mL) or 
kept at 500 mL but administered on a longer time for patients with borderline LVEF (above, but 
close to the eligibility criteria threshold of 40%) and/or for whom there is a risk of cardiac 
decompensation according to investigator’s judgement. The carfilzomib infusion should be started 
after isatuximab infusion is completed. 
8.2.4 Dose modifications  
8.2.4.1 General rules  
Dose modifications are permitted according to the guidelines described in this section. 
Dose reduction and/or cycle delay are permitted in case of toxicity. Patients may have a dose 
omitted (isatuximab and/or carfilzomib and/or dexamethasone) within a cycle if toxicity occurs 
and the patient does not recover within 3 days after the planned day of infusion/administration. 
If a patient experiences several toxicities and there are conflicting recommendations, the most 
conservative dose adjustment recommended (dose reduction/omission/delay appropriate to the 
most severe toxicity) should be followed. Once a dose of carfilzomib or dexamethasone has been 
decreased, intra-patient re-escalation back to the previous dose level is not permitted, except for 
dexamethasone in case of dexamethasone if maintained on Day 8, and 9 and decision was taken 
after patient request for convenience to omit carfilzomib dosing on Days 8 and 9  
(see Section 8.2.1). If a dose reduction is required, it is to be applied compared to the last dose 
level received by the patient. 


 
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Administration of the study treatment (isatuximab and/or carfilzomib and/or dexamethasone) will 
be discontinued in the event of an AE that persists despite appropriate dose modifications or any 
other AE that, in the opinion of the Investigator, warrants discontinuation. 
All changes to study treatment administration must be recorded in the electronic case report form 
(eCRF). 
Patients will receive the next cycle of study treatment after recovery of the toxicity as described 
below.  
A new cycle of study treatment may begin on the scheduled Day 1 of a subsequent cycle if the 
following criteria are met. 
• ANC >1000/ mm3. 
• Platelet count ≥50,000/ mm3. For patients with plasma cells >50% of BM nucleated 
cells at baseline, to initiate Cycle 2, platelet counts should be ≥30,000/mm3 regardless 
response status at end of Cycle 1. During Cycles 2 to 4, platelet counts should be 
≥30,000/mm3, if last response is not better than SD, but if last response is PR or better 
during Cycles 2 to 4, Day 1 next cycle can be administered only if platelet counts 
≥50,000/mm3. For Day 1 administration beyond Cycle 4, platelet counts should be 
≥50,000/mm3. 
• Any other carfilzomib, dexamethasone, or isatuximab related AE that may have 
occurred in the previous cycle has recovered to Grade ≤1 or baseline severity 
(or according to the dose modifications shown in Section 8.2.4.3 and Section 8.2.4.4. 
If these criteria are not met on the scheduled Day 1, Day 1 should be delayed until patients 
recover as defined above and if D1 delay is more than 3 days, the reason should be documented. If 
these criteria are not met within 14 days of the scheduled Day 1 (planned Day 1 Cycle n +1 
corresponds to Day 29 cycle n), the patient should be discontinued from study treatment, unless 
there is strong evidence of clinical benefit to justify continuation of dosing with study treatment. 
The Investigator must discuss the rationale with the sponsor before a decision is taken. A delay 
for patient’s convenience should be avoided during the first cycles and a delay more than 14 days 
has to be discussed with the Sponsor before a decision is taken.   
If there are dose modifications within the previous cycle, these guidelines should be followed for 
the initiation of a new cycle: 
• If carfilzomib dosing was omitted during the previous cycle and was restarted with a 
1-level dose reduction without requiring an interruption for the remainder of the cycle, 
then that reduced dose level will be initiated on Day 1 of the new cycle. Once a dose of 
carfilzomib or dexamethasone has been reduced, intra-patient re-escalation back to the 
previous dose level is not permitted. 
• If there are no other AEs that require a dose reduction and thrombocytopenia and/or 
neutropenia can be managed with supportive measures, no dose reductions are required. 
• Patients may have study treatment dose delay within a cycle if toxicity occurs and recovers 
within the 3 days after the planned day. If toxicity does not recover within these 3 days, 
the dose should be omitted. The reason for a dose delay of more than 1 day and dose 
omission should be documented. Patients will receive the next treatment administration 
after recovery of the toxicity as described in Section 8.2.4.2. 


 
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If one of the study treatments is prematurely permanently discontinued, then other drug(s) can be 
continued until disease progression, unacceptable toxicity, or the patient wishes to discontinue 
further study treatment. The end of study treatment in this case will be 30 day after the date of the 
last study treatment administration. 
8.2.4.2 Modification of isatuximab/carfilzomib/dexamethasone dose levels in case of 
dose reduction  
No dose reduction of isatuximab is permitted. Dose omissions are allowed in case of toxicity. 
If the dose of carfilzomib or dexamethasone requires reduction due to AEs, the dose will be 
reduced by 1 dose level relative to the current dose the patient is receiving. Several dose 
reductions are permitted and weekly doses can be omitted in case of ongoing AEs. Dose reduction 
steps for carfilzomib are shown in Table 1 and dose reduction steps for dexamethasone are shown 
in Table 2. 
Table 1 - Dose levels for carfilzomib dose reduction  
Starting dose (IV) 
Dose level -1 
Dose level -2 
Dose level -3 
20 mg/m² 
15 
11 
- 
56 mg/m² 
45 
36 
27 
Table 2 - Dose levels for dexamethasone dose reduction  
Starting dose 
(PO/IV) 
Dose level -1 
Dose level -2 
Dose level -3 
20 mg 
12 
8 
4 


 
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8.2.4.3 Dose adjustments in IKd arm  
Details of the guidelines for dose adjustments in the case of hematologic toxicities are presented 
in Table 3. 
Table 3 - Guidelines for dose adjustments for hematological toxicities - 
isatuximab/carfilzomib/dexamethasone combination  
Adverse event 
Recommended action on isatuximab, carfilzomib, and 
dexamethasone 
Platelets 
 
Platelet count <30 x 109/L  
Platelet count between 
10 x 109/L and 30 x 109/L 
without bleeding 
Day 1 of cycle: Delay Day 1 administration until recoverya 
as defined in Section 8.2.4.1 and maintain same dose.  
Within cycle: Maintain same dose isatuximab, carfilzomib, 
and dexamethasone. 
Platelet count <10 x 109/L 
or evidence of bleeding 
Day 1 of cycle: Delay Day 1 administration until recoverya 
as defined in Section 8.2.4.1 and maintain same dose. 
Within cycle: Hold isatuximab, carfilzomib, and 
dexamethasone until platelets counts improve to ≥10 
x 109/L and/or bleeding is controlled, and then re-start all 
study treatment at the same dose level. 
If delay is >3 days, omit the dose. 
For each subsequent drop in 
platelet count to <30 x 109/L 
Platelet count between 
10 x 109/L and 30 x 109/L 
without bleeding 
Day 1 of cycle: Delay Day 1 administration until recoverya 
as defined in Section 8.2.4.1 and maintain same dose.  
Within cycle: Maintain same dose of isatuximab, 
carfilzomib, and dexamethasone. 
Platelet count <10 x 109/L 
or evidence of bleeding 
Day 1 of cycle: Delay Day 1 administration until recoverya as 
defined in Section 8.2.4.1  and then administer with 
reduction of carfilzomib by 1 dose level and same dose of 
isatuximab and dexamethasone. 
Within cycle: Hold isatuximab, carfilzomib, and 
dexamethasone until platelets counts improve to ≥10 x 109/L 
and/or bleeding is controlled, and then re-start with reduction 
of carfilzomib by 1 dose level and same dose of isatuximab 
and dexamethasone. 
If delay is >3 days, omit the dose. 
Neutropenia 
 
 
Neutrophil count <1.0 x 109/L  
Neutrophil count between 
0.5-1.0 x 109/L  
Day 1 of cycle: Delay Day 1 administration until recoverya 
as defined in Section 8.2.4.1 and maintain same dose.  
Within cycle: Maintain same dose of isatuximab, 
carfilzomib, and dexamethasone.  
Neutrophil count between 
<0.5 x 109/L 
Day 1 of cycle: Delay Day 1 administration until recoverya 
as defined in Section 8.2.4.1 and maintain same dose. 
Within cycle: Full dose isatuximab and dexamethasone 
and omit dose carfilzomib until neutrophil counts improve 
to ≥0.5 x 109/L and then re-start all study treatments at the 
same dose level. 


 
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Adverse event 
Recommended action on isatuximab, carfilzomib, and 
dexamethasone 
For each subsequent drop in 
neutrophil count to <1.0 x 109/L 
Neutrophil count between 
0.5 to 1.0 x 109/L  
Day 1 of cycle: Delay Day 1 administration until recoverya 
as defined in Section 8.2.4.1 and maintain same dose.  
Within cycle: Maintain same dose of isatuximab, 
carfilzomib, and dexamethasone. 
Neutrophil count between 
<0.5 x 109/L 
Day 1 of cycle: Delay Day 1 administration until recoverya 
as defined in Section 8.2.4.1 and maintain same dose. 
Within cycle: Full dose isatuximab and dexamethasone 
and omit dose carfilzomib until neutrophil counts improve 
to ≥0.5 x 109/L and then re-start with reduction of 
carfilzomib by 1 dose level and same dose of isatuximab 
and dexamethasone. 
Febrile neutropenia and/or 
neutropenic infection 
Day 1 of cycle: Delay Day 1 administration until recoverya and add G-CSF until 
ANC >1 x 109/L. 
Within cycle: Omit isatuximab, carfilzomib, and dexamethasone (use of G-CSF can be 
considered) until ANC >1 x 109/L and fever/infection resolved. If no other AEs, then 
resume study treatment at the same dose. If delay is >3 days, omit the dose. 
If further episodes, same instructions, but then reduce by 1 dose level of carfilzomib. 
a A dose delay of up to 14 days between cycles is permitted in order for a patient to recover to their baseline status. Beyond 14 days, the 
patient must be permanently discontinued from the study (see Section 8.2.4.1). 
Dose adjustments for patients treated with isatuximab, carfilzomib, and dexamethasone 
combination in the case of non-hematological toxicity are shown in Table 4. 
Table 4 - Guidelines for dose adjustments for non-hematologic adverse events –  
isatuximab/carfilzomib/dexamethasone combination  
Adverse event 
Recommended action 
 
Isatuximaba 
Carfilzomiba 
Dexamethasonea 
Renal dysfunction 
CrCl ≥15 mL/mins 
Full dose isatuximab and same dose level of carfilzomib and dexamethasone. 
CrCl <15 mL/mins  
Day 1 of cycle: Delay Day 1 administration until CrCl returns to ≥15 mL/minsb. 
Within cycle: Omit isatuximab, carfilzomib, and dexamethasone. When CrCl returns to 
≥15 mL/mins, resume full dose isatuximab, and same dose level of carfilzomib and 
dexamethasone. 
If delay is >3 days, omit the dose. 
Liver function 
 
 
 
AST, ALT, or total bilirubin 
Grade ≥3 
Day 1 of cycle: Delay Day 1 administration until improvement to Grade 2 and then resume 
isatuximab and dexamethasone at the same dose level and reduce carfilzomib by 1 dose 
levelb. 
Within cycle: Full dose isatuximab, dexamethasone at the same dose level, and hold 
carfilzomib until improvement to Grade 2 and resume carfilzomib with dose reduction by 1 dose 
level. 
If delay is >3 days, omit the dose. 
Discontinue carfilzomib if recurrence despite 3 dose reductions. 


 
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Adverse event 
Recommended action 
 
Isatuximaba 
Carfilzomiba 
Dexamethasonea 
Grade 3-4 infection without 
concomitant neutropenia 
Day 1 of cycle: Delay Day 1 administration until systemic treatment of infection completeb. 
Within cycle: Hold study treatment until systemic treatment of infection complete. 
If delay is >3 days, omit the dose. 
Resume isatuximab, carfilzomib, and dexamethasone at the same dose level. 
Peripheral neuropathy 
 
 
 
Grade 2 with pain or Grade 3 
Day 1 of cycle: Delay Day 1 administration until improvement to Grade 2 without pain and 
administer isatuximab and dexamethasone at the same dose level, and reduce carfilzomib by 
1 dose levelb. 
Within cycle: Full dose isatuximab, dexamethasone at the same dose level, and hold 
carfilzomib until improvement to Grade 2 without pain and reduce by 1 dose level. 
Discontinue carfilzomib if recurrence despite 3 dose reductions. 
Grade 4 
Discontinue carfilzomib and hold isatuximab and dexamethasone. When improvement at least 
Grade 2 with pain or Grade 3, resume isatuximab and dexamethasone at the same dose level. 
Cardiac toxicity 
Congestive heart failure 
or Decreased LVEF <40% or 
reduction LVEF to <55% 
with drop greater than 20% 
from baseline 
 
Day 1 of cycle: Delay Day 1 administration until returns to >40%, or if held due to a drop 
to >55% until returns to within 15% of baseline  and resume full dose isatuximab, 
dexamethasone at the same dose level, and based on benefit risk assessment to re-start 
carfilzomib with dose reduced by 1 dose level or to stop carfilzomibb. 
Within cycle: Hold study treatment until returns to >40%, or until returns to within 15% of 
baseline and resume full dose isatuximab, dexamethasone at the same dose level and based 
on benefit risk assessment to re-start carfilzomib with dose reduced by 1 dose level or to stop 
carfilzomib. 
If delay is >3 days, omit the dose. 
Discontinue carfilzomib if recurrence despite 1 dose reduction. 
Myocardial infarction 
Discontinue carfilzomib. 
Day 1 of cycle: Delay Day 1 administration until recovery, resume full isatuximab dose and 
dexamethasone at the same dose level if and when clinically appropriateb. 
Within cycle: After recovery, resume full isatuximab dose and dexamethasone at the same 
dose level if and when clinically appropriate. 
If delay is >3 days, omit the dose. 
Pulmonary hypertension 
Day 1 of cycle: Delay Day 1 administration until recovery or return to baseline value and then 
resume full isatuximab dose and dexamethasone at the same dose level, and based on benefit 
risk assessment to re-start carfilzomib with dose reduced by 1 dose level or to stop 
carfilzomibb. 
Within cycle: Hold study treatment until resolution or return to baseline value and resume 
dexamethasone at the same dose level and based on benefit risk assessment to re-start 
carfilzomib with dose reduced by 1 dose level or to stop carfilzomib. 
If delay is >3 days, omit the dose. 
Discontinue carfilzomib if recurrence despite 1 dose reduction. 
Pneumonitis/interstitial disease (as ADRS were associated with these symptoms) 
Including acute distress 
respiratory syndrome, acute 
respiratory failure 
Day 1 of cycle: Delay Day 1 administration until Grade ≤1, and resume full isatuximab dose 
and dexamethasone at the same dose level, and based on benefit risk assessment to re-start 
carfilzomib with dose reduced by 1 dose level or to stop carfilzomib. 
Within cycle: Hold study treatment until Grade ≤1 and resume full isatuximab dose and 
dexamethasone at the same dose level, and based on benefit risk assessment to re-start 
carfilzomib with dose reduced by 1 dose level or to stop carfilzomib. 
If delay is >3 days, omit the dose. 
Discontinue carfilzomib if recurrence despite 1 dose reduction. 


 
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Adverse event 
Recommended action 
 
Isatuximaba 
Carfilzomiba 
Dexamethasonea 
Thrombotic microangiopathy 
Including thrombotic 
thrombocytopenic purpura 
and hemolytic uremic 
syndrome 
Day 1 of cycle: Delay Day 1 administration until Grade ≤1, and resume full isatuximab dose 
and dexamethasone at the same dose level, and based on benefit risk assessment to re-start 
carfilzomib with dose reduced by 1 dose level or to stop carfilzomib. 
Within cycle: Hold study treatment until Grade ≤1 and resume isatuximab dose and 
dexamethasone at the same dose level, and based on benefit risk assessment to re-start 
carfilzomib with dose reduced by 1 dose level or to stop carfilzomib. 
If delay is >3 days, omit the dose. 
Discontinue carfilzomib if recurrence despite 1 dose reduction. 
Posterior reversible encephalopathy syndrome (PRES) 
Symptom can include 
headaches, altered mental 
status, seizures, visual loss, 
and hypertension 
Discontinue carfilzomib. 
Day 1 of cycle: Delay Day 1 administration until recovery, resume full isatuximab dose and 
dexamethasone at the same dose level if and when clinically appropriateb. 
Within cycle: After recovery, resume full isatuximab dose and dexamethasone at the same 
dose level if and when clinically appropriate. 
If delay is >3 days, omit the dose. 
Edema excluding infusion associated reaction and excluding edema from cardiac origin 
Grade ≥3 (limiting function 
and unresponsive to therapy 
or anasarca) 
Day 1 of cycle or within 
cycle: Maintain full dose 
isatuximab as planned. 
Day 1 of cycle or within cycle: 
Maintain full dose carfilzomib 
as planned. 
Diuretics as needed, and 
decrease dexamethasone 
dose by 1 dose level; if 
edema persists despite 
above measures, decrease 
dose another dose level. If 
symptoms persist despite 
second reduction, 
dexamethasone permanently 
discontinued. 
Confusion or mood alteration not related to PRES 
Grade ≥2 (interfering with 
function ± daily activities) 
Day 1 of cycle or within 
cycle: Maintain full dose 
isatuximab as planned. 
Day 1 of cycle or within cycle: 
Maintain same dose level of 
carfilzomib as planned. 
Hold dexamethasone until 
symptoms resolve. Restart 
with 1 dose level reduction. 
If symptoms persist despite 
above measures, 
dexamethasone permanently 
discontinued. 
Herpes zoster 
Hold study treatment until lesions are dry, then resume all at the same dose level with 
appropriate prophylaxis. 
Gastrointestinal Dyspepsia, gastric or duodenal ulcer, gastritis 
Grade 1-2 (requiring medical 
management) 
Day 1 of cycle or within 
cycle: Maintain full dose 
isatuximab as planned. 
Day 1 of cycle or within cycle: 
Maintain same dose level of 
carfilzomib as planned. 
Maintain same dose level of 
dexamethasone. Treat with 
H2 blockers, sucralfate, or 
omeprazole. If symptoms 
persist despite above 
measures, decrease 
dexamethasone dose by 
1 dose level. 


 
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Adverse event 
Recommended action 
 
Isatuximaba 
Carfilzomiba 
Dexamethasonea 
Grade >3 (requiring 
hospitalization or surgery) 
Day 1 of cycle: Delay Day 1 administration until recoveryb.Then, restart full dose isatuximab 
and same dose level of carfilzomib, and decrease dexamethasone by 1 dose level of current 
dose along with concurrent therapy with H2 blockers, sucralfate, or omeprazole. 
Within cycle: Hold study treatment until symptoms adequately controlled. Then, restart full dose 
isatuximab and same dose level of carfilzomib, and decrease dexamethasone by 1 dose level 
of current dose along with concurrent therapy with H2 blockers, sucralfate, or omeprazole. 
If delay >3 days, omit the dose. 
If symptoms persist despite above measures, dexamethasone permanently discontinued. 
Acute pancreatitis 
Dexamethasone permanently discontinued. 
Day 1 of cycle: Delay Day 1 administration until recoveryc and re-start full dose isatuximab and 
same dose level of carfilzomibb. 
Within cycle: Hold all study treatment until recovery and re-start full dose isatuximab and same 
dose level of carfilzomib. 
If delay is >3 days, omit the dose. 
Hyperglycemia 
Grade ≥3  
Day 1 of cycle or within 
cycle: Maintain full dose 
isatuximab as planned. 
Day 1 of cycle or within cycle: 
Maintain same dose level of 
carfilzomib as planned. 
Treatment with insulin or oral 
hypoglycemic agents as 
needed. If uncontrolled 
despite above measures, 
decrease dose by 1 dose 
level until levels are 
satisfactory. 
Muscle weakness 
Grade ≥2 (symptomatic and 
interfering with function 
± daily activities) 
Day 1 of cycle or within 
cycle: Maintain full dose 
isatuximab as planned. 
Day 1 of cycle or within cycle: 
Maintain same dose level of 
carfilzomib as planned. 
Decrease dexamethasone by 
1 dose level. If weakness 
persists despite above 
measures decrease dose by 
1 level. If symptoms persist, 
dexamethasone permanently 
discontinued. 
Any other drug related non-
hematologic Grade 3-4 AE 
(please also refer to  
Section 8.2.9 for handling of 
TLS) 
Day 1 of cycle: Delay Day 1 administration until recovery and apply rules of dose modification 
described belowb. 
Within cycle:  
For isatuximab attribution, omit dose if the event has not recovered within 3 days. Resume at 
full dose when toxicity has improved to Grade 2 or less or to baseline grade. Second episode, 
isatuximab discontinuation. 
For dexamethasone attribution omit dose if the event has not recovered within 3 days. Resume 
with 1 dose level decrease when toxicity has resolved to Grade 2 or less or to baseline grade. 
Second episode, apply new dose reduction. Third episode, dexamethasone discontinuation. 
For carfilzomib attribution, hold dose. Resume with 1 dose level decrease when toxicity has 
improved to Grade 2 or less or recovered to baseline grade. Second episode, apply new dose 
reduction. Third episode, carfilzomib discontinuation. 
a Patients may have isatuximab, carfilzomib, and/or dexamethasone dose omission within a cycle if certain toxicities do not recover within 
3 days following the day of planned infusion (see Section 8.2.4.1). 
b A dose delay of up to 14 days between cycles is permitted in order to recover to the patient´s baseline status. Beyond 14 days, the patient 
must be permanently discontinued from the study (see Section 8.2.4.1). 
c See Section 10.6.1 for IAR management. 


 
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8.2.4.4 Dose adjustments in Kd arm  
Dose adjustments for patients treated with carfilzomib and dexamethasone combination in the 
case of hematological toxicity are shown in Table 5. 
Table 5 - Guidelines for dose adjustments for hematologic toxicities –  
carfilzomib/dexamethasone combination  
Adverse event 
Recommended action 
Platelets 
Carfilzomib 
Dexamethasone 
Platelet count <30 x 109/L  
Platelet count between 
10 x 109/L and 30 x 109/L 
without bleeding 
Day 1 of cycle: Delay Day 1 administration until recoverya 
as defined in Section 8.2.4.1 and maintain same dose.  
Within cycle: Maintain same dose of carfilzomib and 
dexamethasone 
Platelet count <10 x 109/L 
or evidence of bleeding 
Day 1 of cycle: Delay Day 1 administration until recoverya 
as defined in Section 8.2.4.1 and maintain same dose. 
Within cycle: Hold carfilzomib and dexamethasone until 
platelets counts improve to ≥10 x 109/L and/or bleeding is 
controlled, and then re-start all study treatment at the same 
dose level. 
If delay is >3 days, omit the dose. 
For each subsequent drop in 
platelet count to <30 x 109/L 
Platelet count between 
10 x 109/L and 30 x 109/L 
without bleeding 
Day 1 of cycle: Delay Day 1 administration until recoverya 
as defined in Section 8.2.4.1 and maintain same dose.  
Within cycle: Maintain same dose of carfilzomib and 
dexamethasone. 
Platelet count <10 x 109/L 
or evidence of bleeding 
Day 1 of cycle: Delay Day 1 administration until recoverya 
as defined in Section 8.2.4.1  and then administer with 
reduction of carfilzomib by 1 dose level and same dose of 
dexamethasone. 
Within cycle: Hold carfilzomib and dexamethasone until 
platelets counts improve to ≥10 x 109/L and/or bleeding is 
controlled, and then re-start with reduction of carfilzomib by 
1 dose level and same dose of dexamethasone. 
If delay is >3 days, omit the dose. 
Neutropenia 
 
 
Neutrophil count <1.0 x 109/L  
Neutrophil count between 
0.5-1.0 x 109/L  
Day 1 of cycle: Delay Day 1 administration until recoverya 
as defined in Section 8.2.4.1 and maintain same dose.  
Within cycle: Maintain same dose of carfilzomib and 
dexamethasone.  
Neutrophil count between 
<0.5 x 109/L 
Day 1 of cycle: Delay Day 1 administration until recoverya 
as defined in Section 8.2.4.1 and maintain same dose. 
Within cycle: Hold carfilzomib and dexamethasone until 
neutrophil counts improve to ≥0.5 x 109/L and then re-start 
all study treatment at the same dose level. 
If delay is >3 days, omit the dose. 


 
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Adverse event 
Recommended action 
For each subsequent drop in 
neutrophil count to <1.0 x 109/L 
Neutrophil count between 
0.5-1.0 x 109/L  
Day 1 of cycle: Delay Day 1 administration until recoverya 
as defined in Section 8.2.4.1 and maintain same dose.  
Within cycle: Maintain same dose of carfilzomib and 
dexamethasone. 
Neutrophil count between 
<0.5 x 109/L 
Day 1 of cycle: Delay Day 1 administration until recoverya 
as defined in Section 8.2.4.1 and maintain same dose. 
Within cycle: Hold carfilzomib and dexamethasone until 
neutrophil counts improve to ≥0.5 x 109/L and then re-start 
with reduction of carfilzomib by 1 dose level and same 
dose of dexamethasone. 
If delay is >3 days, omit the dose. 
Febrile neutropenia and/or 
neutropenic infection 
Day 1 of cycle: Delay Day 1 administration until recoverya. and add G-CSF until 
ANC >1 x 109/L. 
Within cycle: Omit carfilzomib and dexamethasone (use of G-CSF can be considered) 
until ANC >1 x 109/L and fever/infection resolved. If no other AEs, then resume study 
treatment at the same dose. If delay is >3 days, omit the dose. 
If further episodes, same instructions, but then reduce by 1 dose level of carfilzomib. 
a A dose delay of up to 14 days between cycles is permitted in order for a patient to recover to their baseline status. Beyond 14 days, the 
patient must be permanently discontinued from the study (see Section 8.2.4.1). 
Dose adjustments for patients treated with carfilzomib and dexamethasone combination in the 
case of non-hematological AEs are shown in Table 6. 
Table 6 - Guidelines for dose adjustments for non-hematologic adverse events –  
carfilzomib/dexamethasone combination  
Adverse event 
Recommended action 
 
Carfilzomiba 
Dexamethasonea 
Renal dysfunction 
CrCl ≥15 mL/mins 
Same dose level of carfilzomib and dexamethasone. 
CrCl <15 mL/mins  
Day 1 of cycle: Delay Day 1 administration until CrCl returns to ≥15 mL/mins.b 
Within cycle: Hold carfilzomib and dexamethasone. When CrCl returns to ≥15 mL/mins, 
resume same dose level of carfilzomib and dexamethasone. 
If delay is >3 days, omit the dose. 
Liver function 
AST, ALT, or total bilirubin Grade 
≥3 
Day 1 of cycle: Delay Day 1 administration until improvement to Grade 2 and then resume 
dexamethasone at the same dose level and reduce carfilzomib by one dose levelb. 
Within cycle: Dexamethasone at the same dose level, and omit carfilzomib until 
improvement to Grade 2 and then resume carfilzomib with dose reduction by 1 dose level. 
Discontinue carfilzomib if recurrence despite 3 dose reductions. 
Grade 3-4 infection without 
concomitant neutropenia 
Day 1 of cycle: Delay Day 1 administration until systemic treatment of infection completeb. 
Within cycle: Hold study treatment until systemic treatment of infection complete. 
If delay is >3 days, omit the dose. 
Resume carfilzomib and dexamethasone at the same dose level. 


 
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Adverse event 
Recommended action 
 
Carfilzomiba 
Dexamethasonea 
Peripheral neuropathy 
Grade 2 with pain or Grade 3 
Day 1 of cycle: Delay Day 1 administration until improvement to Grade 2 without pain and 
administer dexamethasone at the same dose level and reduce carfilzomib by 1 dose level. 
Within cycle: Dexamethasone at the same dose level and hold carfilzomib until 
improvement to Grade 2 without pain and reduce by 1 dose level. 
Discontinue carfilzomib if recurrence despite 3 dose reductions. 
Grade 4 
Discontinue carfilzomib and hold dexamethasone. When improvement at least Grade 2 
with pain or Grade 3 resume dexamethasone at the same dose level.  
Cardiac toxicity 
Congestive heart failure 
or  
Decreased LVEF <40% or 
reduction LVEF to <55% with 
drop greater than 20% from 
baseline 
 
Day 1 of cycle: Delay Day 1 administration until returns to >40% or, if held due to a drop, 
to >55%, until returns to within 15% of baseline and resume dexamethasone at the same 
dose level, and carfilzomib with dose reduced by 1 dose level based on benefit risk 
assessmentb. 
Within cycle: Hold study treatment until returns to >40%, or until returns to within 15% of 
baseline and resume dexamethasone at the same dose level and carfilzomib with dose 
reduced by 1 dose level based on benefit risk assessment. 
If delay is >3 days, omit the dose. 
Discontinue carfilzomib if recurrence despite 1 dose reduction. 
Myocardial infarction 
Discontinue all study treatment. 
Pulmonary hypertension 
Day 1 of cycle: Delay Day 1 administration until recovery or return to baseline value and 
then resume dexamethasone at the same level, and based on benefit risk assessment to 
re-start carfilzomib with dose reduced by 1 dose level or to stop carfilzomibb. 
Within cycle: Hold study treatment until resolution or return to baseline value and resume 
dexamethasone at the same dose level and carfilzomib with dose reduced by 1 dose level 
based on benefit risk assessment. 
If delay is >3 days, omit the dose. 
Discontinue study treatment if recurrence despite 1 dose reduction. 
Pneumonitis/interstitial disease (as ADRS were associated with these diagnoses) 
Including acute distress 
respiratory syndrome, acute 
respiratory failure 
Day 1 of cycle: Delay Day 1 administration until Grade ≤1, and based on benefit risk 
assessment to re-start carfilzomib with dose reduced by 1 dose level and same dose 
dexamethasone or to stop study treatment. 
Within cycle: Hold study treatment until Grade ≤1 and based on benefit risk assessment to 
re-start carfilzomib with dose reduced by 1 dose level and same dose of dexamethasone 
or to stop study treatment. 
If delay is >3 days, omit the dose. 
Discontinue study treatment if recurrence despite 1 dose reduction. 
Thrombotic microangiopathy 
Including thrombotic 
thrombocytopenic purpura and 
hemolytic uremic syndrome 
Day 1 of cycle: Delay Day 1 administration until Grade ≤1, and based on benefit risk 
assessment to re-start carfilzomib with dose reduced by 1 dose level and same dose 
dexamethasone or to stop study treatment. 
Within cycle: Hold study treatment until Grade ≤1 and based on benefit risk assessment to 
re-start carfilzomib with dose reduced by 1 dose level and same dose of dexamethasone 
or to stop study treatment. 
If delay is >3 days, omit the dose. 
Discontinue study treatment if recurrence despite 1 dose reduction. 


 
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Adverse event 
Recommended action 
 
Carfilzomiba 
Dexamethasonea 
Posterior reversible encephalopathy syndrome (PRES) 
Symptom can include headaches, 
altered mental status, seizures, 
visual loss and hypertension 
Discontinue all study treatment. 
Edema excluding infusion associated reaction and excluding edema from cardiac origin 
Grade ≥3 (limiting function and 
unresponsive to therapy or 
anasarca) 
Day 1 of cycle or within cycle: Maintain 
full dose carfilzomib as planned. 
Diuretics as needed and decrease 
dexamethasone dose by 1 dose level; if 
edema persists despite above measures, 
decrease dose another dose level. If 
symptoms persist despite second reduction, 
dexamethasone permanently discontinued. 
Confusion or mood alteration not related to PRES 
Grade ≥2 (interfering with 
function ± daily activities) 
Day 1 of cycle or within cycle: Maintain 
same dose level of carfilzomib as 
planned. 
Hold dexamethasone until symptoms resolve. 
Restart with 1 dose level reduction. If 
symptoms persist despite above measures, 
dexamethasone permanently discontinued. 
Herpes zoster 
Hold study treatment until lesions are dry, then resume all at the same dose level with 
appropriate prophylaxis. 
Gastrointestinal Dyspepsia, gastric or duodenal ulcer, gastritis 
Grade 1-2 (requiring medical 
management) 
Day 1 of cycle or within cycle: Maintain 
same dose level of carfilzomib as 
planned. 
Treat with H2 blockers, sucralfate, or 
omeprazole. If symptoms persist despite 
above measures, decrease dexamethasone 
dose by 1 dose level. 
Grade ≥3 (requiring 
hospitalization or surgery) 
Day 1 of cycle: Delay Day 1 administration until recovery.c Then, restart same dose level 
of carfilzomib, and decrease dexamethasone by one dose level of current dose along with 
concurrent therapy with H2 blockers, sucralfate, or omeprazole. 
Within cycle: Hold study treatment until symptoms adequately controlled. Then, restart 
same dose level of carfilzomib, and decrease dexamethasone by 1 dose level of current 
dose along with concurrent therapy with H2 blockers, sucralfate, or omeprazole. 
If delay >3 days, omit the dose. 
If symptoms persist despite above measures, dexamethasone permanently discontinued. 
Acute pancreatitis 
Dexamethasone permanently discontinued. 
Day 1 of cycle: Delay Day 1 administration until recoveryc and re-start same dose level of 
carfilzomib. 
Within cycle: Hold all study treatment until recovery and re-start same dose level of 
carfilzomib. 
Hyperglycemia 
Grade ≥3  
Day 1 of cycle or within cycle: Maintain 
same dose level of carfilzomib as 
planned. 
Treatment with insulin or oral hypoglycemic 
agents as needed. If uncontrolled despite 
above measures, decrease dose by 1 dose 
level until levels are satisfactory. 
Muscle weakness 
Grade ≥2 (symptomatic and 
interfering with function ± daily 
activities) 
Day 1 of cycle or within cycle: Maintain 
same dose level of carfilzomib as 
planned. 
Decrease dexamethasone by 1 dose level. If 
weakness persists despite above measures 
decrease dose by 1 level. If symptoms persist 
dexamethasone permanently discontinued. 


 
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Adverse event 
Recommended action 
 
Carfilzomiba 
Dexamethasonea 
Any other drug related 
non-hematologic Grade 3-4 AE 
(please also refer to Section 8.2.9 
for handling of TLS) 
Day 1 of cycle: Delay Day 1 administration until recoveryc and apply rules of dose 
modification described below. 
Within cycle:  
For dexamethasone attribution omit dose if the event has not recovered within 3 days. 
Resume with 1 dose level decrease when toxicity has resolved to Grade 2 or less or to 
baseline grade. Second episode, apply new dose reduction. Third episode, 
dexamethasone discontinuation. 
For carfilzomib attribution, hold dose. Resume with 1 dose level decrease when toxicity 
has improved to Grade 2 or less or recovered to baseline grade. Second episode, apply 
new dose reduction. Third episode, carfilzomib discontinuation. 
a Patients may have carfilzomib and/or dexamethasone dose omission within a cycle if certain toxicities do not recover within 3 days 
following the day of planned infusion (see Section 8.2.4.1). 
b A dose delay of up to 14 days between cycles is permitted in order to recover to the patient´s baseline status. Beyond 14 days, the patient 
must be permanently discontinued from the study (see Section 8.2.4.1). 
c See Section 10.6.1 for IAR management. 
8.2.5 Infusion reactions  
Patients should receive premedications prior to isatuximab and carfilzomib infusion as detailed in 
Section 8.2.2 to reduce the risk and severity of IARs commonly observed with mAbs and with 
carfilzomib. Infusion associated reactions (including, for example, NCI-CTCAE v4.03 terms 
‘infusion related reaction’, ‘anaphylactic reaction’, or ‘cytokine release syndrome’) are defined as 
AEs related to product administration with onset typically within 24 hours from the start of the 
infusion. Possible increase in creatinine has been reported on the subsequent day of carfilzomib 
administration which may be the clinical sequelae of rapid tumor lysis and/or cytokine release. 
Please refer to the current edition of the Investigator’s brochure for IARs manifestations reported 
in patients treated with isatuximab and refer to carfilzomib product information for IARs 
manifestation reported with carfilzomib. 
In case of IAR while receiving or after isatuximab/carfilzomib administration, additional 
medication can be provided for symptom treatment as per Investigator judgment including 
diphenhydramine 25 mg IV (or equivalent) and methylprednisolone 100 mg IV, IV fluids, 
vasopressors, oxygen, bronchodilators, and acetaminophen or paracetamol. These patients must be 
informed of the potential risk of recurrent IARs. 
Further treatment with isatuximab (subsequent infusions) with the fixed rate: 
•  In case of Grade 2 IR during second infusion, infusion could be restarted at one-half of 
the initial infusion rate (25 mL/hour) when the IR improves to Grade ≤1. If symptoms do 
not recur after 30 minutes, the infusion rate may be increased by 50 mL/hour increments 
every 30 minutes, until the total volume is infused to maximum rate of 200 mL/hr. 
• In case of Grade 2 IR during third infusion and subsequent, infusion could be restarted at 
one-half (100 mL/hour) of the infusion rate (100 mL/hour) when the IR improves to  
Grade ≤1. If symptoms do not recur after 30 minutes, the infusion rate may be increased 
by 50 mL/hour increments every 30 minutes, until the total volume is infused to maximum 
rate 200 mL/hr.  


 
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Patients with a Grade 3 or 4 IAR must have the causative study treatment permanently 
discontinued and appropriate supportive therapy should be administered. If there is no possibility 
to distinguish which drug induced the IAR, study treatment should be permanently discontinued. 
In case of Grade 3 or 4 IAR occurring during isatuximab infusion, carfilzomib infusions will be 
postponed by one day (eg, planned D1 will be done on D2 and planned D2 will be done on D3) 
assuming that the IAR improved to Grade ≤1.  
Grade ≥3 IARs must be reported as AESIs (see Section 10.4.1.3). 
Table 7 - Management of infusion associated reactions  
NCI-CTCAE v4.03 criteria definition 
Intervention recommendation 
Mild (Grade 1) 
Infusion interruption or intervention not indicated 
Continuation of isatuximab/carfilzomib infusion per the 
judgment of the Investigator following close direct monitoring 
of the patient’s clinical status. Isatuximab/carfilzomib infusion 
may be stopped at any time if deemed necessary. If stopped, 
IAR will be classified as Grade 2 as per NCI-CTCAE. 
Moderate (Grade 2) 
Therapy or infusion interruption indicated but responds 
promptly to symptomatic treatment (eg, antihistamines, 
NSAIDs, narcotics, IV fluids); prophylactic medications 
indicated for ≤24 hours 
Stop isatuximab/carfilzomib infusion. Give additional 
medication with IV diphenhydramine 25 mg IV (or equivalent,  
see Section 8.2.3) and/ or IV methylprednisolone 100 mg (or 
equivalent) as needed. Isatuximab/carfilzomib may be 
resumed only after patient recovery, with slower infusion rate 
for isatuximab and with close monitoring. 
Severe or life-threatening (Grade 3 or 4) 
Grade 3: Prolonged (eg, not rapidly responsive to 
symptomatic medication and/or brief interruption of infusion); 
recurrence of symptoms following initial improvement; 
hospitalization indicated for clinical sequelae 
Grade 4: Life-threatening consequences; urgent intervention 
indicated 
Stop isatuximab/carfilzomib infusion. Give additional 
medication with diphenhydramine 25 mg IV (or equivalent,  
see Section 8.2.3) and/ or IV methylprednisolone 100 mg 
(or equivalent) and/or epinephrine as needed. If responsible 
drug has been clearly identified, permanent discontinuation of 
this drug. If responsible drug cannot be clearly identified, 
definitive study treatment discontinuation. 
Note: The infusion should be completed within 16 hours from the end of infusion preparation or a new infusion should be prepared with the 
remaining dose to be administered the same day. 
8.2.6 Posterior reversible encephalopathy syndrome and progressive multifocal 
leukoencephalopathy  
Patients should be monitored for any new or worsening neurologic, cognitive or behavioral signs 
and symptoms. 
If posterior reversible encephalopathy syndrome (PRES) or progressive multifocal 
leukoencephalopathy (PML) is suspected, study treatment should be interrupted and the 
Investigator should refer patient to a specialist and appropriate diagnosis testing should be 
initiated.  
If PRES or PML is confirmed, carfilzomib should be discontinued. The full dose of isatuximab 
and dexamethasone at the same dose level should be resumed if and when clinically appropriate. 
If the delay is more than 14 days, the study treatment should be discontinued unless there is strong 
evidence of clinical benefit to justify continuation of dosing with isatuximab and dexamethasone. 
The Investigator must discuss the rationale with the sponsor before a decision is taken. 


 
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8.2.7 Hepatitis B virus infection  
An active hepatitis B (defined as a known positive HBsAg) is an exclusion criterion. Patients with 
resolved HBV infection (HBsAg negative and anti-HBc and/or anti-HBs positive) are allowed to 
be enrolled. HBV reactivation was noted in MM patients with resolved HBV infection who are 
treated with immunosuppressive chemotherapy and either novel agents. Following identification 
of risk of hepatitis B virus (HBV) infection reactivation among patients treated with carfilzomib 
reported in September 2019, HBV serology (HBsAg, hepatitis B core antibody [anti-HBc] and 
hepatitis B surface antibody [anti-HBs]) should be done once for patients still receiving 
carfilzomib with unknown HBV status. Serology will be repeated if clinically indicated. Patients 
with HBsAg positive and/or anti-HBc antibody positive should also have HBV DNA testing by 
polymerase chain reaction. 
To consider consulting a specialist for patients who test positive for HBV during study treatment 
with carfilzomib. 
For patients who are carriers of HBV (HBsAg negative and anti-HBc positive [13]), prophylaxis 
with antivirals should be considered. These patients should be closely monitored for signs and 
symptoms of active HBV infection throughout and following the end of treatment with 
carfilzomib (up to 3 months or initiation of further anticancer therapy).  
Carfilzomib should be withheld for patients with active HBV infection until infection is 
adequately controlled. The safety of resuming carfilzomib after HBV reactivation is adequately 
controlled is not known.  
Patients with HBV positive serology should be monitored throughout the study treatment and in 
follow-up up to 3 months or initiation of further anticancer therapy. 
8.2.8 Cardiac failure  
Death due to cardiac arrest has occurred within a day of carfilzomib administration. New onset or 
worsening of pre-existing CHF with decreased left ventricular function or myocardial ischemia 
has occurred following administration of carfilzomib. Cardiac failure events (eg, cardiac failure 
congestive, pulmonary edema, and ejection fraction decreased) were reported in 7% of patients. 
Close monitoring should therefore be done for cardiac complications, which should be managed 
promptly. 
Any patients with symptoms of CHF or any other suspected acute cardiac event, whether or not 
drug related, must have study treatment held until resolution. After the event has resolved or 
returned to baseline, treatment may continue at a reduced carfilzomib dose. In case of recurrence 
occurs despite 1 dose level reduction of carfilzomib, after the event has resolved or returned to 
baseline, carfilzomib will be discontinued and the full dose of isatuximab and dexamethasone at 
the same level dose can be continued. Treatment may continue at a reduced carfilzomib dose. 
In the case of any sign of persistent CHF or LV dysfunction as described in Table 4 and Table 5, 
or if there is no resolution of CHF after 2 weeks, study treatment is to be discontinued unless there 
is strong evidence of clinical benefit to justify continuation of dosing with isatuximab and 
dexamethasone. The Investigator must discuss the rationale with the sponsor before a decision is 
taken. 


 
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8.2.9 Tumor Lysis syndrome  
Tumor lysis syndrome may occur and is a life threatening event. Hydration prior carfilzomib is 
required for all patients prior D1 and D2 infusions of Cycle 1 and is left to Investigator judgment 
for further cycles.  
The patients at greatest risk of TLS are those with high tumor burden prior to treatment. These 
patients should be monitored closely and appropriate precautions should be taken (such as use of 
prophylactic uric acid lowering agents [eg, allopurinol or rasburicase], regular measurement of 
electrolytes).  
Tumor lysis syndrome has to be managed according to site usual practice. Table 8 provides some 
parameters to be checked in case of TLS suspicion and high level recommendations for TLS 
management. Abnormalities listed in Table 8 do not support exclusively TLS diagnosis and any 
differential diagnosis also needs to be assessed if appropriate.  
After recovery, study treatment can be re-administered as planned at the same dose.  
Table 8 - Management of tumor lysis syndrome  
TLS main possible diagnosis criteria 
Recommended action 
Laboratory TLS: ≥2 simultaneous abnormalities within 3 days prior to and up to 
7 days after treatment start: 
• 
Uric acid >8 mg/dL (>475.8 µ mol/L) 
• 
Potassium >6.0 mmol/L 
• 
Phosphorus >4.5 mg/dL (>1.5 mmol/L) 
• 
Corrected calcium <7.0 mg/dL (<1.75 mmol/L), ionized calcium 
<1.12 mg/dL (<0.3mmol/L)a  
Omit study treatment until all serum 
chemistries have resolved.  
Ensure adequate hydration, correct 
laboratory abnormalities, fluid overload, 
uric acid lowering agents (such as 
rasburicase), electrolyte, or acid-base 
deviation. 
Monitor TLS complications including renal 
functions. 
Reinstitute study treatment at full dose 
after resolution. 
Clinical TLS: Laboratory TLS in addition to 1 of the following complications: 
• 
Acute kidney injury: Increase in the serum creatinine level of 0.3 mg/dL 
(26.5 µ mol/L) or the presence of oliguria, defined as an average urine 
output of <0.5 mL/kg/hour for 6 hours. 
• 
Seizures, cardiac dysrhythmia, neuromuscular irritability (tetany, 
paresthesias, muscle twitching, carpopedal spasm, Trousseau’s sign, 
Chvostek’s sign, laryngospasm, bronchospasm), hypotension, or heart 
failure probably or definitely caused by hypocalcemia. 
• 
Dysrhythmias probably or definitely caused by hyperkalemia. 
a The corrected calcium level in milligrams per deciliter = measured calcium level in milligrams per deciliter + 0.8 x (4-albumin in grams per 
deciliter). 
Adapted from Howard et al (14). 
8.2.10 Other adverse drug reactions  
For Grade ≥3 ADRs except fatigue, local reaction, fluid retention, anemia, and other ADRs that 
are uncomfortable but do not cause serious morbidity, study treatment should be held for a 
maximum of 2 weeks from the planned date of next cycle until resolution to Grade ≤1, then 
reinstituted, if medically appropriate. A reduction of subsequent doses will be left to the 
Investigator’s judgment.  


 
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8.3 
BLINDING PROCEDURES  
During the trial, administration of isatuximab is to be open-label, and no attempt will be made to 
blind administration. 
Despite the open-label administration of isatuximab, assessment of outcomes will be based on the 
review of the data objectively collected for disease evaluation (radiological assessment and central 
laboratory disease assessments) by IRC blinded to study treatment arms.  
Blinding rules for the sponsor study team will be detailed in a separate document.  
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP  
All eligible patients will be randomly assigned to a treatment group (either IKd arm or Kd arm) in 
a 3:2 ratio using an IRT. Patient assignment to a treatment group will be performed according to a 
stratified randomization list according to number of prior lines 1 vs. >1 and R-ISS I or II versus 
III versus not classified (inconclusive FISH unless stage can be determined on LDH, albumin, and 
β2 microglobulin only). 
After each patient has completed the necessary screening visit procedures, the corresponding 
baseline eCRFs have been completed and the patient is deemed eligible for study entry by the 
Investigator or designee based on the laboratory evaluations as defined in the study flow chart, the 
study site will contact the IRT. 
Screen failure patients can be re-screened and all screen procedures will have to be re-started for 
these patients.  
The randomization strata will be used by the IRT to assign the patient to the IKd or Kd arm 
according to the predefined randomization schedule. Details of the IRT procedure will be 
provided in the IRT Site Manual. 
WARNING: Randomization will be blocked if study treatment is not available at site level. A 
minimum of time will be required between screening registration call and study treatment delivery 
at site level. Please consider this time between screening call and randomization call, which 
indicated in the IRT manual. 
Study treatment should be initiated within 3 working days after randomization. 
8.5 
INVESTIGATIONAL MEDICINAL PRODUCT PACKAGING AND LABELING  
8.5.1 Isatuximab  
Isatuximab is packaged in 30 mL glass vials fitted with elastomeric closure. 
Packaging is in accordance with the administration schedule. The content of the labeling is in 
accordance with the local regulatory specifications and requirements. 


 
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8.5.2 Carfilzomib  
Please refer to package insert for further details for formulation and handling purposes. 
For carfilzomib supplied by the Sponsor, the content of the labeling is in accordance with the 
local regulatory specifications and requirements.  
8.5.3 Dexamethasone IV/PO  
Please refer to package insert for further details for formulation and handling purposes. 
For dexamethasone supplied by the Sponsor, the content of the labeling is in accordance with the 
local regulatory specifications and requirements.  
8.6 
STORAGE CONDITIONS AND SHELF LIFE  
8.6.1 Isatuximab  
Investigators or other authorized persons (eg, Pharmacists) are responsible for storing isatuximab 
in a secure and safe place with restricted access in accordance with local regulations, labeling 
specifications, policies, and procedures.  
Control of isatuximab storage conditions, especially control of temperature (eg, refrigerated 
storage), and information on in-use stability and instructions for handling the Sanofi compound 
should be managed according to the rules provided by the Sponsor. 
Isatuximab is to be stored at +2°C to +8°C (36°F to 46°F). All vials must be kept in their box until 
use. 
No protection from light is required for storage in the infusion bags. 
Details of the storage conditions for the diluted solution are provided in the Pharmacy Manual. 
8.6.2 Carfilzomib  
Please refer to package insert for storage conditions. 
8.6.3 Dexamethasone IV/PO  
Please refer to package insert for storage conditions. 
8.7 
RESPONSIBILITIES  
The Investigator, the hospital pharmacist, or other personnel allowed to store and dispense the 
study treatment will be responsible for ensuring that the study treatment used in the clinical trial is 
securely maintained as specified by the Sponsor and in accordance with applicable regulatory 
requirements. 


 
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All study treatment will be dispensed in accordance with the Investigator's prescription and it is 
the Investigator's responsibility to ensure that an accurate record of study treatment issued and 
returned is maintained. 
Any quality issue noticed with the receipt or use of a study treatment (deficiency in condition, 
appearance, pertaining documentation, labeling, expiration date, etc.) must be promptly notified to 
the Sponsor. Some deficiencies may be recorded through a complaint procedure  
(see Section 10.4.5). 
A potential defect in the quality of study treatment may be subject to initiation of a recall 
procedure by the Sponsor. In this case, the Investigator will be responsible for promptly 
addressing any request made by the Sponsor, in order to recall the study treatment and eliminate 
potential hazards. 
Under no circumstances will the Investigator supply study treatment to a third party (except for 
DTP shipment, for which a courier company has been approved by the Sponsor), allow the study 
treatment to be used other than as directed by this clinical trial protocol, or dispose of study 
treatment in any other manner. 
8.7.1 Treatment accountability and compliance  
Administration of the study treatment will be supervised by the Investigator or Subinvestigator. 
The person responsible for dispensing study treatment is required to maintain adequate records of 
the study treatment. These records (eg, drug movement form) include the date the study treatment 
is received from the Sponsor, dispensed for patient and destroyed or returned to the Sponsor. 
The packaging batch number (PR Nr) on the vial must be recorded on the drug accountability 
form. 
The person responsible for study treatment administration to the patient will record precisely the 
date and the time of the study treatment administration to the patient. 
For dexamethasone PO, a patient diary will be used to document all oral dexamethasone (if not 
administered at the site level). 
8.7.2 Return and/or destruction of treatments  
Partially-used and used study treatment will be destroyed at the study site according to the 
standard practices of the site after an accurate accountability has been performed and signed by 
the Investigator (or the Pharmacist). A detailed treatment log form of the destroyed study 
treatment will be established with the Investigator (or the Pharmacist) and countersigned by the 
Investigator and the Monitoring Team. 
The Investigator must not destroy the unused study treatment unless Sanofi provides written 
authorization. 


 
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8.8 
CONCOMITANT MEDICATION  
A concomitant medication is any treatment received by the patient concomitantly to any study 
treatment(s). 
All treatments being taken by the patient 21 days prior to randomization, at any time during the 
treatment period and up to 30 days after the last dose are regarded as prior and concomitant 
treatments respectively, and will be reported on the appropriate pages of the eCRF. 
Concomitant medications are allowed if not listed in prohibited medications and if these are 
considered necessary for the patient's welfare and are unlikely to interfere with the investigational 
product. They may be given at the discretion of the Investigator and recorded in the eCRF. 
Antiviral prophylaxis, antibacterial prophylaxis and thromboprophylaxis will be done according 
to site/Investigator practice and local labelling of carfilzomib. For patients who are HBV carriers, 
prophylaxis with antivirals should be considered. 
Co-treatment of dexamethasone with CYP3A inhibitors should be avoided unless the benefit 
outweighs the increased risk of systemic corticosteroid side-effects, in which case patients should 
be monitored for systemic corticosteroid side-effects (please refer to dexamethasone package 
insert). 
8.8.1 G-CSF prophylaxis  
Prophylactic administration of G-CSF in a patient who is experiencing recurrent difficulties with 
neutropenia, or therapeutic use in patients with serious neutropenic complications (such as tissue 
infection, sepsis syndrome, or fungal infection) may be considered at the Investigator’s discretion, 
consistent with American Society of Clinical Oncology guidelines (2006) in order to decrease the 
risk of neutropenia specially in patients with baseline extensive BM involvement and/or low 
neutrophil count. 
8.8.2 Prohibited concomitant therapy  
• 
Concurrent treatment with any other anti-myeloma therapy not specified in the protocol, 
including immunotherapy, hormonal therapy, targeted therapy, biological therapies, other 
investigational drug, or curative radiotherapy. However, palliative radiotherapy may be 
given to control pain. The irradiated area should be as small as possible and should never 
involve more than 20% of the BM in any given 3-week period. In all such cases, the 
possibility of tumor progression should be ruled out by physical, biochemical, and 
radiological assessments of the tumor. The irradiated area cannot be used as a parameter 
for response assessment. 
• 
Concomitant systemic corticosteroids, other than as part of the protocol-specified 
therapeutic regimen or for treatment of hypersensitivity reaction, are prohibited. 
Additional glucocorticoids, antihistamines, and analgesics for the management of IAR are 
permitted. Inhaled glucocorticosteroids may be used whenever indicated. 
• 
Live vaccines should be avoided; however, given the increased risk of infection, routine 
vaccinations are recommended for the patients and their contacts. Prophylactic vaccination 
is recommended for influenza A and B virus, pneumococci, and hemophilus influenza. 


