A Randomized, Phase 3, Open Label Study Evaluating Subcutaneous Versus Intravenous Administration of Isatuximab in Combination With Pomalidomide and Dexamethasone in Adult Patients With Relapsed and/or Refractory Multiple Myeloma (RRMM)
Phase: PHASE3
Conditions: Plasma Cell Myeloma Recurrent
Sponsor: Sanofi

 
 
 
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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 
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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: Sanofi OneDocument Version 6.0, dated 25-JUN-2021 
Page 1 
 AMENDED CLINICAL TRIAL PROTOCOL 04  
Protocol title: 
A randomized, Phase 3, open label study evaluating 
subcutaneous versus intravenous administration of 
isatuximab in combination with pomalidomide and 
dexamethasone in adult patients with relapsed and/or 
refractory multiple myeloma (RRMM) 
Protocol number: 
EFC15951 
Amendment number: 
04 
Compound number 
(INN/Trademark): 
SAR650984 
isatuximab/SARCLISA® 
Brief title: 
SC versus IV isatuximab in combination with pomalidomide 
and dexamethasone in RRMM 
Acronym: 
IRAKLIA 
Study phase: 
Phase 3 
Sponsor name: 
Sanofi-Aventis Recherche & Développement 
Legal registered address:  
82 Avenue Raspail, 94250 Gentilly, FRANCE 
Monitoring team’s 
representative name and 
contact information 
 
 
 
 
Regulatory agency identifier number(s): 
IND: 
143013 
NCT: 
NCT05405166 
WHO: 
U1111-1261-5846 
EUDAMED: 
CIV-22-06-039616 
EU trial number 
2023-508869-32 
Other: 
Not applicable 
Pediatric investigation plan: Not applicable 
Date: 
10-Jul-2024 
Total number of pages: 219 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY 
 
Document 
Country/countries 
impacted by amendment 
Date, version 
Amended Clinical Trial Protocol 04 
All 
10-Jul-2024, Version 1 (electronic 4.0) 
Amended Clinical Trial Protocol 03 
All 
03-Oct-2023, Version 1 (electronic 3.0) 
Amended Clinical Trial Protocol 02  
All 
15-Mar-2023, Version 1 (electronic 2.0) 
Amended Clinical Trial Protocol 01  
All 
11-Oct-2022, Version 1 (electronic 1.0) 
Original Protocol 
 
17-Feb-2022, Version 1 (electronic 3.0) 
Amended protocol 04 (10 July 2024) 
This amended protocol 04 (amendment 04) is considered to be non-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 because it does not significantly impact the safety or 
rights of the participants, and/or the reliability and robustness of the data generated in the clinical 
trial. 
OVERALL RATIONALE FOR THE AMENDMENT 
The purpose of this amendment is to implement language related to new CTA European 
regulation, to correct typos and few inconsistencies, and to provide few clarifications. 
Protocol amendment summary of changes table 
Section # and 
Name 
Description of Change 
Brief Rationale 
Title page 
The Legal registered address has been added. 
New address 
Title page 
EudraCT was replaced by EU trial number 2023-508869-32. 
“Pediatric investigational plan number: Not applicable” was added in 
the Regulatory agency identifier number(s) table. 
To comply with EU CTR. 
Section 1.1 
Synopsis 
The subsection “Regulatory agency identifier number(s)” was added. 
The heading “Overall design” was renamed to “Overall design 
synopsis”. 
The heading “Intervention groups” was renamed to “Study arms and 
duration”. 
The heading “Non-Investigational Medicinal Products (Premedication)” 
was renamed to “Auxilliary Medicinal Products (Premedication)”. 
To comply with recent update 
of Sanofi protocol template 
language. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 1.3 
Schedule of 
Activities (SoA), 
Table 1, Footnote y 
and z 
First and second sub-pointers in foontnote y and z updated replacing 
“or initiation of further anti-myeloma therapy” by “even if further 
anti-myeloma therapy is started before PD”. 
 
To correct inconsistency 
between SoA table, footnotes 
y and z versus footnote d of 
the SoA and Section 4.5. 
Section 6 Study 
intervention(s) and 
concomitant therapy 
The text of this section was updated. 
To comply with EU CTR. 
Section 6.1.2 
Auxillary medicinal 
products 
The Section 6.1.2 “Non investigational medicinal products” was 
renamed to “Auxillary medicinal products”. 
The ATC codes for all standard premedication regimens were added. 
To comply with EU CTR. 
Section 6.2.1 
Responsibilities 
The sentence "study treatment" was updated by “IMP/AxMP/device” in 
this section. 
To comply with EU CTR. 
Section 6.5.5 
Management of 
infusion reactions 
and injection site 
reactions 
The text of Table 15 was updated as follows: 
ISRs: 
If during administration: Interrupt isatuximab administration and resume 
only with an administration with pauses after recovery to G1 or better. 
Report AE and AESI.  
In case the reaction occurs during the D-15 at-home administration, 
definitely stop the at-home injection and contact investigator site. 
Applicable for manual push 
which is not method of 
administration in the study. 
Section 6.5.6 Tumor 
lysis syndrome 
The text of Table 17 was updated as follows: 
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 μmol/L). 
• 
Potassium >6.0 mmol/L. 
• 
Phosphate >4.5 mg/dL (>1.5 mmol/L). 
• 
Corrected calcium <7.0 mg/dL (<1.75 mmol/L), ionized 
calcium <1.12 mg/dL (0.3 mmol/L). 
To correct typo errors. 
Section 6.7 
Treatment of 
overdose 
The text of this section was updated. 
To comply with EU CTR. 
Section 6.8 Prior 
and concomitant 
therapy 
The Section “6.8 Prior and concomitant therapy” was