 
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9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT  
9.1 
PRIMARY ENDPOINT  
The primary endpoint is PFS. 
Progression free survival is defined as the time from the date of randomization to the date of first 
documentation of PD (as determined by the IRC) or the date of death from any cause, whichever 
comes first. Response will be determined according to IMWG criteria. Progression based on 
paraprotein will be confirmed based on 2 consecutive assessments. 
The following disease assessment procedures will be performed at screening (for eligibility), at 
Cycle 1 Day 1 prior to study treatment administration (baseline for response assessment), Day 1 
of every cycle during treatment up to progression, EOT, and for patients who discontinue study 
treatment without PD, every month during follow-up until PD (even patients who would initiate 
further anti-myeloma therapy without PD): 
• M protein quantification (serum and 24-hour urine, protein immunoelectrophoresis, and 
IF) (central laboratory). After Cycle 1 Day 1, IF will be done in case of undetectable M 
protein (serum and urine). 
• Serum free light chains quantification (central laboratory). 
• Quantitative immunoglobulins (central laboratory). 
• Bone marrow aspiration (or biopsy as clinically indicated) at baseline (bone marrow 
disease involvement, FISH, and MRD), and then in case of VGPR or better (local 
laboratory for bone marrow disease involvement and central laboratory will be done to 
assess MRD). 
• Bone disease assessment: 
- 
Skeletal survey or low-dose whole body computed tomography (CT) scan at baseline, 
then once a year, and anytime during the study if clinically indicated. 
• Extramedullary disease (plasmacytoma) assessment (including bone plasmacytoma): 
- 
If known extramedullary disease at baseline, CT scan or magnetic resonance imaging 
(MRI) is to be done at baseline, repeated every 12 weeks (±1 week) until PD (even for 
patients who would initiate further anti-myeloma therapy without PD), and if clinically 
indicated. 
- 
If suspected extramedullary disease (plasmacytoma) at baseline, CT scan or MRI is to 
be done at baseline and in case plasmacytoma is confirmed, CT scan or MRI is to be 
repeated every 12 weeks (±1 week) until PD (even for patients who would initiate 
further anti-myeloma therapy without PD), and if clinically indicated. 
- 
At any time during study treatment in case of suspicion of progression of existing 
plasmacytoma or if clinically indicated in a patient with no previous positive image for 
extramedullary disease. 
Note: For bone lesion assessment and extramedullary disease, the same modality 
(skeletal survey or low-dose whole-body CT scan; CT scan or MRI) should be used 
throughout the study for each individual patient. All imaging must be sent for central 
review. 


 
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Central labs will be used for investigator’s assessment of response and continuation of treatment 
decisions. Response/progression will be determined according to IMWG criteria (Appendix F). 
Response/progression based on paraprotein will be confirmed based on 2 consecutive 
assessments. A blinded IRC will evaluate disease response at each cycle including progression 
and response status of each patient per IMWG criteria (Appendix F) and as described in the IRC 
Charter. The IRC assessment of response will be performed using results from central laboratory, 
central assessment of radiological images and, if any, local bone marrow assessment (plasma cell 
infiltration). Further details on the handling of missing disease assessments and the IRC process 
for determining the date of disease progression and overall objective response are described in the 
IRC Charter and/or the statistical analysis plan (SAP). 
Progressive disease (IMWG criteria) is defined for patients with measurable serum and/or urine 
M protein as any one of the following (biological criteria in 2 consecutive assessments):: 
• Increase of ≥25% in Serum M-component from nadir (the absolute increase must be 
≥0.5 g/dL); serum M component increases ≥1 g/dL in 2 consecutive assessments are 
sufficient to define relapse if starting M component is ≥5 g/dL; and/or  
• Increase of ≥25% in Urine M-component from nadir (the absolute increase must be 
≥200 mg/24 hour); and/or  
• Definite development of new bone lesions or soft tissue extramedullary disease or increase 
≥50% from nadir in the sum of perpendicular diameters of existing soft tissue 
extramedullary disease lesions if >1 lesion or ≥50% increase in the longest diameter of a 
previous soft tissue extramedullary disease lesion >1 cm in short axis. 
Clinical deterioration could be considered progression in the primary analysis of PFS if IRC 
considers clinical data reported in the CRF supports clinical progression. In case of 
hypercalcemia, a full disease assessment will be performed in order to identify any measurable 
parameter of myeloma progression (eg, serum and urine M protein, lytic lesions assessment and 
plasmacytoma assessment) and potential alternative causes of hypercalcemia should be ruled out. 
Progression cannot be diagnosed on FLC progression only. 
Patients with only FLC measurable disease are not allowed in the protocol.  
In case of both serum and urine M protein becomes below level of eligibility on efficacy 
laboratory performed on Cycle 1 Day 1, please refer to Appendix F for assessment of progression 
and overall response. 
9.2 
SECONDARY ENDPOINTS  
9.2.1 Key secondary efficacy endpoints  
The key secondary efficacy endpoints are:  
• 
ORR: Best overall response per patient will be assessed in order to determine ORR, 
defined as the proportion of patients with stringent complete response (sCR), CR, VGPR, 
and PR as best overall response as assessed by the IRC using the IMWG response criteria. 
Bone marrow biopsy can be done for sCR assessment as per investigator decision.  
• 
Rate of VGPR or better: Defined as the proportion of patients with sCR, CR, and VGPR. 


 
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• 
Rate of VGPR or better with MRD negativity (15): Defined as the proportion of 
patients for whom MRD assessed by sequencing is negative at any time after first dose of 
study treatment. Minimal residual disease will be assessed centrally by next-generation 
sequencing in BM samples from patients who achieve VGPR or better, to determine the 
depth of response at the molecular level. Threshold for negativity will be at least 10-5. 
Bone marrow aspirates will be collected at screening and at the time of VGPR or better 
confirmation. If the patient presents with VGPR or better but is determined MRD positive, 
another BM sample will be collected 3 months (3 cycles) later, in order to identify late 
negativity. A third sample may be collected after another 3 months, if the patient remains 
MRD positive and is still being treated. No more than 3 on-treatment BM samples are to 
be obtained unless a patient achieves CR after a third BM sample MRD positive 
performed during VGPR. In this case no more than 3 additional BM samples will be 
collected. Therefore, a maximum of 6 BMA could be performed by patient (no more than 
3 per category of response). However, because BMA is invasive procedure, the following 
guidance is given in the purpose to limit as much as possible the number of BMA. 
For patients with CR without previous documentation of VGPR, first bone marrow for 
MRD assessment will be collected at time of confirmation of CR (ie, at the second time 
point showing CR) If patient is determined MRD positive, another BM sample will be 
collected 3 months (3 cycles) later, in order to identify late negativity. A third sample may 
be collected after another 3 months if the patient remains MRD positive and is still being 
treated. 
For patients with VGPR:  
- 
First bone marrow will be collected when VGPR is confirmed at the second time point 
or at a later time point as per investigator judgement based on kinetic of M protein 
decrease and/or if a plateau phase is reached (plateau is defined as variation less than 
20% over 12 weeks [16]).  
- 
If MRD is positive on first BMA, a second BMA will be collected 3 months later 
(3 cycles) to identify late negativity.  
- 
In case of MRD is still positive on second BMA made while patient is in VGPR, the 
timing to perform the third BMA can be postponed until CR achievement.  
- 
In case of the patient becomes CR and patient was MRD positive on the last BMA 
performed during VGPR, a BMA will be done for MRD assessment at time of 
confirmation of CR.   
- 
After the first BMA during CR is done and in case patient was MRD positive on this 
BMA, the additional BMA planned by the protocol can be discussed with the patient. 
• 
CR rate: Defined as the proportion of patients with sCR and CR. Patients with 
demonstrated isatuximab interference will be considered in the BOR category 
corresponding to the M protein assessment obtained without interference, when the 
antibody-capture interference assay will be available. 
• 
OS: Defined as the time from the date of randomization to death from any cause. 


 
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9.2.2 Other secondary efficacy endpoints  
Other secondary efficacy endpoints will be evaluated as follows: 
• DOR: Defined as the time from the date of the first IRC determined response for patients 
achieving PR or better to the date of first documented PD determined by IRC or death, 
whichever happens first.  
• TTP: Defined as time from randomization to the date of first documentation of PD 
(as determined by the IRC). 
• PFS2: Defined as time from the date of randomization to the date of first documentation 
of PD (as assessed by investigator) after initiation of further anti-myeloma treatment or 
death from any cause, whichever happens first. 
• Time to first response: Defined as the time from randomization to the date of first IRC 
determined response (PR or better) that is subsequently confirmed. 
• Time to best response: Defined as the time from randomization to the date of first 
occurrence of IRC determined best overall response (PR or better) that is subsequently 
confirmed. 
9.2.3 Safety endpoints  
Safety in terms of TEAEs/AEs/SAEs, IARs, ECOG PS, laboratory parameters, vital signs, and 
findings from physical examination will be assessed through the study and will be reported in the 
eCRF. 
Adverse event data will be collected throughout the study. Treatment-emergent AEs are defined 
as AEs that develop, worsen (according to the Investigator opinion), or become serious during the 
treatment period. The treatment period is defined as the time from first dose of study treatment up 
to 30 days after last dose of study treatment. Adverse events and laboratory parameters will be 
graded using NCI-CTCAE v4.03 (Appendix E). 
Full details of safety reporting and AE monitoring procedures are provided in Section 10.4 and 
Section 10.7. 
9.2.4 Patient-reported outcomes (HRQL/health economic variables/other endpoints)  
Patient-reported outcome measures to be included are the European Organization for Research 
and Treatment of Cancer (EORTC) Quality of Life questionnaire with 30 questions (QLQ-C30), 
the EORTC myeloma module with 20 items (QLQ-MY20), and the European Quality of Life 
Group measure with 5 dimensions and 5 levels per dimension (EQ-5D-5L). Each questionnaire is 
described in this section and presented in Appendix I (QLQ-C30), Appendix J (QLQ-MY20), and 
Appendix K (EQ-5D-5L). 
All 3 questionnaires have been designed for self-completion. All PROs are in electronic form 
(ePROs) and are to be completed at the site by the patient using the study tablet provided. To 
minimize any bias, patients will fill out the ePROs before clinician assessments and discussion of 
their clinical condition, treatment plan, AEs, and any other related topics that could influence 
patient’s perception and feelings prior to responding to the questions. 


 
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Timing of Assessments 
Cycle 1 Day 1 will serve as the baseline assessment for all patients. While on treatment, ePROs 
are to be completed prior to treatment on Day 1 of every cycle, at the EOT visit and at 90 ±5  days 
after last study treatment administration. The time estimated to complete the EORTC QLQ-C30 
and the EORTC QLQ-MY20 together is approximately 10 to 15 minutes. The time estimated to 
complete the EQ-5D-5L is approximately 5 to 10 minutes. 
Since the patients are to complete ePRO questionnaires on their own, there will be 20 minutes 
time allocated for training patients on ePRO technology at Cycle 1 Day 1 visit. Meanwhile, 
assistance will be provided if a patient needs longer time to learn or have training questions  
(eg, a refresher) during consequent cycles. For the ePRO data it is mandatory that a key person 
(eg, research nurse) at each center be responsible for ePRO data collection, in order to optimize 
compliance of the patient and to ensure completeness of the data. 
The planned statistical analysis of the 3 ePROs will be detailed in the SAP. 
9.2.4.1 EORTC QLQ-C30  
The EORTC QLQ-C30 is a cancer-specific instrument that contains 30 items and provides a 
multidimensional assessment of HRQL (17, 18, 19). The validity and reliability of the EORTC 
QLQ-C30 has been established in various types of cancers (20). 
The EORTC QLQ-C30 provides a comprehensive assessment of the principal HRQL dimensions 
identified as relevant by cancer patients (physical functioning, emotional functioning, cognitive 
functioning, role functioning, social functioning, global HRQL, and impact of symptoms and of 
toxicities). The EORTC QLQ-C30 is one of the standard instruments used in oncology for the 
evaluation of new cancer therapies.  
The QLQ-C30 is composed of 3 domains with multi-item scales. These include: 
• Global health status (GHS)/quality of life (2 items). 
• Functional scales: 
- 
Physical functioning (5 items). 
- 
Role functioning (2 items). 
- 
Emotional functioning (4 items). 
- 
Cognitive functioning (2 items). 
- 
Social functioning (2 items). 
• Symptom scales/items: 
- 
Fatigue (3 items). 
- 
Nausea and vomiting (2 items). 
- 
Pain (2 items). 
- 
Dyspnea; Insomnia; Appetite loss; Constipation; Diarrhea; Financial impact (item 
each). 
Scoring is based on 4-point Likert scales and 7-point numerical rating scales. All of the scales and 
single-item measures range in score from 0 to 100. A higher score for a functional scale/GHS 
represents a higher/healthy level of HRQL, whereas a higher score for symptoms/ items represents 
a higher level of symptomatology/problems. The recall period for this instrument is 1 week. 


 
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9.2.4.2 EORTC QLQ-MY20  
The EORTC QLQ-MY20 is to be used in conjunction with the EORTC QLQ-C30 to assess 
symptoms and side effects due to the treatment or the disease which impact HRQL in patients 
with MM (21, 22). It contains 20 items, 4 independent subscales covering 2 functional domains:   
• Symptom scales: 
- 
Disease symptoms (6 items). 
- 
Side-effects of treatment (10 items). 
• Function scale: 
- 
Future perspective (3 items). 
- 
Body image (1 item). 
Scores are based on the 4-point Likert scale ranging from "Not at all" to "Very much", ranging by 
items from 0 to 100. Higher scores for Disease Symptoms and Side Effects of Treatment indicate 
more symptoms and side effects and lower HRQL, whereas a high score for Future Perspective 
and Body Image represents better outcomes. 
These are reliable and valid measures of HRQL in cancer patients and the 2 EORTC instruments 
(QLQ-C30 and QLQ-MY20) together (50 items) take approximately 15 minutes on average to 
administer. The instruments have been validated and used in many countries. 
9.2.4.3 EQ-5D-5L  
The EQ-5D-5L is a standardized measure of health status that provides a simple, generic measure 
of health utility, and consists of 2 sections: descriptive and visual analog scale (VAS). 
The descriptive system consists of 5 dimensions:  
• Mobility. 
• Self-care. 
• Usual activities. 
• Pain/discomfort. 
• Anxiety/Depression. 
Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, 
and extreme problems. Once the data have been collected and a database created, a scoring 
function can be used to assign a value (ie, EQ-5D™ index score) to self-reported health states 
from a set of population-based preference weights. For the US general population, the possible 
EQ-5D™ index scores range from -0.11 (ie, 33333) to 1.0 (ie, 11111) on a scale where 
0.0 = death and 1.0 = perfect health. 
The VAS records the respondent’s self-rated health on a 20 cm vertical VAS with endpoints 
labelled ‘the best health you can imagine’ and ‘the worst health you can imagine’, anchored from 
0 to 100 respectively. This information can be used as a quantitative measure of health as judged 
by the individual respondents. 


 
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The instrument is designed for self-completion by patients. Response options are measured with a 
5-point Likert scale with higher scores indicate better HRQL. The EQ-5D™ produces 3 types of 
data for each respondent:  
• A profile indicating the extent of problems on each of the 5 dimensions represented by a 
5-digit descriptor 
• A population preference weighted-health index score based on the descriptive system 
• A self-reported assessment of health status based on the EQ-VAS 
9.2.5 Pharmacokinetics  
Pharmacokinetic evaluation for isatuximab will be performed in all patients in the IKd arm. Blood 
samples will be collected from all patients treated with isatuximab up to Cycle 10 using a sparse 
sampling strategy in order to assess the PK profile of isatuximab using population PK approach.  
In a subset of approximately 12 patients from the IKd arm, blood samples will be collected at 
selected time points at Cycle 1 Day 15 for carfilzomib PK evaluation. Non evaluable patients will 
be replaced (see Section 11.3.3 for definition of evaluable patient). 
9.2.5.1 Sampling time  
The sampling times for blood collection can be found in the PK Flow Chart (Section 1.3). 
• It is of utmost importance to collect all blood samples at the specified times and according 
to the specifications. 
• Samples not collected, missed or lost, for any reason should be recorded.  
• Actual days and times of blood collection should be recorded in the eCRF.  
• The days and the times of drug administration should also be precisely recorded.  
9.2.5.2 Pharmacokinetics handling procedure  
Special procedures for collection, storage, and shipment will be provided in a separate laboratory 
manual. 
9.2.5.3 Bioanalytical method  
The bioanalytical method is summarized in Table 9. The sites of bioanalyses will be specified in 
the PK manual. 
Table 9 - Bioanalytical methods for isatuximab and carfilzomib pharmacokinetic analysis  
Analyte 
Isatuximab 
Carfilzomib 
Matrix 
Plasma 
Plasma 
Analytical technique 
ELISA 
LC-MS/MS 
Assay volume 
100 μL 
250 μL 
Lower limit of quantification 
0.500 ng/mL 
0.250 ng/mL 
Site of bioanalysis 
Refer to PK manual 
Refer to PK manual 
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9.2.5.4 Pharmacokinetics parameters  
9.2.5.4.1 Non-compartmental analysis for carfilzomib  
The following PK parameters will be calculated with PKDMS software (Pharsight) using 
non-compartmental methods from plasma of carfilzomib concentrations. The parameters will 
include, but may not be limited to, the following: 
Table 10 - List of pharmacokinetic parameters and definitions  
Parameters 
Definition 
Ceoi 
Concentration observed at the end of IV infusion 
Cmax 
Maximum concentration observed after the first infusion 
tmax 
Time to reach Cmax 
Clast 
Last concentration observed above the lower limit of quantification 
tlast 
Time of Clast 
Ctrough 
Plasma concentration observed just before treatment administration during repeated dosing 
AUClast 
Area under the plasma concentration versus time curve calculated using the trapezoidal method from time 0 
to tlast 
AUC 
Area under the plasma concentration versus time curve extrapolated to infinity according to the following 
equation : AUC= AUClast + Clast/λz 
9.2.5.4.2 Population approach for isatuximab  
Blood concentrations of isatuximab will be used for population PK analysis by non-linear mixed 
effects modeling. Additional details of the analysis plan and the results will be provided in a 
separate document. This analysis will involve an estimation of inter-patient PK variability, the 
population PK parameters estimates, and the assessments of carfilzomib and pathophysiologic 
covariate effects on CL and possibly on volume if warranted. Empirical Bayesian estimation of 
individual parameters and of individual exposure (AUCs, Cmax and trough) will also be performed. 
The PK estimates will then be investigated as prognostic factors for clinical outcome, including 
safety and efficacy endpoints, if possible. 
9.2.6 Immunogenicity  
Human ADA to isatuximab will be assessed for the IKd patients only on Day 1 prior to 
isatuximab administration from Cycle 1 to Cycle 10. Blood samples will be collected for ADA 
detection according to the Flow Charts (see Section 1.2 and Section 1.3). 
It is of utmost importance to collect all blood samples at the specified times and according to the 
specifications. 
Samples missed or lost, for any reason should be recorded. Actual times of blood collection 
should be recorded in the eCRF. The days of sampling and times of drug administration should 
also be precisely recorded. 


 
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Special procedures for collection, storage, and shipment will be provided in a separate laboratory 
manual. 
Bioanalytical method used for immunogenicity assessment is summarized in Table 11. 
Table 11 - Bioanalytical method for isatuximab immune response assessment  
Analyte 
Isatuximab 
Matrix 
Plasma 
Analytical technique 
Polyethylene glycol precipitation and acid dissociation method (PandA) 
Assay volume 
100 μL 
Lower limit of detection 
Not applicable 
Site of bioanalysis 
Refer to PK manual 
A sample will be considered as ADA positive if ADA is detected ie, sample generates an assay 
signal equal to or greater than the cut-point in the screening assay and is tested positive in the 
confirmatory assay. 
A sample will be considered as ADA inconclusive if ADAs are not detected but drug is present in 
the same sample at a level that can interfere in the ADA detection method then the negative ADA 
result cannot be incontrovertibly confirmed. 
In case of positivity or inconclusive sample at Cycle 10, additional assessment of ADA will be 
performed 3 months later. No further ADA will be sampled, even if this 3-month sample is 
positive. 
If isatuximab is stopped prior to carfilzomib and dexamethasone and prior to Cycle 10 and last 
ADA is positive or inconclusive, one additional sampling time for ADA evaluation will be 
collected 3 months later. No further ADA will be sampled, even if this 3-month sample is 
positive. For patients with less than 10 cycles at the cut-off date, the ADA sample collection will 
be stopped from the cut-off date. If last ADA before the final PFS analysis cut-off date is positive, 
one additional sampling time for ADA evaluation should be collected 3 months later. No further 
ADA will be sampled, even if this 3-month sample is positive. 
The sampling times for ADA detection of isatuximab can be modified based on the updated 
knowledge of isatuximab immunogenicity. 
Definitions:  
• Pre-existing ADA: Defined as ADA that are present in samples drawn during the 
pre-treatment period (ie, before the first isatuximab administration). 
• Treatment-induced ADA: Defined as ADA that developed at any time during the ADA 
on-study observation period in patients without pre-existing ADA (including patients 
without pre-treatment samples). 
• Treatment boosted ADA: Defined as pre-existing ADA with an increase in titer during the 
ADA on-study observation period. 


 
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• Transient ADA response: 
- 
Treatment-induced ADA detected only at 1 sampling time point during the treatment 
or follow-up observation period (excluding the last sampling time point, which ought 
to be considered persistent unless shown to be undetectable at a later time) or 
- 
Treatment-induced ADA detected at 2 or more sampling time points during the 
treatment (including follow-up period if any), where the first and last ADA-positive 
samples (irrespective of any negative samples in between) are separated by a period 
less than 16 weeks, and the patient’s last sampling time point is ADA-negative. 
• Persistent ADA response: 
- 
Treatment-induced ADA detected at 2 or more sampling time points during the 
treatment (including follow-up period if any), where the first and last ADA-positive 
samples (irrespective of any negative samples in between) are separated by at least 
16 weeks. 
• Intermediate ADA response 
- 
Only the last sampling time point is positive or 
- 
The last two samples separated by a period less than 16 weeks are positive. 
• ADA positive patients: Defined as patients with at least 1 treatment-induced or 
treatment-boosted ADA positive sample at any time following the first isatuximab 
administration. 
• ADA prevalence: Defined as the sum of the number of patients with pre-existing ADA and 
the number of patients with treatment induced ADAs, divided by the number of evaluable 
patients. 
• ADA incidence: Defined as the number of ADA positive patients divided by the number 
of evaluable patients. 
9.3 
EXPLORATORY ENDPOINTS  
9.3.1 Exploratory biomarker analysis  
A blood sample will be collected on Day 1 of Cycle 1. Leukocyte DNA will be extracted and 
analyzed for immune genetic determinants (such as Fcγ receptor polymorphisms) and correlated 
with parameters of clinical response. 
In IKd arm only, an additional blood sample will be collected at all time-points to evaluate the 
potential interference of isatuximab in the M protein assessment (central laboratory) up to 
Cycle 30. This sample will be collected after Cycle 30 and until disease progression only for 
patients who reach at least VGPR at this cycle. In case of isatuximab is stopped before 
progression, sample interference assay will be collected up to 3 months or PD, whichever comes 
first. After Cycle 1 Day 1, IF sample is analyzed in case of M protein is 0 g/dL in all patients. In 
addition, in order to identify patients with potential isatuximab interference, IF samples will be 
analyzed also in patients with serum M protein ≤0.2 g/dL. 


 
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In addition to the 3 cytogenetic abnormalities (del(17p), t(4:14) and t(14:16)) assessed by FISH at 
baseline to determine R-ISS stage which is stratification factor, other cytogenetic abnormalities 
such as but not limited to del (1p) and gain (1q) deletion will be assessed and correlated with 
parameters of clinical response. 
9.4 
FUTURE USE OF SAMPLES  
For patients who have consented to it, the samples that are unused or left over after testing may be 
used for other research purposes (excluding genetic analysis providing information on the 
likelihood of developing a disease) related to isatuximab efficacy, safety, and metabolism, or 
related to MM. 
These other research analyses will help to understand either disease subtypes or drug response, to 
develop and/or validate a bioassay method, and/or to identify new drug targets or biomarkers.  
These samples will remain labelled with the same identifiers used during the study 
(ie, patient ID). They will be transferred to a Sanofi site (or a subcontractor site) which can be 
located outside of the country where the study is conducted. The Sponsor has included safeguards 
for protecting patient confidentiality and personal data (see Section 14.3 and Section 14.5). These 
samples may be stored for a period of up to 5 years after completion of the final study report. 
After that period, any samples remaining will be destroyed. 
9.5 
APPROPRIATENESS OF MEASUREMENTS  
Each of the efficacy and safety assessments chosen for use in this study is considered well 
established and relevant in a hemato-oncology setting. In addition, suitable steps have been built 
into each of these assessments to ensure their reliability and accuracy and to minimize any risks to 
patient safety. 


 
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10 
STUDY PROCEDURES  
10.1 
VISIT SCHEDULE  
All patients entering the study must be evaluated according to the schedule outlined in the 
Flow Charts (see Section 1.2 and Section 1.3) and described below. The results of the evaluation 
will be recorded in the eCRF pages until the patients are no longer followed. 
10.1.1 Screening/baseline  
The screening assessments are to be performed within 21 days prior to randomization, unless 
indicated otherwise. All of the inclusion criteria (and none of the exclusion criteria) must be met, 
and informed consent must be signed by the patient before any study-specific procedure is 
performed. Inform consent can be signed more than 21 days prior to randomization. Screening 
time indicates in which time frame exams used to support eligibility have to be done prior to 
randomization. 
The following procedures are to be performed/assessed: 
• Signed informed consent. 
• Demography (age, gender, and race) and medical/surgical history (including smoking 
status). 
• Myeloma history and prior anti-myeloma treatment: Includes date of initial diagnosis of 
symptomatic MM, stage and type of disease at diagnosis and study entry (heavy and light 
chain component) and previous anti-myeloma therapy (including transplant if any, drug 
name, start and stop dates, intent, date of progression, best response, and reason for 
discontinuation). 
• Physical examination (≤7 days prior to randomization): Includes examination of main 
body systems including neurological, digestive, respiratory (signs and symptoms, 
respiratory rate), hepatic and spleen span, and lymph node examinations. Patient’s weight 
and height will be recorded. 
• Vital signs including blood pressure, heart rate, body temperature, and respiratory rate. 
• Cardiac ultrasonography (MUGA scan or MRI are accepted if it is the site practice). 
• 12-lead electrocardiogram (ECG). 
• ECOG PS. 
• Prior medications use in the 21 days prior to randomization. 
• All AEs/SAEs occurring after signed informed consent for all patients. 
Local laboratory assessments 
• Serum or urine pregnancy test to be performed prior to randomization (should be within 
7 days prior to first study treatment administration) for females of childbearing potential.  
• Hematology: Hemoglobin, hematocrit, red blood cells (RBC), white blood cells (WBC) 
with differential and platelet count. 


 
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• Blood chemistry: AST, ALT, bilirubin (total and direct), alkaline phosphatase, LDH, 
sodium, potassium, chloride, bicarbonate or carbon dioxide (venous) (if bicarbonate or 
carbon dioxide are assessed only on arterial blood at site level, to be done only if clinically 
indicated), calcium, corrected serum calcium, magnesium, phosphate, uric acid, serum 
creatinine and estimated creatinine clearance (MDRD Formula), urea or blood urea 
nitrogen (BUN), fasting glucose (according to site guidelines), albumin, and total protein. 
• Coagulation: Prothrombin time or international normalized ratio and activated partial 
thromboplastin time. 
• Quantitative or semi quantitative (according to site practice and if semi quantitative 
method can provide with an absolute numeric value of the parameters) urinalysis: RBCs, 
protein, glucose, pH, ketones, bilirubin, and leucocytes. 
• Serum β2-microglobulin. 
• Complete blood phenotyping (IKd arm only) if not already available (C,c; E,e; Kell. Kidd; 
Duffy; S,s is recommended, if not available follow site’s standard) and antibody screening 
(Indirect Coombs Test or Indirect Antiglobulin Test [IAT]), after randomization and prior 
to study treatment initiation. The blood type card will be kept by the patient with the study 
card. Blood transfusions are to be recorded in the eCRF. The blood bank needs to be 
informed that the patient is receiving a treatment with an anti-CD38 and a potential 
interference with the Coombs test is possible. 
Disease assessment: 
• Laboratory disease assessment (central laboratory): 
- 
Serum M protein: Immunoelectrophoresis and IF. 
- 
Urine M protein (24-hour urine): Immunoelectrophoresis and IF. 
- 
Serum FLCs: Quantification and ratio involved/non-involved. 
- 
Immunoglobulins: IgG, IgA, IgM, IgD, and IgE (IgD or E only if the heavy chain 
component of the disease is known to be E or D). 
• Bone marrow aspirate will be collected (local and central laboratory): 
- 
FISH (including, but may not be limited to, del(17p), t(4:14), t(14:16) and MRD 
analyses in central laboratory. Central laboratory samples for FISH will be collected 
and analyzed for all patients; R-ISS used as stratification factor will be assessed with 
FISH central laboratory results. Additional cytogenetic abnormalities will be tested 
including, but may not be limited to, del (1p) and gain (1q). Central laboratory samples 
for MRD will be collected for all patients but will be analyzed only for patients who 
will reach VGPR or better. 
- 
Bone marrow disease assessment (plasma cells involvement) in local laboratory. 
For this assessment, biopsy can be done if clinically indicated.  
Note: In case of randomization would be delayed due to unplanned event after BMA was done, 
BMA will not need to be done again if BMA remains within 8 weeks prior to randomization. 


 
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• Radiological disease assessment: 
- 
Skeletal survey (including skull, spine, all long bones, pelvis, and chest) or low dose 
whole body CT scan at baseline (see Appendix M, within 21 days prior to 
randomization). 
- 
Extramedullary disease (plasmacytoma) assessment (including bone plasmacytoma): 
- 
If known extramedullary disease at baseline, CT scan or MRI is to be done at 
baseline until PD (even for patients who would initiate further anti-myeloma 
therapy without PD). 
- 
If suspected extramedullary disease (plasmacytoma) at baseline, CT scan or MRI is 
to be done at baseline. 
Note: For bone lesion assessment and extramedullary disease, the same modality (skeletal survey 
or low-dose whole body CT scan; CT scan or MRI) should be used throughout the study for each 
individual patient. All imaging should be sent for central review. Intravenous contrast is 
recommended if not medically contra-indicated. Patients who have contra-indication to CT scan 
with IV contrast may have MRI exams performed instead. 
10.1.2 Randomization  
Randomization will take place once the consented patient has completed all the necessary 
screening procedures and is deemed eligible for study entry by the Investigator or designee (based 
on myeloma specific results from central laboratory [see below] and hematology/biochemistry 
local laboratory results). 
Results for central paraprotein must be available before the patient is randomized.  
All eligible patients must be randomized by contacting the IRT (see Section 8.3). 
The results of the screening examinations will be recorded in each randomized patient’s eCRF. 
Source documentation to support the screening results must be maintained in the patient’s medical 
record. Every effort should be done to start treatment within 3 working days of randomization. 
10.1.3 Treatment period  
Procedures to be performed on Day 1, Day 8 and on Day 15 can be performed within one day 
prior to study treatment administration unless specified otherwise. This is not applicable for 
samples to be drawn on D2, D9 and D16.  
10.1.3.1 Cycle 1 (Days 1-2, Days 8-9, Days 15-16, and Days 22-23)  
The following procedures are to be performed/assessed prior to first study treatment 
administration in both arms unless specified otherwise: 
• Physical examination on Days 1, 8, 15, and 22: Only main diagnoses will be reported in 
the eCRF as AEs or medical history. Signs and symptoms related to MM ongoing on 
Day 1 Cycle 1 will be recorded in AE page. 


 
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• Vital signs including blood pressure, heart rate, body temperature, and respiratory rate on 
Days 1, 2, 8, 9, 15, and 16 in both arms, plus on Day 22 in the IKd arm. In the IKd arm, 
vital signs are to be measured prior to start of each isatuximab infusion, 1 hour after start 
of each infusion, and at the end of each infusion. 
• 12-lead ECG on Day 1 if Screening test >7 days prior Day 1. 
• ECOG PS on Day 1. 
• Study treatment administration: 
- 
Isatuximab (IKd only) on Days 1, 8, 15, and 22. 
- 
Carfilzomib: Days 1, 2, 8, 9, 15, and 16. 
- 
Dexamethasone: Days 1, 2, 8, 9, 15, 16, 22, and 23. Oral dexamethasone will be 
recorded in patient diaries when not taken at site level. 
• ePROs on Day 1: EORTC QLQ-C30, QLQ-MY20, and EQ-5D-5L. 
• All AEs/SAEs throughout the cycle. 
• Concomitant medications from 21 days prior to randomization and then throughout the 
cycle. 
Local laboratory assessments: 
• Blood Chemistry 
- 
Full blood biochemistry prior to Day 1 if Screening test >7 days prior Day 1, and on 
Days 8, 15, and 22 administration: AST, ALT, bilirubin (total and direct), alkaline 
phosphatase, LDH, sodium, potassium, chloride, bicarbonate or carbon dioxide 
(venous) (if bicarbonate or carbon dioxide are assessed only on arterial blood at site 
level, to be done only if clinically indicated), calcium, corrected serum calcium, 
magnesium, phosphate, uric acid, serum creatinine and estimated creatinine clearance 
(MDRD Formula), urea or BUN, fasting glucose (according to site guidelines), 
albumin, and total protein. 
- 
Restricted biochemistry on Days 2, 9, and 16: Sodium, potassium, chloride, 
bicarbonate or carbon dioxide (venous), urea or BUN, serum creatinine, and estimated 
creatinine clearance (MDRD formula). 
• Hematology on Day 1 if Screening test >7 days prior Day 1, and on Days 1, 8, 15, and 22: 
Hemoglobin, hematocrit, RBC, WBC with differential and platelet count. 
• Serum or urine pregnancy test for females of childbearing potential.  
Central laboratory disease assessments: 
Values of the tests performed on Day 1 of Cycle 1 (prior to study treatment administration) will 
be the reference value to assess response during study treatment. Assessments on Day 1 include: 
• Serum M protein: Immunoelectrophoresis and IF. 
• Urine M protein (24-hour urine): Immunoelectrophoresis and IF. 
• Serum FLCs: Quantification and ratio involved/non-involved. 
• Immunoglobulins: IgG, IgA, IgM, IgD, and IgE (IgD or E only if the heavy chain 
component of the disease is known to be E or D). 


 
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Any unplanned laboratory disease assessment should be sent to central laboratory. 
Central laboratory assessments: 
• Immune genetic determinants (such as Fcγ receptor polymorphism). 
• IKd arm only: 
- 
Blood sample collection for PK (see Section 1.3). 
- 
Blood sample collection on Day 1 for ADA evaluation. 
- 
An additional blood sample will be collected to evaluate the potential interference of 
isatuximab in the M protein assessment (central laboratory). 
If clinically indicated only: 
• Coagulation at any time during the cycle. 
• Urinalysis at any time during the cycle: quantitative (RBC, protein, glucose, pH, ketones, 
bilirubin, and leucocytes) or qualitative (dipstick: blood, protein, glucose, pH, ketones, 
bilirubin, and leucocytes). 
• Bone marrow aspirate (BMA) for: 
- 
MRD analyses in central laboratory. Central laboratory samples for MRD will be 
collected only for patients who will reach VGPR or better (when it is confirmed). 
- 
Bone marrow disease assessment (% plasma cells) in case of VGPR or better (when it 
is confirmed) (local laboratory). Bone marrow biopsy can be done for sCR assessment 
as per Investigator decision.  
• Radiological disease assessment (the same method of assessment as at Screening is to be 
used throughout the study): 
- 
Skeletal survey (including skull, spine, all long bones, pelvis, and chest). 
- 
Extramedullary disease (plasmacytoma) assessment. 
10.1.3.2 Subsequent cycles (Days 1-2, Days 8-9, Days 15-16, and Days 22-23)  
The following procedures are to be performed/assessed prior to Day 1 administration in both arms 
unless specified otherwise: 
• Physical examination: Only the main diagnoses will be reported in the eCRF as AEs. 
• Vital signs including blood pressure, heart rate, body temperature, and respiratory rate on 
Days 1, 2, 8, 9, 15, and 16 in both arms. In the IKd arm, vital signs are to be measured 
prior to start of each isatuximab infusion, 1 hour after start of each infusion and at the end 
of each infusion (on Days 1 and 15 up to Cycle 4 and as clinically indicated). 
• 12-lead ECG. 
• ECOG PS. 
• Study treatment administration: 
- 
Isatuximab (IKd only) on Days 1 and 15. 
- 
Carfilzomib: Days 1, 2, 8, 9, 15, and 16. 
- 
Dexamethasone: Days 1, 2, 8, 9, 15, 16, 22, and 23. Oral dexamethasone will be 
recorded in patient diaries when not taken at site level. 


 
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• ePROs: EORTC QLQ-C30, QLQ-MY20, and EQ-5D-5L. 
• All AEs/SAEs throughout the cycle. 
• Concomitant medications at any time during the treatment period and up to 30 days after 
the last dose. 
Local laboratory assessments: 
• Blood chemistry: 
- 
Full blood biochemistry prior to Day 1 administration: AST, ALT, bilirubin (total and 
direct), alkaline phosphatase, LDH, sodium, potassium, chloride, bicarbonate or 
carbon dioxide (venous) (if bicarbonate or carbon dioxide are assessed only on arterial 
blood at site level, to be done only if clinically indicated), calcium, corrected serum 
calcium, magnesium, phosphate, uric acid, serum creatinine and estimated creatinine 
clearance (MDRD Formula), urea or BUN, fasting glucose (according to site 
guidelines), albumin, and total protein. 
- 
Restricted biochemistry prior to Days 8 and 15 administrations at Cycle 2, and then 
prior to Day 15 administration of each cycle thereafter: Sodium, potassium, chloride, 
bicarbonate or carbon dioxide (venous), urea or BUN, serum creatinine, and estimated 
creatinine clearance (MDRD formula). 
• Hematology prior to Days 1 and 15 administrations: Hemoglobin, hematocrit, RBC, WBC 
with differential and platelet count. 
• Serum or urine pregnancy test is to be done within one day before each cycle initiation for 
females of childbearing potential. 
• Indirect Coombs test will be repeated once after study treatment initiation on Day 1 at 
Cycle 2 or on Day 1 of a later cycle if not done at Cycle 2, only for patients in IKd arm. 
• One HBV serology test (HBsAg, anti-HBc and anti-HBs) in patients with HBV status 
unknown in September 2019. Patients with HBsAg positive and/or anti-HBc antibody 
positive should have also HBV DNA testing by polymerase chain reaction. To be repeated 
if clinically indicated.  
Central laboratory disease assessment: 
Assessments on Day 1 include: 
• Serum M protein: Immunoelectrophoresis and IF. 
• Urine M protein (24-hour urine): Immunoelectrophoresis and IF.  
After Cycle 1 Day 1, IF to be done if UPEP is negative in patients whose disease is 
evaluable in urine. The 24-hour urine collection should be completed prior new cycle 
initiation. If urine M protein is negative at baseline and Cycle 1 Day 1, this assessment is 
to be repeated every 3 cycles only (Cycle 4, Cycle 7, Cycle 10, etc) to confirm CR on 
blood labs. 
• Serum FLCs: Quantification and ratio involved/non-involved. 
• Immunoglobulins: IgG, IgA, IgM, IgD, and IgE (IgD or E only if the heavy chain 
component of the disease is known to be E or D). 
Any unplanned laboratory disease assessment should be sent to central laboratory. 


 
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Central laboratory assessments IKd arm only: 
• Blood sample collection for PK (see Section 1.3) up to Cycle 10. Pharmacokinetic samples 
are stopped after Cycle 10. 
• Blood sample collection on Day 1 up to Cycle 10 for ADA evaluation. In case of 
ADA positive or inconclusive at Cycle 10, one additional ADA will be sampled 3 months 
later. No further ADA will be sampled, even if this 3-month sample is positive. 
• An additional blood sample will be collected at all time-points to evaluate the potential 
interference of isatuximab in the M protein assessment (central laboratory) up to Cycle 30. 
This sample will be collected after Cycle 30 for patients who reach at least VGPR at this 
cycle until disease progression. In case of isatuximab is prematurely stopped definitive 
treatment discontinuation, sample interference assay will be collected up to 3 months after 
isatuximab discontinuation or PD, whichever comes first. 
If clinically indicated only: 
• Coagulation at any time during the cycle. 
• Urinalysis at any time during the cycle: Quantitative (RBC, protein, glucose, pH, ketones, 
bilirubin, and leucocytes) or qualitative (dipstick: blood, protein, glucose, pH, ketones, 
bilirubin, and leucocytes). 
• Bone marrow aspirate will be collected for: 
- 
MRD analyses in central laboratory. Central laboratory samples for MRD will be 
collected only for patients who will reach VGPR or better (when it is confirmed). If a 
patient presents ≥ VGPR but is determined MRD positive, another BM sample will be 
collected 3 months (3 cycles) later, in order to identify late negativity. A third sample 
may be collected after another 3 months if the patient remains MRD positive and is 
still being treated. No more than 3 post-baseline samples are to be obtained unless a 
patient achieves CR after a third BM sample MRD positive performed during VGPR. 
In this case, no more than 3 additional BM samples will be collected. Therefore, a 
maximum of 6 BMA could be performed by patient (no more than 3 per category of 
response). However, because BMA is invasive procedure, the following guidance is 
given in the purpose to limit as much as possible the number of BMA. 
For patients with CR without previous documentation of VGPR, first bone marrow 
for MRD assessment will be collected at time of confirmation of CR (ie, at the second 
time point showing CR) If patient is determined MRD positive, another BM sample 
will be collected 3 months (3 cycles) later, in order to identify late negativity. A third 
sample may be collected after another 3 months if the patient remains MRD positive 
and is still being treated. 
For patients with VGPR:  
- 
First bone marrow will be collected when VGPR is confirmed at the second time 
point or at a later time point as per investigator judgement based on kinetic of M 
protein decrease and/or if a plateau phase is reached (plateau is defined as variation 
less than 20% over 12 weeks [16]).  
- 
If MRD is positive on first BMA, a second BMA will be collected 3 months later 
(3 cycles) to identify late negativity.  


 
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- 
In case of MRD is still positive on second BMA made while patient is in VGPR, 
the timing to perform the third BMA can be postponed until CR achievement.  
- 
In case of the patient becomes CR and patient was MRD positive on the last BMA 
performed during VGPR, a BMA will be done for MRD assessment at time of 
confirmation of CR.   
- 
After the first BMA during CR is done and in case patient was MRD positive on 
this BMA, the additional BMA planned by the protocol can be discussed with the 
patient. 
- 
Bone marrow disease assessment (plasma cells involvement) in local laboratory in 
case of VGPR or better (when it is confirmed).  
In case of VGPR, plasma cell infiltration assessment is mandatory for patients in 
IKd arm with residual serum M protein of Ig G ≤ 0.5 g/dL and/or residual kappa IF 
positivity in urine, due to potential interference between isatuximab and M protein.  
In case of CR on M protein, plasma cell infiltration assessment is mandatory in 
IKd arm and in Kd arm, unless a previous assessment was made within 3 months and 
showed plasma cells ≤5%. 
Bone marrow biopsy can be done for sCR assessment as per investigator decision. 
• Radiological disease assessment (the same method of assessment as at Screening is to be 
used throughout the study): 
- 
Skeletal survey (including skull, spine, all long bones, pelvis, and chest X-rays) or 
whole body CT scan once a year and additional exam as clinically indicated. 
- 
Extramedullary disease (plasmacytoma) assessment every 12 weeks in case of existing 
plasmacytoma at baseline or as clinically indicated if no plasmacytoma at baseline. 
10.1.4 End of treatment  
The EOT visit will occur 30 days after last study treatment administration or before further 
anti-myeloma therapy initiation whichever comes first. The following procedures are to be 
performed at the EOT visit: 
• Physical examination. 
• Vital signs. 
• 12-lead ECG. 
• ECOG PS. 
• Serum or urine pregnancy for females of childbearing potential. 
• ePROs (EORTC QLQ-C30, QLQ-MY20, and EQ-5D-5L). 
• All AEs/SAEs occurring up to 30 days after last study treatment administration (will be 
collected in last treatment cycle). 
• Concomitant medications up to 30 days from last study treatment administration. 


 
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Local laboratory tests: 
• Blood chemistry: AST, ALT, bilirubin (total and direct), alkaline phosphatase, LDH, 
sodium, potassium, chloride, bicarbonate or carbon dioxide (venous) (if bicarbonate or 
carbon dioxide are assessed only on arterial blood at site level, to be done only if clinically 
indicated), calcium, corrected serum calcium, magnesium, phosphate, uric acid, serum 
creatinine and estimated creatinine clearance (MDRD Formula), urea or BUN, fasting 
glucose (according to site guidelines), albumin, and total protein. 
• Hematology: hemoglobin, hematocrit, RBC, WBC with differential and platelet count. 
Central laboratory disease assessment: 
• Serum M protein: Immunoelectrophoresis and IF. 
• Urine M protein (24-hour urine): Immunoelectrophoresis and IF. 
• Serum FLCs: Quantification and ratio involved/non-involved. 
• Immunoglobulins: IgG, IgA, IgM, IgD, and IgE (IgD or E only if the heavy chain 
component of the disease is known to be E or D). 
Any unplanned laboratory disease assessment should be sent to central laboratory. 
Central laboratory assessment IKd arm only: 
• Additional blood sample collected until disease progression for patients who experienced 
at least a VGPR up to 3 months after end of isatuximab (central laboratory). 
• ADA if the “3-month later” sample time is needed and occurs at EOT visit. No further 
ADA will be sampled, even if this 3-month sample is positive. 
If clinically indicated only: 
• Coagulation. 
• Urinalysis: quantitative (RBC, protein, glucose, pH, ketones, bilirubin, and leucocytes) or 
qualitative (dipstick: blood, protein, glucose, pH, ketones, bilirubin, and leucocytes). 
• Bone marrow aspirate will be collected for: 
- 
MRD analyses in central laboratory. Central laboratory samples for MRD will be 
collected only for patients who will reach VGPR or better (when it is confirmed). If a 
patient presents ≥ VGPR but is determined MRD positive, another BM sample will be 
collected 3 months (3 cycles) later, in order to identify late negativity. A third sample 
may be collected after another 3 months if the patient remains MRD positive and is 
still being treated. No more than 3 post-baseline samples are to be obtained unless a 
patient achieves CR after a third BM sample MRD positive performed during VGPR. 
In this case, no more than 3 additional BM samples will be collected. Therefore, a 
maximum of 6 BMA could be performed by patient (no more than 3 per category of 
response). However, because BMA is invasive procedure, the following guidance is 
given in the purpose to limit as much as possible the number of BMA. 
For patients with CR without previous documentation of VGPR, first bone marrow 
for MRD assessment will be collected at time of confirmation of CR (ie, at the second 
time point showing CR) If patient is determined MRD positive, another BM sample 


 
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will be collected 3 months (3 cycles) later, in order to identify late negativity. A third 
sample may be collected after another 3 months if the patient remains MRD positive 
and is still being treated. 
For patients with VGPR:  
- 
First bone marrow will be collected when VGPR is confirmed at the second time 
point or at a later time point as per investigator judgement based on kinetic of M 
protein decrease and/or if a plateau phase is reached (plateau is defined as variation 
less than 20% over 12 weeks [16]).  
- 
If MRD is positive on first BMA, a second BMA will be collected 3 months later 
(3 cycles) to identify late negativity.  
- 
In case of MRD is still positive on second BMA made while patient is in VGPR, 
the timing to perform the third BMA can be postponed until CR achievement.  
- 
In case of the patient becomes CR and patient was MRD positive on the last BMA 
performed during VGPR, a BMA will be done for MRD assessment at time of 
confirmation of CR.   
- 
After the first BMA during CR is done and in case patient was MRD positive on 
this BMA, the additional BMA planned by the protocol can be discussed with the 
patient. 
- 
Bone marrow disease assessment (plasma cells involvement) in local laboratory in 
case of VGPR or better (when it is confirmed).  
In case of VGPR, plasma cell infiltration assessment is mandatory for patients in IKd 
arm with residual serum M protein of Ig G ≤0.5 g/dL and/or residual kappa IF 
positivity in urine, due to potential interference between isatuximab and M protein.  
In case of CR on M protein, plasma cell infiltration assessment is mandatory in IKd 
arm and in Kd arm, unless a previous assessment was made within 3 months and 
showed plasma cells ≤5%. 
Bone marrow biopsy can be done for sCR assessment as per investigator decision. 
• Radiological disease assessment (the same method of assessment as at Screening is to be 
used throughout the study): 
- 
Skeletal survey (including skull, spine, all long bones, pelvis, and chest X-rays) or 
whole body CT scan once a year and additional exam as clinically indicated. 
- 
Extramedullary disease (plasmacytoma) assessment every 12 weeks in case of existing 
plasmacytoma at baseline or as clinically indicated if no plasmacytoma at baseline. 
10.1.5 Post study treatment follow-up  
Periodicity of follow-up visits to be performed after last study treatment administration will 
depend on reason of study treatment discontinuation: 
• Every 3 months for patients with previous confirmed disease progression. 
• Monthly for patients without previous confirmed disease progression up to confirmed 
disease progression (even if further anti-myeloma has been initiated before PD), and then 
every 3 months. 


 
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The following procedures are to be performed at each follow-up visit, whatever periodicity of 
FU visit:  
• All ongoing related AEs/all SAEs to be reported and followed up until resolution or 
stabilization, all new AEs (serious or not) related to study treatment up until resolution or 
stabilization and any second primary malignancy. 
• Further anti-myeloma therapies: Drug name, start and stop date, best overall response and 
date of PD according to Investigator assessment will be collected. 
• Survival status. 
For all patients, ePRO questionnaires 90 days after last study treatment administration will be 
completed (which corresponds to first FU visit in case of study treatment discontinuation due to 
PD or second FU visit in case of study treatment discontinuation without PD).   
Serum or urine pregnancy test for females of childbearing potential will be performed monthly 
during follow-up up to 3 months in the Kd and 5 months in IKd, and can be performed at home 
for the patients with follow-up every 3 months or if date of test does not match with a FU visit. 
The following procedures are to be performed every month in addition to the procedures above 
for patients without previous confirmed disease progression (even patients who would initiate 
further anti-myeloma therapy without PD, unless otherwise specified): 
• Central laboratory disease assessment: 
- 
Serum M protein: Immunoelectrophoresis and IF. 
- 
Urine M protein (24-hour urine): Immunoelectrophoresis and IF. 
- 
Serum FLCs: Quantification and ratio involved/non-involved. 
- 
Immunoglobulins: IgG, IgA, IgM, IgD, and IgE (IgD or E only if the heavy chain 
component of the disease is known to be E or D). 
Any unplanned laboratory disease assessment should be sent to central laboratory. 
• Central laboratory assessment IKd arm only: 
- 
In IKd arm only, additional blood sample collected until disease progression for 
patients who experienced at least a VGPR up to 3 months after end of isatuximab 
(central laboratory). 
• Radiological disease assessment (the same method of assessment as at Screening is to be 
used throughout the study) if indicated: 
- 
Skeletal survey (including skull, spine, all long bones, pelvis, and chest X-rays) or 
whole body CT scan once a year and additional exam as clinically indicated. 
- 
Extramedullary disease (plasmacytoma) assessment every 12 weeks in case of existing 
plasmacytoma at baseline or as clinically indicated if no plasmacytoma at baseline. 
• Bone marrow aspirate will be collected (except if further anti myeloma therapy is 
started): 
- 
For MRD analyses in central laboratory. Central laboratory samples for MRD will be 
collected only for patients who will reach VGPR or better (when it is confirmed). If a 
patient presents ≥ VGPR but is determined MRD positive, another BM sample will be 


 
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collected 3 months (3 cycles) later, in order to identify late negativity. A third sample 
may be collected after another 3 months if the patient remains MRD positive and is 
still being treated. No more than 3 post-baseline samples are to be obtained unless a 
patient achieves CR after a third BM sample MRD positive performed during VGPR. 
In this case, no more than 3 additional BM samples will be collected. Therefore, a 
maximum of 6 BMA could be performed by patient (no more than 3 per category of 
response). However, because BMA is invasive procedure, the following guidance is 
given in the purpose to limit as much as possible the number of BMA. 
For patients with CR without previous documentation of VGPR, first bone marrow 
for MRD assessment will be collected at time of confirmation of CR (ie, at the second 
time point showing CR) If patient is determined MRD positive, another BM sample 
will be collected 3 months (3 cycles) later, in order to identify late negativity. A third 
sample may be collected after another 3 months if the patient remains MRD positive 
and is still being treated. 
For patients with VGPR:  
- 
First bone marrow will be collected when VGPR is confirmed at the second time 
point or at a later time point as per investigator judgement based on kinetic of M 
protein decrease and/or if a plateau phase is reached (plateau is defined as variation 
less than 20% over 12 weeks [16]).  
- 
If MRD is positive on first BMA, a second BMA will be collected 3 months later 
(3 cycles) to identify late negativity.  
- 
In case of MRD is still positive on second BMA made while patient is in VGPR, 
the timing to perform the third BMA can be postponed until CR achievement.  
- 
In case of the patient becomes CR and patient was MRD positive on the last BMA 
performed during VGPR, a BMA will be done for MRD assessment at time of 
confirmation of CR.   
- 
After the first BMA during CR is done and in case patient was MRD positive on 
this BMA, the additional BMA planned by the protocol can be discussed with the 
patient. 
- 
For bone marrow disease assessment (plasma cells involvement) in local laboratory in 
case of VGPR or better (when it is confirmed).  
In case of VGPR, plasma cell infiltration assessment is mandatory for patients in IKd 
arm with residual serum M protein of Ig G ≤0.5 g/dL and/or residual kappa IF 
positivity in urine, due to potential interference between isatuximab and M protein.  
In case of CR on M protein, plasma cell infiltration assessment is mandatory in IKd 
arm and in Kd arm, unless a previous assessment was made within 3 months and 
showed plasma cells ≤5%. 
Bone marrow biopsy can be done for sCR assessment as per investigator decision. 


 
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10.1.6 After Implementation of Amended Protocol #10  
Death date will be collected when site is informed of death. In addition, survival status will be 
collected twice a year after the implementation of amended protocol #10 until death, or OS 
analysis cut-off date, whichever comes first.   
Patients still on study treatment at the implementation of amended protocol #10 can continue 
study treatment until at least 1 treatment discontinuation criterion as defined in Section 10.3.2 is 
met. Patients will be managed according to the site practice. The following information will be 
collected during the study treatment administration: 
• IP administration. 
• All SAEs regardless of relationship to study treatment, AEs considered related to study 
treatment and any second primary malignancy. 
• Hematology and biochemistry, or any other laboratory results supporting the reported 
AEs. 
• Other procedures supporting the reported AEs. 
• Serum or urine pregnancy test for females of childbearing potential 
• End of treatment reason. 
• If patients received 10 or less cycles at the cut-off date and last ADA prior the final PFS 
analysis cut-off date is positive or inconclusive, additional ADA 3 months later sample to 
be done. No further ADA will be sampled, even if this 3-month sample is positive (central 
laboratory). 
No follow-up information will be collected after these patients discontinue study treatment except: 
• All SAEs still ongoing at the end of study treatment and all AEs considered as related to 
study treatment still ongoing or occurring after the end of study treatment, which will be 
followed until resolution/stabilization. 
• Survival status and further anti-myeloma therapies twice a year if study treatment is 
stopped before the OS cut-off date. 
• Serum or urine pregnancy test for females of childbearing potential will be performed 
monthly during follow-up up to 3 months in the Kd and 5 months in IKd, and can be 
performed at home. 
10.1.7 Post OS analysis cut-off date  
Patients still on study treatment at the OS analysis cut-off date can continue study treatment until 
at least 1 treatment discontinuation criterion as defined in Section 10.3.2 is met. Patients will be 
managed according to the site practice. The following information will be collected during the 
study treatment administration: 
• IP administration. 
• All SAEs regardless of relationship to study treatment and AEs considered related to study 
treatment. 
• Hematology and biochemistry, or any other laboratory results supporting the reported 
AEs. 


 
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• Other procedures supporting the reported AEs. 
• Serum or urine pregnancy test for females of childbearing potential 
• End of treatment reason. 
• Death date and reason if occurred during study treatment.  
No follow-up information will be collected after these patients discontinue study treatment except: 
• All SAEs still ongoing at the end of study treatment and all AEs considered as related to 
study treatment still ongoing or occurring after the end of study treatment, which will be 
followed until resolution/stabilization. 
• Death date and reason if occurred in follow-up period due to related AE. 
• Serum or urine pregnancy test will be performed monthly during follow-up up to 3 months 
in the Kd and 5 months in IKd, and can be performed at home. 
10.2 
DEFINITION OF SOURCE DATA  
Source data includes all information in original records and certified copies of original records of 
clinical findings, observations, or other activities necessary for the reconstruction and evaluation 
of the trial. Source data are contained in source documents. 
Source documents are original documents, data, and records (eg, hospital records, clinical and 
office charts, laboratory notes, memoranda, patient diaries or evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, copies or transcripts certified after 
verification as being accurate and complete, microfiches, photographic negatives, microfilm or 
magnetic media, X-rays, patient files, and records kept at the pharmacy, at the laboratories, and at 
medical-technical departments) involved in the clinical study. Source documentation must be 
maintained to support information provided within a CRF. 
10.3 
HANDLING OF PATIENT PERMANENT TREATMENT DISCONTINUATION AND OF 
PATIENT STUDY DISCONTINUATION  
The study treatment should be continued whenever possible. Any study treatment discontinuation 
must be fully documented in the eCRF. In any case, the patient should remain in the study as long 
as possible. 
Pregnancy will lead to definitive treatment discontinuation in all cases. 
10.3.1 Permanent treatment discontinuation with investigational medicinal product(s)  
Permanent treatment discontinuation is any treatment discontinuation associated with the 
definitive decision from the Investigator not to re-expose the patient to the study treatment at any 
time during the study, or from the patient not to be re-exposed to the study treatment whatever the 
reason. 


 
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10.3.2 List of criteria for permanent treatment discontinuation  
The patients may withdraw from treatment with the study treatment if they decide to do so, at any 
time and irrespective of the reason, or this may be the Investigator’s decision. All efforts should 
be made to document the reason(s) for treatment discontinuation and this should be documented 
in the eCRF. 
Isatuximab, carfilzomib, and/or dexamethasone can be discontinued prematurely. The patient will 
remain on study treatment until the last study treatment is discontinued. The reason for premature 
discontinuation will be captured in the appropriate eCRF page. 
All efforts should be made to document the reason for discontinuation of treatment with the study 
treatment:  
• At the patient’s request, at any time and irrespective of the reason (consents withdrawal), 
or at the request of their legally authorized representative. “Legally authorized 
representative” is considered to be an individual or judicial or other body authorized under 
applicable law to consent on behalf of a prospective patient to the patient’s participation in 
the procedure(s) involved in the research. Withdrawal of consent for treatment should be 
distinguished from withdrawal of consent for follow-up visits and from withdrawal of 
consent for non-patient contact follow-up, eg, medical records check. Patients requesting 
withdrawal should be informed that withdrawal of consent for follow-up may jeopardize 
the public health value of the study. The Investigator should make every effort to 
re-contact the patient, to identify the reason why he/she decided to withdraw, and to 
determine his/her health status, including at least his/her vital status.  
• If, in the Investigator’s opinion, continuation of the study treatment would be detrimental 
to the patient’s wellbeing, such as: 
- 
Disease progression. 
- 
Unacceptable AE. 
- 
Poor compliance to the study protocol. 
- 
Any other reason such as intercurrent illness that prevents further administration of 
study treatment (will be specified). 
• Patient is lost to follow-up. 
If patients are clinically stable, and possibly deriving clinical benefit from therapy with minimal 
toxicity, the patient will be maintained on treatment for the maximum period of time defined in 
Section 6.2. 
Patients who have been withdrawn from the study treatment cannot be re-included in the study. 
Their inclusion and treatment number must not be re-used. 
10.3.3 Handling of patients after permanent treatment discontinuation  
Patients will be followed-up according to the study procedures specified in this protocol up to the 
scheduled date of study completion, or up to recovery or stabilization of any AE to be 
followed-up as specified in this protocol, whichever comes last. 


 
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If possible, and after the permanent discontinuation of treatment, the patients will be assessed 
using the procedure normally planned for the EOT and follow-up visits. 
All cases of permanent treatment discontinuation must be recorded by the Investigator in the 
appropriate pages of the eCRF when considered as confirmed. 
10.3.4 Procedure and consequence for patient withdrawal from study  
The patients may withdraw from the study before study completion if they decide to do so, at any 
time and irrespective of the reason without any effect on their care. However, if patients no longer 
wish to take the study treatment, they will be encouraged to remain in the study. 
The Investigators should discuss with them key visits to attend. The value of all their study data 
collected during their continued involvement will be emphasized as important to the public health 
value of the study. 
Patients who withdraw from the study treatment should be explicitly asked about the contribution 
of possible AEs to their decision, and any AE information elicited must be documented.  
All study withdrawals must be recorded by the Investigator in the appropriate screens of the eCRF 
and in the patient’s medical records. In the medical record, at least the date of the withdrawal and 
the reason should be documented. 
In addition, a patient may withdraw his/her consent to stop participating in the study. Withdrawal 
of consent for treatment should be distinguished from withdrawal of consent for follow-up visits 
and from withdrawal of consent for non-patient contact follow-up, eg, medical record checks. The 
site should document any case of withdrawal of consent. 
For patients who fail to return to the site, unless the patient withdraws consent for follow-up, the 
Investigator must make the best effort to recontact the patient (eg, contact patient’s family or 
private physician, review available registries or health care databases), and to determine his/her 
health status, including at least his/her vital status. Attempts to contact such patients must be 
documented in the patient’s records (eg, times and dates of attempted telephone contact, receipt 
for sending a registered letter). 
The SAP will specify how these patients lost to follow-up for their primary endpoint will be 
considered. 
Patients who have withdrawn from the study cannot be re-randomized (treated) in the study. Their 
inclusion and treatment numbers must not be reused.  


 
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10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING  
10.4.1 Definitions of adverse events  
10.4.1.1 Adverse event  
An AE is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment. 
10.4.1.2 Serious adverse event  
An SAE is any untoward medical occurrence that at any dose: 
• Results in death, or 
• Is life-threatening, or 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which 
the patient was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
• Requires inpatient hospitalization or prolongation of existing hospitalization, or 
• Results in persistent or significant disability/incapacity, or 
• Is a congenital anomaly/birth defect, or 
• Is a medically important event. 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize the 
patient or may require medical or surgical intervention (ie, specific measures or corrective 
treatment) to prevent one of the other outcomes listed in the definition above. 
Note: The following list of medically important events is intended to serve as a guideline 
for determining which condition has to be considered a medically important event. The list 
is not intended to be exhaustive: 
- 
Intensive treatment in an emergency room or at home for: 
- 
Allergic bronchospasm. 
- 
Convulsions (seizures, epilepsy, epileptic fit, absence, etc.). 
- 
Development of drug dependence or drug abuse. 
- 
Suicide attempt or any event suggestive of suicidality. 
- 
Syncope, loss of consciousness (except if documented as a consequence of blood 
sampling). 
- 
Bullous cutaneous eruptions. 


 
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10.4.1.3 Adverse event of special interest  
An adverse event of special interest (AESI) is an AE (serious or nonserious) of scientific and 
medical concern specific to isatuximab, for which ongoing monitoring and immediate notification 
by the Investigator to the Sponsor is required. Such events may require further investigation in 
order to characterize and understand them. Adverse events of special interest may be added, 
modified or removed during a study by protocol amendment. 
The following AEs are considered AESIs: 
• IARs Grade ≥ 3 (please refer to the current edition of the Investigator’s brochure for IARs 
manifestations reported in patients treated with isatuximab). An IAR is a related AE 
typically with onset within 24 hours from the start of drug infusion. 
• Pregnancy of a female patient entered in a study as well as pregnancy occurring in a 
female partner of a male patient entered in this study (see Section 10.4.1.4). 
• Symptomatic overdose (serious or nonserious) with study treatment (isatuximab or 
carfilzomib or dexamethasone) / NIMP (see Section 10.4.1.5): 
- 
An overdose (accidental or intentional) with the study treatment is an event suspected 
by the Investigator or spontaneously notified by the patient (not based on systematic 
pills count). 
- 
Of note, asymptomatic overdose has to be reported as a standard AE. 
10.4.1.4 Pregnancy  
Pregnancy of a female patient entered in a study (as well as pregnancy occurring in a female 
partner of a male patient entered in this study) will be recorded as an AE in all cases. It will be 
qualified as a SAE only if it fulfills SAE criteria (See Section 10.4.1.2). 
In the event of pregnancy in a female patient, study treatment should be discontinued and the 
Monitoring Team should be informed immediately (within 24 hours), even if the event does not 
fulfill a seriousness criterion, using the AE form together with the SAE complementary form to be 
sent to the representative of the Monitoring Team whose name, address and fax number appear on 
page 2 of the clinical trial protocol. 
Follow-up of the pregnancy is mandatory until the outcome has been determined and for up to 
1 year after the delivery of a newborn. 
10.4.1.5 Overdose  
In case of accidental or intentional overdose (at least 30% above the intended administered dose  
of isatuximab and carfilzomib at each administration, at least 30% above the intended 
administered dose of dexamethasone at each cycle) with the study treatment, even not fulfilling a 
seriousness criterion, is to be reported to the Sponsor immediately (within 24 hours) using the AE 
form together with the SAE complementary form to be entered in the eCRF. 
Non-investigational medicinal product overdose is defined as at least twice the intended dose 
within the intended therapeutic interval. 


 
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10.4.2 General guidelines for reporting adverse events  
• All AEs, regardless of seriousness or relationship to study treatment, spanning from the 
signature of the informed consent form until the end of the study as defined by the protocol for 
that patient, are to be recorded on the corresponding page(s) or screen(s) of the eCRF. 
• Whenever possible, diagnosis or single syndrome should be reported instead of symptoms. 
The Investigator should specify the date of onset, intensity, action taken with respect to 
study treatment, corrective treatment/therapy given, additional investigations performed, 
outcome, and his/her opinion as to whether there is a reasonable possibility that the AE 
was caused by the study treatment or by the study procedure(s). 
• The Investigator should take appropriate measures to follow all AEs until clinical recovery 
is complete and laboratory results have returned to normal, or until progression has been 
stabilized, or until death, in order to ensure the safety of the patients. This may imply that 
observations will continue beyond the last planned visit per protocol, and that additional 
investigations may be requested by the monitoring team up to as noticed by the Sponsor. 
Patients who experience an ongoing SAE or an AESI, at the prespecified study end-date, 
should be followed until resolution, stabilization, or death and related data will be 
collected. The duration of post-study follow-up and reporting of AEs will be specified  
(eg, until recovery). 
• When treatment is prematurely discontinued, the patient’s observations will continue until 
the end of the study as defined by the protocol for that patient. 
• Laboratory abnormalities are to be recorded as AEs only if the lead to an action taken on 
study treatment (dose reduction, dose delay, dose interruption, study treatment 
discontinuation) or if they are serious. 
• Vital signs or ECG abnormalities are to be recorded as AEs only if:  
- 
Symptomatic and/or  
- 
Requiring either corrective treatment or consultation, and/or  
- 
Leading to study treatment discontinuation or modification of dosing, and/or  
- 
Fulfilling a seriousness criterion, and/or  
- 
Defined as an AESI. 
Instructions for AE reporting are summarized in Table 12. 
10.4.3 Instructions for reporting serious adverse events  
In the case of occurrence of an SAE, the Investigator or any designees must immediately: 
• ENTER (within 24 hours) the information related to the SAE in the appropriate screens of 
the eCRF; the system will automatically send a notification to the monitoring team after 
approval of the Investigator within the eCRF or after a standard delay. 
• There may be instances when copies of medical records for certain cases are requested by 
Sanofi. In such case, care should be taken to ensure that the patient's identity is protected 
and the patient's identifiers in the study are properly mentioned on any copy of a source 
document provided to the Company. For laboratory results, include the laboratory normal 
ranges.  


 
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• All further data updates should be recorded in the eCRF, as appropriate, within 24 hours of 
knowledge of the SAE. In addition, every effort should be made to further document any 
SAE that is fatal or life-threatening within a week (7 days) of the initial notification. 
• A back-up plan (using a paper CRF process) is available and should be used when the 
eCRF system does not work. 
Any SAE brought to the attention of the Investigator at any time after the end of the study for the 
patient and considered by him/her to be caused by the study treatment with a reasonable 
possibility, should be reported to the monitoring team. 
10.4.4 Guidelines for reporting adverse events of special interest  
For AESIs, the Sponsor must be informed immediately (ie, within 24 hours), as per SAE 
notification guidelines described in Section 10.4.3, even if not fulfilling a seriousness criterion, 
using the corresponding screens in the eCRF. Instructions for AE reporting are summarized in 
Table 12. 
10.4.5 Guidelines for reporting product complaints  
Any defect in the study treatment must be reported as soon as possible by the Investigator to the 
monitoring team that will complete a product complaint form within required timelines. 
Appropriate information (eg, samples, labels or documents like pictures or photocopies) related to 
product identification and to the potential deficiencies may need to be gathered. The Investigator 
will assess whether or not the quality issue has to be reported together with an AE or SAE. 
Table 12 - Summary of adverse event reporting instructions  
Event 
category 
Reporting 
timeframe 
Specific events in this 
category 
Case Report Form completion 
AE form 
Safety  
Complementary 
Form 
Other 
specific 
forms 
Adverse Event 
(non-SAE, 
non-AESI) 
Routine 
Any AE that is not SAE or AESI 
Yes 
No 
No 
Serious Adverse 
Event (non-AESI 
or AESI) 
Expedited 
(within 24 
hours) 
Any AE meeting seriousness criterion 
per Section 10.4.1.2 
Yes 
Yes 
No 
Adverse Event 
of Special 
Interest  
Expedited 
(within 24 
hours) 
IARs of Grade ≥3 
Yes 
Yes 
No 
 
 
Pregnancy 
Yes 
Yes 
Yes 
 
 
Symptomatic overdose 
Yes 
Yes 
No 


 
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10.5 
OBLIGATIONS OF THE SPONSOR  
During the course of the study, the Sponsor will report in an expedited manner: 
• All SAEs that are both unexpected and at least reasonably related to the study treatment, to 
the regulatory authorities, independent ethics committee (IECs)/institutional review boards 
(IRBs) as appropriate and to the Investigators. 
• All SAEs that are expected and at least reasonably related to study treatment to the 
regulatory authorities, according to local regulations. 
• The AESIs listed in Section 10.4.1.3 to the regulatory authorities requiring such reporting. 
Adverse events that are considered expected will be specified by the reference safety information 
(see the current version of the Investigator’s Brochure). 
The Sponsor will report all safety observations made during the conduct of the trial in the clinical 
study report. 
10.6 
SAFETY INSTRUCTIONS  
10.6.1 Guidelines for the management of potential infusion associated reactions  
Patients should routinely receive premedications prior to study treatment infusion as detailed in 
Section 8.2.2 to reduce the risk and severity of IARs commonly observed with mAbs. 
Details for management of IARs are provided in Section 8.2.5. 
10.6.2 Guidelines for the management of tumor lysis syndrome  
Details for the management of TLS are provided in Section 8.2.9. 
10.7 
ADVERSE EVENTS MONITORING  
All adverse events will be managed and reported in compliance with all applicable regulations, 
and included in the final clinical study report. 


 
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11 
STATISTICAL CONSIDERATIONS  
The statistical considerations presented in this section forms the basis for the SAP, which will 
provide accurate definitions and detailed specifications for the analyses to be performed on the 
data collected from this study. A final SAP will be issued prior to first patient treated. 
11.1 
DETERMINATION OF SAMPLE SIZE  
The sample size calculation is based on the primary efficacy endpoint (ie, PFS). The following 
assumptions were used: 
• Kd arm has a median PFS of 19 months. 
• IKd arm will have 41% risk reduction in hazard rate in comparison to Kd arm. The 
targeted hazard ratio is 0.59. Assuming proportional hazards, this is expected to 
correspond to an improvement in the true median PFS time from 19 months to 32 months. 
• Log-rank test at a 1-sided 2.5% significance level. 
• 3:2 randomization ratio (IKd:Kd). 
• An interim analysis for efficacy assessment of PFS is planned when 65% of the 159 PFS 
events will be observed. An O’Brien and Fleming α-spending function will be used to 
obtain the nominal significance levels for the interim and final analyses of PFS  
(see Section 11.5 for details). 
Based on the above assumptions, a total of 159 PFS events are needed to achieve a 90% power for 
the study.  
In addition, with a total of 300 patients (180 patients in IKd arm and 120 patients in Kd arm) and 
assuming a uniform accrual rate of 19 patients per month, the final PFS analysis cut-off date is 
expected to be approximately 36 months after first patient in. 
Calculations were made using East 6.4 software. 
11.2 
DISPOSITION OF PATIENTS  
Screened patients are defined as any patients who signed the study informed consent. 
Randomized patients consist of all patients with a signed informed consent who have been 
allocated a randomization number by the IRT, regardless of whether the patient was treated or not. 
Patients treated without being randomized will not be considered as randomized and will not be 
included in any analysis population. The safety experience of such patients will be reported 
separately. 
For any patient randomized more than once, only the data associated with the first randomization 
will be used in any analysis population. The safety experience associated with any later 
randomization will be assessed separately. 
The number of screened patients as well as the number and percentage of patients included in the 
analysis populations defined in Section 11.3 will be provided. 


 
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A summary of the reasons for definitive and premature treatment discontinuation by treatment 
group will be provided. 
11.3 
ANALYSIS POPULATIONS  
11.3.1 Efficacy populations  
11.3.1.1 Intent-to-treat population  
The intent-to-treat (ITT) population is the randomized population. All patients who have given 
their informed consent and for whom there is confirmation of successful allocation of a 
randomization number by the IRT will be included in this population. Patients will be analyzed 
according to the treatment group allocated by IRT, regardless of whether the patients received any 
study treatment or receive a different study treatment from that to which they were randomized. 
This population is the primary population for all efficacy analyses. 
11.3.2 Safety population  
The safety population will include ITT patients who received at least 1 dose or a part of a dose of 
study treatment.  
This population is the primary population for the analysis of all safety parameters. All analyses 
using this population will be based on the actual treatment received. For instance, patients who 
receive at least 1 isatuximab dose (even incomplete) during the trial, will be allocated to the 
IKd arm. 
11.3.3 Pharmacokinetic population  
The PK population will include safety population patients from the IKd arm who receive at least 
1 dose of isatuximab, even if incomplete, with data for at least 1 PK concentration available 
post-baseline.  
11.3.4 ADA population  
The ADA population will include safety population patients from the IKd arm with a least 1 ADA 
assessment during the ADA on-study observation period with a reportable result. 
11.4 
STATISTICAL METHODS  
A list of study endpoints and their definitions are provided in Section 9. 
Continuous data will be summarized for each treatment group using number of available 
observations, mean, standard deviation, median, minimum, and maximum. Categorical and 
ordinal data will be summarized using number and percentage of patients. 


 
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11.4.1 Extent of study treatment exposure and compliance  
The extent of study treatment exposure will be assessed and summarized by actual treatment 
received within the safety population. 
The following variables will be described to summarize the overall study treatment exposure 
(all study treatments together): 
• Overall number of cycles started, defined by the total number of cycles in which at least 
one dose of any study treatments is administered. 
• Overall duration of exposure in weeks defined as [(last day of last cycle – first day of first 
cycle)/7]. 
The first day of the first cycle is defined as the date of the first dose of study treatment at Cycle 1. 
The last day of last cycle is defined as the last date among the following: 
• Date of last dose of isatuximab + 7 days if last cycle is Cycle 1 or date of last dose of 
isatuximab + 14 days if last cycle is Cycle 2 or later,  
• Date of last dose of carfilzomib + 7 days if the last dose is administered on Day 1 or 8; or 
date of last dose of carfilzomib + 6 days if the last dose is administered on Day 2 or 9; or 
date of last dose of carfilzomib + 14 days if the last dose is administered on Day 15; or 
date of last dose of carfilzomib + 13 days is the last dose is administered on Day 16, 
• Date of last dose of dexamethasone + 7 days if the last dose is administered on Days 1, 8, 
15, or 22; or date of last dose of dexamethasone + 6 days if the last dose is administered on 
Days 2, 9, 16, or 23. 
Cycle delay will be computed to describe overall dose modification. A cycle is deemed to have 
been delayed if the start date of the current cycle is >28 + 3 days beyond the start date of the 
previous cycle (planned cycle duration is 28 days). 
In addition, the following variables will be summarized with descriptive statistics for isatuximab, 
carfilzomib, and dexamethasone separately: 
• Number of cycles started with each drug. 
• Duration of exposure in weeks, defined as: 
- 
For isatuximab:  
[date of last dose of isatuximab + 7 days - first dose of isatuximab] / 7 if last cycle is 
Cycle 1 or [date of last dose of isatuximab + 14 days - first dose of isatuximab] / 7 if 
last cycle is Cycle 2 or later, 
- 
For carfilzomib:  
[date of last dose of carfilzomib + 7 days - first dose of carfilzomib] / 7 if the last dose 
is administered on Day 1 or 8; or [date of last dose of carfilzomib + 6 days - first dose 
of carfilzomib] / 7 if the last dose is administered on Day 2 or 9; or  
[date of last dose of carfilzomib + 14 days - first dose of carfilzomib] / 7 if the last 
dose is administered on Day 15; or  
[date of last dose of carfilzomib + 13 days - first dose of carfilzomib] / 7 if the last 
dose is administered on Day 16, 


 
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- 
For dexamethasone: [date of last dose of dexamethasone + 7 days - first dose of 
dexamethasone] / 7 if the last dose is administered on Days 1, 8, 15, and 22; or  
[date of last dose of dexamethasone + 6 days - first dose of dexamethasone] / 7 if the 
last dose is administered on Days 2, 9, 16, and 23. 
• Cumulative dose: The cumulative dose is the sum of all doses administered from first to 
last dose. 
• Actual dose intensity: Defined as the cumulative dose divided by the duration of exposure. 
• Relative dose intensity (RDI): Defined as the ratio of the actual dose intensity to the 
planned dose intensity. The RDI is an indicator of the feasibility of the chosen schedule of 
administration. 
• Number of infusions (excluding dexamethasone). 
• Infusion interruption (excluding dexamethasone): An infusion is considered to be 
interrupted if the administration is stopped during an infusion before it is completed 
regardless it is further restarted or not. 
• Infusion/dose delay within cycle: An infusion/dose is deemed to have been delayed if the 
actual start date is >1 day beyond the theoretical day of treatment. Infusion/dose delay 
does not apply to the first infusion/dose of each cycle, in which case it is considered as 
cycle delay.  
• Dose reduction: A dose is considered to be administered at a reduced dose if the actual 
dose administered at the current administration is at least one level below the prior 
administration. In addition, if the dose of carfilzomib is not increased to 56 mg/m2 from 
C1D8 as planned per protocol, this will be also considered as a dose reduction. Although 
not allowed in the study protocol for isatuximab, potential dose reduction will be screened 
and reported in the clinical study report.  
• Dose omission: A dose is considered omitted if the dose is not administered for the 
scheduled visit and there are positive dose(s) afterwards. 
11.4.2 Analyses of efficacy endpoints  
11.4.2.1 Analysis of primary efficacy endpoint  
Primary analysis will consist of PFS comparison between IKd arm versus Kd arm through a 
log-rank test procedure stratified by stratification factors as entered in the IRT (ie, number of 
previous lines of therapy and R-ISS). The significance levels at the interim and final analyses will 
be determined using alpha-spending function (see Section 11.5). 
This analysis will be performed on the ITT population. 
The analysis of PFS will be based on the following censoring rules: 
• If progression and death are not observed before the PFS analysis cut-off date or the date 
of initiation of further anti-myeloma treatment, PFS will be censored at the date of the last 
valid disease assessment not showing disease progression performed prior to initiation of a 
further anti-myeloma treatment (if any) or the analysis cut-off date, whichever comes first.  
• A patient without an event (death or disease progression) and without any valid 
post-baseline disease assessments will be censored at the day of randomization (Day 1). 


 
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The date of disease progression is the date of the first documented (that is subsequently 
confirmed, if based on paraprotein) progression according to IMWG criteria as assessed by IRC 
(see Appendix F). 
The final PFS analysis cut-off date will be the date when the 159th event (first occurrence of either 
disease progression or death due to any cause) assessed by the IRC has been observed. 
The estimates of the hazard ratio and corresponding (1-2α) % CI (α being the one-sided nominal 
significance level: α=0.023 at final analysis and 0.005 at PFS interim analysis) will be provided 
using a Cox proportional hazard model stratified by the stratification factors as entered in the IRT. 
The median PFS and probabilities of being progression free at different time points calculated 
using the Kaplan-Meier method as well as corresponding CI will be presented by treatment arm. 
The Kaplan-Meier PFS curves will also be presented. 
Sensitivity analyses of PFS will be performed (eg, different censoring rules and PFS assessed by 
the Investigator). In particular, a sensitivity analysis has been added to evaluate the impact of late 
progressions and deaths. In this sensitivity analysis, progressions or deaths occurring more than 
8 weeks after the last disease assessment (corresponding to two consecutive missed assessments) 
will be censored at the earliest of the date of last valid disease assessment without evidence of 
progression before initiation of new anti-myeloma treatment and the cut-off date. Subgroup 
analyses of PFS (eg, by high risk cytogenetic status, number of prior lines of treatment) will also 
be conducted. 
11.4.2.2 Analyses of secondary efficacy endpoints  
11.4.2.2.1 Analysis of key secondary efficacy endpoints  
Key secondary endpoints other than OS will be analyzed in the ITT population at the time of the 
primary and/or the final analysis of PFS (based on data collected up to the PFS analysis cut-off 
date). The CR rate will only be tested for comparison when the antibody-capture interference 
assay will be available. 
Key secondary endpoints other than OS will be summarized with descriptive statistics per 
treatment arm. The (1-2α) % 2-sided CI will be computed using the Clopper-Pearson method. 
These endpoints will be compared between treatment arms using Cochran Mantel Haenszel 
stratified method. 
For analysis purpose, subjects in the ITT population without MRD assessment will be considered 
as having positive MRD. In addition, analyses on MRD negativity rate will be also performed on 
the ITT population but restricted to patients with VGPR or better as per investigator, as 
exploratory analyses. 
The OS analysis will be similar to what is described for PFS and will be performed approximately 
3 years after the primary PFS analysis cut-off date. The analysis of OS will consist of comparison 
between the IKd arm versus Kd arm through a log-rank test procedure stratified by stratification 
factors as entered in the IRT (ie, number of previous lines of therapy and R-ISS) at the 1-sided 
level of 0.025. The analysis will be based on the following censoring rule: 
• Patients without death prior to the OS analysis cut-off date will be censored at the last date 
the patient was known to be alive or the OS analysis cut-off date, whichever comes first. 


 
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The estimates of the hazard ratio and corresponding 95% CI will be provided using a Cox 
proportional hazard model stratified by the stratification factors as entered in the IRT. The median 
OS and probabilities of being surviving at different time points calculated using the Kaplan-Meier 
method as well as corresponding CI will be presented by treatment arm. The Kaplan-Meier OS 
curves will also be provided. 
Subgroup analyses of OS (eg, by high risk cytogenetic status, number of prior lines of treatment) 
will also be conducted. 
11.4.2.2.2 Analysis of other secondary efficacy endpoints  
Other secondary endpoints will be analyzed at the time of the primary analysis and/or the final 
PFS analysis. 
The analyses of TTP, PFS2, DOR, time to first response and time to best response will be similar 
to what is described for PFS and will be based on the following censoring rules:  
• TTP: If progression is not observed before the PFS analysis cut-off date or the date of 
initiation of further anti-myeloma treatment, TTP will be censored at the date of the last 
valid disease assessment not showing disease progression performed prior to initiation of a 
further anti-myeloma treatment (if any) or the analysis cut-off date, whichever comes first. 
• PFS2: For patients alive without a progression after initiation of further anti-myeloma 
treatment before the PFS analysis cut-off date, PFS2 will be censored at the date of the last 
follow-up visit not showing disease progression after initiation of further anti-myeloma 
treatment or the analysis cut-off date, whichever comes first. 
• DOR: In the absence of the confirmation of subsequent disease progression or death 
before the analysis cut-off date, the DOR will be censored at the date of the last valid 
disease assessment not showing disease progression performed prior to initiation of a 
further antimyeloma treatment or the analysis cut-off date, whichever is earlier. 
• Time to first response: in the absence of response, patients will be censored at the earliest 
of the date of the last valid disease assessment before disease progression or death, the 
date of the last valid disease assessment before initiation of a further anti-myeloma 
treatment (if any) or the analysis cut-off date, whichever comes first. 
• Time to best response: The same censoring rules as time to first response will be used 
11.4.2.3 Multiplicity considerations  
Hypothesis testing of the key secondary efficacy endpoints will be carried out. A closed test 
procedure will be used to control the type I error rate meaning that no further testing will be 
performed unless the significance level had been reached on PFS. The hierarchical procedure will 
be then performed according to the following order: 
• ORR at the time of the primary PFS analysis and/or the final PFS analysis. 
• Rate of VGPR or better at the time of the primary PFS analysis on and/or the final PFS 
analysis. 


 
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• Rate of VGPR or better with MRD negativity at the time of the primary PFS analysis 
and/or the final PFS analysis. 
• CR rate will only be tested for comparison when the antibody-capture interference assay 
will be available 
• OS tested at End-of-Study.  
The significance levels at the interim and final analyses will be determined using alpha-spending 
function specific to each endpoint (see Section 11.5). The primary analysis of PFS corresponds 
either to the positive interim analysis or the final PFS analysis. 
No update of PFS, ORR, rate of VGPR or better, VGPR or better with MRD negativity rate, and 
rate of CR will be provided at the time of OS analysis. 
11.4.3 Analyses of safety data  
All safety analyses will be performed on the safety population unless otherwise specified. The 
summary of safety results will be presented by actual treatment group. The analysis of the safety 
variables will be essentially descriptive and no systematic testing is planned. 
For each of the safety parameters, a baseline value will be defined as the last value or 
measurement taken up to the first dose in the study. 
The observation period will be divided into 3 periods: 
• The pre-treatment period is defined as the time form the signed informed consent date up 
to the first dose of study treatment. 
• The treatment period is defined as the time from the first dose of study treatment up to the 
last dose of study treatment +30 days. 
• The post-treatment period is defined as the period of time starting the day after the end of 
the treatment period up to the end of the study. 
11.4.3.1 Adverse events  
Adverse event observation period: 
• Pre-treatment AEs are defined as any AE reported during the pre-treatment period. 
• TEAEs are defined as AEs that developed or worsened or became serious during the 
treatment period. 
• Post-treatment AEs are defined as AEs that developed or worsened or become serious 
during the post-treatment period. 
The primary focus of AE reporting will be on TEAEs. Pre-treatment and post-treatment AEs will 
be described separately. 
All AEs will be graded according NCI-CTCAE v4.03 (Appendix E) and coded to a lower-level 
term, preferred term (PT), high-level term (HLT), high-level group term (HLGT), and associated 
primary system organ class (SOC) using the version of Medical Dictionary for Regulatory 
Activities currently in effect at Sanofi at the time of database lock. 


 
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The grade will be taken into account in the summary. For patients with multiple occurrences of 
the same AE, the maximum (worst) grade by period of observation will be used. Summaries will 
be provided for all grades combined and for Grade ≥3 (including Grade 5). Missing grades, if any, 
will be included in the “all grades” category.  
Method for handling incomplete dates of onset will be described in SAP. 
Regarding treatment discontinuation, following definitions will be used: 
• Premature treatment discontinuation is defined as the discontinuation of at least 1 of the 
study treatments but at least 1 is continued. 
• Definitive treatment discontinuation is defined as the discontinuation of all the study 
treatments. 
11.4.3.2 Treatment-emergent adverse events  
An overview table summarizing the number (%) of patients with the following TEAEs will be 
generated for the safety population: 
• TEAEs any grade. 
• TEAEs of Grade ≥3. 
• TEAEs of Grade 3 or 4. 
• TEAEs of Grade 5 (any TEAE with a fatal outcome during the treatment period). 
• Serious TEAEs. 
• Serious treatment-related TEAEs. 
• TEAE leading to definitive (all study drugs) discontinuation. 
• TEAE leading to premature discontinuation of isatuximab. 
• TEAE leading to premature discontinuation of carfilzomib. 
• TEAE leading to premature discontinuation of dexamethasone. 
• IARs of Grade ≥3. 
• Treatment-related TEAEs. 
• Treatment-related TEAEs of Grade ≥3. 
The number and percentage of patients experiencing TEAEs by primary SOC and PT will be 
summarized by NCI CTCAE grade (all grades and Grade ≥3). Similar tables will be prepared for 
treatment-related TEAEs, AESIs, TEAEs leading to permanent/premature discontinuation, 
TEAEs leading to dose modification, serious TEAEs, TEAEs with fatal outcome, and AEs/SAEs 
occurring during the post-treatment dosing period. 
Sorting within tables should ensure the same presentation for the set of all AEs within the 
observation period (pre-treatment, on-treatment, and post-treatment). For that purpose, the table of 
all TEAEs presented by SOC and PT sorted by internationally agreed order and decreasing 
frequency of PTs within SOCs will define the presentation order for all other tables unless 
otherwise specified. Sorting will be based on results for the IKd arm. 
The number and percentage of patients experiencing TEAEs presented by primary SOC, HLGT, 
HLT, and PT sorted by SOC internationally agreed order, then by alphabetic order of HLGT, 
HLT, and PT will be provided. This table will be provided for all TEAEs, serious TEAEs, and 
TEAEs leading to permanent/premature treatment discontinuation. 


 
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11.4.3.3 Deaths  
An overview of Grade 5 AEs will be provided summarizing number (%) of patients with any: 
• Grade 5 AE (TEAE and post-treatment). 
• Fatal TEAE (regardless date of death/period). 
- 
Grade 5 TEAE (TEAE with a fatal outcome during the treatment period). 
- 
Any TEAE leading to death during the post-treatment period (worsened to Grade 5 in 
the post-treatment period). 
• Post-treatment Grade 5 AE (excluding a TEAE that worsened to Grade 5 during the 
post-treatment period). 
The following death summaries will be generated for the safety population: 
• Number (%) of patients who died by study period (treatment, and post-treatment) and 
reasons for death (disease progression, AE, other) by treatment received. 
• Listing of deaths in non-randomized patients or randomized but not treated patients (this 
listing will be generated on the screened patients). 
• All TEAEs leading to death by primary SOC and PT, sorted by the internationally agreed 
SOC order and by decreasing incidence of PTs. 
• All TEAEs related to treatment and leading to death by primary SOC and PT sorted by the 
internationally agreed SOC order and by decreasing incidence of PTs. 
• Number (%) of patients with TEAE(s) leading to death regardless of relationship and 
related to study treatment by Primary SOC, HLGT, HLT, and PT. 
• Summary of AEs leading to death, by Primary SOC and PT. 
- 
In context of disease progression (death within 30 days from last study treatment 
administration and the cause of death is disease progression). 
- 
In context other than disease progression (death within 30 days from last study 
treatment administration and for whom cause of death is not disease progression, or the 
death occurred more than 30 days from last study treatment administration and the 
cause of death is AE). 
11.4.3.4 Other safety evaluation  
11.4.3.4.1 Laboratory data  
Clinical laboratory values will be analyzed after conversion into standard international units. 
International units will be used in all listings and tables. Hematological and biochemistry results 
will be graded according to NCI-CTCAE v4.03, when applicable. For patients with multiple 
occurrences of the same laboratory variable during the treatment period, the maximum grade 
(worst) per patient will be used. 
For hematological parameters and for some selected biochemistry parameters, Sanofi generic 
ranges (lower limit of normal, ULN) are defined and will be used for grading. For other 
biochemistry parameters (eg, for hepatic enzymes ALT, AST, alkaline phosphatase, total 
bilirubin), grading will be derived using local laboratory normal ranges. 


 
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The number and proportion of patients with abnormal laboratory tests at baseline (ie, last 
assessment before the first dose of study treatment administration) will be presented by grade and 
all grades together. A similar table showing abnormalities during the treatment period will be 
provided. The denominator used for percentage calculation is the number of patients with at least 
1 evaluation of the laboratory test during the considered observation period. 
For laboratory tests for which NCI-CTCAE v4.03 scale is not applicable, potentially clinically 
significant abnormality (PCSA) values are defined as abnormal values considered medically 
important by the Sponsor according to predefined criteria/thresholds based on literature review. 
The PCSA criteria will determine which patients had at least 1 PCSA during the treatment period, 
taking into account all evaluations performed during the on-treatment period, including 
nonscheduled or repeated evaluations. The incidence of PCSA any time during the on-treatment 
period will be summarized by treatment group irrespective of the baseline level. 
11.4.3.4.2 ECOG Performance Status  
A shift table of baseline ECOG PS versus best and worst ECOG PS on treatment will be provided. 
11.4.3.4.3 Vital signs  
For blood pressure/heart rate parameters, the incidence of PCSAs prior to study treatment 
administration at any cycle during the on-treatment period will be summarized by treatment group 
whatever the baseline level and/or according to the following baseline categories: 
• Normal/missing. 
• Abnormal according to PCSA criterion or criteria. 
The incidence of PCSAs during and after isatuximab administration at any cycle during the 
treatment period in the IKd arm will also be summarized. 
11.4.3.4.4 Electrocardiogram  
The incidence of patients with at least 1 abnormal ECG at any time during the treatment period 
will be summarized by treatment group irrespective of the baseline level and/or according to the 
following baseline status categories:  
• Normal/missing. 
• Abnormal. 
11.4.4 Analyses of pharmacokinetic and pharmacodynamic variables  
11.4.4.1 Analysis of pharmacokinetic variables  
Individual concentrations and PK parameters of carfilzomib will be summarized by descriptive 
statistics (such as mean, geometric mean, median, standard deviation, standard error of the mean 
[SEM], coefficient of variation [CV], minimum, and maximum).  
The population PK of isatuximab will be characterized in the population of patients in the 
IKd arm, using a nonlinear mixed effect model based on PK data from Phase I/II studies and III in 


 
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which intensive and sparse blood sampling protocols were used. The population estimates from 
this analysis will provide a prior distribution from which individual Bayesian estimates of the 
PK parameters for each patient in this study will be derived. 
Pharmacokinetic parameters of isatuximab will be summarized by descriptive statistics (such as 
mean, geometric mean, median, standard deviation, SEM, CV, minimum, and maximum). 
11.4.5 Analysis of immunogenicity variables  
The observation period for ADAs will be divided into 2 periods: 
• The ADA pre-treatment period will be defined as the time that informed consent is signed 
until the first isatuximab administration. 
• The ADA on-study observation period will be defined as the time from the first isatuximab 
administration until the end of the study. 
Patients with at least 1 evaluable ADA result during the ADA pre-treatment period will be 
considered as evaluable at baseline. Patients with at least 1 evaluable ADA result during the ADA 
on-study observation period will be considered evaluable during the on-study observation period. 
The immunogenicity for isatuximab will be assessed by summarizing the number (%) of patients 
with pre-existing ADA and ADA negative at baseline, and by summarizing the number (%) of 
ADA positive patients (including treatment-induced ADA and treatment boosted ADA) during the 
on-study observation period. 
Anti-drug antibody prevalence and ADA incidence will be also described. 
The impact of positive immune response will be evaluated on efficacy, PK, and safety endpoints, 
when relevant. 
11.4.6 Analyses of biomarker variables  
Biomarker endpoints will be analyzed using patients from the ITT population who have at least 
1 evaluable assessment on the biomarker of interest. 
Each genetic biomarker will be summarized with descriptive statistics by treatment group and 
overall. Further analyses will be described in the SAP.  
11.4.7 Analyses of PRO (health-related quality of life/health economics variables)  
The PRO endpoints for each of the 3 selected HRQL and health utility instruments (EORTC 
QLQ-C30, QLQ-MY20, and EQ-5D-5L) will be analyzed in patients from the safety population 
who have completed the baseline and at least 1 post-baseline assessment. 
For each questionnaire the compliance profile over time will be summarized (number and 
percentage of forms received versus expected, and number and percentage of forms evaluable 
versus expected). Reasons for non-completion will be summarized. 


 
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A descriptive summary at each visit and change from baseline will be provided for each group for 
the following variables: 
• EORTC QLQ-C30: GHS/quality of life scale, the 5 functional scales (physical, emotional, 
cognitive, role, and social), the 3 symptom scales (fatigue, nausea/vomiting, and pain) and 
the 6 additional single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and 
financial impact). 
• QLQ-MY20: Future perspective, body image, disease symptoms and side effects of 
treatment. 
• EQ-5D-5L: Health state utility value and VAS scores. 
11.5 
INTERIM ANALYSIS  
An interim analysis for efficacy assessment of PFS is planned when 65% of the 159 PFS events 
have been observed. The interim PFS cut-off date is expected approximately 24 months after the 
FPI.  
An O’Brien and Fleming α-spending function will be used to obtain the nominal significance 
levels for the interim and final analyses of survival on PFS. The 1-sided nominal significance 
level to terminate the study for efficacy at 65% information fraction (103 PFS events) is 0.005 
(corresponding to a HR of 0.6). The 1-sided nominal significance level to declare superiority of 
IKd at the final analysis (159 events) is 0.023 (corresponding to a HR of 0.725). In case of 
positive results at interim analysis, PFS results will be updated in a descriptive way (non-
inferential analysis) at the analysis cut-off date when 159 PFS events are observed. 
For the key secondary endpoints, the significance levels at the interim and final analyses will be 
determined using α-spending function specific to each endpoint, except if the information fraction 
is 100% at the interim analysis of PFS (ie, information on secondary endpoints available for every 
patient). For ORR and rate of VGPR or better, a Pocock-type boundary will be used. For rate of 
VGPR or better and MRD negative rate, the O’Brien-Fleming alpha-spending function will be 
used. OS will be tested only at End-of-Study (ie, 3 years after the primary PFS analysis cut-off 
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12 
ETHICAL AND REGULATORY CONSIDERATIONS  
12.1 
ETHICAL AND REGULATORY STANDARDS  
This clinical trial will be conducted by the Sponsor, the Investigator, and delegated Investigator 
staff and Subinvestigator, in accordance with consensus ethics principles derived from 
international ethics guidelines, including the Declaration of Helsinki, and the International 
Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) 
guidelines for Good Clinical Practice (GCP), all applicable laws, rules, and regulations. 
This clinical trial will be recorded in a free, publicly accessible, internet-based registry, no later 
than 21 days after the first patient enrollment, in compliance with applicable regulatory 
requirements and with Sanofi public disclosure commitments.  
The Investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC Determining whether an incidental finding should be returned to a participant 
and, if it meets the appropriate criteria, to ensure the finding is returned (an incidental 
finding is a previously undiagnosed medical condition that is discovered unintentionally 
and is unrelated to the aims of the study for which the tests are being performed). The 
following should be considered when determining the return of an incidental finding: 
- 
The return of such information to the study participant (and/or his/her designated 
healthcare professional, if so designated by the participant) is consistent with all 
applicable national, state, or regional laws and regulations in the country where the 
study is being conducted, and 
- 
The finding reveals a substantial risk of a serious health condition or has reproductive 
importance, AND has analytical validity, AND has clinical validity.  
- 
The participant in a clinical study has the right to opt out of being notified by the 
Investigator of such incidental findings. In the event that the participant has opted out 
of being notified and the finding has consequences for other individuals, eg, the 
finding relates to a communicable disease, Investigators should seek independent 
ethical advice before determining next steps. 
- 
In case the participant has decided to opt out, the Investigator must record in the site 
medical files that she/he does not want to know about such findings. 
According to the Regulation No 536/2014 of the European Parliament and the Council of the 
European Union and as specified by the applicable regulatory requirements in non-European 
Union/European Economic Area countries, Sanofi, as the clinical trial Sponsor, needs to report to 
the concerned regulatory agency/ies serious breaches without undue delay but not later than 
7 calendar days of becoming aware of that breach. A serious breach is defined as a deviation of 
the version of the protocol applicable at the time of the breach or the applicable clinical trial 
regulation that is likely to affect to a significant degree the safety and rights of a subject or the 
reliability and robustness of the data generated in the clinical trial. 


 
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The Sponsor shall ensure that all parties involved in the conduct of the clinical trial promptly 
report any events that might meet the definition of a serious breach. 
Therefore, Investigators shall within 48 hours after being aware of a deviation that might meet the 
definition of a serious breach, report to the Sponsor any suspected serious breach to enable the 
Sponsor to carry out the required assessment and notify the regulatory agency/ies in the event of a 
confirmed serious breach. To that extent, the principal Investigator must have a process in place to 
ensure that the site staff or service providers engaged by the principal Investigator/institution are 
able to identify the occurrence of a (suspected) serious breach and that a (suspected) serious 
breach is promptly reported to the Sponsor through the contacts (e-mail address or telephone 
number) provided by the Sponsor. 
12.2 
INFORMED CONSENT  
The Investigator (according to applicable regulatory requirements), or a person designated by the 
Investigator, and under the Investigator's responsibility, should fully inform the patient of all 
pertinent aspects of the clinical trial including the written information giving approval/favorable 
opinion by the ethics committee (IRB/IEC). All participants should be informed to the fullest 
extent possible about the study, in language and terms they are able to understand. 
Prior to a patient’s participation in the clinical trial, the written informed consent form should be 
signed, name filled in and personally dated by the patient or by the patient’s legally acceptable 
representative, and by the person who conducted the informed consent discussion. A copy of the 
signed and dated written informed consent form will be provided to the patient.  
The informed consent form used by the Investigator for obtaining the patient's informed consent 
must be reviewed and approved by the Sponsor prior to submission to the appropriate ethics 
committee (IRB/IEC) for approval/favorable opinion. 
For a regional or national emergency declared by a governmental agency, contingency measures 
refer to Appendix N. 
12.3 
HEALTH AUTHORITIES AND INSTITUTIONAL REVIEW BOARD/INDEPENDENT 
ETHICS COMMITTEE (IRB/IEC)  
As required by local regulation, the Investigator or the Sponsor must submit this clinical trial 
protocol to the health authorities (competent regulatory authority) and the appropriate IRB/IEC, 
and is required to forward to the respective other party a copy of the written and dated 
approval/favorable opinion signed by the chairman with IRB/IEC composition. 
The clinical trial (study number, clinical trial protocol title and version number), the documents 
reviewed (clinical trial protocol, informed consent form, Investigator’s Brochure with any 
addenda or labeling documents (summary of product characteristics, Investigator’s curriculum 
vitae, etc.) and the date of the review should be clearly stated on the written (IRB/IEC) 
approval/favorable opinion. 


 
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The study treatment will not be released at the study site and the Investigator will not start the 
study before the written and dated approval/favorable opinion is received by the Investigator and 
the Sponsor. 
During the clinical trial, any amendment or modification to the clinical trial protocol should be 
submitted to the health authorities (competent regulatory authority), as required by local 
regulation, in addition to the IRB/IEC before implementation, unless the change is necessary to 
eliminate an immediate hazard to the patients, in which case the health authorities (competent 
regulatory authority) and the IRB/IEC should be informed as soon as possible. They should also 
be informed of any event likely to affect the safety of patients or the continued conduct of the 
clinical trial, in particular any change in safety. All updates to the Investigator’s Brochure will be 
sent to the IRB/IEC and to health authorities (competent regulatory authority), as required by 
local regulation. 


 
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13 
STUDY MONITORING  
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S)  
The Investigator is required to ensure compliance with all procedures required by the clinical trial 
protocol and with all study procedures provided by the Sponsor (including security rules). The 
Investigator agrees to provide reliable data and all information requested by the clinical trial 
protocol (with the help of the eCRF, Discrepancy Resolution Form [DRF], or other appropriate 
instrument) in an accurate and legible manner according to the instructions provided and to ensure 
direct access to source documents by Sponsor representatives. 
If any circuit includes transfer of data particular attention should be paid to the confidentiality of 
the patient's data to be transferred. 
The Investigator may appoint such other individuals as he/she may deem appropriate as 
Subinvestigators to assist in the conduct of the clinical trial in accordance with the clinical trial 
protocol. All Subinvestigators shall be appointed and listed in a timely manner. The 
Subinvestigators will be supervised by and work under the responsibility of the Investigator. The 
Investigator will provide them with a copy of the clinical trial protocol and all necessary 
information. 
13.2 
RESPONSIBILITIES OF THE SPONSOR  
The Sponsor of this clinical trial is responsible to regulatory authorities for taking all reasonable 
steps to ensure the proper conduct of the clinical trial as regards ethics, clinical trial protocol 
compliance, and integrity and validity of the data recorded on the eCRFs. Thus, the main duty of 
the monitoring team is to help the Investigator and the Sponsor maintain a high level of ethical, 
scientific, technical, and regulatory quality in all aspects of the clinical trial. 
At regular intervals during the clinical trial, the site will be contacted, through monitoring visits, 
letters, or telephone calls, by a representative of the monitoring team to review study progress, 
Investigator and patient compliance with clinical trial protocol requirements, and any emergent 
problems. These monitoring visits will include but not be limited to review of the following 
aspects: patient informed consent, patient recruitment and follow-up, SAE documentation and 
reporting, AESI documentation and reporting, AE documentation, study treatment allocation, 
patient compliance with the study treatment regimen, study treatment accountability, concomitant 
therapy use, and quality of data. Monitoring details describing strategy (eg, risk-based initiatives 
in operations and quality such as Risk Management and Mitigation Strategies and Analytical 
Risk-Based Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote or on-site monitoring) are 
provided in separate study documents. 


 
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13.3 
SOURCE DOCUMENT REQUIREMENTS  
According to the ICH GCP, the monitoring team must check the eCRF entries against the source 
documents, except for the pre-identified source data directly recorded in the eCRF. The informed 
consent form will include a statement by which the patient allows the Sponsor’s duly authorized 
personnel, the ethics committee (IRB/IEC), and the regulatory authorities to have direct access to 
original medical records which support the data on the eCRFs (eg, patient's medical file, 
appointment books, original laboratory records, etc.). These personnel, bound by professional 
secrecy, must maintain the confidentiality of all personal identity or personal medical information 
(according to confidentiality and personal data protection rules). 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST  
It is the responsibility of the Investigator to maintain adequate and accurate eCRFs (according to 
the technology used) designed by the Sponsor to record (according to Sponsor instructions) all 
observations and other data pertinent to the clinical investigation in a timely manner. All eCRFs 
should be completed in their entirety in a neat, legible manner to ensure accurate interpretation of 
data. 
Should a correction be made, the corrected information will be entered in the eCRF overwriting 
the initial information. An audit trail allows identifying the modification.  
Data are available within the system to the Sponsor as soon as they are entered in the eCRF. 
The computerized handling of the data by the Sponsor may generate additional requests (DRF) to 
which the Investigator is obliged to respond by confirming or modifying the data questioned. The 
requests with their responses will be managed through the eCRF. 
13.5 
USE OF COMPUTERIZED SYSTEMS  
The complete list of computerized systems used for the study is provided in a separate document 
which is maintained in the Sponsor trial master file. 


 
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14 
ADDITIONAL REQUIREMENTS  
14.1 
CURRICULUM VITAE  
A current copy of the curriculum vitae describing the experience, qualification and training of 
each Investigator and Subinvestigator will be signed, dated, and provided to the Sponsor prior to 
the beginning of the clinical trial. 
14.2 
RECORD RETENTION IN STUDY SITES  
The Investigator must maintain confidential all study documentation, and take measures to 
prevent accidental or premature destruction of these documents. 
The Investigator should retain the study documents at least 15 years after the completion or 
discontinuation of the clinical trial. 
However, applicable regulatory requirements should be taken into account in the event that a 
longer period is required. 
The Investigator must notify the Sponsor prior to destroying any study essential documents 
following the clinical trial completion or discontinuation. 
If the Investigator's personal situation is such that archiving can no longer be ensured by him/her, 
the Investigator shall inform the Sponsor and the relevant records shall be transferred to a 
mutually agreed upon designee.  
14.3 
CONFIDENTIALITY  
All information disclosed or provided by the Sponsor (or any company/institution acting on their 
behalf), or produced during the clinical trial, including, but not limited to, the clinical trial 
protocol, personal data in relation to the patients, the CRFs, the Investigator's Brochure, and the 
results obtained during the course of the clinical trial is confidential, prior to the publication of 
results. The Investigator and any person under his/her authority agree to undertake to keep 
confidential and not to disclose the information to any third party without the prior written 
approval of the Sponsor. 
However, the submission of this clinical trial protocol and other necessary documentation to the 
ethics committee (IRB/IEC) is expressly permitted, the IRB/IEC members having the same 
obligation of confidentiality. 
The Subinvestigators shall be bound by the same obligation as the Investigator. The Investigator 
shall inform the Subinvestigators of the confidential nature of the clinical trial. 
The Investigator and the Subinvestigators shall use the information solely for the purposes of the 
clinical trial, to the exclusion of any use for their own or for a third party's account. 


 
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14.4 
PROPERTY RIGHTS  
All information, documents, and study treatment provided by the Sponsor or its designee are and 
remain the sole property of the Sponsor. 
The Investigator shall not and shall cause the delegated Investigator staff/Subinvestigator not to 
mention any information or the Product in any application for a patent or for any other intellectual 
property rights. 
All the results, data, documents, and inventions, which arise directly or indirectly from the clinical 
trial in any form, shall be the immediate and exclusive property of the Sponsor. 
The Sponsor may use or exploit all the results at its own discretion, without any limitation to its 
property right (territory, field, continuance). The Sponsor shall be under no obligation to patent, 
develop, market, or otherwise use the results of the clinical trial. 
As the case may be, the Investigator and/or the Subinvestigators shall provide all assistance 
required by the Sponsor, at the Sponsor's expense, for obtaining and defending any patent, 
including signature of legal documents. 
14.5 
DATA PROTECTION  
• The patient's personal data, which are included in the Sponsor database shall be treated in 
compliance with all applicable laws and regulations. 
• When archiving or processing personal data pertaining to the Investigator and/or to the 
patients, the Sponsor shall take all appropriate measures to safeguard and prevent access to 
this data by any unauthorized third party. 
• The Sponsor also collects specific data regarding Investigator as well as personal data 
from any person involved in the study which may be included in the Sponsor’s databases, 
shall be treated by both the Sponsor and the Investigator in compliance with all applicable 
laws and regulations. 
Patient race or ethnicity (including ‘Caucasian/white, Black, Asian/Oriental’) will be collected in 
this study because these data are required by several regulatory authorities (eg, on Afro-American 
population for the Food and Drug Administration, on the Japanese population for the 
Pharmaceuticals and Medical Devices Agency in Japan, or on the Chinese population for the 
China Food and Drug Administration in China). 
The data collected in this study will only be used for the purpose(s) of the study and to document 
the evaluation of the benefit/risk ratio, efficacy, and safety of the product(s). They may be further 
processed if they have been anonymized. 
The contract between Sponsor, Investigators, and study sites specifies responsibilities of the 
parties related data protection, including handling of data security breaches and respective 
communication and cooperation of the parties. Accordingly, the Investigator and the institution 
will promptly notify the Sponsor about any data security breaches and detail in the notification the 
nature of the breach, the categories (eg, Sponsor’s personnel, study participants or their relatives, 


 
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healthcare professionals, etc.), the approximate number of subjects concerned, the type and 
approximate number of data records concerned and the likely consequences of the breach. The 
institution and/or Investigator will investigate the causes of the data security breach and take 
actions to minimize the effects of said breach. The institution and/or Investigator will record all 
information relating to the breach, including the results of their own investigations and 
investigations by authorities, as applicable, and will take all measures as necessary to prevent 
future data security breaches. 
14.6 
INSURANCE COMPENSATION  
The Sponsor certifies that it has taken out a liability insurance policy covering all clinical trials 
under its sponsorship. This insurance policy is in accordance with local laws and requirements. 
The insurance of the Sponsor does not relieve the Investigator and the collaborators from any 
obligation to maintain their own liability insurance policy. An insurance certificate will be 
provided to the IECs/IRBs or regulatory authorities in countries requiring this document.  
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES  
For the purpose of ensuring compliance with the clinical trial protocol, GCP, and applicable 
regulatory requirements, the Investigator should permit auditing by or on the behalf of the 
Sponsor and inspection by regulatory authorities. 
The Investigator agrees to allow the auditors/inspectors to have direct access to his/her study 
records for review, being understood that these personnel is bound by professional secrecy, and as 
such will not disclose any personal identity or personal medical information. 
The Investigator will make every effort to help with the performance of the audits and inspections, 
giving access to all necessary facilities, data, and documents. 
As soon as the Investigator is notified of a planned inspection by the authorities, he will inform 
the Sponsor and authorize the Sponsor to participate in this inspection. 
The confidentiality of the data verified and the protection of the patients should be respected 
during these inspections. 
Any result and information arising from the inspections by the regulatory authorities will be 
immediately communicated by the Investigator to the Sponsor. 
The Investigator shall take appropriate measures required by the Sponsor to take corrective 
actions for all problems found during the audit or inspections. 


 
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14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE  
14.8.1 By the Sponsor  
The Sponsor has the right to terminate the participation of either an individual site or the study at 
any time, for any reason, including but not limited to the following:  
• The information on the product leads to doubt as to the benefit/risk ratio. 
• Patient enrollment is unsatisfactory. 
• The Investigator has received from the Sponsor all study treatment, means, and 
information necessary to perform the clinical trial and has not included any patient after a 
reasonable period of time mutually agreed upon. 
• Noncompliance of the Investigator or Subinvestigator, delegated staff with any provision 
of the clinical trial protocol, and breach of the applicable laws and regulations or breach of 
the ICH GCP. 
• The total number of patients are included earlier than expected. 
In any case the Sponsor will notify the Investigator of its decision by written notice. 
14.8.2 By the Investigator  
The Investigator may terminate his/her participation upon 30 days' prior written notice if the study 
site or the Investigator for any reason becomes unable to perform or complete the clinical trial. 
In the event of premature discontinuation of the study or premature close-out of a site, for any 
reason whatsoever, the appropriate IRB/IEC and regulatory authorities should be informed 
according to applicable regulatory requirements. 
14.9 
CLINICAL TRIAL RESULTS  
The Sponsor will be responsible for preparing a clinical study report and to provide a summary of 
study results to the Investigator. 
14.10 PUBLICATIONS AND COMMUNICATIONS  
The Investigator undertakes not to make any publication or release pertaining to the study and/or 
results of the study prior to the Sponsor’s written consent, being understood that the Sponsor will 
not unreasonably withhold its approval. 
As the study is being conducted at multiple sites, the Sponsor agrees that, consistent with 
scientific standards, a primary presentation or publication of the study results based on global 
study outcomes shall be sought. However, if no multicenter publication is submitted, underway, 
or planned within 12 months of the completion of this study at all sites, the Investigator shall have 
the right to publish or present independently the results of this study in agreement with other 


 
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Investigators and stakeholders. The Investigator shall provide the Sponsor with a copy of any such 
presentation or publication for review and comment at least 30 days in advance of any 
presentation or submission for publication. In addition, if requested by the Sponsor, any 
presentation or submission for publication shall be delayed for a limited time, not to exceed 
90 days, to allow for filing of a patent application or such other justified measures as the Sponsor 
deems appropriate to establish and preserve its proprietary rights. 
The Investigator shall not use the name(s) of the Sponsor and/or its employees in advertising or 
promotional material or publication without the prior written consent of the Sponsor.  
The Sponsor shall not use the name(s) of the Investigator and/or the collaborators in advertising or 
promotional material or publication without having received his/her and/or their prior written 
consent(s). 
The Sponsor has the right at any time to publish the results of the study. 


 
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15 
CLINICAL TRIAL PROTOCOL AMENDMENTS  
All appendices attached hereto and referred to herein are made part of this clinical trial protocol. 
The Investigator should not implement any deviation from, or changes to the clinical trial protocol 
without agreement by the Sponsor and prior review and documented approval/favorable opinion 
from the IRB/IEC and/or notification/approval of health authorities (competent regulatory 
authority) of an amendment, as required by local regulation, except where necessary to eliminate 
an immediate hazard(s) to clinical trial patients, or when the change(s) involves only logistical or 
administrative aspects of the trial. Any change agreed upon will be recorded in writing, the 
written amendment will be signed by the Investigator and by the Sponsor and the signed 
amendment will be filed with this clinical trial protocol. 
Any amendment to the clinical trial protocol requires written approval/favorable opinion by the 
IRB/IEC prior to its implementation, unless there are overriding safety reasons. 
In case of substantial amendment to the clinical trial protocol, approval from the health authorities 
(competent regulatory authority) will be sought before implementation. 
In some instances, an amendment may require a change to the informed consent form. The 
Investigator must receive an IRB/IEC approval/favorable opinion concerning the revised informed 
consent form prior to implementation of the change and patient signature should be re-collected if 
necessary. 


 
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16 
APPENDICES  
Appendix A 
Revised international staging system  
Disease staging is to be done according to R-ISS (12).  
R-ISS will be classified undetermined in case of inconclusive FISH, unless Stage can be 
determined on lactate dehydrogenase, albumin, and β2 microglobulin only. 
 


 
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Appendix B 
Modification of diet in renal disease (MDRD) equation  
Glomerular filtration rate (mL/mins/1.73 m2) = 175 x (Scr)-1.154 x (Age)-0.203 x (0.742 if Female) x 
(1.212 if African-American) 
 
 


 
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Appendix C 
Contraceptive guidance and collection of pregnancy information  
No reproductive toxicology studies have been conducted with isatuximab, so the most 
conservative contraceptive recommendation has to be followed. Females of childbearing potential 
or male subjects with female partners of childbearing potential shall be required to use effective 
contraceptive methods starting 2 weeks before first study treatment administration, while on 
therapy and for 12 weeks for Kd and 5 months for IKd following the last dose of study treatment. 
DEFINITIONS 
Nonreproductive potential 
1. Premenopausal female with 1 of the following: 
- 
Documented hysterectomy. 
- 
Documented bilateral salpingectomy. 
- 
Documented bilateral oophorectomy. 
2. Postmenopausal: 
- 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, a single FSH measurement is insufficient. 
- 
Females on HRT and whose menopausal status is in doubt will be required to use 1 of 
the highly effective contraception methods if they wish to continue their HRT during 
the study. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before study enrolment. 
Reproductive potential 
A woman is considered of reproductive potential (WOCBP), ie, fertile, following menarche and 
until becoming postmenopausal unless permanently sterile. Permanent sterilization methods 
include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. 
CONTRACEPTIVE GUIDANCE 
Male subjects 
• Male subjects with heterosexual partners of reproductive potential (WOCBP) are eligible 
to participate if they agree to use the following during the protocol defined timeline: 
- 
Refrain from donating sperm 
and 
- 
At least 1 of the following conditions applies: 
- 
Are and agree to remain abstinent from penile-vaginal intercourse on a long term and 
persistent basis, when this is their preferred and usual lifestyle 
or 
- 
Agree to use a male condom plus an additional contraceptive method with a failure 
rate of 1% per year (see table for female subjects). 
• Men with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile-vaginal intercourse or use a male condom for the time defined in the protocol. 


 
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Female subjects: 
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctlya 
• Combined (estrogen- and progestogen-containing ) hormonal contraception associated with inhibition of ovulationb 
- 
Oral. 
- 
Intravaginal. 
- 
Transdermal. 
• Progestogen-only hormone contraception associated with inhibition of ovulationb 
- 
Oral. 
- 
Injectable. 
Highly Effective Methods That Are User Independent 
• Implantable progestogen-only hormone contraception associated with inhibition of ovulationb 
• IUD 
• IUS 
• Bilateral tubal occlusion 
• Vasectomized partner 
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the sole sexual partner of 
the woman of childbearing potential and the absence of sperm has been confirmed. If not, an additional highly effective 
method(s) of contraception should be used. Spermatogenesis cycle is approximately 90 days.) 
• Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse 
during the entire period of risk associated with the study treatment. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the study and the preferred and usual lifestyle of the subject.) 
NOTES: 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with local regulations 
regarding the use of contraceptive methods for subjects participating in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study treatment, which may reduce the efficacy of the contraceptive 
method. In this case 2 highly effective methods of contraception should be used during the treatment period and for at least 3 months 
for Kd and 5 months for IKd after the last dose of study treatment. 
 
COLLECTION OF PREGNANCY INFORMATION 
Male subjects with partners of reproductive potential who become pregnant  
• The Investigator will attempt to collect pregnancy information on any female partner of a 
male study subject who becomes pregnant while participating in this study. This applies 
only to subjects who receive study treatment. 
• After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy.  
• Partner will also be followed to determine the outcome of the pregnancy. Information on 
the status of the mother and child will be forwarded to the Sponsor.  
• Generally, follow-up will be no longer than 1 year following the estimated delivery date. 
Any termination of the pregnancy will be reported regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.  


 
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Female subjects who become pregnant  
• The Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study.  
• Information will be recorded on the appropriate form and submitted to the Sponsor within 
24 hours of learning of a participant's pregnancy.  
• Participant will be followed to determine the outcome of the pregnancy. The Investigator 
will collect follow-up information on participant and neonate, which will be forwarded to 
the Sponsor. Generally, follow-up will not be required for longer than 1 year beyond the 
estimated delivery date.  
• Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.  
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication 
or elective termination of a pregnancy will be reported as an AE or SAE.  
• A spontaneous abortion is always considered to be an SAE and will be reported as such. 
• Any SAE occurring as a result of a post-study pregnancy which is considered reasonably 
related to the study treatment by the Investigator, will be reported to the Sponsor as it will 
be described in the full protocol. While the Investigator is not obligated to actively seek 
this information in former study subjects, he or she may learn of an SAE through 
spontaneous reporting.  


 
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Appendix D 
Eastern Cooperative Oncology Group performance status scale  
 
Performance 
Status 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary 
nature, eg, light house work, office work. 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities; up and about more than 
50% of waking hours. 
3 
Capable of only limited selfcare; confined to bed or chair more than 50% of waking hours. 
4 
Completely disabled; cannot carry on any selfcare; totally confined to bed or chair. 
5 
Dead. 
Developed by the Eastern Cooperative Oncology Group, 
, Group Chair (23). 
 


 
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Appendix E 
National Cancer Institute Common Terminology Criteria for Adverse 
Events  
Refer to NCI-CTCAE v4.03 in the Study Reference Manual, or online at the following NCI 
website:  
https://www.eortc.be/services/doc/ctc/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 
Toxicity grade should reflect the most severe degree occurring during the evaluated period, not an 
average. 
When 2 criteria are available for similar toxicities, the one resulting in the more severe grade 
should be used. 
The evaluator must attempt to discriminate between disease/treatment and related 
signs/symptoms. 


 
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Appendix F 
International Myeloma Working Group Response Criteria  
Disease response will be assessed using the updated International Myeloma Working Group 
Response Criteria (IMWG) (24). A confirmation assessment for disease response within 4 weeks 
is required in this protocol (either PR or better, or PD). 
As a reminder, patients with measurable FLC only at screening are not eligible in the study. 
M protein value on Cycle 1 Day 1 will be taken as baseline value for response assessment. 
PD cannot not be diagnosed on FLC increase only, even in patients for whom serum and urine 
M protein become below level of eligibility on efficacy laboratory performed on Cycle 1 Day 1 
(see below the table for assessment of overall response and progression diagnosis of these 
patients). 
Adapted from updated International Myeloma Working Group Response Criteria 
IMWG MRD criteria (requires CR as defined below) 
Sustained 
MRD-negative 
MRD negativity in the marrow (NGF or NGS, or both) and by imaging as defined below, confirmed minimum 
of 1 year apart. Subsequent evaluations can be used to further specify the duration of negativity (eg, MRD-
negative at 5 years) 
Flow MRD-
negative 
Absence of phenotypically aberrant clonal plasma cells by NGF on BMAs using the EuroFlow standard 
operation procedure for MRD detection in multiple myeloma (or validated equivalent method) with a minimum 
sensitivity of 1 in 105 nucleated cells or higher 
Sequencing 
MRD-negative 
Absence of clonal plasma cells by NGS on BMA in which presence of a clone is defined as less than two 
identical sequencing reads obtained after DNA sequencing of BMAs using the LymphoSIGHT platform (or 
validated equivalent method) with a minimum sensitivity of 1 in 105 nucleated cells or higher  
Imaging-
positive 
MRD-negative 
MRD negativity as defined by NGF or NGS plus disappearance of every area of increased tracer uptake 
found at baseline or a preceding PET/CT or decrease to less mediastinal blood pool SUV or decrease to less 
than that of surrounding normal tissue 
Standard IMWG response criteria 
Response 
IMWG criteria 
CR 
• Negative immunofixation on the serum and urine and 
• disappearance of any soft tissue plasmacytomas and 
• <5% plasma cells in BMAs. 
Two consecutive assessments are needed. No known evidence of progressive disease or new bone 
lesions if radiographic studies were performed 
sCR 
CR as defined above plus: 
• Normal FLC ratio (0.26 to 1.65) and 
• Absence of clonal cells in BM by immunohistochemistry (κ/λ ratio ≤4:1 or ≥1:2 for κ and λ patients, 
respectively, after counting ≥100 plasma cells).  
Two consecutive assessments of laboratory parameters are needed. No known evidence of 
progressive disease or new bone lesions if radiographic studies were performed 
VGPR 
• Serum and urine M protein detectable by immunofixation but not on electrophoresis or 
• ≥90% reduction in serum M protein plus urine M protein level <100 mg/24 hour. 
• ≥90% decrease in the sum of the products of maximal perpendicular diameter compared to baseline in soft 
tissue plasmacytoma. 
Two consecutive assessments are needed. No known evidence of progressive disease or new bone 
lesions if radiographic studies were performed. 


 
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PR 
• ≥50% reduction of serum M protein and reduction in 24 hours urinary M protein by ≥90% or to <200 mg/24 
hour 
• In addition to the above listed criteria, if present at baseline, a ≥50% reduction in the size (sum of the 
products of the maximal perpendicular diameters) of soft tissue plasmacytomas is also required 
Two consecutive assessments are needed. No known evidence of progressive disease or new bone 
lesions if radiographic studies were performed. 
MR 
 
≥25% but ≤49% reduction in serum M protein and reduction in 24h urine M protein by 50 to 89%, which still 
exceed 200 mg/24 hour. 
In addition to the above listed criteria, if present at baseline, ≥50% reduction in size (SPD) of soft tissue 
plasmacytomas is also required. 
Two consecutive assessments are needed. No known evidence of progressive disease or new bone 
lesions if radiographic studies were performed. 
Stable 
Disease 
• Not meeting criteria for CR, VGPR, PR, MR or progressive disease. 
No known evidence of progressive disease or new bone lesions if radiographic studies were 
performed. 
Progressive 
disease 
Any 1 or more of the following criteria: 
Increase of ≥25% from lowest confirmed value in any 1 of the following criteria: 
• Serum M protein (the absolute increase must be ≥0.5 g/dL). 
• Serum M protein increase ≥1 g/dL if the lowest M component was ≥5 g/dL. 
• Urine M-component (the absolute increase must be ≥200 mg/24 hour). 
Appearance of new lesion(s), ≥50% increase from nadir in SPD of >1 lesion, or ≥50% increase in the longest 
diameter of a previous lesion >1 cm in short axis. 
Two consecutive assessments are needed for PD on M protein. 
Abbreviations: CR = complete response, FLC = free light chain, IMWG = International Myeloma Working Group, M = monoclonal, MRD = 
minimal residual disease, NGF = next-generation flow, NGS = next-generation sequencing, PD = progressive disease, PET = positron 
emission tomography, MR = minor response, PR = partial response, sCR = stringent complete response, SD = stable disease, SPD = sum of 
the products of the maximal perpendicular diameters of measured lesions, SUV = maximum standardized uptake value, VGPR = very good 
partial response. 
Patients with disease only measurable by FLC are not allowed. 
A plasmacytoma that has been radiated is not suitable for response assessment; however, it must 
be monitored to assess for progressive disease. 
For patients achieving VGPR by other criteria, a soft tissue plasmacytoma must decrease by more 
than 90% in the sum of the products of the maximal perpendicular diameters of measured lesions 
(SPD) compared with baseline. 
For IgA and IgD myeloma, quantitative immunoglobulin measurements are preferred for 
assessments, the same percentage changes apply fornserum M-spike (see table above). 
Definite increase in the size of existing bone lesions or soft tissue plasmacytomas is defined as 
below:  
• ≥50% increase in the size of at least one bidimensionally measurable lesion (in comparison 
with the measurements at Nadir) or appearance of a new lesion.  
• Pathological fracture or collapse of bone are not necessarily evidence of disease 
progression.  


 
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Reminder: definitions of Response and Progression are based on IMWG Uniform Reporting 
Criteria: 
• Any response (sCR, CR, VGPR, PR) or progression needs to be confirmed by 
two consecutive disease assessments according to the Study Flow Chart. A disease 
assessment at one time point not matched by the same disease assessment at the next time 
point will be considered unconfirmed (except for progression by imaging, BM plasma cell 
counts, where one time point is adequate for confirmed progression). 
• Urine M protein is not needed to document PR or minor response if baseline urine 
M protein was not measurable; however, it is still required for CR and very good PR. 
• Documentation of response requires two consecutive readings of the applicable disease 
parameter (serum M protein, urine M protein), performed at any time (no minimum 
interval is required, it can be done the same day); however, to confirm response or 
progressive disease, 2 discrete samples are required; testing cannot be based upon the 
splitting of a single sample. 
• Patients will continue in the last confirmed response category until there is confirmation of 
progression or improvement to a higher response status; patients cannot move to a lower 
response category. 
• Percent decreases for response calculations are from baseline values (Cycle 1 Day 1). 
• Percent increases for progression calculations are from lowest response values or baseline 
values, whichever is the smaller number. The lowest value does not need to be confirmed. 
• The lowest confirmed value before suspected progression will be used as baseline for 
calculation of progression; if a serum and/or urine spike is considered too low to 
quantitate, this value can be assigned as 0 as a baseline for documentation of subsequent 
progressive disease. Patients will be considered to have progressive disease if they meet 
the criteria for progression by a variable that was not considered measurable at baseline; 
however, for patients who had a measurable serum or urine M-spike at baseline, 
progression cannot be defined by increases in serum FLC alone. 
Patients with serum and urine M protein below level of eligibility on efficacy laboratory 
performed on Cycle 1 Day 1 (eg, patients with only FLC measurable disease according to 
IMWG, M-protein value >0 [or IF positive] and <0.5 g/dL): 
• These patients can have only 2 possible overall response: CR, non-PD or PD. 
• Patients with M-protein (urine and/or serum) below the level of measurability 
(M protein value >0 [or IF positive] and <0.5 g/dL) can have CR, non-PD, or PD 
responses only according to the increase or decrease of M protein or extramedullary 
disease if applicable, following the IMWG criteria. 
• Patients with FLC measurable disease only (M protein = 0 and IF negative), can have 
either non-PD or PD responses (PD will be an absolute increase of >10 mg/dL in the 
difference between involved and uninvolved FLC). 
• Patients with serum M protein value >0 g/dL (or serum IF positive) and <0.5 g/dL, 
independently of FLC can only be qualified as: CR, non-PD, or PD. 
AND/OR 


 
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• Patients with urine M protein value >0 mg/24h (or urine IF positive) and <200 mg/24h, 
independently of FLC can only be qualified as: CR, non-PD, or PD. 
OR 
• Patients with serum M protein value = 0 g/dL and serum IF for intact Ig negative and urine 
M-protein = 0 mg/24h and urine IF negative, independently of FLC can only be qualified 
as: non-PD or PD. 


 
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Appendix G 
Guidelines for the determination of the number of prior lines of 
therapy in Multiple Myeloma  
Line of Therapy 
A line of therapy consists of ≥1 complete cycle of a single agent, a regimen consisting of a 
combination of several drugs, or a planned sequential therapy of various regimens (eg, 3 to 
6 cycles of initial therapy with bortezomib-dexamethasone followed by stem cell transplantation 
[SCT] consolidation, and lenalidomide maintenance is considered 1st line). 
New line of Therapy 
A treatment is considered a new line of therapy if any 1 of the following 3 conditions are met: 
Start of a new line of treatment after discontinuation of a previous line. If a treatment 
regimen is discontinued for any reason and a different regimen is started, it should be 
considered a new line of therapy. A regimen is considered to have been discontinued if all the 
drugs in that given regimen have been stopped. A regimen is not considered to have been 
discontinued if some of the drugs of the regimen, but not all, have been discontinued. 
The reasons for discontinuation, addition, substitution, or SCT do not influence how lines are 
counted. It is recognized that reasons for change may include end of planned therapy, toxicity, 
progression, lack of response, inadequate response. 
The unplanned addition or substitution of 1 or more drugs in an existing regimen. 
Unplanned addition of a new drug or switching to a different drug (or combination of drugs) 
due to any reason is considered a new line of therapy. 
SCT: In patients undergoing >1 SCT, except in the case of a planned tandem SCT with a 
predefined interval (such as 3 months), each SCT (autologous or allogeneic) should be 
considered a new line of therapy regardless of whether the conditioning regimen used is the 
same or different. It is recommended that data on type of SCT also be captured. 
Planned tandem SCT is considered 1 line. Planned induction and/or consolidation, maintenance 
with any SCT (frontline, relapse, autologous, or allogeneic) is considered 1 line. 
Interruptions and dose modifications 
• If a regimen is interrupted or discontinued for any reason and the same drug or 
combination is restarted without any other intervening regimen, then it should be counted 
as a single line. 
• However, if a regimen is interrupted or discontinued for any reason, and then restarted at a 
later time point but 1 or more other regimens were administered in between, or the 
regimen is modified through the addition of 1 or more agents, then it should be counted as 
2 lines. 
• Modification of the dosing of the same regimen should not be considered a new line of 
therapy. 
Based on Rajkumar, Richardson and San Miguel, 2015 (25). 


 
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Appendix H 
Definition of relapsed and refractory myeloma  
Refractory Myeloma: 
Refractory myeloma is defined as disease that is non-responsive (failure to achieve MR or 
develops PD while on therapy) while on primary or salvage therapy, or progresses within 60 days 
of last therapy. There are 2 categories of refractory myeloma: 
• Relapsed and refractory myeloma: Defined as disease that is non-responsive while on 
salvage therapy or progresses within 60 days of last therapy in patients who have achieved 
MR or better at some point previously to then progressing in their disease course. 
• Primary refractory myeloma: Defined as disease that is non-responsive in patients who 
have never achieved MR or better with any therapy. It includes patients who never achieve 
MR or better in whom there is no significant change in M protein and no evidence of 
clinical progression; as well as primary refractory, progressive disease where patients meet 
criteria for true progressive disease. 
Relapsed myeloma 
Relapsed myeloma is defined as previously treated myeloma which progresses and requires the 
initiation of salvage therapy but does not meet the criteria for either primary refractory myeloma 
or relapsed and refractory myeloma. 
Adapted from Rajkumar et al, 2011 (26). 


 
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Appendix I 
EORTC-QLQ-C30 scales, items, and clinically important differences  
 
 


 
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Appendix J 
QLQ-MY20 scales, items, and clinically important differences  
 
 


 
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Appendix K 
EQ-5D-5L scales, items, and clinically important differences  


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©EuroQol Research Foundation. EQ-5D™ is a trade mark of the EuroQol Research Foundation 


 
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Appendix L 
CD38 blood test interference guideline AABB2016  
 


 
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Appendix M 
Low dose whole body CT scan  
Low dose whole body CT scan (LDWB CT) allows radiation dose reduction compared to 
conventional exam and lasts usually no more than 2 minutes. It is done without oral or IV contrast 
and patient position is supine, head first, arms at the side (32, 33). 
Example of parameters used to perform a LDWB CT: 
• FOV – mm (small) adapted to subject’s circumference 
• Technical Factors – 16 x 1.5 collimation/0.5 rotation time 
• Tube current – 50-70 mAs (could exceed 70 mAs for larger subjects) 
• Image Reconstruction – Bone kernel/512 x 512 matrix 
• Long bones should be covered: through knees and elbows 
All sites have the option of adapting this protocol or using their own local LDWB or 
manufacturer’s recommended protocol.  
PET CT scan are not allowed for assessment of the disease.  


 
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Appendix N 
Contingency measures for a regional or national emergency that is 
declared by a governmental agency  
COVID-19 Pandemic Contingency Measures: 
Continuation of the study in the event of a regional or national emergency declared by a 
governmental agency: 
A regional or national emergency declared by a governmental agency (eg, public health 
emergency, natural disaster, pandemic, and terrorist attack) may prevent access to the clinical trial 
site. 
Contingency procedures are suggested for an emergency that prevents access to the study site, to 
ensure the safety of the participants, to consider continuity of the clinical study conduct, protect 
trial integrity, and assist in maintaining compliance with GCP in Conduct of Clinical Trials 
Guidance. Sponsor agreement MUST be obtained prior to the implementation of these procedures 
for the duration of the emergency. 
The decision for each individual participant to remain and/or start in the study should be made on 
a case by case basis based on best Investigator medical judgment. The clinical judgment of the 
treating physician should guide the management plan of each participant based on individual 
benefit/risk assessment and the evolving situation at the site.  
When participants are already randomized and/or treated, attempts should be made to perform all 
assessments in accordance with the protocol to the extent possible. 
When possible, the focus should be on IMP administration and safety blood collection 
(eg, biochemistry and hematology). However, all efforts should be made to perform the 
measurements of key parameters for efficacy endpoints (eg, tumor assessments). The deviations 
from the study protocol (eg, treatment delay, omission, tests not performed…) should be 
documented in the source document and collected in the appropriate pages of the eCRF. 
Procedures to be considered in the event of a regional or national emergency declared by a 
governmental agency: 
• If onsite visits are not possible, remote visits (eg, with home nurses, home health vendor, 
etc) may be planned for the collection of possible safety data.  
• If onsite visits are not possible visit windows may be extended for assessment of safety 
and/or efficacy data that cannot be obtained remotely. 
• The Direct-to-Patient supply of oral dexamethasone from the site/sponsor where allowed 
by local regulations and agreed upon by participant (Section 8.1). 
Contingencies implemented due to emergency will be documented. 
The impact of the regional or national emergency declared by a governmental agency on study 
conduct will be assessed. Additional analyses may be performed to evaluate the impact on 
efficacy (eg, missing data due to the emergency) and safety. 


 
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For a regional or national emergency declared by a governmental agency, contingency procedures 
may be implemented for the duration of the emergency. The participant or their legally authorized 
representative should be verbally informed prior to initiating any changes that are to be 
implemented for the duration of the emergency (eg, study visit delays/treatment extension, use of 
local labs) (Section 12.2). 


 
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Appendix O 
Protocol amendment history  
The “Protocol Amendment Summary of Changes Table” for the current amendment is located 
directly before the Clinical Trial Summary section of this amended protocol. 
Amended Protocol 09 (14-September-2021) 
Last patient in (LPI) occurred in March 2019, so patients randomized in the study and still on 
treatment are now treated for at least 2 years and half with a regimen requiring coming to the 
study site 2 days weekly 3 out of 4 weeks. The purpose of this amendment was to allow to omit 
carfilzomib dosing on Days 8 and 9 in case a patient requests for a more convenient schedule and 
in case Investigator judges that the maximum benefit is reached. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
8.2.1 Study treatments (IMP) 
Addition of the possibility to omit carfilzomib 
dosing on Days 8 and 9 if a patient asks for a 
more convenient schedule and Investigator 
agrees because she/he judges that the 
maximum benefit is reached. 
Two administrations per 
week for a duration of more 
than 2 years can become 
tiring for the patients.  
8.2.4.1 General rules 
If dexamethasone dosing is maintained on 
Days 8 and 9 while carfilzomib on Days 8 and 9 
is omitted, possibility to re-increase the dose of 
dexamethasone if dose previously reduced, 
based on Investigator judgement.  
Omission of carfilzomib on 
Days 8 or 9 could allow in 
some cases re-increase the 
dose of dexamethasone 
previously decreased.  
Appendix O (Protocol amendment history) 
Amendments to amended protocol 08 are 
summarized. 
History of amendments to 
this protocol added. 
Amended Protocol 08 (11-March-2021) 
Based on the positive interim PFS data, the treatment effect of IKd is expected to be better than 
initially anticipated in comparison to Kd. A descriptive PFS analysis is added when approximately 
180 PFS events have been reached. Based on more PFS events accumulated, this additional 
analysis would help to better characterize the distribution of PFS in a descriptive way for the IKd 
arm. With approximately 180 PFS events planned, the possibility of observing the median PFS 
time for the IKd arm is expected to be increased. 
Clarification of accidental or intentional overdose of isatuximab and carfilzomib is defined by 
each administration and dexamethasone will be defined by cycle.  
Appendix N is added for contingency measures for a regional or national emergency declared by a 
governmental agency. 


 
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Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Names and Addresses Page 
Sponsor information added 
Sponsor information added 
according to regulatory 
requirements 
Clinical Trial Summary: 
Assessment Schedule, Other 
examinations for disease 
assessment:  
“additional” and “twice a year until death, or OS 
analysis cut-off date, whichever comes first” were 
added. The word final was changed to “additional” 
Frequency of survival status 
collection have been increased 
from once to twice a year to better 
follow the occurrence of the events 
Clinical Trial Summary: Statistical 
Considerations, Primary Analysis 
“An additional PFS analysis will be performed when 
approximately 180 events assessed by the IRC have 
been observed to better characterize the distribution 
of PFS in the IKd arm in a descriptive way. This 
analysis will be performed at the latest 15 months 
after the 159 PFS event analysis cut-off date in case 
of the approximately 180 PFS events are not 
observed at that time” was added 
To better characterize the 
distribution of PFS in a descriptive 
way for the IKd arm, including the 
increased possibility of observing 
median PFS 
Clinical Trial Summary: Statistical 
Considerations, Interim Analysis, 
Planned PFS and OS cut-of dates 
“Efficacy results will be updated in a descriptive way 
(non-inferential analysis) at the time of the PFS 
additional analysis (approximately 180 events)” and  
“The cut-off date for the additional PFS analysis will 
be the date when approximately 180 PFS events 
assessed by the IRC have occurred or 15 months 
after 159 PFS events analysis cut-off date, whichever 
comes first” were added 
To better characterize the 
distribution of PFS in a descriptive 
way for the IKd arm, including the 
increased possibility of observing 
median PFS 
Clinical Trial Summary: Duration of 
Study Period (per patient) 
“Approximately 180” was added to the cut-off date for 
the additional PFS analysis   
 
The last PFS analysis being the 
additional PFS analysis, the cut-off 
for this analysis has been added 
 
 
“or 15 months after 159 PFS events analysis cut-off 
date, whichever comes first” was added 
Survival status collection was changed from “one” to 
“twice a year” and “additional PFS analysis cut-off 
date for all patients still alive at the additional PFS 
analysis cut-off date, until death, or OS analysis cut-
off date, whichever comes first” was added 
Frequency of survival status 
collection have been increased 
from once to twice a year to better 
follow the occurrence of the events 
 
 
The word “final” was changed to “additional” 
 
The last PFS analysis being the 
additional PFS analysis, “final” has 
been updated by “additional” in the 
document where it was necessary 
Section 6.2.1 Duration of study 
participation for each patient 
The word “final” was changed to “additional” 
 
 
“twice a year” and  
“until death, or OS cut-off date, whichever comes 
first” were added 
The last PFS analysis being the 
additional PFS analysis, “final” has 
been updated by “additional” 
Frequency of survival status 
collection have been increased 
from once to twice a year to better 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 6.2.2 Determination of end 
of clinical trial (all patients) 
“An additional PFS analysis will be performed at 
approximately 180 events. The additional analysis 
will be performed at the latest 15 months after the 
159 PFS event analysis cut-off date in case of the 
approximately 180 PFS events are not observed at 
that time” was added 
 
“The end of the study is defined as the date of the 
last visit of the last participant in the study” was 
added 
To better characterize the 
distribution of PFS in a descriptive 
way for the IKd arm, including the 
increased possibility of observing 
median PFS 
 
 
To clarify definition of end of the 
study visit 
Section 6.4 Study Committees 
The words “primary” and “final” were changed to 
“additional” 
The last PFS analysis being the 
additional PFS analysis, “final” has 
been updated by “additional” 
Section 8.2.1 Study treatments 
(IMP): IKd arm (experimental arm) 
The infusion maximum rate was changed from “200” 
to “150” mL/hr for the first infusion done with fixed 
volume 
Typo was fixed  
Section 10.1.6 Post additional PFS 
analysis cut-off date (approximately 
180 PFS events as per IRC) 
“(approximately 180 PFS events as per  
IRC)” was added to the section title  
 
 
 
 
Survival status collection was changed from “once” to 
“twice” a year 
“Death date will be collected when site is informed of 
death. In addition,” was added and “at approximately 
the anniversary date of the final PFS analysis cut-off 
date” was removed 
 
The word “final” was changed to “additional” 
To better characterize the 
distribution of PFS in a descriptive 
way for the IKd arm, including the 
increased possibility of observing 
median PFS 
 
Frequency of survival status 
collection have been increased 
from once to twice a year to better 
follow the occurrence of the events.  
Redundant text was removed. 
 
 
The last PFS analysis being the 
additional PFS analysis, “final” has 
been updated by “additional”  
Section 10.4.1.5 Overdose 
“…of isatuximab and carfilzomib at each 
administration, at least 30% above the intended 
administered dose of dexamethasone at each cycle” 
was added to the definition of overdose for 
isatuximab and carfilzomib 
 
 
To clarify that overdose of 
isatuximab and carfilzomib is 
defined by administration and not 
on the total dose administered on 
over the cycle. Overdose definition 
of dexamethasone is based on all 
the dose over the cycle based on 
different therapeutic index of 
dexamethasone and the two other 
IMPs 


 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 11.4.2.1 Analysis of primary 
efficacy endpoint 
“In particular, a sensitivity analysis has been added to 
evaluate the impact of late progressions and deaths. 
In this sensitivity analysis, progressions or deaths 
occurring more than 8 weeks after the last disease 
assessment (corresponding to two consecutive 
missed assessments) will be censored at the earliest 
of the date of last valid disease assessment without 
evidence of progression before initiation of new anti-
myeloma treatment and the cut-off date” and  
“An additional PFS analysis (non-inferential analysis) 
will be performed when approximately 180 events 
assessed by the IRC have been observed to better 
characterize the distribution of PFS in the Ikd arm in 
a descriptive way. The additional analysis will be 
performed at the latest 15 months after the 159 PFS 
event analysis cut-off date in case of the 
approximately 180 PFS events are not observed at 
that time.” were added  
This analysis has been requested 
by United States Food and Drug 
Administration as post-hoc PFS 
analysis 
 
 
 
 
 
To better characterize the 
distribution of PFS in a descriptive 
way for the IKd arm, including the 
increased possibility of observing 
median PFS 
Section 11.4.2.3 Multiplicity 
considerations 
It is added that “efficacy results will be updated at the 
time of the PFS additional analysis (approximately 
180 events) but will be only descriptive (non-
inferential analysis)”  
Description of the PFS analysis 
added to better characterize the 
distribution of PFS in a descriptive 
way for the IKd arm, including the 
increased possibility of observing 
median PFS   
Section 11.5 Interim analysis 
It is clarified that “in case of positive results at interim 
analysis, PFS results will be updated in a descriptive 
way (non-inferential analysis) at the analysis cut-off 
date when 159 PFS events are observed” 
“Efficacy results will be updated at the time of the 
PFS additional analysis (approximately 180 events) 
but will be only descriptive (non-inferential analysis). 
No α-spending or formal testing is planned for the 
PFS additional analysis” was added  
Clarification added in the protocol 
but already specified in the SAP. 
 
 
Description of the PFS analysis 
added to better characterize the 
distribution of PFS in a descriptive 
way for the IKd arm, including the 
increased possibility of observing 
median PFS   
Section 12.2 Informed consent 
“For a regional or national emergency declared by a 
governmental agency, contingency measures refer to 
Appendix N” was added  
To refer to the added Appendix for 
procedures to inform patient in case 
of regional or national emergency 
declared by governmental agency 
Section 13.2 Responsibilities of the 
Sponsor 
“Monitoring details describing strategy (eg, risk-based 
initiatives in operations and quality such as Risk 
Management and Mitigation Strategies and Analytical 
Risk-Based Monitoring), methods, responsibilities 
and requirements, including handling of 
noncompliance issues and monitoring techniques 
(central, remote or on-site monitoring) are provided in 
separate study documents” was added to the section 
To clarify where the monitoring 
techniques are located. 
Appendix N (Contingency 
measures for a regional or national 
emergency that is declared by a 
government agency, COVID-19 
Pandemic Contingency Measures) 
Appendix N “Contingency measures for a regional or 
national emergency that is declared by a government 
agency, COVID-19 Pandemic Contingency 
Measures” was added 
To clarify the procedure during 
National Emergencies 
Appendix O (Protocol amendment 
history) 
Amendments to protocol v7.0 are summarized. This 
section was shifted down from Appendix N 
History of amendments to this 
protocol added 


 
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Amended Protocol 07 (10-August-2020) 
Instruction for collecting hospitalization report and exams reports in case of serious adverse 
events section is updated. 
Option of direct supplies of oral investigational medicinal products (IMPs) to patients has been 
added in case of regional or national emergency declared by a governmental agency that results in 
travel restrictions, confinement, or restricted site access. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Section 8.1 (Study treatments) 
Option of direct supplies of investigational 
medicinal products (IMPs) to patient has 
been added 
In emergency situations, when patient 
cannot conduct on-site visits, a Sponsor-
approved courier company could deliver 
the IMPs from the site to the patient. 
Section 8.1.1.1, Section 8.2.1, 
Section 8.2.5 
Improvement in isatuximab administration 
implementing the approved administration 
mode with fixed volume. 
Switching to faster infusion schedule with 
a fixed distribution volume will reduce 
hospital chair time (particularly in some 
specific challenging situations like 
pandemic restrictions) and increase 
convenience for patients and sites). 
Section 8.2.2 and Section 8.2.2.1 
Use of ranitidine or equivalent will be 
considered as an optional premedication and 
will be based on Investigators; judgement. 
To provide option to adapt the 
premedication depending on individual 
situation 
Section 10.4.3 
Instruction for collecting hospitalization report 
and exams reports in case of serious 
adverse events has been updated. 
Only necessary copies of medical records 
are to be shared with the Sponsor 
Appendix N (Protocol amendment 
history) 
Amendments to protocol v6.0 are 
summarized. 
History of amendments to this protocol 
added 
Amended Protocol 06 (13-November-2019) 
Censoring rules for the Progression-free survival (PFS) analysis were changed following 
interaction with Health Authorities. PFS2 definition was updated according to this change. 
Hepatitis B virus (HBV) DNA testing by polymerase chain reaction was added for patients with a 
positive hepatitis B surface antigen (HBsAg) test and/or anti-Hepatitis B core (HBc) antibody test.  
Second primary malignancies, if any, should be reported also in follow-up period. 
Statistical sections were updated in line with the changes made in the Statistical Analysis Plan 
(SAP) amendment of July 2019. 


 
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Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Clinical trial summary, 9.2.2 Other 
secondary efficacy endpoints, 11.4.2.1 
Analysis of primary efficacy endpoint, 
11.4.2.2.2 Analysis of other secondary 
efficacy endpoints 
Change in censoring rules for the primary PFS 
analysis and update of PFS2 definition related to this 
change. 
According to Health 
Authorities feedback 
Clinical trial summary, 5.2 Secondary, 
9.2.1 Key secondary efficacy endpoints, 
9.2.2 Other secondary efficacy 
endpoints, 11.4.1 Extent of study 
treatment exposure and compliance, 
11.4.2.2.1 Analysis of key secondary 
efficacy endpoints, 11.4.2.2.2 Analysis 
of other secondary efficacy endpoints, 
11.4.2.3 Multiplicity considerations, 
11.4.7 Analyses of patient reported 
outcomes (health-related quality of 
life/health economics variables), 11.5 
Interim analysis 
Update of statistical sections in order to reflect the 
changes made in the SAP amendment of July 2019: 
 
Update of definitions and analysis of minimal residual 
disease (MRD) negativity rate and complete 
response (CR) rate 
To clarify the definitions 
and the analyses of efficacy 
endpoints 
• 
Update of the handling of multiplicity and 
spending functions for secondary endpoints 
To clarify the analyses of 
efficacy endpoints 
• 
Addition of other secondary endpoints (time 
to first response and time to best response) 
To further characterize the 
efficacy of study treatments 
• 
Update of the definition of overall number 
of cycles started 
To clarify the definition 
• 
Update of the analysis of electronic patient-
reported outcomes (ePROs) 
To clarify the analysis 
1.2 Study flow chart, 8.2.7 Hepatitis B 
virus infection, 10.1.3.2 Subsequent 
cycles (Days 1-2, Days 8-9, 
Days 15-16, and Days 22-23) 
Hepatitis B virus DNA testing by polymerase chain 
reaction was added for patients with a positive 
HBsAg test and/or HBc antibody test 
To complement HBV 
investigations 
Clinical trial summary, 1.2 Study flow 
chart, 6.2.1 Duration of study 
participation for each patient, 10.1.5 
Post study treatment follow-up, 10.1.6 
Post final PFS analysis cut-off date 
Second primary malignancies occurring during the 
follow-up period should be reported 
To secure to collect any 
second primary malignancy 
during follow-up period 
12.1 Ethical and regulatory standards 
Description of Investigator’s responsibility regarding 
incidental findings 
To clarify Investigator’s 
responsibility regarding 
incidental findings 
Entire document 
Editorial changes 
Correction of typographical 
errors and inconsistencies 
between different sections, 
and clarifications 


 
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Amended Protocol 05 (11 September 2019) 
Implementation of safety monitoring measures following identification of 2 new risks related to 
carfilzomib: 
• Carfilzomib may increase risk of progressive multifocal leukoencephalopathy (4 cases 
reported as of 17 July 2019 among 4,156 patients in Amgen Sponsored clinical trials and 
estimated 126, 638 patients in post marketing).  
• Carfilzomib may increase risk of hepatitis B virus reactivation (frequency of Hepatitis B 
virus [HBV] reactivation is 0.1% in Amgen Sponsored clinical trials).  
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Clinical Trial Summary, 
1.2 Study Flow Chart 
8.2.7 Hepatitis B virus Infection 
8.8 Concomitant Medication 
10.1.3.2 Subsequent cycles (Days 1-2, 
Days 8-9, Days 15-16, and Days 22-23) 
Addition of HBV serology assessment in patients with 
unknown HBV status including safety measures. 
Implementation of safety 
monitoring measures 
following identification of 
new risk (hepatitis B virus 
reactivation) related to 
carfilzomib 
8.2.6 Posterior reversible 
encephalopathy syndrome and 
progressive multifocal 
leukoencephalopathy 
Addition of measures for management of progressive 
multifocal leukoencephalopathy 
Implementation of safety 
monitoring measures 
following identification of 
new risk (progressive 
multifocal 
leukoencephalopathy) 
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Amended Protocol 04 (11 June 2019) 
REASON FOR AMENDMENT:  
Based on updated pharmacokinetic characterization of isatuximab, the plasma half-life has been 
re-estimated to 28 days. As duration of contraceptive measures is required to last for 5 half-lives, 
a revised duration of contraceptive measures of 5 months after the last dose of isatuximab is 
required. 
* Contraception duration after end of isatuximab changed from 3 months (12 weeks) to 5 months 
In sections:   Appendix C Contraceptive Guidance and Collection of Pregnancy Information.  
Rationale:  Duration of contraception has been impacted by the updated pharmacokinetic 
characterization of the isatuximab half-life leading to an increase by 2 months (ie, 12 weeks to 
5 months), the time for continuing contraception after the last dose of isatuximab. 
* Pregnancy test will be performed before each cycle and then monthly during the follow-up 
period up to 3 months (12 weeks) in the Kd arm and up to 5 months in the IKd arm  
In sections: Clinical Trial Summary, 1.2 Study Flow Chart, 10.1.3.1 Cycle 1 (Days 1-2, Days 8-9, 
Days 15-16, and Days 22-23), 10.1.3.2 Subsequent cycles (Days 1-2, Days 8-9, Days 15-16, and 
Days 22-23), 10.1.5 Post study treatment follow-up, 10.1.6 Post final PFS analysis cut-off date, 
10.1.7 Post OS analysis cut-off date.  
Rationale: To detect any pregnancy during relevant systemic exposure of study treatment.   
Amended Protocol 03, Amended Protocol 04 (GB) based on Protocol Amendment 04: 
(02 July 2018) 
REASON FOR AMENDMENT:  
The main reason of this amendment is to modify Appendix N, to clarify timing for minimal 
residual disease (MRD) assessment in patient reaching very good partial response (VGPR), and to 
leave possibility to IRC to consider clinical progression as event. Editorial changes, corrections of 
inconsistencies and typographic errors, clarifications, and deletion of redundancies were also 
done. 
* To add Czech Republic in the Appendix N  
In sections:   Appendix N.  
Rationale:  Due to local requirement, Czech Republic is adding in the list of countries where 
pregnancy test is to be performed before each cycle initiation in addition to before study treatment 
initiation and end of treatment.   
* To clarify timing for BMA samplings   
In sections:  clinical trial summary, Section 1.2, Section 9.2.1, Section 10.1.3.2, Section 10.1.4, 
Section 10.1.5.  


 
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Rationale:  Bone marrow aspiration (BMA) is an invasive procedure and study allow up to 6 
BMA. In order to limit as much as possible the number of BMA, wording to trigger BMA has 
been clarified.   
* To include possibility for Independent Response Committee (IRC) to consider clinical 
progression as PD event  
In sections:  Section 9.1.  
Rationale: In absence of radiological and M protein progression, if clinical and biological data all 
together provide with clear evidence of clinical progression based on IRC judgement, in this case 
IRC could consider clinical progression as PFS event.   
* To clarify 2 exclusion criteria  
In sections:   tabulated Clinical Trial Summary, Section 7.2.  
Rationale:  To clarify which type of radiotherapy is allowed within 14 days prior to randomization 
and that therapy (not only chemotherapy) should be completed by at least 5 years in case of prior 
other cancer in medical history.  
* Miscellaneous  
In sections:    Title page, Section 1.1, Section 3, Section 6.1, Section 8.2.2, Section 8.2.3, Section 
8.2.4.1, Section 8.2.8, Section 8.8, Appendix K.  
* Typo on version date of amended protocol 02 GB and protocol amendment 02 GB.  
* Typo in graphical study design.  
* Addition of 2 definitions in abbreviation list.  
* To allow per os diphenhydramide or equivalent in country where the is no longer iv 
formulation.  
* To mention possibility to keep same volume of hydration on a longer time of administration in 
case of cardiac decompensation risk.  
* To clarify some rules of dose modifications.  
* To add protocol recommendations regarding antibacterial prophylaxis and thromboprophylaxis, 
and to add caution regarding co-treatment of dexamethasone with CYP3A inhibitor in 
concomitant medications section.  
* To add copyrights information at the bottom of the EQ-ED questionnaire.  
* Correction of inconsistencies.  


 
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Amended protocol 02, Amended protocol 03 (GB) based on Protocol Amendment 03:  
(08 February 2018) 
REASON FOR AMENDMENT:  
The main reasons of this amendment are to add minimal residual disease (MRD) assessment in 
patients reaching very good partial response (VGPR) and to remove local laboratory disease 
assessment from the protocol. Editorial changes, corrections of inconsistencies and typographic 
errors, clarifications, and deletion of redundancies were also done.  
Modifications implemented through local amendment for United Kingdom (amendment02-gb) is 
included in this global amendment (amendment #3) specifying when changes are applicable for 
UK only, to go back to a unique protocol version for all participating countries.   
* To add MRD assessment in VGPR patients  
In sections:   tabulated Clinical Trial Summary, 1.1, 1.2, 5.2, 9.1, 9.2.1, 10.1.1, 10.1.3.1, 10.1.3.2, 
10.1.4, 10.1.5, 11.4.2.2.1, 11.4.2.3, 11.5, 16.  
Rationale:  Addition of MRD assessment in VGPR patients is based on recent data strongly 
suggesting MRD negativity as prognostic factor for PFS and OS in patients with CR or not. 
Indeed, this has been reported also in patients MRD-negative despite a persistent M-component 
who showed similar PFS and OS to patients with MRD-negative disease in CR (Lahuerta et al, 
JCO 2017). Because the sample size of patients MRD negativity increases, the order of the key 
secondary endpoints is also modified: patients with at least VGPR with MRD negativity will be 
tested prior to patients with CR.   
* To remove local laboratory efficacy samples:  
In sections:   tabulated Clinical Trial Summary, 1.2, 8.4, 9.1, 10.1.1, 10.1.2, 10.1.3.1, 10.1.3.2, 
10.1.4, 10.1.5.  
Rationale:  PFS being the primary endpoint and in order to limit the risk of inconsistency in date 
of progression as per investigator assessment versus as per IRC assessment and to reduce the 
number of blood samples drawn by patient, local laboratory efficacy assessments are removed. 
Investigator will assess disease response using the central laboratory results.   
* To clarify what will be done with the samples collected for the interference of isatuximab with 
M protein measurement by adding a formal exploratory objective.  
In sections:   tabulated Clinical Trial Summary, 5.3.  
Rationale:  Assessment of potential interference was listed in endpoint assessment in section 
9.3.1, but was not listed in exploratory objectives and exploratory endpoints.  
* To add a Coombs test after initiation of isatuximab   
In sections:   tabulated Clinical Trial Summary, 1.1, 1.2, 10.1.3.2.  


 
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Rationale:  Interference in Coombs test has been reported with anti CD38 agents. Coombs test is 
currently planned to be assessed before study initiation for all patients randomized in isatuximab 
arm. A systematic Coombs test is added after initiation of study treatment to describe incidence of 
patients with interference in Coombs test after isatuximab initiation.   
* To change to the frequency of pregnancy test depending on country requirements  
In sections:   tabulated Clinical Trial Summary, 1.2, 10.1.1, 10.1.3.2.  
Rationale:   To provide clarity when the serum pregnancy should be performed. Carfilzomib 
having shown possible fetal harm in preclinical studies, pregnancy test (urine or serum) is to be 
done before each new cycle administration in addition to effective contraception, according to 
country requirement (list of country provided in Appendix N, which is added in this amendment).  
* To allow urine pregnancy test  
In sections:    tabulated Clinical Trial Summary, 1.2, 10.1.1, 10.1.4, 10.1.3.2.  
Rationale:   pregnancy test may be requested before each cycle administration according to local 
requirement; urine test is added as an allowed procedure.  
* To allow semi-quantitative urinalysis   
In sections:   1.2, 10.1.1.  
Rationale:  to allow semi-quantitative instead of quantitative urinalysis if semi-quantitative 
method used at site level can provide with an absolute numeric value of the parameters.     
* To correct rounding error in required number of PFS  
In sections:   Clinical trial summary, sections 6.2.2, 6.3, 11.1, 11.4.2.1, 11.5  
Rationale: number of required PFS events has been corrected from 158 to 159 events. All sections 
impacted and modified in the study protocol are listed above but all are not in the detailed 
description of changes in the amendment.   
* To add grade 5 IARs and symptomatic NIMP overdose as AESI for Adverse Event of Special 
Interest (AESI) reporting  
In section(s):   10.4.1.3.  
Rationale:  Grade 5 IARs are to be considered as AESIs, for reporting purposes.  
* To add duration of contraceptive measure during the study  
In section:   Appendix C  
Rationale:  to have clear instruction on duration of contraceptive measures.  
* Miscellaneous clarifications, correction of inconsistencies   


 
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In sections:   title page, tabulated Clinical Trial Summary, Sections 1.2, 6.1, 6.4, 7.2, 8.1.1.1, 
8.1.1.2, 8.2.1, 8.2.3, 8.2.4.1, 8.2.4.4, 8.2.5, 8.4, 8.8.1, 10.1.3.1, 10.1.6, 12.3, 16, Appendix A, 
Appendix F, Appendix M, Appendix N.  
Rationale: include but not limited to:  
* Correction typo in IND number.  
* Correction that in case of FISH unknown, for some patients the possibility to assess R-ISS is not 
limited to stage III.   
* To provide serologic definition of active hepatitis B and C.  
* To clarify that further anti myeloma therapies will continue to be collected after final PFS 
analysis until OS analysis.   
* Correction of inconsistency between protocol and pharmaceutical manual regarding 
pharmaceutical form.   
* Clarification in instruction of hydration prior carfilzomib and to allow less than 500 mL 
(remaining above 250 mL) during the 2 first infusions for patients at risk of cardiac 
decompensation (as per carfilzomib labelling).  
* Clarification and correction of inconsistencies in dose modifications.  
* G-CSF use is not limited to the first 3 cycles.  
* To correct in which CRF page to report ongoing signs and symptoms related to multiple 
myeloma.  
* To specify that re-screening of patient in case of screen failure is allowed.  
* Editorial correction in IMWG criteria Appendix.  
* To provide clarification on low dose whole body CT scan in a specific Appendix and provide 
with 2 supporting bibliographic references.  
* To specify which countries will have pregnancy test during study treatment in Appendix N  
Amended protocol 02 (GB) based on Protocol Amendment 02 (GB): (30 August 2017) 
* Change to the frequency of pregnancy test  
In section(s): study flow chart (with footnote “i”), and sections 10.1.1 and 10.1.3.2 of the protocol  
Rationale: carfilzomib having shown possible fetal harm in preclinical studies, pregnancy test 
(urine or serum) is to be done before each new cycle administration in addition to effective 
contraception, according to country requirement.   
* To add duration of contraceptive measure during the study  
In section(s): Appendix C  
Rationale: to have clear instruction on duration of contraceptive measures.  


 
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Amended protocol 01 based on Protocol Amendment 01: (21 August 2017) 
 REASON FOR AMENDMENT:  
* Rectification of error in the infusion time of carfilzomib to be consistent with SMPC/PI  
In section(s):   tabulated Clinical Trial Summary (Investigational product(s)), sections 1.2, 1.3.1 
and 8.2.1 of the protocol.  
Rationale:  Rectification of an error in the infusion time of carfilzomib to be consistent with 
SmPC/PI.  As a consequence information on indicative clock time and relative nominal time in 
PK flowchart have also been corrected.  
* Typographical corrections   
In section(s):   1.2, 3, 6.1, 8.2.4.3, 8.2.4.4, 8.2.5 and 9.2.3 of the protocol.  
Rationale:  deletion of duplicate abbreviation, grammatical and cosmetic corrections will not be 
described.   
In addition, other minor changes are listed in the description of changes (next section).  
* Deletion of wording of Absolute neutrophil count   
In section(s):   sections 1.2, 10.1.1, 10.1.3.1, 10.1.3.2 and 10.1.4 of the protocol.  
Rationale:  The wording of ANC is a redundancy when it is with the White Blood Count 
differential. 


 
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17 
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9. Martin T, Gabriel NM, Ajai C, et al. Phase Ib Study of Isatuximab and Carfilzomib in Relapse 
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13. European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines on 
the management of hepatitis B virus infection. J hepatol. 2017; 67(2):370-398. 
14. Howard SC, Jones DP, Pui C-H. The tumour lysis syndrome. N Engl J Med. 
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21. Stead ML, Brown JM, Velikova G, Kaasa S, Wisløff F, Child JA, et al. Development of an 
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Eur J Cancer. 2007;43(11):1670-8. 
23. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and 
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24. Kumar S, Paiva B, Anderson KC, Durie B, Landgren O, Moreau P et al. International 
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26. Rajkumar SV, Harousseau JL, Durie B, Anderson KC, Dimopoulos M, Kyle Ret al. 
Consensus recommendations for the uniform reporting of clinical trials: report of the 
International Myeloma Workshop Consensus Panel 1. Blood 2011:117(18):4691-5. 
27. Delforge M, Minuk L, Eisenmann JC, Arnulf B, Canepa L, Fragasso A, et al.  Health-related 
quality-of-life in patients with newly diagnosed multiple myeloma in the FIRST trial: 
lenalidomide plus low-dose dexamethasone versus melphalan, prednisone, thalidomide. 
Haematologica. 2015;100(6):826-33. 
28. Dimopoulos MA, Terpos E, Goldschmidt H, Alegre A. Treatment with lenalidomide and 
dexamethasone in patients with multiple myeloma and renal impairment. Cancer Treat Rev. 
2012;38(8):1012-9. 
29. Cocks K, Cohen D, Wisløff F, Sezer O, Lee S, Hippe E, et al. An international field study of 
the reliability and validity of a disease-specific questionnaire module (the QLQ-MY20) in 
assessing the quality of life of patients with multiple myeloma. Eur J Cancer. 
2007;43(11):1670-8. 
30. Revicki DA, van den Eertwegh AJ, Lorigan P, Lebbe C, Linette G, Ottensmeier CH, et al. 
Health related quality of life outcomes for unresectable stage III or IV melanoma patients 
receiving ipilimumab treatment. Health Qual Life Outcomes. 2012; 13;10:66. 
31. Kvam AK, Fayers P, Wisloff F. What changes in health-related quality of life matter to 
multiple myeloma patients? A prospective study. European Journal of Haematology 2010; 
84(4):345-53. 
32. Pianko MJ, Terpos E, Roodman GD, Divgi CR, Zweegman S, Hillengass J et al. Whole-Body 
Low-Dose Computed Tomography and Advanced Imaging Techniques for Multiple Myeloma 
Bone Disease. Clin Cancer Res. 2014;20(23):5888-97. 
33. Mangiacavalli S, Pezzatti S, Rossini F, Doni E, Cocito F, Bolis S et al. Implemented myeloma 
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2016;57(7):1539-45. 

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disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
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According to template: QSD-002643 VERSION 7.0 (20-FEB-2019) 
Page 1 
STATISTICAL ANALYSIS PLAN 
Randomized, open label, multicenter study assessing the clinical benefit of 
isatuximab combined with carfilzomib (Kyprolis®) and dexamethasone versus 
carfilzomib with dexamethasone in patients with relapsed and/or refractory 
multiple myeloma previously treated with 1 to 3 prior lines  
SAR650984-EFC15246 
STATISTICIAN: 
 
STATISTICAL PROJECT LEADER: 
 
DATE OF ISSUE: 16-Feb-2023 
Total number of pages: 
99 
NCT03275285


Statistical Analysis Plan  
16-Feb-2023 
SAR650984-EFC15246 - isatuximab 
Version number: 5 
Property of the Sanofi Group - strictly confidential 
Page 2 
TABLE OF CONTENTS  
STATISTICAL ANALYSIS PLAN ................................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................................................................... 5 
1 
OVERVIEW AND INVESTIGATIONAL PLAN ................................................................................ 7 
1.1 
STUDY DESIGN AND RANDOMIZATION ...................................................................................... 7 
1.2 
OBJECTIVES ................................................................................................................................... 7 
1.2.1 
Primary objectives ............................................................................................................................ 7 
1.2.2 
Secondary objectives ....................................................................................................................... 7 
1.2.3 
Exploratory objectives ...................................................................................................................... 8 
1.3 
DETERMINATION OF SAMPLE SIZE ............................................................................................. 8 
1.4 
STUDY PLAN ................................................................................................................................... 9 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL .................................. 9 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN ..................... 10 
2 
STATISTICAL AND ANALYTICAL PROCEDURES .................................................................... 17 
2.1 
ANALYSIS ENDPOINTS ............................................................................................................... 17 
2.1.1 
Demographic and baseline characteristics .................................................................................... 17 
2.1.2 
Prior or concomitant medications (other than anticancer therapies) ............................................. 20 
2.1.3 
Efficacy endpoints .......................................................................................................................... 21 
2.1.3.1 
Primary efficacy endpoint(s) .......................................................................................................... 21 
2.1.3.2 
Secondary efficacy endpoint(s) ...................................................................................................... 24 
2.1.4 
Safety endpoints ............................................................................................................................ 28 
2.1.4.1 
Adverse events variables ............................................................................................................... 28 
2.1.4.2 
Deaths ............................................................................................................................................ 31 
2.1.4.3 
Laboratory safety variables ............................................................................................................ 31 
2.1.4.4 
Vital signs variables ....................................................................................................................... 31 
2.1.4.5 
Electrocardiogram variables .......................................................................................................... 32 
2.1.4.6 
Other safety endpoints ................................................................................................................... 32 
2.1.5 
Pharmacokinetic variables ............................................................................................................. 32 
2.1.5.1 
Population approach for isatuximab............................................................................................... 32 
2.1.5.2 
Non-compartmental analysis for carfilzomib .................................................................................. 32 
2.1.6 
Immunogenicity endpoints ............................................................................................................. 33 


Statistical Analysis Plan  
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2.1.7 
Health-related quality-of-life endpoints .......................................................................................... 34 
2.1.8 
Exploratory biomarker endpoints ................................................................................................... 35 
2.1.9 
Further therapy after discontinuation of investigational medicinal product administration 
during the study .............................................................................................................................. 35 
2.2 
DISPOSITION OF PATIENTS ....................................................................................................... 36 
2.2.1 
Randomization and drug dispensing irregularities ......................................................................... 37 
2.3 
ANALYSIS POPULATIONS ........................................................................................................... 38 
2.3.1 
Efficacy populations ....................................................................................................................... 38 
2.3.1.1 
Intent–to-treat population ............................................................................................................... 38 
2.3.1.2 
Population without trial impact (disruption) due to Covid-19 ......................................................... 38 
2.3.2 
Safety population ........................................................................................................................... 38 
2.3.3 
Pharmacokinetics population ......................................................................................................... 39 
2.3.4 
ADA population .............................................................................................................................. 39 
2.4 
STATISTICAL METHODS ............................................................................................................. 39 
2.4.1 
Demographics and baseline characteristics .................................................................................. 39 
2.4.2 
Prior or concomitant medications (other than anticancer therapies) ............................................. 39 
2.4.3 
Extent of investigational medicinal product exposure .................................................................... 40 
2.4.3.1 
Overall study treatment exposure .................................................................................................. 40 
2.4.3.2 
Isatuximab, carfilzomib or dexamethasone exposure .................................................................... 42 
2.4.4 
Analyses of efficacy endpoints ....................................................................................................... 45 
2.4.4.1 
Analysis of primary efficacy endpoint(s) ........................................................................................ 45 
2.4.4.2 
Analyses of secondary efficacy endpoints ..................................................................................... 51 
2.4.4.3 
Multiplicity issues ........................................................................................................................... 56 
2.4.5 
Analyses of safety data .................................................................................................................. 56 
2.4.5.1 
Analyses of adverse events ........................................................................................................... 57 
2.4.5.2 
Deaths ............................................................................................................................................ 65 
2.4.5.3 
Analyses of laboratory variables .................................................................................................... 66 
2.4.5.4 
Analyses of vital sign variables ...................................................................................................... 67 
2.4.5.5 
Analyses of electrocardiogram variables ....................................................................................... 67 
2.4.5.6 
Analyses of other safety endpoints ................................................................................................ 68 
2.4.6 
Exploratory analyses of biomarker variables ................................................................................. 68 
2.4.6.1 
Genetic variables (immune genetic determinant) .......................................................................... 68 
2.4.6.2 
Descriptive analysis ....................................................................................................................... 68 
2.4.6.3 
Potential interference of isatuximab in the M protein assessment ................................................ 68 
2.4.7 
Analyses of pharmacokinetic variables .......................................................................................... 69 
2.4.8 
Analyses of immunogenicity variables ........................................................................................... 70 
2.4.9 
Analyses of quality of life/health economics variables ................................................................... 70 
2.4.10 
Further therapy after discontinuation of investigational medicinal product administration 
during the study .............................................................................................................................. 70 
2.5 
DATA HANDLING CONVENTIONS .............................................................................................. 71 


Statistical Analysis Plan  
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2.5.1 
General conventions ...................................................................................................................... 71 
2.5.2 
Data handling conventions for secondary efficacy variables ......................................................... 72 
2.5.3 
Missing data ................................................................................................................................... 72 
2.5.4 
Windows for time points ................................................................................................................. 74 
2.5.5 
Unscheduled visits ......................................................................................................................... 74 
2.5.6 
Pooling of centers for statistical analyses ...................................................................................... 74 
2.5.7 
Statistical technical issues ............................................................................................................. 74 
3 
INTERIM ANALYSIS ..................................................................................................................... 75 
4 
DATABASE LOCK ........................................................................................................................ 77 
5 
SOFTWARE DOCUMENTATION ................................................................................................. 78 
6 
REFERENCES ............................................................................................................................... 79 
7 
LIST OF APPENDICES ................................................................................................................. 80 
APPENDIX A 
SOC SORTING ORDER ...................................................................................................... 81 
APPENDIX B 
DESCRIPTION OF SUMMARY TABLES FOR THE ANALYSES OF AES ........................ 82 
APPENDIX C 
POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES CRITERIA ...................... 84 
APPENDIX D 
GENERIC RANGES FOR HEMATOLOGY AND BIOCHEMISTRY PARAMETERS .......... 85 
APPENDIX E 
INTERNATIONAL MYELOMA WORKING GROUP RESPONSE CRITERIA ..................... 86 
APPENDIX F 
DESCRIPTION OF PRIMARY AND SENSITIVITY ANALYSES OF PFS ........................... 90 
APPENDIX G 
EORTC QLQ-C30 AND QLQ-MY20 ITEMS, SCALES AND SCORES .............................. 95 
APPENDIX H 
DEFINITIONS OF REGIONS .............................................................................................. 98 
APPENDIX I 
DESCRIPTION OF PFS2 ANALYSIS ................................................................................... 99 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
 
ADA: 
anti-drug antibody 
ADI: 
actual dose intensity 
AE: 
adverse event 
AESI: 
adverse event of special interest 
ATC: 
atonomical therapeutic chemical 
AUC: 
area under the curve 
BOR: 
best overall response 
BSA: 
body surface area 
CA: 
cytogenetic (chromosomal) abnormalities 
CEOI: 
concentration at end of infusion 
CI: 
confidence interval 
CR: 
complete response 
CV: 
coefficient of variation 
DMC: 
data monitoring committee 
DOR: 
duration of response 
ECOG: 
eastern cooperative oncology group 
eCRF: 
electronic case report form 
eGFR: 
estimated glomerular filtration rate 
EORTC: 
European organization for Research and Treatment of Cancer  
EQ: 
EuroQol 
FLC: 
free light chain 
HLGT: 
high level group term 
HLT: 
high-level term 
HRQL: 
health-related quality of life 
IMP: 
investigational medicinal product 
IMWG: 
International Myeloma Working Group 
IR: 
infusion reaction 
IRC: 
independent response committee 
IRT: 
Interactive Response Technology 
ISS: 
International staging system 
ITT: 
intent-to-treat 
LLT: 
lower-level term 
MDRD: 
modification of diet in renal disease 
MedDRA: 
medical dictionary for regulatory activities 
MM: 
multiple myeloma 
MR: 
minimal response 
MRD: 
minimal residual disease 
MY: 
myeloma specific module 
NCI-CTCAE: 
national cancer institute common terminology criteria for adverse events 
NE: 
non-evaluable 
ORR: 
overall response rate 


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OS: 
overall survival  
PCSA: 
potentially clinically significant abnormality 
PD: 
progressive disease 
PDy: 
pharmacodynamics 
PFS: 
progression free survival 
PK: 
pharmacokinetic(s) 
PR: 
partial response 
PS: 
performance status  
PT: 
preferred term 
QLQ: 
quality of life questionnaire 
RDI: 
relative dose intensity 
R-ISS: 
revised international staging system 
RS: 
raw score 
SAE: 
serious adverse event 
sCR: 
stringent complete response 
SD: 
stable disease 
SEM: 
standard error of the mean 
SOC: 
system organ class 
SPD: 
sum of the products of the maximal perpendicular diameters of measured lesions 
TEAE: 
treatment-emergent adverse event 
TT1R: 
time to first response 
TTBR: 
time to best response 
TTP: 
time to progression 
VAS: 
visual analogue scale 
VGPR: 
very good partial response 
WHO-DD: 
World Health Organization-Drug Dictionary 
 
 


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1 
OVERVIEW AND INVESTIGATIONAL PLAN   
1.1 
STUDY DESIGN AND RANDOMIZATION  
This is a prospective multicenter, multinational, randomized, open label, parallel group, 2-arm 
study assessing the clinical benefit of isatuximab at 10 mg/kg weekly in the first cycle (4 weeks) 
and then biweekly combined with carfilzomib (at 20 mg/m2 for the 2 first infusions and then at 
56 mg/m2 for the subsequent infusions) administered twice weekly 3 out of 4 weeks and 
dexamethasone (20 mg) administered twice weekly versus carfilzomib at 20/56 mg/m2 twice 
weekly 3 out of 4 weeks and dexamethasone (20 mg) twice weekly in patients with relapsed 
and/or refractory multiple myeloma (MM) previously treated with 1 to 3 prior lines. 
After confirmation of eligibility criteria, patients will be randomly assigned to one of the two 
following arms in a 3:2 ratio using an Interactive Response Technology (IRT): 
• 
Isatuximab in combination with carfilzomib and low-dose dexamethasone  
(IKd [experimental] arm). 
• 
Carfilzomib and low-dose dexamethasone (Kd [control] arm). 
The duration of the study for a patient will include a period for screening of up to 3 weeks. The 
cycle duration is 28 days. Patients will be treated until disease progression, unacceptable adverse 
event (AE), or patient decision to stop the study treatment. 
Randomization will be stratified according to: 
• 
number of prior lines (1 vs. >1).  
• 
Revised International Staging System (R-ISS) stage (I or II vs. III vs. not classified).  
Approximately 300 patients (180 patients in IKd arm and 120 patients in Kd arm) will be 
randomized from approximately 73 sites. 
1.2 
OBJECTIVES  
1.2.1 Primary objectives  
The primary objective of this study is to demonstrate the benefit of IKd arm in the prolongation of 
progression free survival (PFS) using the International Myeloma Working Group (IMWG) criteria 
(see Appendix E) as compared to Kd arm in patients with relapsed and/or refractory MM 
previously treated with 1 to 3 lines of therapy. 
1.2.2 Secondary objectives  
The key efficacy objectives are as follows: 
1. To evaluate overall response rate (ORR).  
2. To evaluate rate of very good partial response (VGPR) or better. 
3. To evaluate rate of VGPR or better (IMWG criteria) with minimal residual disease (MRD) 
negativity in both arms. 


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4. To evaluate complete response (CR) rate in both arms (IMWG criteria).  
5. To evaluate overall survival (OS) in both arms. 
Other secondary objectives are as follows: 
1. To evaluate safety in both arms. 
2. To evaluate duration of response (DOR) in both arms. 
3. To evaluate time to progression (TTP) in both arms. 
4. To evaluate PFS2 (see definition in Section 2.1.3.2.2) in both arms. 
5. To evaluate time to first response (TT1R) in both arms. 
6. To evaluate time to best response (TTBR) in both arms.  
7. To determine the pharmacokinetic (PK) profile of isatuximab and carfilzomib when 
combined together. 
8. To evaluate immunogenicity of isatuximab in isatuximab arm. 
9. To evaluate generic and disease- and treatment-specific health-related quality of life 
(HRQL), and changes in HRQL, health state utility, and health status in both arms. 
1.2.3 Exploratory objectives  
Exploratory objectives are as follows: 
1. To explore PK and pharmacodynamics (PDy) relationship.  
2. To explore the relationship between immune genetic determinants and efficacy endpoints. 
3. To explore relationship between chromosomal abnormalities not part of R-ISS including 
but not limited to del (1p) and 1q21+ and efficacy endpoints. 
4. To explore the impact of M-protein measurement without isatuximab interference on best 
overall response assessment. 
1.3 
DETERMINATION OF SAMPLE SIZE  
The sample size calculation is based on the primary efficacy endpoint (ie, PFS). The following 
assumptions were used: 
• 
Kd arm has a median PFS of 19 months. 
• 
IKd arm will have 41% risk reduction in hazard rate in comparison to Kd arm. The 
targeted hazard ratio is 0.59. Assuming proportional hazards, this is expected to 
correspond to an improvement in the true median PFS time from 19 months to 32 months. 
• 
Log-rank test at an overall 1-sided 2.5% significance level. 
• 
3:2 randomization ratio (IKd:Kd). 
• 
An interim analysis for efficacy assessment of PFS is planned when 65% of the PFS 
events will be observed. An O’Brien and Fleming α-spending function will be used to 
obtain the nominal significance levels for the interim and final analyses of PFS  
(see Section 3 for details). 
Based on the above assumptions, a total of 159 PFS events are needed to achieve a 90% power for 
the study.  


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Three hundred patients (180 patients in IKd arm and 120 patients in Kd arm) would be adequate 
to achieve the targeted number of events for PFS. Assuming a uniform accrual rate of 19 patients 
per month, the final PFS analysis cut-off date is expected to be approximately 36 months after 
first patient in. 
Calculations were made using East 6.4 software. 
1.4 
STUDY PLAN  
The complete study plan is presented in Section 1 of the protocol. 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL  
The protocol amendment history table below gives the timing, rationale, and key details of major 
changes to the protocol statistical section. All changes were performed after the first patient 
randomized (15-Nov-2017) and before the planned interim analysis (early 2020).  
Table 1 - Protocol amendment statistical changes  
Amendment 
Number 
Date 
Approved 
Rationale 
Description of statistical changes 
10 
24-Nov-2022 
Median PFS was reached at the final 
PFS analysis; therefore, additional 
descriptive PFS analysis is no longer 
necessary. 
Text related to additional descriptive PFS analysis was 
removed. 
8 
11-Mar-2021 
To better characterize the distribution 
of PFS in a descriptive way for the 
IKd arm, including the increased 
possibility of observing median PFS 
An additional PFS analysis will be performed when 
approximately 180 events assessed by the IRC have 
been observed to better characterize the distribution 
of PFS in the IKd arm in a descriptive way. 
This analysis will be performed at the latest 15 
months after the 159 PFS event analysis cut-off date 
in case of the approximately 180 PFS events are not 
observed at that time 
 
 
This analysis has been requested by 
United States Food and Drug 
Administration as post-hoc PFS 
analysis 
A sensitivity analysis has been added to evaluate the 
impact of late progressions and deaths. In this 
sensitivity analysis, progressions or deaths occurring 
more than 8 weeks after the last disease assessment 
(corresponding to two consecutive missed 
assessments) will be censored at the earliest of the 
date of last valid disease assessment without 
evidence of progression before initiation of new anti-
myeloma treatment and the cutoff date. 
7 
13-Nov-2019 
Health authorities (FDA) feedback 
Change in censoring rules for the primary PFS 
analysis to consider the initiation of further anti-
myeloma therapy.  
Update of PFS2 definition related to this change. 
 
 
Update of statistical sections in order 
to reflect the changes made in the 
SAP amendment 1 of July 2019 
Please refer to table 2 in Section 1.6 


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Amendment 
Number 
Date 
Approved 
Rationale 
Description of statistical changes 
3 
08-Feb-2018 
Error in number of PFS events 
Modification of the number of events required for the 
final PFS analysis: 159 instead of 158 events 
 
 
Recent data strongly suggests MRD 
negativity is a prognostic factor for 
PFS and OS not only in patients with 
CR. Patients who were MRD-
negative despite a persistent M-
protein component showed similar 
PFS and OS to patients who were 
MRD-negative with CR  
To add MRD assessment in patients with VGPR  
 
 
The order of key secondary endpoints 
was revised after the addition of MRD 
assessment in patients with VPGR 
Modification of the order of key secondary endpoints: 
MRD negativity rate in patients with VGPR or better 
will be tested prior to CR rate 
 
 
Updates related to the statistical 
section of the protocol made in the 
initial version of the SAP were 
included in the statistical section of 
the protocol 
Clarifications of infusion/dose delay and dose 
reduction 
Confidence interval of primary and key secondary 
endpoints: replace 95% by (1-2α)% 
Quality of life: replace 95% confidence intervals by 
SEM in the graph of mean of EQ-5D-5L VAS and the 
mean of index utility score over time. 
Corrections of typos 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN  
The statistical analysis plan history table below gives the timing, rationale, and key details for 
major changes to the statistical analysis features in the statistical analysis plan.   
The initial SAP was approved on 20-Nov-2017. The cutoff date of interim analysis with 103 PFS 
events (65% information fraction) was on 07-Feb-2020 and the cutoff date of final analysis with 
163 PFS events was on 14-Jan-2022. This version of SAP is for the planned analyses at OS final 
analysis and to remove the additional PFS analysis (at approximately 180 PFS events) added in 
amended protocol #10 due to uncertainty that median PFS would be reached at the time of the 
final PFS analysis.  


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Table 2 - Statistical analysis plan statistical changes  
SAP 
version 
number 
Date 
approved 
Rationale 
Description of statistical changes 
5 
16-Feb-2023 
“Cytogenetic abnormality” was 
replaced by the right term 
“chromosomal abnormality” 
“Cytogenetic abnormality” was replaced by “chromosomal 
abnormality” 
 
 
Description of IR medications by 
infusion mode 
Description of IR medications depending on the mode of 
administration (initial mode of administration and fixed 
volume administration mode).  
 
 
Description of Prior anti-myeloma 
treatments by regimen 
Description of Prior anti-myeloma treatments by treatment 
arm and by regimen. 
 
 
Description of patients still on study 
was added 
In patient disposition, Addition of the number of patients 
who ended the study and the reason 
 
 
Overall response after the initiation of 
further therapy 
Description of overall response after the initiation of anti-
CD38 therapy and other selected drugs class as further 
anti-myeloma therapy  
Description of overall response after the initiation of further 
anti-myeloma therapy by treatment arm and by line 
 
 
Description of the follow-up duration 
regardless of deaths 
Addition of the time from randomization to efficacy cut-off 
date (months). 
 
 
Analyses for OS was added 
Addition of OS in patients with high-risk chromosomal 
abnormalities 
Addition of OS by further therapy with daratumumab  
Addition of OS by BOR as per IRC and MRD status 
Addition of OS by chromosomal abnormality at study entry 
Addition of OS by lenalidomide and bortezomib 
 
 
Change as per protocol amendment 
10 
Median PFS was reached at the final 
PFS analysis; therefore, additional 
descriptive PFS analysis is no longer 
necessary. 
Deleting of the additional PFS analysis planned when 
approximately 180 events assessed by the IRC. 
 
4 
07-Mar-2022 
Descriptive analyses by second 
primary malignancies 
Addition of demographic characteristic, exposure, disease 
characteristic at study entry will be described by SPM 
status. 
Efficacy data (PFS and OS) will be presented also by SPM 
status 
 
 
Descriptive analyses and new 
population defined to assess the 
impact of Covid-19 and the 
contingency measures related to the 
pandemic in case of regional or 
national emergency declared by a 
governmental agency 
In safety, analysis of TEAEs related to Covid-19 has been 
added. 
In disposition, premature and definitive treatment 
discontinuation related to Covid-19 (AE and other, other = 
link to pandemic situation) will be identified. 
Critical and major protocol deviations related to Covid-19 
pandemic situation will be identified 
Definition for population without trial impact (disruption) due 
to Covid-19 pandemic situation has been added 
In exposure, cycles delayed and dose omissions due to 
Covid-19 pandemic situation will be identified. 


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SAP 
version 
number 
Date 
approved 
Rationale 
Description of statistical changes 
4 
07-Mar-2022 
MRD negativity rate in CR patients is 
a relevant prognostic marker for PFS 
and OS outcomes and has been 
added as post-hoc PFS analysis. 
Addition of MRD negativity rate in patients with CR. In 
addition, sensitivity analyses to assess the impact of 
missing data could be performed (tipping point analysis, 
multiple imputation). 
 
 
PFS by MRD status has been added 
as post-hoc PFS analysis at interim 
analysis. 
Addition of PFS analysis by MRD status 
Addition of PFS analysis by MRD status censoring death 
event due to Covid-19 infections 
 
 
Description of PFS2 by daratumumab 
intake  
Addition of PFS2 analysis by daratumumab intake 
 
 
Change of statistical method for the 
sensitivity analysis of OS 
Sensitivity analyses to account for possibly informative 
censoring due to initiation of further anti-myeloma 
treatment could be performed (eg, Rank Preserving 
Structural Failure Time (RPSFT) model and inverse 
probability of censoring weighting (IPCW) method). The 
same analyses could be performed to account for possibly 
informative censoring due to initiation of daratumumab. 
In addition, sensitivity analyses to assess the impact of 
Covid-19 on the study could be performed (ie, Analysis of 
OS on the population without trial impact (disruption) due to 
Covid-19 and analysis of OS censoring the death event 
due to Covid-19 infections) 
 
 
Sensitivity analyses of PFS to assess 
the impact of Covid-19 on the study 
could be performed 
Addition of  
• 
Analysis of PFS on the population without trial impact 
(disruption) due to Covid-19 and 
• 
Analysis of PFS censoring the death event due to 
Covid-19 infections) 
 
 
Since the PFS endpoint met its 
statistical significance at the planned 
interim analysis of 103 PFS events 
(65% information fraction), all future 
analyses of PFS endpoint are non-
inferential. 
 
All observed PFS events up to the 
final PFS analysis cut-off date will be 
used for PFS final analysis and PFS 
additional analysis. 
This sensitivity analysis #6 is not applicable because all 
observed PFS event will be conserved in the analyses. 
 
 
Subgroup analyses was added to 
further evaluate the efficacy in 
specific subgroup 
The following subgroup analyses have been added: 
• 
Chromosomal abnormality (1q21+) 
• 
Chromosomal abnormality (gain 1q21)  
• 
Chromosomal abnormality (amplification 1q21) 
 
 
Subgroup analyses were added to 
further evaluate the overall response 
by new antimyeloma therapy 
Description of overall response after the initiation of 
daratumumab as further anti-myeloma therapy by 
treatment arm 


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SAP 
version 
number 
Date 
approved 
Rationale 
Description of statistical changes 
4 
07-Mar-2022 
Change as per protocol amendment 8 
To better characterize the distribution 
of PFS in a descriptive way for the 
IKd arm, including the increased 
possibility of observing median PFS 
An additional PFS analysis will be performed when 
approximately 180 events assessed by the IRC have been 
observed to better characterize the distribution of PFS in 
the IKd arm in a descriptive way. 
This analysis will be performed at the latest 15 months 
after the 159 PFS event analysis cut-off date in case of the 
approximately 180 PFS events are not observed at that 
time 
 
 
Change as per protocol amendment 8 
This analysis has been requested by 
United States Food and Drug 
Administration as post-hoc PFS 
analysis 
A sensitivity analysis has been added to evaluate the 
impact of late progressions and deaths. In this sensitivity 
analysis, progressions or deaths occurring more than 8 
weeks after the last disease assessment (corresponding to 
two consecutive missed assessments) will be censored at 
the earliest of the date of last valid disease assessment 
without evidence of progression before initiation of new 
anti-myeloma treatment and the cutoff date. 
 
 
For patients with suspected 
isatuximab interference on serum 
M-protein IFE, the SEBIA 
HYDRASHIFT 2/4 isatuximab IFE 
test will be used by the central lab to 
specifically measure the endogenous 
M-protein. It is the new test. 
Addition of the number (%) of patients who changed their 
response with the new test. The time to first CR/sCR in 
patients with SEBIA HYDRASHIFT 2/4 isatuximab IFE test 
will be described.  
In addition, sensitivity analysis has been added using 
hybrid BOR based on the IRC’s assessment available for 
the interim analysis plus the IRC’s assessment for the 
newly collected response data after the interim analysis. 
 
 
1q21 gain corresponds to 3 copies 
only. The right term for the 
chromosomal abnormalities including 
at least 3 copies is 1q21+. 
Gain 1q was replaced by 1q21+ including gain 1q (3 copies 
only) and amplification (at least 4 copies)  
3 
05-Mar-2020 
Change per protocol amendment 7: 
Health authorities (FDA) feedback 
Change in censoring rules for the primary PFS analysis to 
consider the initiation of further anti-myeloma therapy. This 
new censoring rule has been also applied for time to 
progression.  
Update of PFS2 definition related to this change.   
 
 
Efficacy: to clarify some analyses  
Descriptive statistics on patients who achieved a confirmed 
response will be also provided to summarize time to first 
response and time to best response. 
Clarify that sensibility analysis #6 will be performed only for 
final analysis     
 
 
Safety analyses added to better 
characterize the safety profile 
The following analysis has been added: 
most frequent (≥10% of patients in IKd arm and ≥5% 
higher in IKd arm compared to Kd arm) TEAEs 
 
 
EPRO is considered as an efficacy 
endpoint 
Change the analysis population for EPRO from safety 
population to ITT population 
 
 
Correction 
Correct the definition of hepatic mild impairment in 
Section 2.5.1 


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SAP 
version 
number 
Date 
approved 
Rationale 
Description of statistical changes 
2 
22-Jul-2019 
Change as per protocol amendment 
3: error in number of PFS events 
Modification of the number of events required for the final 
PFS analysis: 159 instead of 158 events 
 
 
Change as per protocol amendment 
3: Recent data strongly suggests 
MRD negativity is a prognostic factor 
for PFS and OS not only in patients 
with CR. Patients who were MRD-
negative despite a persistent M-
protein component showed similar 
PFS and OS to patients who were 
MRD-negative with CR 
To add MRD assessment in patients with VGPR 
 
 
Change as per protocol amendment 
3: The order of key secondary 
endpoints was revised after the 
addition of MRD assessment in 
patients with VPGR  
Modification of the order of key secondary endpoints: MRD 
negativity rate in patients with VGPR or better will be tested 
prior to CR rate  
 
 
Change as per protocol amendment 
4: include the possibility for 
Independent Response Committee 
(IRC) to consider clinical progression 
as PD event 
In section 2.1.3.1, symptomatic deterioration (as assessed 
by the investigator) can be considered as progression in 
the primary analysis of PFS if IRC considers clinical data 
reported supports clinical progression. 
 
 
Efficacy: based on clinical 
consideration, death due to PD 
occurring within 45 days after first 
documentation of PD will be used to 
confirm PD 
Death due to PD occurring within 45 days after a first 
documentation of PD based on  
M-protein is considered as confirmation of PD 
 
 
Sensitivity analysis for PFS was 
added to further evaluate the efficacy 
of study treatments 
The following sensitivity analysis has been added: 
Analysis of PFS as per investigator assessment, ignoring 
symptomatic deterioration  
 
 
Subgroup analysis was added to 
further evaluate the efficacy in 
specific subgroup 
The following subgroup analysis has been added: 
• 
Regulatory region 
 
 
Efficacy: some subgroup analyses 
were removed because not deemed 
relevant based on number of patients 
and/or further clinical evaluation 
The following subgroup analyses have been removed: 
• 
Ethnicity 
• 
Chromosomal abnormality del(17p) 
• 
Existing plasmacytoma 
• 
Previous therapy with anti-CD38 mAb 
 
 
Efficacy: some subgroup analyses 
were modified based on number of 
patients 
The following subgroup analyses have been modified: 
• 
Geographical regions 
• 
ECOG-PS 
• 
Chromosomal abnormality (del(17p), t(4;14), t(14;16)) 
• 
eGFR at baseline 
• 
MM type at study entry 


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SAP 
version 
number 
Date 
approved 
Rationale 
Description of statistical changes 
2 
22-Jul-2019 
Efficacy: to clarify some definitions 
and analyses 
The following definitions have been updated: 
• 
MRD negativity rate 
• 
CR rate  
The following analyses have been updated: 
• 
Evaluation of confounding for primary analysis 
• 
Analysis of MRD negativity rate (will be performed on 
ITT population for key secondary endpoint and on ITT 
population with VGPR or better as exploratory 
analysis) 
• 
Analysis of CR rate (CR rate will only be tested for 
comparison when the antibody-capture interference 
assay will be available). 
• 
Further details on the handling of multiplicity and 
spending functions for secondary endpoints 
 
 
Subcategories of VGPR were added 
to further characterize the efficacy of 
study treatments 
The following subcategories were added: 
• 
Biochemical CR 
• 
Near CR 
 
 
Additional exploratory endpoints were 
added to further characterize the 
efficacy of study treatments 
The following endpoints were added: 
• 
Time to first response 
• 
Time to best response 
• 
Overall response rate based on investigator 
assessment 
• 
Best overall response based on investigator 
assessment 
• 
Renal response 
 
 
Safety analyses added to better 
characterize the safety profile 
The following analyses have been added: 
• 
Cumulative exposure to treatment in patient-years 
• 
Infusions without IR medication 
• 
Indirect Coombs test 
• 
Subgroup analyses on TEAEs 
• 
Some additional exposure-adjusted analyses of 
TEAEs 
• 
Cardiac AEs: SMQs ”Ischaemic heart disease”, 
“Cardiomyopathy”, “Embolic and thrombotic events” 
(venous and arterial), HLGT “Vascular hypertensive 
disorders” 
• 
Hemolytic disorders 
• 
Tumor lysis syndrome 
• 
Autoimmune disorders 
• 
Second primary malignancies 
• 
More specifications on analyses of neutropenic 
complications and thrombocytopenia and 
hemorrhages 
 
 
The following data handling 
conventions were updated to give the 
formulas in standard unit 
• 
eGFR formula (MDRD) 
• 
Corrected calcium formula  


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SAP 
version 
number 
Date 
approved 
Rationale 
Description of statistical changes 
2 
22-Jul-2019 
To clarify some definitions and 
analyses other than for efficacy 
The following definitions have been updated: 
• 
Baseline value 
• 
Type of measurable paraprotein 
• 
Overall number of cycles started 
• 
Planned dose intensity of carfilzomib 
• 
Number of prior lines 
The following analyses have been updated: 
• 
Dose modification of carfilzomib 
• 
Analysis of chromosomal abnormalities 
• 
Analysis of PK parameters 
• 
Analyses of ePROs 
• 
Analyses of prior/concomitant medications and IR 
medications 
• 
Analyses of vital signs (addition of plots) 
• 
Analyses of laboratory parameters (deletion of 
analyses according to bone marrow involvement 
category at baseline) 
• 
Analysis of all treatment-emergent adverse event(s) 
leading to dose modification 
• 
Description of IRs 
• 
Analysis of medical/surgical history 
 
 


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2 
STATISTICAL AND ANALYTICAL PROCEDURES  
2.1 
ANALYSIS ENDPOINTS  
2.1.1 Demographic and baseline characteristics  
The baseline value is defined as the last available value or measurement before or on the date of 
first dose of study treatment (earliest date of isatuximab, carfilzomib and dexamethasone). 
For M-protein (serum and urine), an unscheduled assessment performed on the date of first study 
treatment administration (cycle 1 day 1) will be considered as baseline value. For other 
parameters, unscheduled assessments or repeated tests (eg, vital signs) performed on the day of 
first study treatment administration will be considered as post baseline. This definition applies to 
all variables unless otherwise specified. For patients randomized and not treated, the baseline 
value is defined as the last available value obtained before or on the date of the randomization.  
All baseline safety and efficacy parameters (apart from those listed below) are presented along 
with the on-treatment summary statistics in the safety and efficacy sections (Section 2.4.5 and 
Section 2.4.4). 
Demographic characteristics 
Demographic variables are gender (Male, Female), race (White, Black, Asian, American Indian or 
Alaska Native, Native Hawaiian or other Pacific Islander, Not reported, Unknown), ethnicity 
(Hispanic or Latino, Not Hispanic or Latino, Not reported, Unknown), geographical region 
(Europe, America, Asia, Other countries, see definition in Appendix H), regulatory region 
(Western countries, Other countries, see definition in Appendix H) and age in years (quantitative 
and qualitative variable : <65, [65 - 75[ and ≥75 years).  
Medical or surgical history 
Medical or surgical history includes relevant history of previous or associated pathologies other 
than MM including respiratory medical history. This information will be coded using the version 
of Medical Dictionary for Regulatory Activities (MedDRA) currently in effect at Sanofi at the 
time of database lock or one version down.  
In addition, smoking habits including smoking status at study entry will be collected in a specific 
eCRF page. 
MM characteristics at initial diagnosis   
The following MM characteristics at initial diagnosis will be described: 
• 
Cancer diagnosis (as collected in eCRF). 
• 
Time from initial diagnosis of MM to randomization (in years). 
• 
MM type (heavy and light chain component, as collected in eCRF). 
• 
Bi-clonal status (as collected in eCRF). 
• 
International staging system (ISS) stage (as collected in eCRF). 


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MM characteristics at study entry (before randomization unless otherwise specified) 
The following MM characteristics at study entry will be described: 
• 
ISS stage derived from β2-microglobulin level in mg/L and albumin in g/L (Table 3). In 
addition, β2-microglobulin level in mg/L (quantitative results and by category: <3.5 mg/L, 
[3.5-5.5 mg/L[ and ≥5.5 mg/L) and albumin in g/L (quantitative results and by category: 
<35 g/L and ≥35 g/L) will be provided. 
• 
R-ISS stage derived as defined in Table 4 from β2-microglobulin, albumin, serum LDH 
and chromosomal abnormalities [CA] as described below. In addition, serum LDH 
(quantitative results and by category: ≤ULN, >ULN) will be provided. 
• 
CA determined from central FISH assessment: number and percentage of patients  
- 
by chromosomal abnormality such as del(17p), t(4;14), t(14;16) as well as 1q21+. 
Abnormality is defined as at least 30% of abnormal plasma cells with t(4;14), t(14;16) 
or ≥3 copies of 1q and at least 50% of abnormal plasma cells for del(17p), 1q21+ 
abnormality includes gain 1q21 (only 3 copies) and amplification 1q21 (≥4 copies of 
1q) 
- 
by type of risk as defined for R-ISS (standard risk vs high-risk [defined as presence of 
del(17p) and /or translocation t(4;14) and /or translocation t(14;16) abnormality] vs 
unknown/missing),  
- 
 by number of abnormalities (no chromosomal abnormality vs only 1 chromosomal 
abnormality vs 2 chromosomal abnormalities vs 3 chromosomal abnormalities vs 
unknown/missing).  
- 
by multiple chromosomal abnormalities:  
- 
del(17p) and t(4,14) 
- 
del(17p) and t(14,16) 
- 
1q21+ and del(17p) 
- 
1q21+ and t(4,14) 
- 
1q21+ and t(14,16) 
- 
1q21+, del(17p) and t(4;14) 
- 
1q21+, del(17p) and t(14;16) 
• 
M protein at baseline: serum M protein level in g/dL (quantitative results and by category: 
<0.5 g/dL and  ≥0.5g/dL), urine M protein level in mg/24 hours (quantitative results and 
by category: <200 mg/24 hours and  ≥200 mg/24 hours), serum M protein and urine M 
protein by category (serum M protein <0.5 g/dL and urine M protein <200 mg/24 hours vs 
serum M protein ≥0.5 g/dL and urine M protein  ≥200 mg/24 hours). 
• 
MM type (heavy and light chain components, as collected in eCRF). 
• 
Bi-clonal status (as collected in eCRF). 
• 
Refractory status. 
- 
Relapsed and refractory: non-responsive while on salvage therapy or progresses within 
60 days of last therapy in patients who have achieved minimal response (MR) or better 
at some point previously before then progressing in their disease course, 
- 
Primary refractory: never achieve MR or better in any prior therapies, 
- 
Relapse: all cases not meeting the relapse and refractory or primary refractory 
definition. 


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• 
% of plasma cells in bone marrow at baseline (quantitative and qualitative variables: 
0%, ]0-5%[, [5-20%[, [20-50%[ and ≥50%).  
• 
Patients with plasmacytoma (as per investigator and independent response committee 
(IRC)). 
• 
Patients with bone lesions (and number of lesions) (as per investigator and IRC). 
Table 3 - ISS staging definition  
Stage 
Definition  
Stage I 
β2-microglobulin <3.5 mg/L and albumin ≥35 g/L 
Stage II 
[β2-microglobulin <3.5 mg/L and albumin <35 g/L] or [β2-microglobulin 3.5 - <5.5 mg/L] 
Stage III 
β2-microglobulin ≥5.5 mg/L 
Table 4 - R-ISS staging definition  
Stage 
Definition  
Stage I 
β2-microglobulin <3.5 mg/L and albumin ≥35 g/L and no high-risk CA and LDH ≤ULN 
Stage II 
Not R-ISS Stage I or III 
Stage III 
β2-microglobulin ≥5.5 mg/L and either high-risk CA by iFISH or LDH >ULN 
Not classified 
inconclusive iFISH unless stage III can be determined on LDH and β2 microglobulin only 
High-risk CA by iFISH: Presence of del(17p) and /or translocation t(4;14) and /or translocation t(14;16) abnormality 
CA: Chromosomal abnormalities  
iFISH: interphase fluorescent in situ hybridization  
Prior anti-myeloma therapies 
• 
Prior anti-myeloma treatments:   
Prior anti-myeloma treatments are collected by regimen in the eCRF. The following 
variables will be summarized/derived from eCRF data: 
- 
Number of prior regimens (quantitative and qualitative variable: 1, 2, 3, 4, 5, 6, >6), 
- 
Number of prior lines (a line of therapy consists of ≥1 complete cycle of a single agent 
or a regimen consisting of a combination of several drugs, or a planned sequential 
therapy of various regimens) (quantitative and qualitative variable: 1, 2, 3, >3),  
- 
Main anti-myeloma therapies by class and agent: 
- 
Alkylating agents: such as cyclophosphamide, melphalan, bendamustine, 
- 
Proteasome inhibitors: such as bortezomib, carfilzomib, ixazomib, 
- 
Immunomodulators: such as lenalidomide, thalidomide, pomalidomide,  
- 
Monoclonal antibodies: such as elotuzumab (anti SLAMF7 agent), 
daratumumab (anti CD 38 agent) and anti CD38 agents other than 
daratumumab (including MOR202),  
- 
Anthracyclines, 
- 
Vinca alkaloids, 
- 
Corticosteroids, 
- 
HDAC inhibitors. 


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- 
The refractory status to immunomodulators, proteasome inhibitors and to both 
immunomodulators and proteasome inhibitors will be derived. A patient will be 
considered to be refractory to a drug if any of the following conditions is met: 
- 
Progression date and end date are complete and progression is before drug end 
date or within (≤) 60 days of drug end date. If only the day is missing for either 
date or both dates, the 2 dates should be separated by no more than 1 month, 
- 
Best overall response is stable disease (SD) or PD, 
- 
Reason for treatment discontinuation is “Progressive disease”. 
- 
Description of last regimen given prior to study entry: 
- 
Time from completion of last line of treatment to first study treatment 
administration (months), 
- 
Main treatments,  
- 
Best response to last regimen, 
- 
Duration of last regimen of therapy, 
- 
Refractory status as defined above, 
- 
Reason for treatment discontinuation. 
• 
Prior transplant: number (%) of patients with at least one transplant, number (%) of 
patients with at least two transplants, type of transplant (autologous, allogenic). 
• 
Prior surgery: number (%) of patients with any prior surgery related to MM, type of 
procedure and time from last surgery to first study treatment administration (months). 
• 
Prior radiotherapy: number (%) of patients with any prior radiotherapy related to MM, 
intent and time from last radiotherapy to first study treatment administration (months).  
Other baseline characteristics 
Other baseline characteristics include weight, body surface area (BSA), eastern cooperative 
oncology group (ECOG) performance status (PS) and left ventricular ejection fraction at baseline 
as well as randomization strata (as defined in Section 1.1) as per IRT. 
Any technical details related to computation described in Section 2.5. 
2.1.2 Prior or concomitant medications (other than anticancer therapies)  
All medications taken within 21 days before randomization and up to 30 days after the last study 
treatment administration are to be reported in the case report form pages. 
All medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD) 
using the version currently in effect at Sanofi at the time of database lock. 
• 
Prior medications are those the patient used prior to the first dose of study treatments.  
Prior medications can be discontinued before first administration or can be ongoing during 
treatment phase.   
• 
Concomitant medications are any treatments received by the patient concomitantly to any 
investigational medicinal product (IMP), from first dose to last dose of study treatments + 
30 days.  A given medication can be classified both as a prior medication and as a 
concomitant medication. Any anti-cancer treatment administered after the date of the last 
study treatment administration will not be considered as a concomitant medication and 


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will be regarded as a further anti-myeloma therapy (see Section 2.1.9). The analysis of 
concomitant medications will include the infusion reaction (IR) medications. 
IR medications  
As defined in Section 8.2.2 of the study protocol, patients will routinely receive premedications 
prior to isatuximab and carfilzomib infusions to reduce the risk and severity of infusion reactions 
(IRs) commonly observed with monoclonal antibodies and carfilzomib. Several premedications 
including dexamethasone are recommended prior to isatuximab infusions whereas dexamethasone 
is the single premedication when carfilzomib is administered without isatuximab. Premedications 
are defined in the protocol as non-investigational medicinal product(s) and should be reported in a 
specific form of the eCRF. Dexamethasone being part of both the premedication (for isatuximab 
and carfilzomib) and the study treatment, dexamethasone administration data will be reported 
only in the IMP administration page and will not be summarized as IR premedication, unless if 
additional dexamethasone is given as IR premedication. In case of dexamethasone is prematurely 
stopped and other study treatment are continued, it could be replaced by other premedication if 
still needed as defined in the protocol. 
Analysis of premedications will focus on those given for prophylactic intent on the days of 
isatuximab administrations in IKd arm as no or very few premedications will be recorded when 
carfilzomib is administered without isatuximab.  
Medications given in curative intent of IR will be analyzed for both arms. 
Any technical details related to computation, dates, imputation for missing dates are described in 
Section 2.5. 
2.1.3 Efficacy endpoints  
2.1.3.1 Primary efficacy endpoint(s)  
The primary endpoint is PFS defined as the time from the date of randomization to the first 
documented date of PD (as determined by the IRC) or the date of death from any cause, 
whichever comes first.  
If PD and death are not observed before the analysis cut-off date or the date of initiation of further 
anti-myeloma treatment, PFS will be censored at the date of the last valid disease assessment not 
showing PD performed prior to initiation of a further anti-myeloma treatment (if any) or the 
analysis cut-off date, whichever comes first. A patient without an event (death or PD) and without 
any valid post-baseline disease assessments will be censored at the day of randomization (Day 1). 
An IRC blinded to the randomization arm will evaluate disease assessments at each time point and 
determine disease response including progression status per IMWG criteria (1) (Appendix E).  
The full details regarding the determination of the PD are provided in the protocol and the IRC 
charter. Disease assessments performed after the final PFS analysis will not be reviewed by the 
IRC. The date of disease progression as determined by the IRC will be used for primary PFS 
analysis. 
Additional details regarding the definition of PFS and handling of events and censoring are given 
in Appendix F. 


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Other censoring rules used for sensitivity analyses are provided in Section 2.4.4.1.1. Any 
technical details, related to computation, dates, and imputation for partial/missing dates, are 
described in Section 2.5. 
The cut-off date for the final analysis of PFS (if not previously stopped at interim analysis) is 
expected to be the date when the 159th event (first occurrence of either disease progression 
(assessed by the IRC) or death due to any cause) has been observed. If the final number of events 
is higher than planned, a sensitivity analysis including these additional events may be performed 
(See Section 2.4.4.1.1) for details). 
Since the PFS endpoint met its statistical significance at the planned interim analysis of 103 PFS 
events (65% information fraction), all future analyses of PFS endpoint are non-inferential. All 
observed PFS events up to the PFS analysis data cut-off date will be used for analysis.  
Assessment of progression 
Response and progression as per IRC will be determined on the basis of central laboratory 
findings, radiological evaluation if any and investigator information (bone marrow 
biopsy/aspiration if any) according to IMWG criteria. In addition, IRC can consider clinical 
progression if clinical data supports it (including new lesions based on physical exam). 
Progression based on paraprotein will have to be confirmed based on 2 consecutive assessments. 
A M protein assessment performed after the initiation of a further anti-myeloma treatment will be 
used to confirm progressive disease. Death due to progressive disease occurring within 45 days of 
the first documentation of progression on M protein (regardless initiation of further therapies) is 
considered as a confirmation of the progression.  
Symptomatic deterioration (as assessed by the investigator) will not be considered as progression 
in the primary analysis of PFS, except if IRC considers clinical data reported supports clinical 
progression. 
Progression cannot be diagnosed on free light chain (FLC) increase only. Disease response for 
patients with non-measurable M-Protein on Cycle 1 Day 1 is detailed in Appendix E. 
Efficacy assessment will be performed on Day 1 of every cycle during treatment. After treatment 
discontinuation, for patients who discontinued study treatment for reasons other than progression, 
disease assessments will be performed every month for laboratory disease assessment (central 
laboratory), every 12 weeks (±1 week) for radiological assessment in case of extramedullary 
disease (plasmacytoma) at baseline and once a year and as clinically indicated for bone lytic 
disease assessment (skeletal survey or whole body CT-scan) until confirmation of PD (including 
patients who initiated further anti-myeloma therapy without PD). 
Date of disease progression  
The date of the disease progression is the earliest date that indicates disease progression (provided 
that the progression is subsequently confirmed in case of progression requiring confirmation) 
according to IMWG criteria as assessed by IRC. Details are provided in the Independent Review 
Charter.  


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Determination of the PFS status for the primary analysis 
The following rules will be applied to determine if a patient has an event or is censored for the 
PFS primary analysis for all regions excluding US: 
• 
For a patient who did not die and did not reach progressive disease before the cut-off date, 
the patient is censored, and the censoring date is determined as follows: 
- 
If the patient received any further anti-myeloma treatment, then the censoring date is 
the date of last valid disease assessment without evidence of PD before the start of 
further anti-myeloma treatment, or the cut-off date, whichever comes first, 
- 
If the patient did not take any further anti-myeloma treatment then the censoring date 
is the date of last valid disease assessment without evidence of PD or the cut-off date, 
whichever comes first. 
• 
 For a patient who died or reached progressive disease before the cut-off date: 
- 
If the patient received any further anti-myeloma treatment before death or progression 
is documented, then the censoring date is the date of last valid disease assessment 
without evidence of PD before the start of further anti-myeloma treatment, 
- 
If the patient reached the PFS endpoint before initiation of further anti-myeloma 
treatment, the date of the event will be the date of progressive disease or death if no 
progression occurred. 
Following FDA’s request to update the primary PFS analysis, the primary PFS analysis for US 
includes an additional censoring rule for late progressions and deaths. For US, the following rules 
will be applied to determine if a patient has an event or is censored for the PFS primary analysis: 
• 
For a patient who did not die and did not reach progressive disease before the cut-off date, 
the patient is censored, and the censoring date is determined as follows: 
- 
If the patient received any further anti-myeloma treatment, then the censoring date is 
the date of last valid disease assessment without evidence of PD before the start of 
further anti-myeloma treatment, or the cut-off date, whichever comes first, 
- 
If the patient did not take any further anti-myeloma treatment, then the censoring date 
is the date of last valid disease assessment without evidence of PD or the cut-off date, 
whichever comes first. 
• 
 For a patient who died or reached progressive disease before the cut-off date: 
- 
If the patient received any further anti-myeloma treatment before death or progression 
is documented, then the censoring date is the date of last valid disease assessment 
without evidence of PD before the start of further anti-myeloma treatment, 
- 
If the patient reached the PFS endpoint before initiation of further anti-myeloma 
treatment, the date of the event will be the date of progressive disease or death if no 
progression occurred. 
- 
Progressions or deaths occurring more than 8 weeks after the last disease assessment 
(corresponding to two consecutive missed assessments) will be censored at the earliest 
of the date of last valid disease assessment without evidence of progression before 
initiation of new anti-myeloma treatment and the cut-off date. 


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Valid disease assessment 
A valid post-baseline disease assessment is one for which the “time point response” is not  
“non-evaluable” (NE). In addition, disease assessment with missing date will not be considered 
valid. 
Within a time point, if several exams are performed at different dates for a time point not showing 
disease progression, the date of last valid disease assessment is the date of latest exam. 
Non-evaluable cases 
Missing exams: if one protocol planned examination is missing for a given disease assessment, 
the overall response should generally be NE unless there is clear evidence of progression 
(independently of the missing examination) or response assessment should be downgraded to the 
IMWG response criteria when the missing exam is not required. Specific rules applying to 
missing serum or urine M-protein are described in the IRC charter. 
For the primary analysis of PFS, progression or death occurring after a disease evaluation with an 
overall time point response(s) equal to NE will be considered as an event in the analysis.  
Such progression or death will be censored in the PFS sensitivity analysis #5 if occurring more 
than 8 weeks after the last valid disease assessment without progression.   
2.1.3.2 Secondary efficacy endpoint(s)  
2.1.3.2.1 Key secondary efficacy endpoints  
The key secondary efficacy endpoints are: 
• 
ORR, as per IMWG criteria 
• 
Rate of VGPR or better, as per IMWG criteria 
• 
MRD negativity rate in patients with VGPR or better, as per IMWG criteria 
• 
CR rate, as per IMWG criteria 
• 
OS 
Best Overall Response (BOR)  
BOR is defined as the best response, using the IRC’s assessment of response, from the start of 
treatment until disease progression (as defined in Section 2.1.3.1), death, initiation of further  
anti-myeloma treatment or cutoff date, whichever occurs first. The ordering of evaluations from 
best to worse is: stringent complete response (sCR), CR, VGPR, partial response (PR), MR, SD, 
PD, NE. 
Moreover, for patients with VGPR as BOR, the following subcategories will be assessed by the 
IRC: biochemical CR and near CR.  
• 
Biochemical CR: negative immunofixation of both serum and urine M-protein, with 
missing bone marrow data. 
• 
Near CR: serum and/or urine M-component detectable by immunofixation but not on 
electrophoresis. 


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A confirmation assessment for disease response is required in this study (either MR or better, or 
PD, except PD diagnosed on radiological assessment). 
In addition, BOR according to investigator assessment will be provided. 
Hybrid BOR 
For the analysis after interim analysis when the SEBIA HYDRASHIFT 2/4 isatuximab IFE test is 
available, the derivation of this item will be based on the IRC’s assessment available for the 
interim analysis (ie, using conventional IFE test) plus the IRC’s assessment for the newly 
collected response data after the interim analysis (ie, adjusted by SEBIA HYDRASHIFT 2/4 
isatuximab IFE test). The response results determined by IRC at time of the interim analysis will 
remain as it is for the hybrid BOR derivation.  
ORR:  
Defined as the proportion of patients with sCR, CR, VGPR and PR as BOR as assessed by the 
IRC using the IMWG response criteria. For patients with non-measurable M-protein on Cycle 1 
Day1, only the following overall responses are possible: CR, non-PD and PD (see Appendix E). 
In addition, ORR according to investigator assessment will be provided. 
Rate of VGPR or better: 
Defined as the proportion of patients with sCR, CR and VGPR as BOR. 
MRD negativity rate in patients with VGPR or better: 
Defined as the proportion of patients for whom MRD is negative at any timepoint after first dose 
of study treatment. The percentage will be calculated using the number of patients in ITT 
population as denominator. MRD status will be assessed among patients with VGPR or better by 
next-generation sequencing. Threshold for negativity will be 10-5. MRD status in a patient will be 
negative if at least one result of the assessment is negative in this patient otherwise MRD will be 
considered as positive (MRD status reported as positive, indeterminate, missing or unevaluable). 
For analysis purpose, patients in the ITT population without MRD assessment will be considered 
as having positive MRD.  
CR rate:  
Defined as the proportion of patients with sCR and CR as BOR. 
Patients with demonstrated isatuximab interference will be considered in the BOR category 
corresponding to the M protein assessment obtained without interference, when the antibody-
capture interference assay will be available. 
M-protein follow-up by serum immunofixation electrophoresis (IFE) is part of the International 
Myeloma Working Group (IMWG) criteria to assess treatment response. Therefore, it is crucial 
that the isatuximab band is not confused with the endogenous M-protein of the patient during IFE 


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interpretation. For patients with suspected isatuximab interference on serum M-protein IFE, the 
SEBIA HYDRASHIFT 2/4 isatuximab IFE test will be used by the central lab to specifically 
measure the endogenous M-protein. This will be applied retrospectively for samples collected 
prior to the interim analysis and samples collected after interim analysis. At time of this 
retrospective analysis, an analysis with the conventional IFE test will also be performed on the 
same banked samples, permitting to compare with the original results reported at time of interim 
analysis. This will be used to demonstrate the sample stability and that retrospectively 
measurement of M protein without isatuximab interference with banked samples is valid. Patients 
with updated M protein results following the use of SEBIA HYDRASHIFT 2/4 isatuximab IFE 
will be reviewed by IRC to determine the response at the time points with updated IFE test results. 
The CR rate at time of final PFS analysis will be based IRC determined response based on the 
updated IFE test results using SEBIA HYDRASHIFT 2/4 isatuximab IFE test. 
MRD negativity rate in patients with CR or better: 
Defined as the proportion of patients with CR or better and for whom MRD is negative by next-
generation sequencing at any timepoint after first dose of study treatment. The percentage will be 
calculated using the number of patients in ITT population as denominator. 
PFS in Minimal Residual Disease negative and positive patients 
Progression-free survival (as defined in Section 2.1.3.1) by MRD status will be assessed. The 
same definition of progression, and same censoring rules as for the PFS endpoint will be used. 
PFS by SPM status 
Progression-free survival (as defined in Section 2.1.3.1) by SPM status will be assessed. The same 
definition of progression, and same censoring rules as for the PFS endpoint will be used. 
OS:  
Defined as the time from the date of randomization to death from any cause. If death is not 
observed before the analysis cut-off date, OS will be censored at the last date the patient is known 
to be alive or at the cut-off date, whichever comes first. 
2.1.3.2.2 Other secondary efficacy endpoints  
Other secondary efficacy endpoints will be evaluated as follows: 
• 
TTP: defined as time from randomization to the date of first documentation of PD (as 
determined by the IRC). If progression is not observed before the analysis cut-off date or 
the date of initiation of further anti-myeloma treatment, TTP will be censored at the date 
of the last valid disease assessment not showing disease progression performed prior to 
initiation of a further anti-myeloma treatment (if any) or the analysis cut-off date, 
whichever comes first. 
For the US only, this parameter will be updated by adding an additional censoring rule for 
late progressions and deaths. Progressions or deaths occurring more than 8 weeks after the 


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last valid disease assessment (ie, after >2 consecutive missed scheduled disease 
assessments) will be censored at the date of last valid disease assessment without evidence 
of progression before initiation of new anti-myeloma treatment (if any) or the PFS analysis 
cut-off date, whichever comes first. 
• 
PFS2: defined as time from the date of randomization to the date of first documentation of 
PD (as reported by the investigator) after initiation of further anti-myeloma treatment or 
death from any cause, whichever happens first. For patients alive without a progression 
after initiation of further anti-myeloma treatment before the analysis cut-off date, PFS2 
will be censored at the date of the last follow-up visit not showing disease progression 
after initiation of further anti-myeloma treatment or the analysis cut-off date, whichever 
comes first. Additional details regarding the definition of PFS2 and handling of events and 
censoring are given in Appendix I. 
• 
DOR: defined as the time from the date of the first IRC determined response that is 
subsequently confirmed for patients achieving PR or better to the date of first documented 
PD determined by IRC or death, whichever happens first.  DOR will be censored at the 
date of the last valid disease assessment not showing PD performed prior to initiation of a 
new anti-myeloma treatment (if any) or the analysis cut-off date, whichever occurs first. 
For the US only, this parameter will be also updated by adding an additional censoring 
rule for late progressions and deaths.  
• 
TT1R: defined as the time from randomization to the date of first IRC determined 
response (PR or better) that is subsequently confirmed. In the absence of response, patients 
will be censored at the earliest of the date of the last valid disease assessment before 
disease progression or death, the date of the last valid disease assessment before initiation 
of a further anti-myeloma treatment (if any) or the analysis cut-off date, whichever comes 
first. 
• 
TTBR: defined as the time from randomization to the date of first occurrence of IRC 
determined best overall response (PR or better) that is subsequently confirmed. In the 
absence of response, patients will be censored at the earliest of the date of the last valid 
disease assessment before disease progression or death, the date of the last valid disease 
assessment before initiation of a further anti-myeloma treatment (if any) or the analysis 
cut-off date, whichever comes first. 
• 
Renal response:  
- 
A complete renal response is defined as an improvement in eGFR from  
<50 mL/min/1.73m2 at baseline to ≥60 mL/min/1.73m2 in at least 1 assessment during 
the on-treatment period.  
- 
A partial response is defined as an improvement in eGFR from <15 mL/min/1.73m2 at 
baseline to at least 1 assessment in the range [30 to 60[ mL/min/1.73m2 during the on-
treatment-period.  
- 
A minor response is defined as an improvement in eGFR from <15 mL/min/1.73m2 at 
baseline to at least 1 assessment in the range [15 to 30[ mL/min/1.73m2 during the  
on-treatment-period  or from [15 to 30[ mL/min/1.73m2 at baseline to at least 1 
assessment in the range [30 to 60[ mL/min/1.73m2 during the on-treatment-period.  
- 
A durable renal response is defined as a response that lasted ≥60 days. 


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2.1.4 Safety endpoints  
The safety analysis will be based on the AEs and other safety information, such as clinical 
laboratory data, vital signs, weight and ECOG PS. 
Observation period  
The observation period starts from the time when the patient gives informed consent and is 
divided into 3 periods: 
• 
The pre-treatment period is defined as the time from the signed informed consent date up 
to the first dose of study treatments.  
• 
The treatment period is defined as the time from the first dose of study treatments 
administration to the last dose of study treatments + 30 days. 
• 
The post treatment period is defined as the period of time starting the day after the end of 
the treatment period up to the end of the study (as defined in the protocol). 
2.1.4.1 Adverse events variables  
AEs (including serious adverse events [SAE] and AEs of special interest [AESIs]) will be 
collected from the time of signed informed consent until the end of study treatment. After end of 
study treatment, all ongoing SAEs, all ongoing related AEs and all new AEs (serious or not) 
related to study treatment will be reported and followed up until resolution or stabilization. 
Adverse event observation period: 
• 
Pre-treatment AEs are defined as any AE reported during the pre-treatment period. 
• 
Treatment-emergent adverse events (TEAEs) are defined as AEs that developed or 
worsened or became serious during the treatment period. 
• 
Post-treatment AEs are defined as AEs that developed or worsened or become serious 
during the post-treatment period. 
All AEs (including SAEs and AESI) will be graded according to National cancer institute 
common terminology for adverse events (NCI-CTCAE) v4.03 and coded to a lower-level term 
(LLT), preferred term (PT), high-level term (HLT), high-level group term (HLGT) and associated 
primary system organ class (SOC) using the version of Medical Dictionary for Regulatory 
Activities (MedDRA) currently in effect at Sanofi at the time of database lock or one version 
down. 
Other significant adverse events 
Other significant adverse events will include AESIs, IRs, respiratory AEs, cardiac AEs, hemolytic 
disorders, tumor lysis syndrome, autoimmune disorders and second primary malignancies. 
Specific hematological analyses will be also provided.  


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Adverse events of special interest 
AESIs include the following events: 
• 
IRs of Grade ≥3.  
• 
Pregnancy of female patient entered in this study as well as pregnancy occurring in a 
female partner of a male entered in this study. 
• 
Symptomatic overdose (serious or non-serious) with study treatment (isatuximab or 
carfilzomib or dexamethasone) or NIMP. 
Infusion reactions 
IRs are commonly observed with monoclonal antibodies and carfilzomib and typically occur 
within 24 hours from the start of the infusion.  
Whenever possible, a diagnosis of the IR (eg, cytokine release syndrome, infusion related 
reaction, anaphylactic reaction, or any other term chosen by the investigator) will be reported by 
the investigator in a specific AE page instead of individual symptoms. In addition, symptoms of 
the IRs will be reported on a separate eCRF form.   
Analysis of IRs will be performed based on the investigator’s reporting of IRs (using investigator 
reported term collected in the specific AE forms). 
In addition, an analysis based on any TEAEs (both regardless of relationship and related TEAEs) 
occurring within 24 hours from the start of any isatuximab or any carfilzomib infusion (ie, TEAEs 
with onset on the same calendar day of the infusion or on the following day) will be performed. 
A similar analysis including TEAEs occurring within 24 hours from the start of any isatuximab or 
any carfilzomib infusion and within the “Hypersensitivity and CRS” CMQ will be also performed. 
Moreover, all TEAEs (not only limited to those occurring within 24h of any isatuximab and any 
carfilzomib administration) from the above listed CMQ will also be analyzed. 
Respiratory AEs 
Analysis of selected respiratory TEAEs will focus particularly on the following groupings:  
• 
Lower Respiratory adverse events, selected using CMQ “Lower respiratory events”. 
• 
Respiratory infections, selected using CMQ “Respiratory infections”. 
Late respiratory adverse events (ie, occurring, worsening or becoming serious more than 30 days 
after last dose) will be analyzed as part of the post-TEAEs analysis. 
Cardiac AEs 
Analysis of cardiac events will focus on: 
• 
SMQ “Cardiac failure” (narrow).  
• 
CMQ “Cardiac”.  
• 
SMQ “Ischaemic heart disease” (narrow).  
• 
SMQ “Cardiomyopathy” (narrow). 


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• 
SMQ “Embolic and thrombotic events, venous” (narrow).  
• 
SMQ “Embolic and thrombotic events, arterial” (narrow). 
• 
HLGT “Vascular hypertensive disorders”. 
Hemolytic disorders 
Hemolytic disorders will be selected using the TEAEs from the SMQ ‘Haemolytic disorders’ 
(broad+narrow).  
Moreover, hemolytic disorders that occurred within 8 days after the blood cell transfusion (red 
blood cells or platelets) will be displayed.  
Tumor lysis syndrome 
Tumor lysis syndrome will be identified using the TEAEs from the CMQ ‘Tumor lysis 
syndrome’. 
Autoimmune disorders 
Autoimmune disorders will be selected using the TEAEs from the CMQ ‘GLB_HLGT 
Autoimmune disorders’ 
Second primary malignancies 
Second primary malignancies will be selected using the CMQ ‘Second primary malignancies’ and 
will be sub-categorized as ‘haematological’, ‘non-hematological skin tumors’, ‘non-hematological 
non-skin tumors’ and “other tumors”.  
The time to first SPM onset is defined as the date of first SPM AE date – date of first treatment 
+1. If a patient does not have SPM event, it will be censored at death date, last contact date or 
cut-off date, whichever comes first.  
Neutropenia and neutropenic complications 
Neutropenia (from laboratory abnormalities) will be displayed along with neutropenic 
complications (neutropenic infections, febrile neutropenia). 
Neutropenic complications will be analyzed using the following data source: 
• 
Febrile neutropenia selected using CMQ ‘Febrile neutropenia’. 
• 
Neutropenic infections: defined as NCI-CTCAE Grade ≥2 infections from SOC 
‘Infections and Infestations’ (selected using CMQ ‘GLB_SOC infections and 
infestations’) concomitant with NCI-CTCAE Grade 3-4 neutropenia from laboratory 
results. Infection and Grade 3-4 neutropenia will be considered as concomitant if one of 
the following conditions is met:  
- 
Neutrophils count value measured the day of the start of the AE infection,  
- 
The last neutrophils count value measured before the start date of the AE infection is 
within 7 days before the start of the AE infection,  
- 
The first neutrophils count value measured after the start date of the AE infection is 
within 2 days after the start of the AE infection. 


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Thrombocytopenia and hemorrhages 
• 
Thrombocytopenia will be analyzed based on laboratory results. 
• 
Hemorrhages will be selected using the TEAEs from the SMQ ‘Haemorrhage terms (excl 
laboratory terms)’ (narrow). 
• 
Severe thrombocytopenia (ie, ≥Grade 4) will be displayed with concomitant hemorrhage if 
relevant (ie, in case of imbalance between treatment arms). The first hemorrhagic event 
occurring within 8 days after any occurrence of the thrombocytopenia (laboratory) will be 
used for this analysis.     
Covid-19 infection 
Covid-19 infection will be identified using the TEAEs from the CMQ ‘COVID19 specific list’.  
2.1.4.2 Deaths  
The deaths observation periods are per the observation periods defined above.  
• 
Death on-treatment:  deaths occurring during the treatment period.  
• 
Death post-treatment:  deaths occurring during the post-treatment period.  
2.1.4.3 Laboratory safety variables  
Clinical laboratory data that will be analyzed consists of blood analyses (including hematology 
and biochemistry). Clinical laboratory values will be converted into standard international units 
that will be used in all listings and tables. 
Blood samples for clinical laboratories will be taken as defined in the study flowchart and as 
clinically indicated.  The laboratory parameters (excluding those used for disease assessment) will 
be classified as follows:   
• 
Hematology  
- 
Red blood cells and platelets: hemoglobin and platelet count,  
- 
White blood cells: white blood cell count, neutrophils and lymphocytes. 
• 
Biochemistry 
- 
Metabolism: fasting glucose and albumin, 
- 
Electrolytes: sodium, potassium, chloride, corrected serum calcium, magnesium and 
phosphate, 
- 
Renal function: serum creatinine, estimated glomerular filtration rate (eGFR) by 
modification in diet in renal disease (MDRD) formula, blood urea nitrogen and uric 
acid, 
- 
Liver parameters: alanine aminotransferase, aspartate aminotransferase, alkaline 
phosphatase and total bilirubin. 
Technical formulas are described in Section 2.5.1. 
2.1.4.4 Vital signs variables  
Vital signs include: heart rate, systolic and diastolic blood pressure and weight. 


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2.1.4.5 Electrocardiogram variables  
Electrocardiogram assessments will be described as normal or abnormal. An interpretation of the 
results (normal/abnormal) is to be entered in the eCRF. In case of abnormal result, a description of 
the finding should be reported. 
2.1.4.6 Other safety endpoints  
Other safety endpoints will include ECOG PS and indirect Coombs test. 
2.1.5 Pharmacokinetic variables  
2.1.5.1 Population approach for isatuximab  
The population PK parameters of isatuximab and their inter-patient PK variability will be 
estimated.  
Empirical Bayesian estimation of individual parameters and of individual exposure (Area Under 
the Curve [AUC], Cmax and Ctrough) will also be performed.  
In addition, Ctroughobs defined as plasma concentration observed before treatment administration 
during repeated dosing and concentrations at end of infusion (CEOI) will be provided.  
Analysis of PK variables except Ctroughobs and concentrations at end of infusion (CEOI) for 
isatuximab could be presented in a separate report. 
2.1.5.2 Non-compartmental analysis for carfilzomib  
The following PK parameters will be calculated with PKDMS software (Pharsight) using 
non-compartmental methods from plasma of carfilzomib concentrations. The parameters will 
include, but may not be limited to, the following: 
Table 5 - List of pharmacokinetic parameters and definitions  
Parameters 
Definition 
Ceoi 
Concentration observed at the end of IV infusion 
Cmax 
Maximum concentration observed after the first infusion 
tmax 
Time to reach Cmax 
Clast 
Last concentration observed above the lower limit of quantification 
tlast 
Time of Clast 
Ctrough 
Plasma concentration observed just before treatment administration during repeated dosing 
AUClast 
Area under the plasma concentration versus time curve calculated using the trapezoidal method from time 0 
to tlast 
AUC 
Area under the plasma concentration versus time curve extrapolated to infinity according to the following 
equation: AUC= AUClast + Clast/λz 


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2.1.6 Immunogenicity endpoints  
Human anti-drug antibodies (ADAs) to isatuximab will be assessed during the study as described 
in the protocol for the IKd arm only and will be analyzed using the ADA population  
(see Section 2.3.4). 
Periods of observation: 
• 
ADA pre-treatment period: The ADA pre-treatment period is defined as the time from 
signed informed consent to the first isatuximab administration.  
• 
ADA on-study observation period: the ADA on-study observation period is defined as the 
time from first isatuximab administration until the end of the study. 
ADA attributes: 
• 
Pre-existing ADAs are defined as ADAs that are present in samples drawn during the 
ADA pre-treatment period. 
• 
Treatment boosted ADAs are defined as pre-existing ADA with an increase in titer value 
during the ADA on-study observation period of at least two titer steps.  Assuming a 2-fold 
serial dilution schema is used for the study, this means that the post-treatment sample titer 
value is at least (≥) 4-fold of pre-treatment titer value. 
• 
Treatment induced ADAs are defined as ADAs that developed at any time during the 
ADA on-study observation period in patients without pre-existing ADA (including 
patients without pre-treatment samples). 
• 
Transient ADA response is defined by:  
- 
Treatment-induced ADA detected only at one sampling time point during the ADA  
on-study observation period (excluding the last sampling time point, which ought to be 
considered persistent unless shown to be undetectable at a later time) OR,  
- 
Treatment-induced ADA detected at two or more sampling time points during the  
on-study observation period, where the first and last ADA-positive samples 
(irrespective of any negative samples in between) are separated by a period less than 
16 weeks and the subject’s last sampling time point is ADA-negative.  
• 
Persistent ADA response is defined by treatment-induced ADA detected at two or more 
sampling time points during the ADA on-study observation period, where the first and last 
ADA-positive samples (irrespective of any negative samples in between) are separated by 
a period of at least 16 weeks.  
• 
Indeterminate ADA response is defined by: 
- 
Treatment induced ADA detected only in the last sampling time point OR, 
- 
Treatment-induced ADA detected in the last two sampling time points (both positive), 
separated by a period of less than 16 weeks.  
ADA response endpoints: 
• 
ADA positive patients are defined as patients with at least one treatment-induced or 
treatment-boosted ADA positive sample at any time during the ADA on-study observation 
period. 
• 
ADA prevalence is defined as the sum of the number of patients with pre-existing ADA 
and the number of patients with treatment induced ADAs, divided by the number of 
patients in the ADA population. 


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• 
ADA incidence is defined as the number of ADA positive patients divided by the number 
of patients in the ADA population. 
2.1.7 Health-related quality-of-life endpoints  
Health-related quality of life (HRQL) will be assessed using: 
• 
The European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire – Cancer specific module with 30 items (EORTC QLQ-C30) (2, 3).  
• 
The EORTC QLQ myeloma-specific module with 20 items (MY20) (4, 5). 
• 
The EuroQol measure with 5-dimensions and 5-levels per dimension EQ-5D-5L (6, 7). 
EORTC QLQ-C30 and EORTC QLQ-MY20 
The QLQ-C30 incorporates a Global Health Status/QoL scale, five functional scales (Physical 
functioning [PF2], Role functioning [RF2], Cognitive functioning [CF], Emotional functioning 
[EF] and Social functioning [SF]), three symptom scales (Fatigue [FA], Pain [PA] and 
Nausea/Vomiting [NV]) and six additional single items (Dyspnea [DY], Insomnia [SL], Appetite 
Loss [AP], Constipation [CO], Diarrhea [DI] and Financial Difficulties [FI]) as symptoms 
commonly reported by cancer patients and the perceived financial impact of the disease. 
A higher score for a global health status/functional scale represents a higher/healthy level of 
HRQL, whereas a higher score for symptoms/ items represents a higher level of 
symptomatology/problems. 
The EORTC QLQ-MY20 (MY20) is meant for use among patients with MM cancer. It is 
comprised of: 
• 
2 functional scales (body image, future perspective). 
• 2 symptoms scales (disease symptoms and side-effects of treatment). 
Higher scores for “disease symptoms” and “side effects of treatment” indicate more symptoms 
and side effects and lower HRQL, whereas a high score for “future perspective” and “body 
image” represents better outcomes. 
Raw scores (RS) for the EORTC are calculated using EORTC QLQ-C30 and EORTC QLQ-
MY20 scoring formulas (detailed in Appendix G): 
• 
RS is the mean of the component items. 
• 
For functional scales: Score = [1− ((RS− 1)/range)] x 100. 
• 
For symptom scales/single items scales and the Global health status/QoL scale:  
Score = [(RS − 1)/ range] x 100. 
The range is the difference between the maximum and the minimum response to individual items. 
EQ-5D-5L 
The EQ-5D-5L comprises the EQ-5D 5 dimensions (mobility, self-care, usual activities, 
paint/discomfort and anxiety/depression) and a visual analogue scale (VAS).  


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Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems 
and extreme problems. Overall health state is then defined as a 5-digit number. The health utility 
index value will be calculated using the crosswalk value sets provided in the EQ-5D-5L Index 
Value Calculator created by the EuroQol Group and using mapping function developed by Van 
Hout et al.(8). The value sets based on UK population will be used for all countries.  
The EQ VAS records the respondent’s self-rated health on a 20 cm vertical VAS with endpoints 
labelled 0 (‘the worst health you can imagine’) to 100 (‘the best health you can imagine’). This 
information can be used as a quantitative measure of health as judged by the individual 
respondents. EQ VAS will be described as given by patient. 
Rules of handling with missing items are detailed in Appendix G for the EORTC questionnaires.  
For the EQ-5D-5L, the health utility score will be missing if response to one or more dimension is 
missing. 
2.1.8 Exploratory biomarker endpoints  
A blood sample will be collected on Day 1 of Cycle 1. Leukocyte DNA will be extracted and 
analyzed for immune genetic determinants (such as Fcγ receptor polymorphisms). Parameters of 
clinical response will be evaluated in each type of immune genetic determinants. 
In IKd arm only, an additional blood sample will be collected at all time-points to evaluate the 
potential interference of isatuximab in the M protein assessment (central laboratory) up to 
Cycle 30. This sample will be collected beyond Cycle 30 and until disease progression for patients 
who reach at least VGPR at cycle 30. In case of isatuximab is discontinued before progression, 
sample interference assay will be collected up to 3 months after last isatuximab administration or 
PD, whichever comes first. 
In addition to the 3 chromosomal abnormalities (del(17p), t(4:14) and t(14:16)) assessed by FISH 
at baseline to determine R-ISS stage which is stratification factor, other chromosomal 
abnormalities such as but not limited to del (1p) and 1q21+ deletion will be assessed by central 
laboratory. Parameters of clinical response will be evaluated in each of these chromosomal 
abnormalities. 
2.1.9 Further therapy after discontinuation of investigational medicinal product 
administration during the study  
Further therapies after discontinuation of IMP include further anti-myeloma treatments.  
Time to Next Treatment 
Time to next treatment is defined as the time from randomization to the start of further anti-
myeloma treatment. Patients who do not receive any further anti-myeloma treatment before the 
cut-off date will be censored at the date of their last follow-up visit or the cut-off date, whichever 
comes first. Patients with no follow-up visit will be censored at their last study treatment 
administration or the cut-off date whichever comes first. 


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2.2 
DISPOSITION OF PATIENTS  
This section describes patient disposition for both patient study status and the patient analysis 
populations. 
Screened patients are defined as any patients who signed the study informed consent.  
Randomized patients consist of all patients with a signed informed consent form who have been 
allocated a randomization number by the IRT, regardless of whether the patient was treated or not. 
For patient study status, the total number of patients in each of the following categories will be 
presented in the clinical study report using a flowchart diagram or summary table: 
• 
Screened patients. 
• 
Screen failure patients and reasons for screen failure (if any). 
• 
Randomized patients. 
• 
Randomized but not treated patients. 
• 
Randomized and treated patients. 
• 
Patients who discontinued study treatment.  
• 
Patients still on treatment. 
• 
Patients still on study 
• 
Status at last study contact.  
• 
Patients with date of last contact obtained before the cut-off date and duration from last 
contact to cut-off date (0-2weeks, 2-4 weeks, 4-8 weeks, >8 weeks). 
A summary of the reasons for definitive and premature treatment discontinuation by treatment 
group will be provided. Definitive treatment discontinuation is defined as the discontinuation of 
all the study drugs. Premature treatment discontinuation is defined as the discontinuation of at 
least one of the study drugs but at least one is continued. Reasons for definitive and premature 
treatment discontinuation as “adverse event” (Covid-19 infection (AE)) and “Other” related to 
Covid-19 pandemic situation will be also displayed, when applicable. Listing of the reasons for 
treatment discontinuation and patients still on treatment at time of the analysis will be provided, 
when applicable. 
A summary of the reasons for end of study by treatment group will be provided. Reasons for end 
of study as “Death” will be also displayed, when applicable. Listing of patients who ended the 
study for other reason will be provided. 
For all categories of patients (except for the screened and non-randomized categories) percentages 
will be calculated using the number of randomized patients as the denominator. 
In addition, the number and percentage of randomized patients will be presented for each of the 
6 stratification levels (number of prior lines = 1 and R-ISS stage = I or II;  
number of prior lines = 1 and R-ISS stage = III …) and by treatment group. 
All critical or major deviations potentially impacting efficacy analyses, randomization, and 
drug-dispensing irregularities and other major or critical deviations will be summarized in tables 
giving numbers and percentages of deviations by treatment group. Critical and major protocol 


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deviations will be also displayed separately as related versus not related to Covid-19 pandemic 
situation if applicable. 
Additionally, the following analysis populations will be summarized by treatment group: 
• 
Randomized population. 
• 
Efficacy population: intent-to-treat (ITT) population.  
• 
Population without trial impact (disruption) due to Covid-19 infection (AE) and/or 
pandemic situation. 
• 
Safety population. 
• 
Pharmacokinetics population. 
• 
ADA population.  
Definitions of study populations are provided in Section 2.3. Reasons for exclusion from the 
population without trial impact (disruption) due to Covid-19 infection (AE) and/or pandemic 
situation will be summarized. 
2.2.1 Randomization and drug dispensing irregularities  
Randomization and drug-dispensing irregularities occur whenever: 
1. A randomization is not in accordance with the protocol-defined randomization method, 
such as a) a patient is randomized based on an incorrect stratum or b) a patient is 
randomized twice. 
OR 
2. A patient is dispensed an IMP kit not allocated by the protocol-defined randomization, 
such as a) a patient at any time in the study is dispensed a different IMP than as allocated 
or b) a non-randomized patient is treated with IMP reserved for randomized patients. 
Randomization and drug-dispensing irregularities will be monitored throughout the study and 
reviewed on an ongoing basis. The following irregularities are prospectively defined: 
• 
IMP dispensation without IRT transaction. 
• 
Erroneous therapy dispensation (ie, patient is dispensed a combination of drugs that does 
not correspond to the randomization arm). 
• 
Patient randomized twice. 
• 
Stratification error. 
All randomization and drug-dispensing irregularities will be documented in the clinical study 
report and will be summarized by treatment group on the randomized population (number and 
percentages). Non-randomized but treated patients will be described separately. 


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2.3 
ANALYSIS POPULATIONS  
The randomized population includes all randomized patients as defined in Section 2.2. 
For any patient randomized more than once, only the data associated with the first randomization 
will be used in any analysis population. The safety experience associated with any later 
randomization will be assessed separately. 
2.3.1 Efficacy populations  
2.3.1.1 Intent–to-treat population  
The ITT population is the randomized population. Patients will be analyzed according to the 
treatment group allocated by IRT, regardless of whether the patients receive any study treatment 
or receive a different study treatment from that to which they were randomized. 
This population is the primary population for all efficacy analyses. 
2.3.1.2 Population without trial impact (disruption) due to Covid-19  
This population will include all randomized patients: 
• 
without any critical or major deviation related to Covid-19 
• 
and who did not definitively discontinue treatment due to Covid-19 (infection (AE) and/or 
pandemic situation). 
• 
and who did not definitively discontinue study due to Covid-19 (infection (AE) and/or 
pandemic situation). 
This population could be used for additional analyses to assess the impact of Covid-19 on the 
study. 
2.3.2 Safety population  
The safety population will include ITT patients who received at least 1 dose or a part of a dose of 
the study treatments. This population is the primary population for the analysis of all safety 
parameters. All analyses using this population will be based on the treatment actually received.  
In addition:  
• 
Non-randomized but treated patients will not be part of the safety population; however, 
their safety data will be presented separately. 
• 
Randomized patients for whom it is unclear whether they took the IMP will be included in 
the safety population as randomized. 
• 
Patients receiving at least one isatuximab dose (even incomplete or by error at one cycle) 
during the trial, will be analyzed in the IKd arm. 


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2.3.3 Pharmacokinetics population  
The PK population will include safety population patients from the IKd arm who receive at least 
one dose of isatuximab, even if incomplete, with data for at least one PK concentration available 
post-baseline. 
2.3.4 ADA population  
The ADA population will include safety population patients from the IKd arm with a least 
one ADA assessment during the ADA on-study observation period with a reportable result. 
2.4 
STATISTICAL METHODS  
Continuous data will be summarized using the number of available data, mean, standard 
deviation, median, minimum and maximum for each treatment group. Categorical and ordinal 
data will be summarized using the number and percentage of patients in each treatment group.  
2.4.1 Demographics and baseline characteristics  
Parameters described in Section 2.1.1 will be summarized on the randomized population by 
treatment group (as allocated by IRT) and overall using descriptive statistics.  Analyses for the 
safety population will be included in the appendices if the size of the safety population is different 
(>10%) from the size of the randomized population for any treatment group. Analyses for the 
population without trial impact (disruption) due to Covid-19 will be included in the appendices if 
the size of this population is different (>10%) from the size of the randomized population for any 
treatment group. 
Medical or surgical history will be summarized by SOC and PT (SOC will be sorted according to 
the internationally agreed order and PT by decreasing frequency). In addition, smoking habits will 
be summarized separately. 
Demographic characteristics, MM characteristics at study entry and Prior anti-myeloma 
treatments will be also described by treatment arm and SPM categories (solid tumor [skin or 
non-skin cancer], hematology malignancies, or other non-specified). Prior anti-myeloma 
treatments will be also described by treatment arm and by regimen. 
2.4.2 Prior or concomitant medications (other than anticancer therapies)  
The prior and concomitant medications will be presented for the randomized population.  
Medications will be summarized by treatment group according to the WHO-DD, considering the 
first digit of the anatomical therapeutic chemical (ATC) class (anatomic category) and the 
first 3 digits of the ATC class (therapeutic category).  All ATC codes corresponding to a 
medication will be summarized, and patients will be counted once in each ATC category 
(anatomic or therapeutic) linked to the medication. Therefore, patients may be counted several 
times for the same medication.  


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The table for prior medications will be sorted by decreasing frequency of ATC followed by all 
other therapeutic classes based on the overall incidence across treatment groups.  In case of equal 
frequency regarding ATCs (anatomic or therapeutic categories), alphabetical order will be used. 
The tables for concomitant medications will be sorted by decreasing frequency of ATC followed 
by all other therapeutic classes based on the incidence in the IKd arm. In case of equal frequency 
regarding ATCs (anatomic or therapeutic categories), alphabetical order will be used.  
In addition, other analyses including number (%) of patients with concomitant red blood cells 
transfusions, with concomitant platelets transfusions and with concomitant use of granulocyte 
colony stimulating factor/ granulocyte-macrophage colony stimulating factor (prophylaxis and 
curative intent) will be provided for the safety population. 
IR medications  
Number (%) of patients with IR medications (prophylaxis and curative intent) including 
diphenhydramine (or equivalent), paracetamol and steroids as defined in Section 2.1.2 will be 
provided and will be also displayed depending on the mode of administration (initial mode of 
administration and fixed volume administration mode).ss Number (%) of patients with IR 
medications for prophylaxis intent will be described by infusion number.  Number of infusions 
with prophylactic IR medications, number of infusions with curative IR medications and number 
of infusions without any IR medication will also be summarized. Further analyses on cumulative 
steroids exposure may be performed as needed.  
2.4.3 Extent of investigational medicinal product exposure  
The extent of IMP exposure will be assessed and summarized by actual treatment within the 
safety population (Section 2.3.2). 
2.4.3.1 Overall study treatment exposure  
The following variables will be summarized with descriptive statistics to describe the overall 
study treatment exposure (all study treatments together): 
• 
Overall number of cycles started, defined by the total number of cycles in which at least 
one dose of any study treatments is administered. 
• 
Cumulative exposure to treatment (in patient-years), derived by summing the duration of 
exposure for all patients by treatment group. 
• 
Overall duration of exposure in weeks defined as [(last day of last cycle – first day of first 
cycle)/7]. 
The first day of the first cycle is defined as the date of the first dose of study treatment at Cycle 1. 
The last day of last cycle is defined as the last date among the following: 
• 
Date of last dose of isatuximab + 7 days if last cycle is Cycle 1 or date of last dose of 
isatuximab + 14 days if last cycle is Cycle 2 or later.  
• 
Date of last dose of carfilzomib + 7 days if the last dose is administered on Day 1 or 8; or 
date of last dose of carfilzomib + 6 days if the last dose is administered on Day 2 or 9; or 


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date of last dose of carfilzomib + 14 days if the last dose is administered on Day 15; or 
date of last dose of carfilzomib + 13 days is the last dose is administered on Day 16. 
• 
Date of last dose of dexamethasone + 7 days if the last dose is administered on Days 1, 8, 
15, or 22; or date of last dose of dexamethasone + 6 days if the last dose is administered on 
Days 2, 9, 16, or 23. 
Number of cycles started by patient will be also summarized as a quantitative variable and by 
category (ie, number (%) of patients receiving at least 1 cycle, at least 2 cycles, etc.). 
Cycle delay will be computed to describe overall dose modification. A cycle is deemed to have 
been delayed if the start date of the current cycle is >28 + 3 days beyond the start date of the 
previous cycle (planned cycle duration is 28 days). Cycle start date is defined by the earliest date 
of isatuximab, carfilzomib or dexamethasone administration within a cycle. Cycle delay is not 
defined for the first cycle. 
Cycle delay will be analyzed at the patient and cycle levels by treatment group as follows: 
• 
Patient level: 
- 
Number of patients treated (used for % calculation for this level), 
- 
Number (%) of patients with at least one cycle delay, 
- 
Between 4 and 7 days, 
- 
More than 7 days. 
- 
Number (%) of patients with at least one cycle delay due to Covid-19 pandemic 
situation 
- 
Between 4 and 7 days, 
- 
Between 7 and 14 days, 
- 
Between 14 and 28 days, 
- 
More than 28 days. 
- 
Number (%) of patients with at least one cycle partially done due to Covid-19 
pandemic situation (cycle with at least one dose omission of one study drug due to 
COVID-19 ie, at a visit not done, partially done on site or partially done by phone due 
to COVID-19) 
• 
Cycle level:  
- 
Number of cycles administered (used for % calculation for this level), 
- 
Number (%) of cycles delayed. 
- 
Between 4 and 7 days, 
- 
More than 7 days. 
- 
Number (%) of patients with at least one cycle delay due to Covid-19 pandemic 
situation  
- 
Between 4 and 7 days, 
- 
Between 7 and 14 days, 
- 
Between 14 and 28 days, 
- 
More than 28 days. 
- 
Number (%) of patients with at least one cycle partially done due to Covid-19 
pandemic situation 
Overall extent of exposure will be also described by treatment arm and SPM categories (solid 
tumor [skin or non-skin cancer], hematology malignancies, or other non-specified). 


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2.4.3.2 Isatuximab, carfilzomib or dexamethasone exposure  
The following variables will be summarized with descriptive statistics for isatuximab, 
carfilzomib, and dexamethasone separately to describe exposure to each drug: 
• 
Number of cycles started with each drug.  
• 
Number of cycles started with each drug by patient (as a quantitative variable and by 
category (ie, number (%) of patients receiving at least 1 cycle, at least 2 cycles, etc.). 
• 
Duration of exposure in weeks, defined as: 
- 
For isatuximab:  
[date of last dose of isatuximab + 7 days - first dose of isatuximab] / 7 if last cycle is 
Cycle 1 or [date of last dose of isatuximab + 14 days - first dose of isatuximab] / 7 if 
last cycle is Cycle 2 or later, 
- 
For carfilzomib:  
[date of last dose of carfilzomib + 7 days - first dose of carfilzomib] / 7 if the last dose 
is administered on Day 1 or 8; or [date of last dose of carfilzomib + 6 days - first dose 
of carfilzomib] / 7 if the last dose is administered on Day 2 or 9; or  
[date of last dose of carfilzomib + 14 days - first dose of carfilzomib] / 7 if the last 
dose is administered on Day 15; or  
[date of last dose of carfilzomib + 13 days - first dose of carfilzomib] / 7 if the last 
dose is administered on Day 16,For dexamethasone: 
- 
[date of last dose of dexamethasone + 7 days - first dose of dexamethasone] / 7 if the 
last dose is administered on Days 1, 8, 15, and 22; or  
[date of last dose of dexamethasone + 6 days - first dose of dexamethasone] / 7 if the 
last dose is administered on Days 2, 9, 16, and 23. 
• 
Cumulative dose: the cumulative dose is the sum of all doses administered from first to 
last dose. 
• 
Actual dose intensity (ADI) per week: defined as the cumulative dose divided by the 
duration of exposure in weeks. 
• 
Planned dose intensity per week: corresponds to the sum of the theoretical planned doses 
during the started cycles divided by the theoretical cycle duration expressed in weeks  
(ie, 4 weeks per cycle started). The sum of the theoretical planned doses corresponds to:   
- 
The planned dose at C1D1, regardless of dose changes, multiplied by the theoretical 
total number of doses during the started cycles (4 for cycle 1, 2 for subsequent cycles) 
for isatuximab 
- 
The planned dose at C1D1 (ie, 20 mg/m2), regardless of dose changes, multiplied by 
2 + the planned dose at C1D8 (ie, 56 mg/m2), regardless of dose changes, multiplied 
by 4 for cycle 1 and the planned dose at C1D8 (ie, 56 mg/m2), regardless of dose 
changes, multiplied by 6 for subsequent cycles for carfilzomib  
- 
The planned dose at C1D1, regardless of dose changes, multiplied by the theoretical 
total number of doses (equal to 8) during the started cycles for dexamethasone. 
• 
Relative dose intensity (RDI) in %: defined as the ratio of the ADI to the planned dose 
intensity x 100.  
These analyses will be also provided by treatment arm and SPM categories (solid tumor [skin or 
non-skin cancer], hematology malignancies, or other non-specified). 


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The following variables will be summarized with descriptive statistics for isatuximab, 
carfilzomib, and dexamethasone separately to describe dose modifications for each drug: 
• 
Infusion interruption (excluding dexamethasone): an infusion is considered to be 
interrupted if the administration is stopped during an infusion before it is completed 
regardless it is further restarted or not. 
• 
Infusion/dose delay within cycle: an infusion/dose is deemed to have been delayed if the 
actual start date is >1 day beyond the theoretical day of treatment. Infusion/dose delay 
does not apply to the first infusion/dose of each cycle, in which case it is considered as 
cycle delay.  
• 
Dose reduction: a dose is considered to be administered at a reduced dose if the actual 
dose administered at the current administration is at least one level below the prior 
administration. In addition, if the dose of carfilzomib is not increased to 56 mg/m2 from 
C1D8 as planned per protocol, this will be also considered as a dose reduction.  Dose 
reductions will be determined by using the dose intervals defined in Table 6 for 
carfilzomib and Table 7 for dexamethasone. Although not allowed in the study protocol 
for isatuximab, potential dose reduction as defined in Table 8 will be screened and 
reported in the clinical study report. The first administration will not be counted as a dose 
reduction.   
• 
Dose omission: a dose is considered omitted if the dose is not administered for the 
scheduled visit and there are positive dose(s) afterwards. 
Table 6 - Carfilzomib - Dose reduction criteria  
Starting dose 20 mg/m² 
Starting dose 56 mg/m² 
Actual dose level 
Dose level interval 
Actual dose level 
Dose level interval 
 
 
Dose level -4 (low dose) 
>0 mg/m² and ≤22.5 mg/m² 
Dose level -3 (low dose) 
>0 mg/m² and ≤9 mg/m² 
Dose level -3 (27 mg/m²) 
>22.5 mg/m² and ≤31.5 mg/m² 
Dose level -2 (11 mg/m²) 
>9 mg/m² and ≤13 mg/m² 
Dose level -2 (36 mg/m²) 
>31.5 mg/m² and ≤40.5 mg/m² 
Dose level -1 (15 mg/m²) 
>13 mg/m² and ≤17.5 mg/m² 
Dose level -1 (45 mg/m²) 
>40.5 mg/m² and ≤50.5 mg/m² 
Initial dose (20 mg/m²) 
>17.5 mg/m² 
Initial dose (56 mg/m²) 
>50.5 mg/m² 
Note: if dose is not increased to 56 mg/m² from the third infusion, dose level interval defined for starting dose 56 mg/m2 will be used to 
determine dose reduction at the first administration observed from C1D8 and then dose level interval defined for starting dose 20 mg/m2 will be 
used for subsequent administrations. In case of delayed dose escalation, dose level interval defined for starting dose 56 mg/m2 will be used 
again from the first infusion with planned dose equal to 56 mg/m2. 
Table 7 - Dexamethasone - Dose reduction criteria  
Actual dose level 
Dose level interval 
Dose level -4 (low dose) 
>0 mg and ≤2 mg 
Dose level -3 (4 mg) 
>2 mg and ≤6 mg 
Dose level -2 (8 mg) 
>6 mg and ≤10 mg 
Dose level -1 (12 mg) 
>10 mg and ≤16 mg 
Initial dose (20 mg) 
>16 mg 


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Table 8 - Isatuximab - Dose reduction criteria  
Actual dose level 
Dose level interval 
Dose level -2 (low dose) 
>0 mg and ≤2.5 mg 
Dose level -1 (5 mg) 
>2.5 mg and ≤7.5 mg 
Initial dose (10 mg/kg) 
>7.5 mg 
Dose modification will be analyzed at the patient and total number of infusions levels as follows 
separately for isatuximab and carfilzomib: 
• 
Patient level: 
- 
Number of patients treated (used for % calculation for this level), 
- 
Number (%) of patients with at least one infusion delay, 
- 
Number (%) of patients who did not escalate the carfilzomib dose to 56 mg/m² on the 
third infusion (for patients who have received at least one dose of carfilzomib at or 
after C1D8, carfilzomib table only)  
- 
Number (%) of patients who never escalate the carfilzomib dose to 56 mg/m² 
- 
Number (%) of patients with a delayed carfilzomib dose escalation to 56 mg/m²  
- 
Number of patients who discontinued carfilzomib before C1D8 (carfilzomib table 
only), 
- 
Number (%) of patients with at least one dose reduction, 
- 
Number (%) of patients with at least one dose omission, 
- 
Number (%) of patients with at least 1, 2, 3 or more than 3 dose omission(s) due to 
Covid-19 pandemic situation 
- 
Number (%) of patients with at least 2 consecutive or more than 2 consecutive dose 
omissions due to Covid-19 pandemic situation 
- 
Number (%) patients with a least one infusion interruption 
- 
Number (%) of patients with a least one infusion interrupted and re-started 
- 
Number (%) of patients with a least one infusion interrupted and not completed 
(not re-started) 
• 
Total number of infusions level: 
- 
Total number of infusions (used for % calculation for this level), 
- 
Number of infusions interrupted, 
- 
Number of infusions interrupted and re-started 
- 
Number of infusions interrupted and not completed (not re-started) 
- 
Number of infusions interrupted more than once, 
- 
Number (%, calculated using the total number of infusions interrupted) of 
administrations interrupted at: 
- 
1st infusion, 
- 
2nd infusion, 
- 
Subsequent infusions. 
- 
Time from infusion start to first interruption in minutes (quantitative and qualitative: 
<5, 5-10, 11-30, 31-60, 61-90, 91-120, >120) 


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Moreover, duration of infusion defined as the time from the start (date/time) of infusion to the end 
(date/time) of infusion will be summarized for first and subsequent infusions separately for 
isatuximab and carfilzomib. In addition, exposure data for isatuximab will be also displayed 
depending on the mode of administration (initial mode of administration and fixed volume 
administration mode). 
For dexamethasone, dose modification will be analyzed at the patient level only: 
• 
Number of patients treated (used for % calculation for this level), 
• 
Number (%) of patients with at least one dose delay,  
• 
Number (%) of patients with at least one dose reduction, 
• 
Number (%) patients with a least one dose omission. 
• 
Number (%) of patients with at least 1, 2, 3 or more than 3 dose omission(s) due to 
Covid-19 pandemic situation 
• 
Number (%) of patients with at least 2 consecutive or more than 2 consecutive dose 
omissions due to Covid-19 pandemic situation 
2.4.4 Analyses of efficacy endpoints  
All efficacy analyses will be performed on the ITT population. All analyses using the 
stratification factors will be performed using the stratification factor as per IRT.  
2.4.4.1 Analysis of primary efficacy endpoint(s)  
Primary analysis will consist of PFS comparison between IKd arm versus Kd arm through a 
log-rank test procedure stratified by stratification factors as entered in the IRT (ie, number of 
previous lines of therapy and R-ISS). The nominal significance levels at the interim and final 
analyses will be determined using alpha-spending function (see Section 3) in order to control the 
overall one-sided type 1 error at 2.5%. 
In addition, the following estimates will be provided: 
• 
The hazard ratio and corresponding confidence interval (CI) at (1-2α) % level (α being the 
one-sided nominal significance level: α=0.023 at final analysis, α=0.005 at PFS interim 
analysis) will be estimated using the Cox proportional hazards model stratified by the 
same stratification factors as those used for the log-rank test described above. Underlying 
assumptions of the Cox proportional hazards model will be assessed by graphical methods 
(ie, log-log graphical methods). 
• 
PFS data will be analyzed using the Kaplan-Meier method by treatment group in the ITT 
population: 
- 
Kaplan-Meier estimates of the 25th, 50th and 75th percentiles and their associated 
2-sided 95% CIs will be provided. The confidence intervals will be constructed using a 
log-log transformation of the survival function and the methods of Brookmeyer and 
Crowley, 
- 
Number of patients at risk as well as the probabilities of surviving without disease 
progression at least 6, 12, 18, 24 and 36 months (if possible, depending on the time of 
the analysis) with 2-sided 95% CIs will be estimated for each treatment group using 
the Kaplan-Meier method, 


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- 
Kaplan-Meier curves will be plotted. These plots will include the number of patients at 
risk at key time points by treatment group. 
• 
For patients with events, the type of event (confirmed disease progression or death) will be 
summarized by treatment group using counts and percentages. The type of disease 
progression will also be presented (progression diagnosed on M-protein or radiological 
progression). 
• 
For patients who died without evidence of disease progression, the time from the last valid 
disease assessment to the death will be summarized by treatment group using number, 
mean, standard deviation, median and range. 
• 
The number (%) of censored patients, the reason and timing of their censoring 
(ie, censored at randomization, censored at the last valid disease assessment before the 
initiation of further anti-myeloma treatment, censored at last valid disease assessment 
before the cut-off date, censored at the cut-off date), and the time from the last disease 
assessment to the cut-off date will be summarized by treatment group. For each censoring 
reason, when applicable, distinction will be made between cases where no event was 
observed and cases where an event was observed after the censoring. 
• 
Follow-up duration (months) will be defined as the time interval from the date of 
randomization to the date of last contact with the patient. Patients who have died will be 
censored on their date of death. Median follow-up duration (months) will be estimated 
using the Kaplan-Meier method. 
2.4.4.1.1 Sensitivity analyses  
Sensitivity analyses of PFS will be performed at a 1-sided α level unless otherwise specified. The 
same statistical methods used in the primary analysis will be applied to the PFS data using 
different censoring and event rules or stratification rules as defined below. Additional details are 
provided in Appendix F. 
Sensitivity analysis on PFS endpoints for US only and ex-US will be performed separately.  
The sensitivity analyses for all regions excluding US will include: 
• 
PFS analysis without censoring for further anti-myeloma treatment. 
• 
PFS analysis using investigator assessment of response and considering symptomatic 
deterioration. 
• 
PFS analysis using investigator assessment of response and ignoring symptomatic 
deterioration. 
• 
Initiation of further anti-myeloma treatment considered as PFS event. 
• 
Analysis based on scheduled assessment dates instead of actual assessment dates and late 
PFS events censored (analysis done if lack of adherence to the protocol-defined schedule 
of disease assessments between the treatment groups has been detected).  
• 
PFS analysis using the date of the last observed event as cut-off date (analysis done if 
some events are observed after the PFS analysis cut-off date due to operational aspects). 
• 
Unstratified PFS analysis. 
• 
PFS analysis using stratification factors as per eCRF (if relevant).   


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• 
PFS analysis on the population without trial impact (disruption) due to Covid-19 
• 
PFS analysis censoring death event due to Covid-19 infections (Covid-19 grade 5 TEAEs 
+ death due to other (Covid-19)) 
For US, as the primary analysis of PFS includes an additional censoring rule for late progressions 
and deaths, this additional censoring rule will be applied for all sensitivity PFS analyses same as 
used in ex-US except sensitivity analysis #5 (Analysis based on scheduled assessment dates 
instead of actual assessment dates and late PFS events censored) that already included this 
censoring rule. For sensitivity analysis #2 (PFS analysis using Investigator assessment of response 
including symptomatic deterioration) and #4 (Initiation of further anti-myeloma treatment 
considered as PFS event), this additional censoring rule will be applied to all types of events (PD, 
death and either symptomatic deterioration or initiation of further anti-myeloma therapy). 
Sensitivity analysis #1 (progression based on blinded IRC disease assessment, regardless of 
further anti-myeloma treatment) 
Patients with documented PD or death after the start of further anti-myeloma treatment will not be 
censored at the date of the last valid disease assessment not showing disease progression 
performed prior to initiation of a further anti-myeloma treatment. Progression or deaths occurring 
after any further anti-myeloma treatment will be considered as PFS events in this analysis.  
Sensitivity analysis #2(progression based on investigator’s disease assessment and including 
symptomatic deterioration)  
PFS will be derived using the investigator's disease assessment (as reported in the eCRF) using 
the censoring and event rules from the primary analysis. In addition, in this analysis, symptomatic 
deterioration will be considered as an event. If symptomatic deterioration is observed in the 
absence of documented disease progression per IMWG criteria or prior to documented disease 
progression or death, the date of the PFS event will be the date of symptomatic deterioration.    
Sensitivity analysis #3 (progression based on investigator’s disease assessment and ignoring 
symptomatic deterioration)  
PFS will be derived using the investigator's disease assessment (as reported in the eCRF), 
ignoring symptomatic deterioration and using the censoring and event rules from the primary 
analysis. 
The concordance/discordance between the IRC and the investigator assessment of PD will be 
summarized by treatment group using counts and percentages. For patients with PD per both the 
IRC and the investigator, the concordance of the timing of the events will be summarized by 
treatment group using counts and percentages. 
Sensitivity analysis #4 (progression based on blinded IRC disease assessment and considering 
initiation of further anti-myeloma treatment as an event) 
PFS endpoint will be analyzed based on IRC disease assessment, including initiation of further 
anti-myeloma treatment as an event. If further anti-myeloma treatment is initiated in absence or 
before disease progression is documented per IMWG criteria, the start date of the further anti-
myeloma treatment will be used as the date of PFS event.  


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Sensitivity analysis #5 (progression based on blinded IRC disease assessment, analysis based on 
scheduled assessment dates instead of actual assessment dates and censoring late progressions 
and deaths) 
Adherence to the protocol-defined schedule of disease assessments will be assessed by comparing 
the timing of disease assessments between the treatment groups (the day of the disease assessment 
relative to the date of C1D1). If an imbalance is observed between the treatment groups, the PFS 
endpoint based on the IRC disease assessments will be calculated using nominal assessments days 
instead of the actual assessment days as the progression dates and last valid disease assessment 
dates in the censoring and event rules used for the primary analysis. The visit windows for 
defining uniform progression and assessment dates are provided in Table 9. 
In this sensitivity analysis, progression or death occurring more than 8 weeks after the last valid 
disease assessment without progression will be censored.  
Table 9 - Visit windows for uniform progression and assessments days  
#Window 
Nominal day 
Window for disease 
progression assessment 
 
Baseline 
No window 
1 
Day 29 
Day 2 – Day 43 
2 
Day 57 
Day 44 – Day 71 
3 
Day 85 
Day 72 – Day 99 
4 
… 
… 
In general, the window for the time point of Day 28*n+1 (where n>1) is [Day 28*n – 12, Day 28*n + 15]. Day is determined relative to the date 
of C1D1.  For example, progression occurring from Day 72 up to Day 99 will be assigned to the nominal day, Day 85. 
Sensitivity analysis #6 (sensitivity to number of events observed at the cut-off date)  
The cut-off date for the final PFS analysis is the actual date when the 159th event (first occurrence 
of either disease progression or death due to any cause) has been observed. Due to operational 
aspects some events could be observed after the cut-off date. If appropriate, a sensitivity analysis 
may be performed using the date of the last observed event as cut-off date at the exact nominal 
significance level based on the actual number of events. 
Since the PFS endpoint met its statistical significance at the planned interim analysis of 103 PFS 
events (65% information fraction), all future analyses of PFS endpoint are non-inferential. All 
observed PFS events up to the analysis cut-off date will be used for PFS final analysis. Hence this 
sensitivity analysis #6 is not applicable for the PFS final analysis. 
Sensitivity analysis #7 (sensitivity to stratification) 
In order to assess the robustness of the primary analysis to stratification factors, analysis of PFS 
by using unstratified log-rank test procedure and unstratified Cox’s regression model will be 
performed. 


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Sensitivity analysis #8 (sensitivity to randomization strata) 
In order to assess the robustness of the primary analysis to randomization stratum mistakes (ie, the 
stratum recorded in IRT differs from the actual one), a sensitivity analysis of PFS will be 
performed using the stratification factors as derived from eCRF data, if relevant. 
Sensitivity analysis #9 (sensitivity to assess the impact of Covid-19) 
In order to assess the impact of Covid-19 on the study, a sensitivity analysis of PFS will be 
performed on the population without trial impact (disruption) due to Covid-19 (as defined in 
Section 2.3.1.2). 
Sensitivity analysis #10 (progression based on blinded IRC disease assessment and censoring 
death event due to Covid-19 infections)    
In order to assess the impact of Covid-19, PFS endpoint will be analyzed based on IRC disease 
assessments, censoring death event due to Covid-19 infections (Covid-19 grade 5 TEAEs + death 
due to other (Covid-19)). If patient died from Covid-19 infections (and no progressive disease 
confirmed before), then the patient is censored and the censoring date is the date of last valid 
disease assessment without evidence of PD.  
Other potential sensitivity analyses 
In addition, the following two sensitivity analyses (9) could be performed to account for possibly 
informative censoring due to initiation of further anti-myeloma treatment: 
• 
Delta-adjusted method that specifies that the hazard of having an event for experimental 
subjects who switched to further anti-myeloma treatment is multiplicatively increased 
relative to the hazard for experimental subjects who have not switched. 
• 
Reference-based method that specifies that the hazard for experimental subjects who 
switched to further anti-myeloma treatment lies between the hazard for experimental 
subjects who have not switched and the hazard for the reference control subjects.  
Both methods are suitable for a tipping point analysis by varying the sensitivity parameter 
(or penalty) and examining the resulting treatment effect estimates, confidence intervals and 
p values. In particular, the amount of penalty which overturns the primary analysis results will be 
looked for.  
2.4.4.1.2 Subgroup analyses  
Evaluation of consistency: 
The consistency of the results from the primary analysis will be evaluated across pre-defined 
subgroups in patients with available results. The definition of each subgroup is defined in 
Table 10. Depending upon the study results, additional subgroups may be examined, and 
subgroups with small sample sizes may be combined to create a larger meaningful subgroup. For 
each subgroup, the treatment effect hazard ratio and its associated 2-sided 95% confidence 
interval will be estimated. A forest plot summarizing the results for each subgroup will be 
provided. 


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Evaluation of interactions: 
For each pre-defined factor defined in Table 10, PFS will be analyzed using a non-stratified Cox 
proportional hazards model with terms for the factor, treatment and their interaction. The test of 
the interaction will be performed at the 10% alpha level. 
Table 10 - PFS subgroups analyses: covariates investigated  
Prognostic factor 
Description 
Age  
<65 vs ≥65 years 
Gender 
Male vs female 
Race 
Caucasian vs other 
Region of the world (geographical) 
Europe vs America vs Asia vs Other countries 
Region of the world (regulatory) 
Western countries vs Other countries 
ECOG PS at baseline 
0 or 1 vs >1  
ISS staging at study entry 
I vs II vs III 
R-ISS staging at study entry (IRT) 
I or II vs III vs not classified 
Number of previous lines of therapy (IRT) 
1 vs >1 
Chromosomal abnormality (del(17p), t(4;14), t(14;16)) 
At least one vs. none  
Chromosomal abnormality (1q21+)  
Yes vs No 
Chromosomal abnormality (gain 1q21)  
Yes vs No 
Chromosomal abnormality (amplification 1q21)  
Yes vs No 
MM type at study entry 
IgG vs non IgG 
Previous autologous stem-cell transplantation 
Yes vs No 
Baseline eGFR (MDRD formula) 
<60 vs ≥60 mL/min/1.73 m2 
Previous treatment with proteasome inhibitor  
Yes vs No 
Previous treatment with IMiD a 
Yes vs No 
Previous treatment with proteasome inhibitor and IMiD 
Yes vs No 
Subgroup analyses will be conducted when at least 10 patients will be included in each treatment arm within each subgroup. 
a IMiD: Immunomodulatory imide drugs 
Evaluation of confounding: 
Since the results from the primary analysis could be impacted by confounding factors, any 
potential issues will be examined and, if confirmed, an exploratory analysis of the primary 
endpoint will be done accordingly. A multivariate Cox proportional hazards model will be used to 
identify prognostic factors among the demographic and baseline characteristics factors described 
in the table (except for gain 1q21/ amplification 1q21) above using a stepwise selection procedure 
with a 15% significance level for removing effects. For significant prognostic factors identified in 
the multivariate model, the balance between treatment groups will be assessed. If major 
confounding is identified through screening for treatment group imbalances in a prognostic factor 
at baseline, an exploratory analysis of PFS will be done after adjusting for the prognostic factors 
in the multivariate Cox proportional hazards model. Differences between the adjusted and 
unadjusted models will be discussed in the clinical study report. 


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2.4.4.2 Analyses of secondary efficacy endpoints  
2.4.4.2.1 Analysis of key secondary efficacy endpoints  
ORR, rate of VGPR or better, CR rate and MRD negativity rate  
Key secondary endpoints other than OS will be analyzed in the ITT population and tested at the 
time of the primary and/or the final analysis of PFS analysis. CR rate will only be tested for 
comparison when the antibody-capture interference assay will be available.  
The primary PFS analysis corresponds either to the positive interim PFS analysis (when 
103 events are observed) or the final PFS analysis (when 159 events are observed). In case of 
positive interim PFS analysis, key secondary endpoints will be tested sequentially up to the null 
hypothesis failed to be rejected for a key secondary endpoint (see Section 2.4.4.3). At final PFS 
analysis, the testing procedure will resume where it stopped at interim analysis (if applicable). 
OS will be analyzed and tested only at the final OS analysis cut-off date that is approximately 
3 years after the primary PFS analysis. The significance levels of binary secondary endpoints at 
the interim and final analyses will be determined using spending functions, except if the 
information fraction is 100% at the interim analysis of PFS (see Section 3). BOR, ORR, rate of 
VGPR or better, CR/sCR rate and MRD negativity rate will be summarized with descriptive 
statistics per treatment arm. Confidence intervals at (1-2α) % level (α being the adjusted one-sided 
nominal significance level using alpha-spending function specific to each endpoint at final and 
interim analyses) will be computed for ORR, rate of VGPR or better, CR rate (including sCR), 
MRD negativity rate and MRD negativity rate in patients with CR or better using the 
Clopper-Pearson method. These endpoints will be compared between treatment arms using 
Cochran Mantel Haenszel test stratified by stratification factors as entered in the IRT. The 
stratified odds ratio and its associated 95% CI will be also provided. 
A shift table matching the BOR at the interim analysis and at final analysis will be provided for 
each arm. The BOR at final analysis is based on the SEBIA HYDRASHIFT 2/4 isatuximab IFE 
test, while the BOR at the interim analysis is based on the conventional IFE test.  
For analysis purpose, subjects in the ITT population without MRD assessment will be considered 
as having positive MRD. In addition, analyses on MRD negativity rate will be also performed on 
the ITT population but restricted to patients with VGPR or better as per investigator and restricted 
to patients with CR or better as per investigator, as exploratory analyses.  
A sensitivity analysis of key secondary endpoints described above will be performed using 
investigator’s assessment of response.  
Sensitivity analyses will be conducted to assess the impact of missing data in the analysis of MRD 
negativity rate in patients with CR or better (ie: multiple imputation, tipping point analysis).  
A tipping point analysis that will consider all combinations of the values of missing MRD data in 
the IKd arm and in Kd arm. This will range all the missing value being imputed as negative MRD 
or positive MRD. Following Liublinska and Rubin (10), graphical displays (heat maps) will be 
used to indicate the tipping point analysis results for each combination of imputed missing values. 
Respectively, the stratified odds ratio will be displayed on the heat map for each combination. 


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In addition, MRD negativity in patients with CR or better will be analyzed using multiple 
imputation for CR or better patients who have a missing MRD status. The rate of MRD negativity 
in patients with CR or better will be derived from observed and imputed values. Missing MRD 
status in patients with CR or better will be imputed 50 times to generate 50 complete datasets by 
using the SAS MI procedure based on Fully Conditional Specification (FCS) logistic regression 
method. The logistics regression method will include treatment group as main effect, the baseline 
characteristics values (such as ECOG, age) and stratification factors as entered in the IRT 
(ie, number of previous lines of therapy and R-ISS) as covariate. Each imputed dataset will be 
analyzed with the Cochran Mantel Haenszel test stratified on stratification factors to compare 
treatment arms. Combined estimates of stratified odds ratio and its associated 95% CI from the 
50 imputed datasets will be obtained through the SAS MIANALYZE procedure using Rubin’s 
formulae. The normalizing transformations will be applied to the statistics estimated from each 
imputed dataset before the Rubin’s combination rules. The common odds ratio estimates will be 
log-transformed before combining process and back-transformed after.  
The overall response after the initiation of daratumumab as further anti-myeloma therapy will be 
described by treatment arm with at least the following items: 
• 
Daratumumab regimens overall 
• 
Daratumumab with IMiD and PI 
• 
Daratumumab with IMiD 
• 
Daratumumab with PI 
• 
Daratumumab monotherapy plus or minus steroids 
• 
Daratumumab with Alkyl. Agents 
At time of OS analyses, the overall response after the initiation of anti-CD38 therapies 
(daratumumab or other anti-CD38 agents) and other selected drugs class as further anti-myeloma 
therapy will be described by treatment arm with at least the following items: 
• 
anti-CD38 therapies regimens overall 
• 
anti-CD38 therapies with IMiD and PI 
• 
anti-CD38 therapies with IMiD 
• 
anti-CD38 therapies with PI 
• 
anti-CD38 therapies monotherapy plus or minus steroids 
• 
anti-CD38 therapies with Alkyl. Agents 
• 
anti-BCMA antibodies 
The overall response after the initiation of further anti-myeloma therapy will be described by 
treatment arm and by line. 
PFS in Minimal Residual Disease negative and positive patients 
PFS by MRD status (negative and positive) will be analyzed using the Kaplan-Meier method by 
treatment group. The Kaplan-Meier curves of PFS for MRD negative and positive patients will be 
provided. 
In addition, sensitivity analyses of PFS by MRD status to assess the impact of Covid-19 on the 
study may be performed similarly to the sensitivity analyses #10 described for the primary 


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efficacy endpoint (ie, analysis of PFS by MRD status censoring the death event due to Covid-19 
infections (Covid-19 grade 5 TEAEs + death due to other (Covid-19)). 
PFS by SPM status 
PFS by SPM status (At least one SPM versus No SPM) will be analyzed using the Kaplan-Meier 
method by treatment group. The Kaplan-Meier curves of PFS for patients with at least one SPM 
and without SPM) will be provided. 
OS 
The OS analysis will be performed approximately 3 years after the primary PFS analysis cut-off 
date using the ITT population.  
The analysis of OS will consist of comparison between the IKd arm versus Kd arm through a  
log-rank test procedure stratified by stratification factors as entered in the IRT (ie, number of 
previous lines of therapy and R-ISS) at the 1-sided level of 0.025.  
In addition,  
• 
The estimates of the hazard ratio and corresponding 95% CI will be provided using a Cox 
proportional hazard model stratified by the stratification factors as entered in the IRT. 
Underlying assumptions of the Cox proportional hazard model will be assessed by 
graphical methods (ie, log-log graphical methods)  
• 
OS data will be analyzed using the Kaplan-Meier method by treatment group: 
- 
Kaplan-Meier estimates of the 25th, 50th and 75th percentiles and their associated 
95% CIs will be provided, 
- 
Number of patients at risk as well as the probabilities of surviving at least 12, 24, 36 
and 48 months (if possible, depending on the time of the analysis) with 95% CI will be 
estimated for each treatment group using the Kaplan-Meier method. 
• 
The number of censored patients, the reasons for their censoring (ie, alive at the cut-off 
date, alive at the last contact before the cut-off date, and lost to follow-up) and the time 
between the date of last contact and the cut-off date will be summarized by treatment 
group. 
• 
Kaplan-Meier curves will be plotted.   
OS - Sensitivity analyses 
A sensitivity analysis of OS by using unstratified log-rank test procedure and unstratified Cox’s 
regression model will be performed. In addition, sensitivity analyses to account for possibly 
informative censoring due to initiation of further anti-myeloma treatment (eg: daratumumab, 
anti-CD38 therapies) could be performed (eg, Rank Preserving Structural Failure Time (RPSFT) 
model and inverse probability of censoring weighting (IPCW) method). The same analyses could 
be performed to account for possibly informative censoring due to initiation of anti-CD38 
therapies. 
In addition, sensitivity analyses of OS to assess the impact of Covid-19 on the study may be 
performed similarly to the sensitivity analyses #9 and #10 described for the primary efficacy 


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endpoint (ie, Analysis of OS on the population without trial impact (disruption) due to Covid-19 
and analysis of OS censoring the death event due to Covid-19 infections (Covid-19 Grade 5 
TEAEs + death due to other (Covid-19)). For the analysis of OS censoring the death event due to 
Covid-19 infections, if a patient died due to Covid-19 infections, then the patient is censored at 
the last known alive date, which is one day before date of death. 
OS by SPM status 
OS by SPM status (At least one SPM versus No SPM) will be analyzed using the Kaplan-Meier 
method by treatment group. The Kaplan-Meier curves of OS for patients with at least one SPM 
and without SPM) will be provided. 
Subgroup analyses 
Subgroup analyses on main prognostic factors defined in Table 10 may be performed for the key 
secondary endpoints based on the findings, as exploratory analyses. In addition, supplementary 
subgroup analyses will be added as: 
• 
Previous treatment with lenalidomide 
• 
Refractory to lenalidomide 
• 
Refractory to lenalidomide at last prior regimen 
• 
Previous treatment with bortezomib 
• 
Refractory to bortezomib 
• 
Refractory to bortezomib at last prior regimen 
• 
Chromosomal abnormality del(17p)  
• 
Chromosomal abnormality t(4,14)  
• 
Chromosomal abnormality t(14,16) 
• 
At least one chromosomal abnormality (del(17p), t(4,14), t(14,16), 1q21+)  
• 
Isolated 1q21+ (Present 1q21+ and standard risk CA versus Absent 1q21+ and standard 
risk CA) 
OS by baseline eGFR (MDRD formula) (<60 mL/min/1.73m2 versus ≥60 mL/min/1.73m2) will be 
analyzed using the Kaplan-Meier method by treatment group. The Kaplan-Meier curves will be 
displayed. 
OS will be presented using the Kaplan-Meier method by treatment group in patients with high-
risk chromosomal abnormalities. The Kaplan-Meier curves of OS for these patients will be 
provided. 
Kaplan-Meier curves will be displayed using at least the following categories  
• 
1q21+ status (present versus absent) 
• 
Chromosomal abnormality including 1q21+ status (At least one chromosomal abnormality 
including 1q21+ versus None) 
• 
Number of prior lines of therapy as per IRT (1 versus >1) 
• 
R-ISS stage at study entry as per IRT (I or II versus III versus Not classified) 
• 
Age (<65 years versus ≥65 years) 
• 
Refractory to lenalidomide 


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• 
Previous treatment with lenalidomide 
• 
1q21+ (Present 1q21+ versus Absent 1q21+ versus Present gain 1q21 versus Present 
amplification 1q21) 
OS – other analyses 
OS will be analyzed using the Kaplan-Meier method by further therapy with anti-CD38 therapy 
(Kd - No further therapy with anti-CD38 therapy vs Kd - Further therapy with anti-CD38 therapy 
vs IKd). The associated Kaplan-Meier will be provided. 
In addition, Kaplan-Meier curves will be displayed by BOR as per IRC at time of PFS final 
analysis and MRD in patients (less than PR vs PR vs MRD + and VGPR or better vs MRD –) and 
by treatment arm. Kaplan-Meier curves will be also displayed using the following categories:  
• 
Complete response (sCR or CR) (yes versus no) 
• 
MRD status (MRD negativity versus MRD positivity)  
• 
MRD negativity and complete response (sCR or CR) versus Other 
The time from randomization to efficacy cut-off date (months) will be summarized. 
2.4.4.2.2 Analysis of other secondary efficacy endpoints  
Other secondary endpoints will be analyzed at the time of the primary analysis and/or the final 
PFS analysis in the ITT population. 
The time-to-event endpoints will be analyzed using Kaplan-Meier methods.  
In addition, for patients who achieve a confirmed response, descriptive statistics (n, mean, 
standard deviation, median, range) will also be provided to summarize time to first response and 
time to best response. 
For investigation of renal response, the incidence of PCSAs defined for eGFR (see Section 2.4.5.3 
and Appendix C) during the treatment period will be summarized by treatment group according to 
the following baseline categories: 
• 
Normal 
• 
Abnormal according to PCSA criterion 
The number of patients with complete, partial and minor renal response will be provided by 
treatment group. 
Analysis of other secondary endpoints will be descriptive only. Any testing procedure carried out 
on these endpoints will be considered as exploratory. 
PFS2 by daratumumab intake 
PFS2 by daratumumab intake (Yes versus No) will be analyzed using the Kaplan-Meier method 
by treatment group. The Kaplan-Meier curves of PFS2 for patients with daratumumab intake and 
without daratumumab intake will be provided. 


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PFS2 by anti-CD38 therapy 
At time of OS analyses, in patients with at least one line of further therapy, PFS2 on first line with 
anti-CD38 therapy will be analyzed using the Kaplan-Meier method by treatment group. The 
Kaplan-Meier curves will be provided.  
Moreover, PFS2 by anti-CD38 therapy (Yes versus No) will be analyzed using the Kaplan-Meier 
method by treatment group. The associated Kaplan-Meier curves will be provided. 
2.4.4.3 Multiplicity issues  
Hypothesis testing of the key secondary efficacy endpoints will be carried out. A closed test 
procedure will be used to control the type I error rate meaning that testing on key secondary 
efficacy endpoints will be performed only if the significance level had been reached on PFS and 
testing on subsequent endpoints will continue only if the null hypothesis for the previously tested 
endpoint is rejected.  The hierarchical procedure will be performed according to the following 
order: 
• 
ORR at the time of the primary PFS analysis and/or the final PFS analysis 
• 
Rate of VGPR or better at the time of the primary PFS analysis and/or the final PFS 
analysis 
• 
MRD negativity rate at the time of the primary PFS analysis and/or the final PFS analysis  
• 
CR rate will only be tested at the PFS final analysis for comparison when the antibody-
capture interference assay will be available (ie, the SEBIA HYDRASHIFT 2/4 isatuximab 
IFE test is available)  
• 
OS tested only at end-of-study.  
The significance levels at the interim and final PFS analyses will be determined using alpha-
spending function specific to each endpoint (see Section 3). The primary analysis of PFS 
corresponds either to the positive interim analysis or the final PFS analysis, whichever is first. 
No update of PFS, ORR, rate of VGPR or better, MRD negativity rate and CR rate will be 
provided at the time of OS analysis. 
If the actual number of PFS events in interim analysis is different from the number planned, the 
significance level for the final analysis of the PFS endpoint will be adjusted using the actual total 
number of PFS events at interim analysis and according to the pre-specified alpha-spending 
function. 
2.4.5 Analyses of safety data  
The summary of safety results will be presented by treatment group by using actual treatment.  
General common rules 
All safety analyses will be performed on the safety population as defined in Section 2.3.2, unless 
otherwise specified. 
The analysis of the safety variables will be essentially descriptive, and no systematic testing is 
planned.  Relative risks versus control arm and their 95% confidence intervals may be provided, if 
relevant. 


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2.4.5.1 Analyses of adverse events  
Generalities 
The primary focus of adverse event reporting will be on TEAEs.  Pre-treatment and post-
treatment adverse events will be described separately.  
If an adverse event date of onset (occurrence, worsening, or becoming serious) is incomplete, an 
imputation algorithm will be used to classify the adverse event as pre-treatment, treatment-
emergent, or post-treatment.  The algorithm for imputing date of onset will be conservative and 
will classify an adverse event as treatment emergent unless there is definitive information to 
determine it is pre-treatment or post-treatment.  Details on classification of adverse events with 
missing or partial onset dates are provided in Section 2.5.3. 
Regarding treatment discontinuation, the following definitions will be used: 
• 
Premature treatment discontinuation is defined as the discontinuation of at least one of 
the study drugs but at least one is continued 
• 
Definitive treatment discontinuation is defined as the discontinuation of all the study 
drugs. 
The grade will be taken into account in the summary. For patients with multiple occurrences of 
the same event, the maximum (worst) grade by period of observation is used. Summaries will be 
provided for all grades combined and for Grade >3 (including Grade 5). Missing grades, if any, 
will be included in the “all grades” category (see Section 2.5.3). 
Sorting within tables ensures the same presentation for the set of all adverse events within the 
observation period (pre-treatment, treatment-emergent, and post-treatment).  For that purpose, the 
table of all TEAEs presented by SOC and PT sorted by the internationally agreed SOC order  
(see Appendix A) and decreasing frequency of PTs within SOCs will define the presentation order 
for all other tables unless otherwise specified. Sorting will be based on results for the IKd arm.  
The AE incidence tables presented by primary SOC, HLGT, HLT and PT will present the number 
(n) and percentage (%) of patients experiencing an AE sorted by SOC internationally agreed 
order, then by alphabetic order of HLGT, HLT and PT. 
A summary of tables provided for analyses of adverse events is provided in Appendix B. 
Overview of TEAEs 
An overview of TEAEs including the number (%) of patients with the following events will be 
provided for the safety population: 
• 
TEAE of any grade. 
• 
Grade >3 TEAE. 
• 
Grade 3-4 TEAE. 
• 
Grade 5 TEAE (any TEAE with a fatal outcome during the treatment period). 
• 
Treatment-related TEAE. 


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• 
Treatment-related TEAE of Grade ≥3. 
• 
Serious TEAE. 
• 
Serious treatment-related TEAE. 
• 
TEAE leading to definitive (all study drugs) treatment discontinuation. 
• 
TEAE leading to premature treatment discontinuation of isatuximab. 
• 
TEAE leading to premature treatment discontinuation of carfilzomib. 
• 
TEAE leading to premature treatment discontinuation of dexamethasone. 
• 
AESI: IRs of Grade ≥3 (pregnancy and overdose, if any, will be presented separately). 
Treatment-related TEAEs are TEAEs reported as related to the study regimen in the eCRF.  
Analysis of all treatment-emergent adverse events 
The following frequency distributions of TEAEs (incidence tables) will be provided for the safety 
population, for all grades combined and Grade ≥3: 
• 
All TEAEs by primary SOC, HLGT, HLT, and PT.  
• 
All TEAEs by primary SOC and PT. 
• 
Most frequent (≥5% of patients in any group) TEAEs by primary SOC and PT.  
• 
Most frequent (≥5% of patients in any group) TEAEs by PT.  
• 
Most frequent (≥10% of patients in IKd arm and ≥5% higher in IKd arm compared to Kd 
arm) TEAEs by primary SOC and PT. 
• 
All treatment-related TEAEs by primary SOC and PT. 
• 
Most frequent (≥5% of patients in any group) treatment-related TEAEs by primary SOC 
and PT.  
• 
Most frequent (≥5% of patients in any group) treatment-related TEAEs by PT.  
Analysis of all serious treatment emergent adverse event(s) 
The following frequency distributions of serious TEAEs (incidence tables) will be provided for 
the safety population, for all grades combined and Grade ≥3: 
• 
All serious TEAEs by primary SOC, HLGT, HLT, and PT.  
• 
All serious TEAEs by primary SOC and PT. 
• 
Most frequent (≥2% of patients in any group) serious TEAEs by primary SOC and PT. 
• 
Most frequent (≥2% of patients in any group) serious TEAEs by PT. 
• 
All serious treatment-related TEAEs, by primary SOC and PT.  
• 
Most frequent (≥2% of patients in any group) serious treatment-related TEAEs by primary 
SOC and PT. 
• 
Most frequent (≥2% of patients in any group) serious treatment-related TEAEs by PT. 


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Analysis of all treatment-emergent adverse event(s) leading to treatment discontinuation 
The following frequency distributions of TEAEs leading to treatment discontinuation (incidence 
tables) will be provided for the safety population, for all grades combined and Grade ≥3: 
• 
All TEAEs leading to definitive treatment discontinuation, by primary SOC, HLGT, HLT, 
and PT. 
• 
All TEAEs leading to definitive treatment discontinuation, by primary SOC and PT.  
• 
All TEAEs leading to premature treatment discontinuation of isatuximab, by primary 
SOC, HLGT, HLT, and PT. 
• 
All TEAEs leading to premature treatment discontinuation of isatuximab, by primary SOC 
and PT. 
• 
All TEAEs leading to premature treatment discontinuation of carfilzomib, by primary 
SOC, HLGT, HLT, and PT. 
• 
All TEAEs leading to premature treatment discontinuation of carfilzomib, by primary 
SOC and PT. 
• 
All TEAEs leading to premature treatment discontinuation of dexamethasone, by primary 
SOC, HLGT, HLT, and PT. 
• 
All TEAEs leading to premature treatment discontinuation of dexamethasone, by primary 
SOC and PT. 
Analysis of all treatment-emergent adverse event(s) leading to dose modification  
The following summary tables are based on the investigator’s intent reported in the AE page 
(“action taken”): 
• 
All TEAEs leading to dose reduction of any drug by primary SOC and PT. 
• 
All TEAEs leading to dose reduction of isatuximab by primary SOC and PT. 
• 
All TEAEs leading to dose reduction of carfilzomib by primary SOC and PT. 
• 
All TEAEs leading to dose reduction of dexamethasone by primary SOC and PT. 
• 
All TEAEs leading to dose interruption of any drug by primary SOC and PT. 
• 
All TEAEs leading to dose interruption of isatuximab by primary SOC and PT. 
• 
All TEAEs leading to dose interruption of carfilzomib by primary SOC and PT. 
• 
All TEAEs leading to any dose delay of any drug by primary SOC and PT. 
Of note, as per eCRF completion guideline, action taken for a TEAE leading to dose omission was 
to be reported as dose reduction in the AE page of the eCRF. 
Analysis of other significant adverse events 
Analysis of infusion reactions 
The following summaries will be provided: 
• 
Number (%) of patients experiencing IRs with isatuximab and/or with carfilzomib 
according to investigator reported AEs presented by primary SOC and PT (both sorted by 
decreasing order of frequency) will be summarized by treatment groups and by grades 
(all grades and by grade). 


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• 
Description of the IRs with isatuximab and/or carfilzomib (according to investigator 
reporting) will be summarized by treatment groups:  
- 
Number (%) of patients with at least one IR, 
- 
Number (%) of patients by worst grade of IR, 
- 
Number (%) of patients by action taken, 
- 
Number (%) of patients with corrective treatment given, 
- 
Number (%) of patients with only 1, ≥1, ≥2, ≥3, ≥4 and ≥5 episodes, 
- 
Number (%) of patients with first occurrence of IRs during the first “two days” of 
infusion (C1D1 and C1D2) and subsequent “two days” of infusion (eg, C1D8 and 
C1D9, C1D15 and C1D15), 
- 
Number (%) of patients with occurrence of IR leading to permanent treatment 
discontinuation, isatuximab withdrawal and carfilzomib withdrawal the first day of 
study treatment and subsequent days of infusion if any 
- 
Number (%) of patients with IR during the first “two days” of infusion, the second 
“two days of infusion”, the third “two days” of infusion, the fourth set of infusion  
(1 day for IKD arm only) and subsequent “two days” of infusion, 
- 
Number (%) of patients with at least two episodes of IRs within the same “two days” 
of infusion, 
- 
Total number of IR episodes, 
- 
Grade of IR, 
- 
Day of onset from the first infusion given within the “two days”, 
- 
IR duration (in days). 
• 
Similar description will be also provided depending on the mode of administration (initial 
mode of administration and fixed volume administration) 
• 
Number (%) of patients experiencing TEAEs (related and regardless of relationship) 
within 24 hours from the start of any isatuximab and any carfilzomib infusion presented by 
primary SOC and PT (both sorted by decreasing order of frequency) will be summarized 
by treatment groups and by grades (all grades and Grades ≥3). 
• 
Similar table including all TEAEs (related and regardless of relationship) within 24 hours 
from the start of any isatuximab and any carfilzomib infusion from the selected CMQ 
(see Section 2.1.4.1) will also be performed and presented by SOC and PT (both 
decreasing order of frequency). 
• 
Number (%) of patients experiencing TEAEs (related and regardless of relationship) not 
limited to those occurring within 24hours of any isatuximab and any carfilzomib 
administration from the selected CMQ (see Section 2.1.4.1) will be summarized by 
treatment groups and by grades (all grades and Grades ≥3) and presented by SOC and PT 
(both decreasing order of frequency). 
• 
Number of patients with symptoms of IRs with isatuximab and/or with carfilzomib 
presented by primary SOC and PT (both sorted by decreasing order of frequency) will be 
summarized by treatment groups and by grades (all grades and by grade). 


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Analysis of adverse events of special interest 
The analysis of IRs of Grade ≥3 will be part of the analyses described above for IRs. 
A listing of patients who reported overdose during the study will be provided. This listing will 
include drug with overdose and type of overdose (accidental or intentional, symptomatic or not). 
Moreover, a listing of pregnancies (pregnancy as well as pregnancy of partner) will be provided. 
Respiratory AEs 
Respiratory TEAEs will be analyzed using selections defined in Section 2.1.4.1 and will be 
presented by PT, sorted by decreasing incidence. Post-treatment respiratory AEs will be analyzed 
separately using the post-TEAEs analysis. 
Cardiac TEAEs 
Cardiac TEAEs will be analyzed using selections defined in Section 2.1.4.1. 
TEAEs in the SMQs “Cardiac failure”, Ischaemic heart disease” and “Cardiomyopathy” will be 
presented by primary SOC and PT, sorted by decreasing incidence. 
TEAEs in the SMQs “Embolic and thrombotic events, venous” and “Embolic and thrombotic 
events, arterial” will be presented by SMQ and by decreasing incidence of PT. 
In addition, TEAEs in the SMQ “Cardiac failure” will be presented by PT and by cardiac medical 
history (prior medical history vs no prior medical history) as well as by PT and by LVEF at 
baseline (LVEF [40-50 [%, LVEF [50-60[% and LVEF ≥60%).  
TEAEs in CMQ “Cardiac” will be presented by PT and by cardiac medical history.  
TEAEs in HLGT “Vascular hypertensive disorders” will be presented by PT and by hypertension 
medical history (prior medical history vs no prior medical history). 
Hemolytic disorders 
Hemolytic disorders that occurred within 8 days after the blood cell transfusion will be analyzed 
using selection defined in Section 2.1.4.1 and will be presented by PT. 
A listing of patients with hemolytic disorders will be provided. This listing will include the PT, 
the study day of diagnosis (from first dose of study treatment), the interval to onset from the last 
study treatment before the diagnosis (last drug administered), the duration of AE, the cycle of 
occurrence, the grade, the seriousness, the outcome, the action taken on study treatment, the study 
day of the blood transfusion, and results and sampling date of indirect Coombs test. 
TLS 
A listing of patients with TLS (selected using definition in Section 2.1.4.1) will be provided. 


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Autoimmune disorders 
A listing of patients with autoimmune disorders (selected using definition in Section 2.1.4.1) will 
be provided. This listing will include the PT, the study day of diagnosis (from first dose of study 
treatment), the interval to onset from the last study treatment before the diagnosis (last drug 
administered), the duration of AE, the cycle of occurrence, the grade, the seriousness, the action 
taken on study treatment, and the outcome. 
Second primary malignancies (SPM) 
A listing of patients who reported second primary malignancies (selected using definition in 
Section 2.1.4.1) during the study will be provided. This listing will include at least the following 
items: the PT, the study day of diagnosis (from first dose of study treatment), the number of days 
from last study treatment to diagnosis, prior exposure to anti-myeloma treatments, days from 
initiation of further myeloma treatment to onset, cycle of occurrence, outcome, action taken, 
grade, causal relationship to isatuximab, seriousness and whether or not patient received 
subsequent anti-cancer treatment. Listing of deaths on patients with SPM will be also provided.  
The following summaries will be provided by sub-category (‘haematological’, ‘non-hematological 
skin tumors’, ‘non-hematological non-skin tumors’ and ‘other tumors’): 
• 
Time from 1st dose of study treatment to second primary malignancy (quantitative and 
qualitative, <3, 3 - <6, 6 - 12, >12 months) 
• 
Number of patients experiencing second primary malignancies (worst grade) during the 
following periods: 
- 
Treatment period, 
- 
≥3 months after first study treatment 
- 
Post-treatment period, 
- 
Before further anti-multiple myeloma therapy 
- 
After further anti-multiple myeloma therapy, 
- 
≥3 months after further anti-multiple myeloma therapy, 
In addition, the description of AEs in the CMQ ‘Second primary malignancies’ CMQ (worst 
grade) will be provided by sub-category (‘haematological’, ‘non-hematological skin tumors’, 
‘non-hematological non-skin tumors’ and ‘other tumors’) and by decreasing incidence of PT for: 
• 
All treatment-emergent and post-treatment AEs 
• 
All TEAEs 
These analyses will be also performed by medical history of SPM (yes or no).  
Figure of cumulative incidence rate for time to first SPM will be provided using a Fine and Gray 
method considering death as a competing risk.  
For patients treated with IKd, a multivariate Cox proportional hazards model will be used to 
identify prognostic factors among the demographic and baseline characteristics factors described 
below using a stepwise selection procedure with a 15% significance level for entering effects and 
a 15% significance level for removing effects.  


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Table 11 - Risk factor analyses on time to first SPM : covariates investigated  
Prognostic factor 
Description (if relevant) 
Age  
<75 vs ≥75 years 
Gender 
Male vs female 
Race 
Caucasian vs other 
ISS staging at study entry 
I vs II vs III 
R-ISS staging at study entry (IRT) 
I or II vs III vs not classified 
Number of previous lines of therapy (IRT) 
1 vs >1 
Chromosomal abnormality (del(17p), t(4;14), t(14;16)) At least one vs. none  
ECOG PS at baseline 
0 or 1 vs >1  
Neutrophil count (109/L) at baseline 
 
Hemoglobin (g/L) at baseline 
 
Platelets count (109/L) at baseline 
 
Lymphocytes (109/L) at baseline 
 
Beta 2-microglobulin (mg/L) at baseline 
 
Serum LDH (IU/L) at baseline 
 
Albumin (g/L) at baseline 
 
Previous treatment with IMiD a 
Yes vs No 
Previous treatment with Melphalan 
Yes vs No 
Prior history of SPM 
Yes vs No 
Type of region 
Sunny [Australia / Brazil / Spain / Greece / Italy / Turkey ]  
vs Non-sunny [Canada / Czech Republic / France / United Kingdom / 
Hungary / Japan / Korea, Republic of / New Zealand / Russian 
Federation / United States ] 
a IMiD: Immunomodulatory imide drugs 
Neutropenia and neutropenic complications 
Neutropenia (from laboratory abnormalities) will be displayed along with neutropenic 
complications (febrile neutropenia and neutropenic infections, see Section 2.1.4.1).  
If relevant, duration of Grade 3/4 neutropenia episode, cumulative duration of Grade 3/4 
neutropenia by patient and time to first Grade 3/4 neutropenia will be analyzed using laboratory 
data. 
The start date of a Grade 3/4 laboratory neutropenia episode is defined as the date of first  
Grade 3/4 assessments for that episode. The end date of a Grade 3/4 neutropenia episode is 
defined as the first date of neutropenia assessment afterwards of Grade 1/2 or with no abnormality 
for that episode assuming there will be at least 3 days between the first Grade ≤2 neutropenia and 
the next Grade≥3 assessment (if any). If the start date of a new episode is within 3 days of the 
previous episode, then the two episodes will be considered as one episode. The worst grade of an 
episode is the worst grade of all assessments included in that episode. 
Duration of a Grade 3/4 neutropenia episode (in days) is defined as end date of an episode – start 
date of an episode +1. If a patient does not have an end date of an episode before the cutoff date 


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then the duration of the episode will be censored at the last neutrophil assessment of Grade 3/4 or 
the cutoff date, whichever comes first. 
Time to first Grade 3/4 neutropenia (in days) is defined as: date of the first on-treatment Grade 3/4 
neutropenia assessment – date of first treatment +1. If a patient does not have Grade 3/4 
neutropenia, time to first Grade 3/4 neutropenia will be censored at the last assessment of 
neutropenia of Grade 1/2 or with no abnormality or the cutoff date, whichever comes first. If a 
patient does not have any on-treatment assessment of neutropenia, then the patient will be 
censored at Cycle 1 Day 1. 
Thrombocytopenia and hemorrhages 
The number (%) of patients will be provided for: 
• 
On-treatment thrombocytopenia (laboratory data) identified through grading of laboratory 
data per the NCI-CTCAE 4.03, by grade. 
• 
Hemorrhages as defined in Section 2.1.4.1 by grade. 
• 
Hemorrhages following Grades 4 thrombocytopenia (Lab). The first hemorrhages event 
occurring within 8 days after any occurrence of the thrombocytopenia (Lab) will be used 
for this analysis. 
Covid-19 infection 
TEAEs Covid-19 infection will be analyzed using selections defined in Section 2.1.4.1 and will be 
presented by SOC and PT, sorted by decreasing incidence (all TEAEs, serious TEAE and fatal 
TEAEs). Table or listing of patients with Covid-19 infection after vaccination will be presented. 
Number (%) of patients with Covid-19 vaccination will be presented. 
Subgroup analyses of TEAEs 
The effect of patient baseline characteristics on the incidence of patients with any TEAE 
(overview table) and any TEAE by primary SOC and PT (all grades and Grade ≥3) will be 
summarized by treatment group according to each of the below intrinsic factors, separately: 
• 
Age group: <65, [65 - 75[ and ≥75 years. 
• 
Gender: Male, Female. 
• 
Race: Caucasian, Non-Caucasian. 
• 
Renal status: eGFR ≥60 mL/min/1.73m2 and <60 mL/min/1.73m2. 
• 
Hepatic status: normal and abnormal (defined as mild impairment or moderate impairment 
or severe impairment, see definition in Section 2.5.1). 
Exposure-adjusted analyses of TEAEs 
The event rate per patient-year (the number of patients with an event in question divided by total 
patient-years) will be provided for: 
• 
Overview table (patients with any TEAE, with any Grade ≥3 TEAE, with Grade 5 TEAE, 
with any serious TEAE, with any TEAE leading to definitive treatment discontinuation).  


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• 
Most frequent (≥5% of patients in any group) TEAEs, most frequent (≥5% of patients in 
any group) Grade ≥3 TEAEs by SOC and PT.  
• 
All TEAEs, all Grade ≥3 TEAEs, all serious TEAEs, all Grade ≥3 serious TEAEs by SOC. 
• 
All TEAEs in the Second Primary Malignancies CMQ (worst grade) during the treatment 
period and during the study period by decreasing PT, and by tumor type (solid tumor [skin 
or non-skin cancer], hematology malignancies, or other non-specified). 
For a patient with event, patient year is censored at time of first event; for patient without 
event, it corresponds to length of treatment period as defined in Section 2.1.4. 
Analysis of pre-treatment and post-treatment adverse events  
The following frequency distributions of AEs (incidence tables) will be provided for the safety 
population, for all grades combined and Grade ≥3: 
• 
All pre-treatment AEs by primary SOC and PT, showing the number (%) of patients with 
at least 1 pre-treatment AE, sorted by the internationally agreed SOC order and decreasing 
incidence of PTs within each SOC. 
• 
All pre-treatment SAEs by primary SOC and PT, showing the number (%) of patients with 
at least 1 pre-treatment SAE, sorted by the internationally agreed SOC order and 
decreasing incidence of PTs within each SOC. 
• 
All post-treatment AEs by primary SOC and PT, showing the number (%) of patients with 
at least 1 post-treatment AE, sorted by the internationally agreed SOC order and 
decreasing incidence of PTs within each SOC. 
• 
All post-treatment SAEs by primary SOC and PT, showing the number (%) of patients 
with at least 1 post-treatment SAE, sorted by the internationally agreed SOC order and 
decreasing incidence of PTs within each SOC 
• 
All post-treatment AEs in the CMQ ‘Second primary malignancies’ (worst grade) by 
decreasing PT, and by tumor type (solid tumor [skin or non-skin cancer], hematology 
malignancies, or other non-specified). 
2.4.5.2 Deaths  
An overview of Grade 5 AEs (excluding pre-treatment ones) will be provided summarizing the 
number (%) of patients with any: 
• 
Grade 5 AE (TEAE and post-treatment). 
• 
Fatal TEAE (regardless date of death/period). 
- 
Grade 5 TEAE (TEAE with a fatal outcome during the treatment period), 
- 
Any grade TEAE with a fatal outcome during the post-treatment period (worsened to 
Grade 5 in the post-treatment period). 
• 
Post-treatment Grade 5 AE (excluding a TEAE that worsened to Grade 5 during the post-
treatment period). 


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The following summaries of deaths will be generated for the safety population: 
• 
Number (%) of patients who died by study period (treatment period and post-treatment 
period) and within 60 days from first dose of study treatment and reasons for death 
(disease progression, AE, other) by treatment received. 
• 
All TEAEs leading to death by primary SOC and PT, sorted by the internationally agreed 
SOC order and by decreasing incidence of PTs. 
• 
All TEAEs related to treatment and leading to death by primary SOC and PT sorted by the 
internationally agreed SOC order and by decreasing incidence of PTs. 
• 
Number (%) of patients with TEAE(s) leading to death regardless of relationship and 
related to study treatment by primary SOC, HLGT, HLT, and PT. 
• 
Summary of AEs leading to death, by primary SOC and PT: 
- 
In context of disease progression (death within 30 days from last study treatment 
administration and the cause of death is disease progression), 
- 
In context other than disease progression (death within 30 days from last study 
treatment administration and for whom cause of death is not disease progression, or the 
death occurred more than 30 days from last study treatment administration and the 
cause of death is AE). 
In addition, a listing of deaths in non-randomized patients or randomized but not treated patients 
will be provided on the screened patients. 
2.4.5.3 Analyses of laboratory variables  
Laboratory (hematology and biochemistry) values will be analyzed after conversion into standard 
international units. 
International units will be used in all listings and tables. Hematological and biochemistry results 
will be graded according to NCI-CTCAE v4.03, when applicable. For patients with multiple 
occurrences of the same laboratory variable during the treatment period, the maximum grade 
(worst) per patient will be used. 
For hematological parameters and for some selected biochemistry parameters, sanofi generic 
ranges (lower limit of normal, upper limit of normal) are defined (see list of parameters in 
Appendix D) and will be used for grading. For other biochemistry parameters (eg, for hepatic 
enzymes ALT, AST, alkaline phosphatase, total bilirubin), grading will be derived using local 
laboratory normal ranges. 
The number and proportion of patients with abnormal laboratory tests at baseline will be 
presented by grade and all grades together. A similar table showing abnormalities during the 
treatment period will be provided. The denominator used for percentage calculation is the number 
of patients with at least one evaluation of the laboratory test during the considered observation 
period. 
When appropriate, the summary table will present the frequency of patients with any grade of 
abnormal laboratory tests and with Grade 3-4 abnormal laboratory tests.  


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For eGFR, uric acid, blood urea nitrogen and chloride, potentially clinically significant 
abnormality (PCSA) values will be derived. PCSA values are defined as abnormal values 
considered medically important by the Sponsor according to predefined criteria/thresholds based 
on literature review (see Appendix C). The PCSA criteria will determine which patients had a 
PCSA at baseline and which patients had at least 1 PCSA during the treatment period, taking into 
account all evaluations performed during the treatment period, including non-scheduled or 
repeated evaluations. The incidence of PCSA will be summarized by treatment group at baseline 
as well as at any time during the treatment period irrespective of the baseline level. 
Shift tables showing the number of patients by worst grade during the treatment period will be 
provided according to the grade at baseline of selected parameters (eg, thrombocytopenia, 
neutropenia, lymphopenia, anemia and other tests as appropriate) by treatment group.  
Further analyses including summary of cycle of onset (all grades and Grade ≥3), duration and 
concomitance with other hematological abnormalities may also be provided. 
2.4.5.4 Analyses of vital sign variables  
For blood pressure/heart rate parameters, the incidence of PCSAs taken into account assessments 
done prior to study treatment administration at any cycle during the treatment period will be 
summarized by treatment group whatever the baseline level and/or according to the following 
baseline categories: 
• 
Normal/missing 
• 
Abnormal according to PCSA criterion or criteria 
In IKd arm, as vital signs are measured several times on Cycle 1 Day 1 (just before starting 
infusion, 1 hour after starting infusion, and at end of infusion), only the values corresponding to 
assessments done before starting infusion will be considered for the definition of baseline. 
The incidence of PCSA taken into account assessments done during and after isatuximab 
administration at any cycle during the treatment period will also be summarized in the IKd arm. 
In addition, for heart rate, systolic and diastolic blood pressure, mean with the corresponding 
standard deviation could be plotted over time (at predose of any visit) by treatment group. 
2.4.5.5 Analyses of electrocardiogram variables  
The incidence of patients with at least 1 abnormal ECG at any time during the treatment period 
will be summarized by treatment group irrespective of the baseline level and/or according to the 
following baseline status categories:  
• 
Normal/missing 
• 
Abnormal 
A listing of abnormalities and analysis of AEs in appropriate SMQs (eg, Cardiac) will be provided 
if relevant. 


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2.4.5.6 Analyses of other safety endpoints  
A shift table of baseline ECOG PS versus best and worst ECOG PS on treatment will be provided. 
For indirect Coombs test, a summary of patients in experimental arm with indirect Coombs test 
performed during the on-treatment period will be provided, including the number (%) of patients 
with:  
• 
All tests negative 
• 
At least one positive test 
And among patients with at least one positive test during study treatment, number (%) of patients 
with: 
• 
Negative indirect Coombs test at baseline 
• 
Missing indirect Coombs test at baseline 
• 
Panagglutination (resolved by DTT and not resolved by DTT) 
2.4.6 Exploratory analyses of biomarker variables  
Biomarker endpoints will be analyzed using patients from the ITT population who have at least 
1 evaluable assessment on the biomarker of interest. 
2.4.6.1 Genetic variables (immune genetic determinant)  
2.4.6.2 Descriptive analysis  
Each genetic biomarker will be summarized with descriptive statistics by treatment group and 
overall. Hardy-Weinberg equilibrium will be tested for each genetic biomarker. If there is a strong 
disequilibrium, the genetic biomarker may be removed from the following analyses. 
2.4.6.2.1 Univariate analysis  
Each genetic biomarker will be tested for a potential prognostic and/or predictive effect for PFS.  
A Cox regression model will be conducted separately for each genetic biomarker with a treatment 
effect, a biomarker effect and a biomarker×treatment interaction. 
Benjamini-Hochberg multiple correction procedure will be used to control the False Discovery 
Rate (11). 
Additional analyses using ORR (by considering logistic regression) or OS might also be 
performed. 
2.4.6.3 Potential interference of isatuximab in the M protein assessment  
The following analyses will be performed when the data will be available. 
Number (%) of patients with suspected isatuximab interference with serum M protein 
conventional IFE test and with potential impact on the BOR will be described.  


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The response available for the interim analysis and for the final analysis (including the impact of 
interference for the IKd arm) will be described for each arm. 
A sensitivity analysis will be performed in the IKd arm using hybrid BOR based on the IRC’s 
assessment at the interim analysis (using conventional IFE test) plus the IRC’s assessment for the 
newly collected response data after the interim analysis (using Hydrashift isatuximab IFE test in 
IKd arm). 
Number (%) of patients who changed their response following the HYDRASHIFT 2/4 isatuximab 
IFE test results will be described. A shift table matching the BOR at the interim analysis and at 
final analysis will be provided for patients with Hydrashift isatuximab IFE test in IKd arm. Listing 
of patients who changed their response following the HYDRASHIFT 2/4 isatuximab IFE test 
results and their HYDRASHIFT 2/4 isatuximab IFE test results together with the conventional 
IFE test results will be provided. The patients who had natural improvement in BOR after interim 
analysis will be also listed. 
 
The concordance/discordance between the conventional test results on the same banked samples 
performed at time of interim analysis and time of final analysis for patients with suspected 
isatuximab interference will be summarized by using counts and percentages. Listing will be 
provided. 
The time to first CR or sCR in months will be described in patients with Hydrashift isatuximab 
IFE test. 
2.4.7 Analyses of pharmacokinetic variables  
Individual concentrations and PK parameters of carfilzomib will be summarized by descriptive 
statistics (such as mean, geometric mean, median, standard deviation, standard error of the mean 
[SEM], coefficient of variation [CV], minimum, and maximum).  
Predose concentrations (Ctroughobs) and CEOI for isatuximab will be tabulated with standard 
descriptive statistics by visit. Predose concentrations will be represented graphically as function of 
sampling time (day/cycle) over the study period to visualize the steady state achievement. A 
listing of Ctroughobs for individual patients will also be provided. Ctroughobs will be kept for the 
descriptive statistics if sampling occurs within 7 days ± 1 day after the previous infusion for 
sampling done during Cycle 1 and within 14 days ± 3 days after the previous infusion for 
sampling done for subsequent cycle up to Cycle 10. 
Accumulation ratio will be calculated with CEOI (C2D1 vs C1D1) and Ctrough (C2D1 vs C1D8 
and C4D1 vs C1D8) and will be summarized by descriptive statistics (such as geometric mean, 
arithmetic mean median, standard deviation, standard error of the mean (SEM), coefficient of 
variation (CV), minimum and maximum). 
The population PK of isatuximab will be characterized in the population of patients in the IKd 
arm, using a nonlinear mixed effect model based on PK data from Phase I/II studies and III in 
which intensive and sparse blood sampling protocols were used. The population estimates from 
this analysis will provide a prior distribution from which individual Bayesian estimates of the PK 


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parameters for each patient in this study will be derived. Additional details of the analysis plan 
will be provided in a separate document.   
Pharmacokinetic parameters of isatuximab will be summarized by descriptive statistics (such as 
mean, geometric mean, median, standard deviation, SEM, CV, minimum, and maximum). 
2.4.8 Analyses of immunogenicity variables  
The immunogenicity for isatuximab will be assessed by summarizing the number (%) of patients 
with pre-existing ADA and ADA negative at baseline, and by summarizing the number (%) of 
ADA positive patients (including treatment-induced ADA and treatment boosted ADA) during the 
on-study observation period. Anti-drug antibody prevalence and ADA incidence will be 
described. Data listing of each ADA sample results for patients with ADA positive at baseline or 
on-study will be provided. Further analyses may be performed, such as descriptive statistics on 
titers, time to onset and duration of ADA. 
The impact of positive immune response on efficacy, PK and safety endpoints may be further 
explored by graphical methods or descriptively, depending on ADA prevalence. 
2.4.9 Analyses of quality of life/health economics variables  
PRO endpoints for each of the 3 selected HRQL and health utility instruments (EORTC QLQ-
C30, QLQ-MY20 and EQ-5D-5L) will be analyzed in patients from ITT population. 
For each questionnaire, the compliance profile over time will be summarized on the ITT 
population (number and percentage of forms received versus expected, and number and 
percentage of forms evaluable versus expected). A questionnaire is considered received if a least 
one item on the form is completed. A questionnaire is expected as defined in the study flowchart 
and based on the number of cycles started by the patient. A questionnaire is evaluable if the 
overall response rate is greater than 80%. Reasons for non-completion will be summarized on the 
safety population.  
A descriptive summary at each visit (including EOT and assessment done 90 days after last study 
treatment) and change from baseline will be provided for each group for the following variables: 
• 
EORTC QLQ-C30: global health status/QoL scale, the five functional scales (physical, 
emotional, cognitive, role and social), the three symptom scales (fatigue, nausea/vomiting 
and pain) and the six additional single items (dyspnea, insomnia, appetite loss, 
constipation, diarrhea, and financial difficulties).  
• 
MY20: future perspective, body image, disease symptoms and side effects of treatment.   
• 
EQ-5D-5L: health utility index value and VAS score.  
2.4.10 Further therapy after discontinuation of investigational medicinal product 
administration during the study  
A summary table will be provided for further anti-myeloma treatments based on WHO-DD 
coding. A summary table will be also provided by number of subsequent line and drug class.  


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Time to next treatment 
Time to next treatment will be analyzed using Kaplan-Meier methods.  
At time of OS analyses, the duration between last dose of IMP and subsequent therapy with anti-
CD38 therapy will be described. The duration between last dose of IMP and first subsequent 
therapy with anti-CD38 therapy will be also described. 
2.5 
DATA HANDLING CONVENTIONS  
2.5.1 General conventions  
The following formulas will be used for computation of parameters. 
Demographic formula 
Body surface area value will be derived using the variation of DuBois and DuBois formula: 
𝐵𝑆𝐴= 0.0007184 × 𝑊𝑒𝑖𝑔ℎ𝑡 (𝑘𝑔)0.425 × 𝐻𝑒𝑖𝑔ℎ𝑡 (𝑐𝑚)0.725 
Renal function formula  
eGFR will be derived using the equation of MDRD: 
eGFR = 175 × (Serum_creatinine*0.0113) – 1.154 × (Age) – 0.203 × (0.742 if Female) × (1.212 if 
African American) 
with eGFR in mL/min/1.73 m2, serum creatinine in μmol/L and age in years. 
Corrected calcium formula 
Corrected Calcium (mmol/L) = Serum Calcium (in mmol/L) + 0.8 * 0.25 (4 – (serum albumin 
[in g/L] * 0.1)) 
Hepatic function 
• 
Normal: Total bilirubin ≤Upper limit of Normal (ULN) and aspartate aminotransferase 
(AST) ≤ULN. 
• 
Mild impairment: ULN <Total Bilirubin ≤1.5 × ULN and AST = Any; or Total bilirubin  
≤ULN and AST >ULN. 
• 
Moderate impairment: 1.5 × ULN <Total Bilirubin ≤3 × ULN and AST = Any. 
• 
Severe impairment: Total Bilirubin >3 × ULN and AST = Any. 
Qol formulas 
EORTC QLQ-C30 and QLQ-MY20 raw scores and scores calculation: 
For all scales, RS = mean of the component items. 
For functional scales, Score = (1- ((RS-1)/range)) *100 


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For symptom scales/items and the global health status, Score = (RS-1)/range *100 
The range is the difference between the maximum and the minimum response to individual items. 
See Appendix G. 
Number of prior lines 
If the reason for discontinuation of the last treatment of a regimen is “completed” and there is no 
date of progression or in case of transplantation with no date of progression, the next regimen is 
not a new line of therapy. In other cases, the next regimen is a new line of therapy. 
2.5.2 Data handling conventions for secondary efficacy variables  
Not applicable. 
2.5.3 Missing data  
The analyses and summaries of continuous and categorical variables will be based on observed 
data only. Percentages will be calculated using as denominator the number of patients with non-
missing observation in the considered population. When relevant, the number of patients with 
missing data is presented. 
Handling of disease characteristics missing/partial dates 
• 
If the day is missing, it will be estimated by 1. 
• 
If the month is missing, it will be estimated by 1 (only for medical history variables). 
• 
If the year is missing, no estimation will be performed. 
Handling of medication missing/partial dates  
No imputation of medication start/end dates or times will be performed.  If a medication date or 
time is missing or partially missing and it cannot be determined whether it was taken prior or 
concomitantly, it will be considered a prior, concomitant, and post-treatment medication. 
Imputation of incomplete date for further anti-myeloma treatment start date  
For further anti-myeloma treatments, if the medication start date is missing, it will be imputed as 
follows: 
• 
If the medication start day and month are missing and the medication start year is the same 
as the study treatment end year, the medication start date will be set equal to study 
treatment end date + 1. 
• 
If the medication start day and month are missing and the medication start year is after the 
study treatment end year, the medication start day and month will each be set to 01. 
• 
If the medication start day is missing and medication start year and month is the same as 
the study treatment end year and month, the medication start day will be set equal to the 
study treatment end day + 1. 


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• 
If the medication start day is missing and medication start month is before the study 
treatment end month and the medication start year is the same as study treatment end year, 
the medication start day will be set to 01. 
• 
If the medication start day is missing and the medication start month is after the study 
treatment end month and the medication start year is the same as study treatment end year, 
the medication start day will be set to 01. 
• 
If the medication start day is missing and the medication start month is not missing and the 
medication start year is after the study treatment end year, the medication start day will be 
set to 01. 
• 
If the medication start day, start month and start year is missing, the medication start date 
will be set equal to the study treatment end date + 1. 
Handling of missing/partial death dates 
• 
If the day of the death date is missing, it will be imputed as the first day of the month, 
except if the date of the patient's last contact is in the same month as the death date. In this 
case, the death date is imputed as the date of last contact + 1 day. 
• 
If the day and month of the death date is missing, the date of death will be imputed to the 
first of January of the year, except if the date of the patient's last contact is in the same 
year as the death date.  In this case, the death date will be imputed as the date of last 
contact + 1 day. 
• 
If the death date is missing, no imputation will be done, and the patient will be censored at 
the last contact date. 
Handling of adverse events with missing or partial date of onset 
Missing or partial adverse event onset dates (occurrence or becoming serious) will be imputed so 
that if the partial adverse event onset date information or visit number does not indicate that the 
adverse event started prior to treatment or after the treatment-emergent adverse event period, the 
adverse event will be classified as treatment-emergent.  In case of AEs worsening during the 
study, the emergence will also be based on the cycle of worsening. No imputation of adverse 
event end dates will be performed.  These data imputations are for categorization purpose only 
and will not be used in listings.  No imputation is planned for date of adverse event resolution.  
Missing grade 
If the grade is missing for one of the treatment emergent occurrences of an AE, the maximal 
severity on the remaining occurrences will be considered. If the severity is missing for all the 
occurrences, no imputation will be done, and missing grades will be summarized in the “all 
grades” category. 
Handling of missing assessment of relationship of adverse events to investigational medicinal 
product  
If the assessment of the relationship to the regimen is missing, then the relationship to the regimen 
has to be assumed and the adverse event considered as such in the frequency tables of possibly 
related adverse events, but no imputation should be done at the data level. 


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Handling of potentially clinically significant abnormalities 
 
If a patient has a missing baseline value, he/she will be grouped in the category “normal/missing 
at baseline.” 
For PCSAs with 2 conditions, one based on a change from baseline value and the other on a 
threshold value, with the first condition being missing, the PCSA will be based only on the second 
condition. 
2.5.4 Windows for time points  
Laboratory data 
An episode occurred during a cycle if the date of sampling is after (>) the first day of the cycle, 
but prior or equal (≤) to the first day of the next cycle. 
2.5.5 Unscheduled visits  
Unscheduled visit measurements of laboratory data, vital signs, and ECG will be used for 
computation worst values and/or grades. They will be also used for computation of baseline 
except if they are collected on the day of first study administration. 
2.5.6 Pooling of centers for statistical analyses  
Data from all sites will be pooled together for analyses. 
2.5.7 Statistical technical issues  
Not applicable. 
 


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3 
INTERIM ANALYSIS  
An interim analysis for efficacy assessment of PFS is planned when 65% of the 159 PFS events 
have been observed. The interim PFS cut-off date is expected approximately 24 months after the 
first patient in and all patients are expected to be randomized at the time of the interim PFS 
analysis.  
An O’Brien and Fleming α-spending function will be used to obtain the nominal significance 
levels for the interim and final analyses of survival on PFS. The 1-sided nominal significance 
level to declare overwhelming efficacy at 65% information fraction (103 PFS events) is 0.005 
(corresponding to a HR of 0.6) and to declare superiority of IKd at the final analysis (159 events) 
is 0.023 (corresponding to a HR of 0.725). The stopping boundaries on PFS endpoint at interim 
analysis will be calculated using the actual number of events. 
Interim analysis will be performed by an independent statistician under the supervision of the 
DMC. The DMC will also review secondary efficacy endpoints and safety data available at the 
time of the interim analysis. 
The DMC may declare overwhelming efficacy of the study if the following conditions are met: 
• 
Stopping boundaries are crossed. 
• 
Positive trend observed for key secondary efficacy endpoints. 
• 
Consistency of the treatment effect on the primary efficacy endpoint across subgroups 
such as: age and stratification factors. 
The primary analysis of PFS corresponds either to the positive interim analysis or the final PFS 
analysis. In case of positive results at interim analysis, disease assessments data will be collected 
according to the protocol until the final analysis cut-off date (159 PFS events observed) and PFS 
results will be updated (non-inferential analysis). 
For the key binary secondary endpoints, the significance levels at the interim and final analyses 
will be determined using α-spending function specific to each endpoint, except if the information 
fraction is 100% at the interim analysis of PFS (ie, information on binary secondary endpoints 
available for every patient). For ORR and rate of VGPR or better, a Pocock-type boundary will be 
used. For rate of CR and MRD negativity rate, the O’Brien-Fleming alpha-spending function will 
be used.  
If the null hypothesis for any key efficacy endpoint fails to be rejected at the interim PFS analysis, 
then any subsequent key efficacy endpoint(s) will not be tested until the final PFS analysis. If the 
null hypothesis for an endpoint is rejected at the interim PFS analysis, it will remain being 
rejected and will not be re-tested at final PFS analysis. 
The following examples are provided for illustration purpose regarding IA:  
• 
If PFS is significant at IA, ORR will be subsequently tested at IA based on an overall  
one-sided α level of 0.025, the prespecified spending function and actual information 
fraction.  
- 
If ORR is significant at IA, other key binary secondary endpoints will be tested 
sequentially in a similar fashion, 


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- 
If ORR is not significant, all other key binary secondary endpoints will not be tested. 
At final analysis (without retesting PFS), ORR will be tested again taking α spent at IA 
into consideration. To be specific, the remaining α will be determined by an overall 
one-sided α level of 0.025, the prespecified spending function and actual IA 
information fraction. If ORR is significant at final analysis, other key binary secondary 
endpoints will be tested sequentially in a similar fashion.  
• 
If PFS is not significant at IA and it is significant at final analysis, ORR will be 
subsequently tested. Both ORR at IA and final analysis may be compared to the rejection 
boundaries determined by an overall one-sided α level of 0.025, the prespecified spending 
function and actual IA information fraction. If ORR is significant (crossing boundary at 
either IA or final analysis or both), other key binary secondary endpoints will be tested 
sequentially in a similar fashion. 
The CR rate will only be tested for comparison when the antibody-capture interference assay will 
be available. 
OS will be analyzed only once at the end-of-study (ie, 3 years after the primary PFS analysis cut-
off date). 
In addition, close safety monitoring is planned, and DMC will regularly monitor patient safety. 
More details on formal safety reviews and on interim analysis are given in the DMC charter. 


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4 
DATABASE LOCK  
Estimated cut-off date will be approximately 24 months and 36 months after first patient in for the 
interim PFS analysis and for the final PFS analysis, respectively.  
The cut-off date for analysis of OS will be 3 years after the primary PFS analysis cut-off date. The 
primary PFS analysis corresponds either to the positive interim PFS analysis or the final PFS 
analysis. 
 


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5 
SOFTWARE DOCUMENTATION  
All summaries and statistical analyses will be generated using SAS version 9.4 or higher. 
Biomarkers analyses will be generated using R version 3.4.0 or higher. 


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6 
REFERENCES  
1. Kumar S, Paiva B, Anderson KC, Durie B, Landgren O, Moreau P, et al. International 
Myeloma Working Group consensus criteria for response and minimal residual disease 
assessment in multiple myeloma. Lancet Oncol. 2016;17(8):e328-e46. 
2. Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. The European 
Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for 
use in international clinical trials in oncology. J Natl Cancer Inst. 1993;85(5):365-76. 
3. Fayers PM, Aaronson NK, Bjordal K, Groenvold M, Curran D, Bottomley A. EORTC 
QLQC30 Scoring Manual (3rd edition), on behalf of the EORTC Quality of Life Group. 
Brussels: EORTC, 2001. 
4. Stead ML, Brown JM, Velikova G, Kaasa S, Wisløff 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. 
5. Cocks K, Cohen D, Wisløff F, Sezer O, Lee S, Hippe E, et al. An international field study of 
the reliability and validity of a disease-specific questionnaire module (the QLQ-MY20) in 
assessing the quality of life of patients with multiple myeloma. Eur J Cancer. 
2007;43(11):1670-8. 
6. Brooks R. EuroQol: the current state of play. Health Policy. 1996;37(1):53-72. 
7. Van Reenen M, Janssen B. EQ-5D-5L user guide (version 2.1). EuroQol group. 2015. 
8. Van Hout B, Janssen MF, Feng YS, Kohlmann T, Busschbach J, Golicki D, et al. Interim 
scoring for the EQ-5D-5L: Mapping the EQ-5D-5L to EQ-5D-3L value sets. Value in Health. 
2012;15(5):708-15. 
9. Lu K., Li D, Koch G. Comparison between two controlled multiple imputation methods for 
sensitivity analyses of time-to-event data with possibly informative censoring.  Statistics in 
biopharmaceutical research. 2015;7(3):199-213. 
10. Liublinska V, Rubin DB. Sensitivity analysis for a partially missing binary outcome in a two-
arm randomized clinical trial. Stat. Med. 2014;33:4170-85. 
11. Benjamini Y, Hochberg Y. Controlling the False Discovery Rate: A practical and powerful 
approach to multiple testing. Journal of the Royal Statistical Society. Series B 
(Methodological). 1995;57(1):289-300. 


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7 
LIST OF APPENDICES  
Appendix A SOC sorting order 
Appendix B 
Description of summary tables for the analyses of AEs 
Appendix C 
Potentially clinically significant abnormalities criteria 
Appendix D Generic ranges for hematology and biochemistry parameters 
Appendix E 
International Myeloma Working Group Response Criteria 
Appendix F 
Description of primary and sensitivity analyses of PFS 
Appendix G EORTC QLQ-C30 and QLQ-MY20 items, scales and scores 
Appendix H Definition of regions 
Appendix I 
Description of PFS2 analysis 


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Appendix A 
SOC sorting order  
The internationally agreed order (International Conference on Harmonization (ICH)-endorsed 
guide for MedDRA users on data output) for SOC: 
1. Infections and infestations. 
2. Neoplasms benign and malignant (including cysts and polyps). 
3. Blood and the lymphatic system disorders. 
4. Immune system disorders. 
5. Endocrine disorders. 
6. Metabolism and nutrition disorders. 
7. Psychiatric disorders. 
8. Nervous system disorders. 
9. Eye disorders. 
10. Ear and labyrinth disorders. 
11. Cardiac disorders. 
12. Vascular disorders. 
13. Respiratory, thoracic and mediastinal disorders. 
14. Gastrointestinal disorders. 
15. Hepato-biliary disorders. 
16. Skin and subcutaneous tissue disorders. 
17. Musculoskeletal, connective tissue and bone disorders. 
18. Renal and urinary disorders. 
19. Pregnancy, puerperium and perinatal conditions. 
20. Reproductive system and breast disorders. 
21. Congenital and familial/genetic disorders. 
22. General disorders and administration site conditions. 
23. Investigations. 
24. Injury, poisoning and procedural complications. 
25. Surgical and medical procedures. 
26. Social circumstances. 
27. Product issue. 


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Appendix B 
Description of summary tables for the analyses of AEs  
In addition to the analyses described in the table below, an overview of TEAEs, a table describing the IRs, specific hematological analyses, 
cardiac TEAEs by medical history or LVEF at baseline, subgroup and exposure-adjusted analyses of TEAEs will be provided. 
 
MedDRA coding 
variables 
Sorting  
Layout 
Events 
SOC, HLGT, HLT, and PT 
• Primary SOC: 
internationally agreed order 
• HLGT, HLT, PT: 
alphabetical order 
Treatment groups: n (%) of 
patients with any event (all 
grades combined) and n (%) of 
patients with event of Grade ≥3 
 
• All TEAEs 
• Serious TEAEs 
• TEAEs leading to treatment definitive discontinuation 
• TEAEs leading to premature treatment discontinuation of isatuximab 
• TEAEs leading to premature treatment discontinuation of carfilzomib 
• TEAEs leading to premature treatment discontinuation of dexamethasone 
SOC and PT 
• Primary SOC: 
internationally agreed order 
• PT: decreasing order of 
frequency within each SOC 
defined by the all TEAEs 
table  
Treatment groups: n (%) of 
patients with any event (all 
grades combined) and n (%) of 
patients with event of Grade ≥3 
 
• All TEAEs 
• Most frequent (≥5% of patients in any group) TEAEs 
• Treatment-related TEAEs 
• Most frequent (≥5% of patients in any group) treatment-related TEAEs 
• Serious TEAEs 
• Most frequent (≥2% of patients in any group) serious TEAEs 
• Treatment-related serious TEAEs 
• Most frequent (≥2% of patients in any group) serious treatment-related TEAEs 
• TEAEs leading to treatment definitive discontinuation 
• TEAEs leading to premature treatment discontinuation of isatuximab 
• TEAEs leading to premature treatment discontinuation of carfilzomib 
• TEAEs leading to premature treatment discontinuation of dexamethasone 
• TEAEs leading to dose interruption 
• TEAEs leading to dose delay 
• TEAEs leading to dose reduction 
• Pre-treatment AEs 
• Serious pre-treatment AEs 
• Post-treatment AEs 
• Serious post-treatment AEs 


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MedDRA coding 
variables 
Sorting  
Layout 
Events 
SOC and PT 
• Primary SOC: 
internationally agreed order 
• PT: alphabetical order 
Treatment groups: n (%) of 
patients with any event (all 
grades combined) and n (%) of 
patients with event of Grade 3 
and Grade 4 
• Most frequent (≥10% of patients in IKd arm and ≥5% higher in IKd arm compared to Kd 
arm) TEAEs 
SOC and PT 
• Primary SOC: decreasing 
order of frequency  
• PT: decreasing order of 
frequency 
Treatment groups: n (%) of 
patients with any event (all 
grades combined) and n (%) of 
patients with event by grade 
• IRs (according to investigator reported TEAEs) 
• Covid-19 infection (all TEAEs) 
• Covid-19 infection (serious TEAEs) 
• Covid-19 infection (fatal TEAEs) 
SOC and PT 
• Primary SOC: decreasing 
order of frequency  
• PT: decreasing order of 
frequency  
Treatment groups: n (%) of 
patients with any event (all 
grades combined) and n (%) of 
patients with event of Grade ≥3 
• Symptoms of IRs  
• TEAEs (related and regardless of relationship) within 24 hours from the start of each 
isatuximab and each carfilzomib infusion 
• TEAEs (related and regardless of relationship) from the selected CMQ within 24 hours 
from the start of each isatuximab and each carfilzomib infusion 
• TEAEs (related and regardless of relationship) from the selected CMQ (not limited to 
those occurring within 24 hours from the start of each isatuximab and each carfilzomib 
infusion) 
• TEAES in SMQ “Cardiac failure”, SMQ “Ischaemic heart disease” and SMQ 
“Cardiomyopathy” 
SMQ and PT 
• SMQ: alphabetical order 
• PT: decreasing order of 
frequency within each SMQ 
Treatment groups: n (%) of 
patients with any event (all 
grades combined) and n (%) of 
patients with event of Grade ≥3 
• Embolic and thrombotic events with SMQ “Embolic and thrombotic events, venous” and 
SMQ “Embolic and thrombotic events, arterial” 
PT 
• PT: Decreasing order of 
frequency 
Treatment groups: n (%) of 
patients with any event (all 
grades combined) and n (%) of 
patients with event of Grade ≥3 
• Most frequent (≥5% of patients in any group) TEAEs 
• Most frequent (≥5% of patients in any group) treatment-related TEAEs 
• Most frequent (≥2% of patients in any group) serious TEAEs 
• Most frequent (≥2% of patients in any group) serious treatment-related TEAEs 
• Respiratory TEAEs 
• Hemolytic disorders 
AE=adverse event; HLGT=high-level group term; HLT=high-level term; IR=infusion reaction; MedDRA=Medical Dictionary for Regulatory Activities; n (%)=number and percentage of patients; 
PT=preferred term; SOC=system organ class; TEAE=treatment-emergent adverse event. 


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Appendix C 
Potentially clinically significant abnormalities criteria   
 
Parameter 
PCSA 
Comments 
Clinical Chemistry 
eGFR 
(mL/min/1.73m2) 
(Estimate of GFR 
based on an MDRD 
equation) 
<15 (end stage renal disease) 
≥15 - <30 (severe decrease in GFR) 
≥30 - <60 (moderate decrease in GFR) 
≥60 - <90 (mild decrease in GFR) 
≥90 (normal GFR) 
Use is optional. 
FDA draft Guidance 2010 
Pharmacokinetics in patients with impaired renal 
function-study design, data analysis, and impact on 
dosing and labeling 
Uric Acid 
Hyperuricemia  
Hypouricemia  
 
>408 μmol/L 
<120 μmol/L  
Harrison- Principles of internal Medicine 17th Ed., 
2008. 
Blood Urea Nitrogen ≥17 mmol/L 
 
Chloride 
<80 mmol/L 
>115 mmol/L 
 
Vital signs 
HR 
≤50 bpm and decrease from baseline ≥20 bpm 
≥120 bpm and increase from baseline≥20 bpm 
To be applied for all positions (including missing) 
except STANDING. 
SBP 
≤95 mmHg and decrease from baseline ≥20mmHg 
≥160 mmHg and increase from baseline ≥20 mmHg 
To be applied for all positions (including missing) 
except STANDING. 
DBP 
≤45 mmHg and decrease from baseline ≥10 mmHg 
≥110 mmHg and increase from baseline ≥10 mmHg 
To be applied for all positions (including missing) 
except STANDING. 
Orthostatic 
Hypotension 
Orthostatic SDB 
Orthostatic DBP 
 
 
≤-20 mmHg 
≤-10 mmHg 
 
Weight 
≥5% increase from baseline  
≥5% decrease from baseline 
FDA Feb 2007. 


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Appendix D 
Generic ranges for hematology and biochemistry parameters  
The current list of generic ranges for hematology parameters (for adults) is provided in the table 
below:   
Table 12 - Generic ranges for hematology parameters  
LBTESTCD 
LBTEST 
GENDER 
LBSTRESU 
LBGNNRLO 
HGB 
Hemoglobin 
F 
g/L 
120 
HGB 
Hemoglobin 
M 
g/L 
135 
LYM 
Lymphocytes 
10^9/L 
1 
NEUT 
Neutrophils 
10^9/L 
1,8 
PLAT 
Platelets 
10^9/L 
150 
WBC 
Leukocytes 
10^9/L 
4,5 
EOS 
Eosinophils 
10^9/L 
0 
BASO 
Basophils 
10^9/L 
0 
MONO 
Monocytes 
10^9/L 
0,18 
HCT 
Hematocrit 
F 
% 
0,36 
HCT 
Hematocrit 
M 
% 
0,41 
RBC 
Erythrocytes 
F 
10^12/L 
4 
RBC 
Erythrocytes 
M 
10^12/L 
4,5 
INR 
INR 
 
ratio 
0,8 
Based on NEJM (N Engl J Med 2004;351:1548-63.): “Laboratory Reference Values”, Alexander 
Kratz, M.D., Ph.D., M.P.H., Maryjane Ferraro, Ph.D., M.P.H., Patrick M. Sluss, Ph.D., and Kent 
B. Lewandrowski, M.D. 
The current list of generic ranges for biochemistry parameters (for adults) is provided in the table 
below:   
Table 13 - Generic ranges for biochemistry parameters  
LBTEST 
LBSTRESU 
LBGNNRLO - LBGNNRHI 
Albumin 
g/L 
35 - 55 
Blood Urea Nitrogen (BUN) 
mmol/L 
3,6-7,1 
Calcium 
mmol/L 
2,2 - 2,6 
Corrected calcium 
mmol/L 
2,2 - 2,6 
Glucose 
mmol/L 
3,9 - 7 
Bicarbonate (HCO3) 
mmol/L 
22 - 29 
Carbon dioxide 
mmol/L 
21 - 30 
Potassium 
mmol/L 
3,5 - 5 
Magnesium 
mmol/L 
0,8 - 1,2 
Sodium 
mmol/L 
136 - 145 
Phosphate 
mmol/L 
1 - 1,4 
Protein 
g/L 
55 - 80 
Urea 
mmol/L 
3,6 - 7,1 
 


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Appendix E 
International Myeloma Working Group Response Criteria  
Disease response will be assessed using the updated International Myeloma Working Group 
Response Criteria (IMWG). A confirmation assessment for disease response within 4 weeks is 
required in this protocol (either PR or better, or PD). 
As a reminder, patients with measurable FLC only at screening are not eligible in the study. 
M protein value on Cycle 1 Day 1 will be taken as baseline value for response assessment. 
PD cannot not be diagnosed on FLC increase only, even in patients for whom serum and urine 
M protein become below level of eligibility on efficacy laboratory performed on Cycle 1 Day 1 
(see below the table for assessment of overall response and progression diagnosis of these 
patients). 
Adapted from updated International Myeloma Working Group Response Criteria 
IMWG MRD criteria (requires CR as defined below) 
Sustained MRD-negative 
MRD negativity in the marrow (NGF or NGS, or both) and by imaging as defined below, confirmed 
minimum of 1 year apart. Subsequent evaluations can be used to further specify the duration of 
negativity (eg, MRD-negative at 5 years) 
Flow MRD-negative 
Absence of phenotypically aberrant clonal plasma cells by NGF on BMAs using the EuroFlow 
standard operation procedure for MRD detection in multiple myeloma (or validated equivalent 
method) with a minimum sensitivity of 1 in 105 nucleated cells or higher 
Sequencing 
MRD-negative 
Absence of clonal plasma cells by NGS on BMA in which presence of a clone is defined as less 
than two identical sequencing reads obtained after DNA sequencing of BMAs using the 
LymphoSIGHT platform (or validated equivalent method) with a minimum sensitivity of 1 in 105 
nucleated cells or higher  
Imaging-positive 
MRD-negative 
MRD negativity as defined by NGF or NGS plus disappearance of every area of increased tracer 
uptake found at baseline or a preceding PET/CT or decrease to less mediastinal blood pool SUV 
or decrease to less than that of surrounding normal tissue 
Standard IMWG response criteria 
Response 
IMWG criteria 
CR 
• Negative immunofixation on the serum and urine and 
• Disappearance of any soft tissue plasmacytomas and 
• <5% plasma cells in BMAs. 
Two consecutive assessments are needed. No known evidence of progressive disease or 
new bone lesions if radiographic studies were performed 
sCR 
CR as defined above plus: 
• Normal FLC ratio (0.26 to 1.65) and 
• Absence of clonal cells in BM by immunohistochemistry (κ/λ ratio ≤4:1 or ≥1:2 for κ and λ 
patients, respectively, after counting ≥100 plasma cells).  
Two consecutive assessments of laboratory parameters are needed. No known evidence of 
progressive disease or new bone lesions if radiographic studies were performed 


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Response 
IMWG criteria 
VGPR 
• Serum and urine M protein detectable by immunofixation but not on electrophoresis or 
• ≥90% reduction in serum M protein plus urine M protein level <100 mg/24 hour. 
• ≥90% decrease in the sum of the products of maximal perpendicular diameter compared to 
baseline in soft tissue plasmacytoma. 
Two consecutive assessments are needed. No known evidence of progressive disease or 
new bone lesions if radiographic studies were performed. 
PR 
• ≥50% reduction of serum M protein and reduction in 24 hours urinary M protein by ≥90% or to  
<200 mg/24 hour 
• In addition to the above listed criteria, if present at baseline, a ≥50% reduction in the size (sum 
of the products of the maximal perpendicular diameters) of soft tissue plasmacytomas is also 
required 
Two consecutive assessments are needed. No known evidence of progressive disease or 
new bone lesions if radiographic studies were performed. 
MR 
 
≥25% but ≤49% reduction in serum M protein and reduction in 24h urine M protein by 50 to 89%, 
which still exceed 200 mg/24 hour. 
In addition to the above listed criteria, if present at baseline, ≥50% reduction in size (SPD) of soft 
tissue plasmacytomas is also required. 
Two consecutive assessments are needed. No known evidence of progressive disease or 
new bone lesions if radiographic studies were performed. 
Stable Disease 
•  Not meeting criteria for CR, VGPR, PR, MR or progressive disease. 
No known evidence of progressive disease or new bone lesions if radiographic studies 
were performed. 
Progressive disease 
Any 1 or more of the following criteria: 
Increase of ≥25% from lowest confirmed value in any 1 of the following criteria: 
• Serum M protein (the absolute increase must be ≥0.5 g/dL). 
• Serum M protein increase ≥1 g/dL if the lowest M component was ≥5 g/dL. 
• Urine M-component (the absolute increase must be ≥200 mg/24 hour). 
Appearance of new lesion(s), ≥50% increase from nadir in SPD of >1 lesion, or ≥50% increase in 
the longest diameter of a previous lesion >1 cm in short axis. 
Two consecutive assessments are needed for PD on M protein. 
Abbreviations: CR = complete response, FLC = free light chain, IMWG = International Myeloma Working Group, M = monoclonal, MRD = 
minimal residual disease, NGF = next-generation flow, NGS = next-generation sequencing, PD = progressive disease, PET = positron 
emission tomography, MR = minor response, PR = partial response, sCR = stringent complete response, SD = stable disease, SPD = sum of 
the products of the maximal perpendicular diameters of measured lesions, SUV = maximum standardized uptake value, VGPR = very good 
partial response. 
Patients with disease only measurable by FLC are not allowed. 
A plasmacytoma that has been radiated is not suitable for response assessment; however, it must 
be monitored to assess for progressive disease. 
For patients achieving VGPR by other criteria, a soft tissue plasmacytoma must decrease by more 
than 90% in the sum of the products of the maximal perpendicular diameters of measured lesions 
(SPD) compared with baseline. 
For IgA and IgD myeloma, quantitative immunoglobulin measurements are preferred for 
assessments, the same percentage changes apply fornserum M-spike (see table above). 


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Definite increase in the size of existing bone lesions or soft tissue plasmacytomas is defined as 
below:  
• 
≥50% increase in the size of at least one bidimensionally measurable lesion 
(in comparison with the measurements at Nadir) or appearance of a new lesion.  
• 
Pathological fracture or collapse of bone are not necessarily evidence of disease 
progression.  
Reminder: definitions of Response and Progression are based on IMWG Uniform Reporting 
Criteria: 
• 
Any response (sCR, CR, VGPR, PR) or progression needs to be confirmed by 
two consecutive disease assessments according to the Study Flow Chart. A disease 
assessment at one time point not matched by the same disease assessment at the next time 
point will be considered unconfirmed (except for progression by imaging, BM plasma cell 
counts, where one time point is adequate for confirmed progression). 
• 
Urine M protein is not needed to document PR or minor response if baseline urine M 
protein was not measurable; however, it is still required for CR and very good PR. 
• 
Documentation of response requires two consecutive readings of the applicable disease 
parameter (serum M protein, urine M protein), performed at any time (no minimum 
interval is required, it can be done the same day); however, to confirm response or 
progressive disease, 2 discrete samples are required; testing cannot be based upon the 
splitting of a single sample. 
• 
Patients will continue in the last confirmed response category until there is confirmation of 
progression or improvement to a higher response status; patients cannot move to a lower 
response category. 
• 
Percent decreases for response calculations are from baseline values (Cycle 1 Day 1). 
• 
Percent increases for progression calculations are from lowest response values or baseline 
values, whichever is the smaller number. The lowest value does not need to be confirmed. 
• 
The lowest confirmed value before suspected progression will be used as baseline for 
calculation of progression; if a serum and/or urine spike is considered too low to 
quantitate, this value can be assigned as 0 as a baseline for documentation of subsequent 
progressive disease. Patients will be considered to have progressive disease if they meet 
the criteria for progression by a variable that was not considered measurable at baseline; 
however, for patients who had a measurable serum or urine M-spike at baseline, 
progression cannot be defined by increases in serum FLC alone. 


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Patients with serum and urine M protein below level of eligibility on efficacy laboratory 
performed on Cycle 1 Day 1 (eg, patients with only FLC measurable disease according to 
IMWG, M-protein value >0 [or IF positive] and <0.5 g/dL): 
• 
These patients can have only 2 possible overall responses: CR, non-PD or PD. 
• 
Patients with M-protein (urine and/or serum) below the level of measurability  
(M protein value >0 [or IF positive] and <0.5 g/dL) can have CR, non-PD, or PD 
responses only according to the increase or decrease of M protein or extramedullary 
disease if applicable, following the IMWG criteria. 
• 
Patients with FLC measurable disease only (M protein = 0 and IF negative), can have 
either non-PD or PD responses (PD will be an absolute increase of >10 mg/dL in the 
difference between involved and uninvolved FLC). 
• 
Patients with serum M protein value >0 g/dL (or serum IF positive) and <0.5 g/dL, 
independently of FLC can only be qualified as: CR, non-PD, or PD. 
AND/OR 
• 
Patients with urine M protein value >0 mg/24h (or urine IF positive) and <200 mg/24h, 
independently of FLC can only be qualified as: CR, non-PD, or PD. 
OR 
• 
Patients with serum M protein value = 0 g/dL and serum IF for intact Ig negative and urine 
M-protein = 0 mg/24h and urine IF negative, independently of FLC can only be qualified 
as: non-PD or PD. 


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Appendix F 
Description of primary and sensitivity analyses of PFS  
General rule for censoring for all sensitivity analyses:  
Patient is censored  
• 
at the last valid assessment if this one is done on or before cutoff date,  
• 
at cutoff if the last valid assessment is done after cutoff date,  
• 
at randomization if there is no valid assessment after randomization. 
Initiation of further anti-myeloma therapy must be considered or not for the selection of the last 
valid assessment according to the sensitivity analysis considered.   
The following tables 13 to 18 includes the description of PFS primary analysis and sensitivity 
analyses for all regions except US. The Table 19 includes the description of PFS primary analysis 
for US. The sensitivity analyses for PFS in US will be similar as the one performed for ex-US by 
adding the additional censoring rule for late progression and deaths. 
 
Table 14 - PFS Primary analysis (progression based on blinded IRC disease assessment)  
Situation 
Date of progression or censoring 
Outcome 
No baseline disease assessments 
Date of Randomization 
Censored 
No valid post-baseline disease assessments 
Date of Randomization 
Censored 
Documented Progression prior to initiation of new anti-
myeloma treatment and prior to the cut-off date 
Earliest date among all disease assessments 
with evidence of progression 
Event 
Death without both documented progression and initiation of 
new anti-myeloma treatment prior to the cut-off date 
Date of death 
Event 
Both documented progression prior to initiation of new anti-
myeloma treatment and death prior to the cut-off date 
Date of progression 
Event 
No documented progression according to IRC prior to 
initiation of new anti-myeloma treatment and no death prior 
to the cut-off date  
Earliest of the date of last valid disease 
assessment with no evidence of progression 
before initiation of new anti-myeloma treatment 
and cut-off date 
Censored 
Symptomatic deterioration reported and no documented 
progression according to IRC and no death 
Ignored 
Ignored 
Initiation of new anti-myeloma treatment before 
documented progression according to IRC or before death 
Earliest of the date of last valid disease 
assessment without evidence of progression 
before the initiation of new anti-myeloma 
treatment and cut-off date 
Censored 
  


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Table 15 - PFS sensitivity analysis #1 (progression based on blinded IRC disease assessment and 
ignoring further anti-myeloma treatment)  
Situation 
Date of progression or censoring 
Outcome 
No baseline disease assessments 
Date of Randomization 
Censored 
No valid post-baseline disease assessments 
Date of Randomization 
Censored 
Documented Progression prior to the cut-off date 
Earliest date among all disease 
assessments with evidence of progression 
Event 
Death without documented progression prior to the cut-off date 
Date of death 
Event 
Both documented progression and death prior to the cut-off date 
Date of progression 
Event 
No documented progression according to and no death prior to 
the cut-off date  
Earliest of the date of last valid disease 
assessment without evidence of 
progression and cut-off date  
Censored 
Symptomatic deterioration reported and no documented 
progression according to IRC and no death 
Ignored 
Ignored 
Initiation of new anti-myeloma treatment  
Ignored 
Ignored 
Table 16 - PFS sensitivity analysis #2 (progression based on investigator’s disease assessment 
and including symptomatic deterioration)  
Situation 
Date of progression or censoring 
Outcome 
No baseline disease assessments 
Date of Randomization 
Censored 
No valid post-baseline disease assessments 
Date of Randomization 
Censored 
Death prior to the cut-off date without initiation of new anti-
myeloma treatment or documented progression or symptomatic 
deterioration 
Date of death 
Event 
Documented progression prior to initiation of new anti-myeloma 
treatment and prior to the cut-off date with no symptomatic 
deterioration.  
Earliest date among all disease 
assessments with evidence of progression 
Event 
Both documented progression according to the investigator prior 
to initiation of new anti-myeloma treatment and death prior to the 
cut-off date with no symptomatic deterioration. 
Date of documented progression 
Event 
Symptomatic deterioration prior to initiation of new anti-myeloma 
treatment and prior to the cut-off date with no documented 
progression according to the investigator regardless of death 
occurrence.   
Date of symptomatic deterioration 
Event 
Symptomatic deterioration and documented progression 
according to the investigator prior to initiation of new anti-
myeloma treatment and prior to the cut-off date regardless of 
death occurrence 
Earliest date among symptomatic 
deterioration and documented progression 
Event 
Both no symptomatic deterioration and no documented 
progression according to the investigator prior to initiation of new 
anti-myeloma treatment and prior to the cut-off date, and no 
death prior to the cut-off date 
Earliest of the date of last valid disease 
assessment with no evidence of 
progression before initiation of new anti-
myeloma treatment and cut-off date 
Censored 
Initiation of new anti-myeloma treatment before symptomatic 
deterioration, or before documented progression according to 
investigator or before death 
Earliest of the date of last valid disease 
assessment with no evidence of 
progression before initiation of new anti-
myeloma treatment and cut-off date 
Censored 
 


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Table 17 - PFS sensitivity analysis #3 (progression based on investigator’s disease assessment 
and ignoring symptomatic deterioration)  
Situation 
Date of progression or censoring 
Outcome 
No baseline disease assessments 
Date of Randomization 
Censored 
No valid post-baseline disease assessments 
Date of Randomization 
Censored 
Documented Progression prior to initiation of new anti-myeloma 
treatment and prior to the cut-off date 
Earliest date among all disease 
assessments with evidence of progression 
Event 
Death without documented progression and without initiation of 
new anti-myeloma treatment prior to the cut-off date 
Date of death 
Event 
Both documented progression prior to initiation of new anti-
myeloma treatment and death prior to the cut-off date 
Date of progression 
Event 
No documented progression according to investigator prior to 
initiation of new anti-myeloma treatment and no death prior to the 
cut-off date 
Earliest of the date of last valid disease 
assessment with no evidence of 
progression before initiation of new 
anti-myeloma treatment and cut-off date 
Censored 
Symptomatic deterioration reported and no documented 
progression according to investigator and no death 
Ignored 
Ignored 
Initiation of new anti-myeloma treatment before 
documented progression according to investigator or before 
death  
Earliest of the date of last valid disease 
assessment without evidence of 
progression before the initiation of 
new anti-myeloma treatment and cut-off 
date 
Censored 
Table 18 - PFS sensitivity analysis #4 (progression based on blinded IRC disease assessment and 
including initiation of further anti-myeloma treatment as an event)  
Situation 
Date of progression or censoring 
Outcome 
No baseline disease assessments 
Date of Randomization 
Censored 
No valid post-baseline disease assessments 
Date of Randomization  
Censored 
Documented Progression prior to initiation of new anti-myeloma 
treatment and prior to the cut-off date 
Earliest date among all disease 
assessments with evidence of progression 
Event 
Death without both documented progression and initiation of new 
anti-myeloma treatment and prior to the cut-off date 
Date of death 
Event 
Both documented progression prior to initiation of new anti-
myeloma treatment and death prior to the cut-off date 
Date of progression 
Event 
No documented progression according to IRC prior to initiation of 
new anti-myeloma treatment and prior to the cut-off date and no 
death prior to the cut-off date 
Earliest of the date of last valid disease 
assessment without evidence of 
progression before initiation of new anti-
myeloma treatment and cut-off date 
Censored 
Symptomatic deterioration reported and no documented 
progression according to IRC and no death 
Ignored 
Ignored 
Initiation of new anti-myeloma treatment before documented 
progression according to IRC or before death and before the 
cut-off date 
Start date of new anti-myeloma treatment 
Event 


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Table 19 - PFS sensitivity analysis #5 (progression based on blinded IRC disease assessment, 
assigning uniform progression and assessment dates and censoring late progressions and deaths)  
Situation 
Date of progression or censoring 
Outcome 
No baseline disease assessments 
Date of Randomization 
Censored 
No valid post-baseline disease assessments 
Date of Randomization  
Censored 
Documented progression prior to the cut-off date and within 8 
weeks from last previous valid disease assessment  
Date of the scheduled visit for this time 
window 
Event 
Death without documented progression prior to the cut-off date 
and within 8 weeks from last valid disease assessment 
Date of death 
Event 
Death or Progression after more than one missed laboratory 
disease assessment (ie, more than 8 weeks from last valid 
disease assessment) 
Earliest of the date of last valid disease 
assessment without evidence of 
progression before initiation of new 
antimyeloma treatment and cut-off date 
Censored 
Symptomatic deterioration reported and no documented 
progression according to IRC and no death 
Ignored 
Ignored 
No documented progression according to IRC and no death 
Earliest of the date of last valid disease 
assessment without evidence of 
progression before initiation of new 
antimyeloma treatment and cut-off date 
Censored 
Initiation of new anti-myeloma treatment before documented 
progression according to IRC or before death 
Earliest of the date of last valid disease 
assessment without evidence of 
progression before initiation of new 
antimyeloma treatment and cut-off date 
Censored 
Note: 8 weeks corresponds to twice the time between two disease assessments per protocol (every 2*4 weeks) 


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Table 20 - PFS Primary analysis (censoring late progressions and deaths) for US following FDA’s 
request  
Situation 
Date of progression or censoring 
Outcome 
No baseline disease assessments 
Date of Randomization 
Censored 
No valid post-baseline disease assessments 
Date of Randomization 
Censored 
Documented Progression prior to initiation of new anti-myeloma 
treatment and prior to the cut-off date and within 8 weeks from 
last previous valid disease assessment 
Earliest date among all disease 
assessments with evidence of progression 
Event 
Death without both documented progression and initiation of new 
anti-myeloma treatment prior to the cut-off date and within 
8 weeks from last valid disease assessment 
Date of death 
Event 
Both documented progression prior to initiation of new anti-
myeloma treatment and death prior to the cut-off date, and within 
8 weeks from last previous valid disease assessment 
Date of progression 
Event 
No documented progression according to IRC prior to initiation of 
new anti-myeloma treatment and no death prior to the cut-off 
date  
Earliest of the date of last valid disease 
assessment with no evidence of 
progression before initiation of new anti-
myeloma treatment and cut-off date 
Censored 
Symptomatic deterioration reported and no documented 
progression according to IRC and no death 
Ignored 
Ignored 
Initiation of new anti-myeloma treatment before documented 
progression according to IRC or before death 
Earliest of the date of last valid disease 
assessment without evidence of 
progression before the initiation of new 
anti-myeloma treatment and cut-off date 
Censored 
Earliest of Death or progression occurring more than 8 weeks 
after the last valid disease assessment 
Earliest of the date of last valid disease 
assessment with no evidence of 
progression before initiation of new anti-
myeloma treatment and cut-off date 
Censored 
 Note: 8 weeks corresponds to twice the time between two disease assessments per protocol (every 2*4 weeks) 
 


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Appendix G 
EORTC QLQ-C30 and QLQ-MY20 items, scales and scores  
For QLQ-C30: 


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Statistical Analysis Plan  
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Appendix H 
Definitions of regions  
1. Geographical regions 
 
Europe 
America 
Asia 
Other countries 
Czech Republic 
Brazil 
Japan 
Australia 
France 
Canada 
Republic of Korea  
New Zealand 
Greece 
United States 
 
Russian Federation 
Hungary 
 
 
Turkey 
Italy 
 
 
 
Spain 
 
 
 
United Kingdom 
 
 
 
 
 
2. Regulatory regions  
 
Western countries 
Other countries 
Australia  
Brazil 
Canada 
Czech Republic 
France 
Hungary 
Greece 
Japan 
Italy 
Republic of Korea 
New Zealand 
Russian Federation  
Spain 
Turkey 
United Kingdom 
 
United States 
 
 
 
 
 


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Appendix I 
Description of PFS2 analysis  
Table 21 - PFS2 analysis (progression based on investigator disease assessment)   
Situation 
Date of progression or censoring 
Outcome 
No valid post-baseline disease assessments 
Date of randomization 
Censored 
Death when further anti-myeloma treatment not yet started and 
prior to the cut-off date 
Date of death 
PFS2 event 
No disease progression on study treatment* but disease 
progression or death after initiation of further anti-myeloma 
treatment and prior to the cut-off date 
First progression date after initiation of 
further anti-myeloma therapy reported as 
per investigator or date of death if no 
progression after initiation of further anti-
myeloma treatment  
PFS2 event 
No disease progression on study treatment*, no disease 
progression and no death after initiation of further anti-myeloma 
treatment and prior to the cut-off date 
Earliest of the date of the last follow-up visit 
after initiation of further anti-myeloma 
treatment and the cut-off date. If no 
initiation of further anti-myeloma treatment, 
same date of censoring as for PFS on study 
treatment 
Censored 
Disease progression on study treatment*, no disease 
progression and no death after initiation of further anti-myeloma 
treatment and prior to the cut-off date 
Earliest of the date of the last follow-up visit 
after initiation of further anti-myeloma 
treatment and the cut-off date. If no 
initiation of further anti-myeloma treatment, 
censor at the date of progression on study 
treatment 
Censored 
Disease progression on study treatment*, disease progression 
or death after initiation of further anti-myeloma treatment and 
prior to the cut-off date 
First progression date after initiation of 
further anti-myeloma therapy reported as 
per investigator or date of death if no 
progression after initiation of further anti-
myeloma treatment 
PFS2 event 
* disease progression on study treatment or in follow-up but before initiation of further anti-myeloma treatment as per investigator including 
symptomatic deterioration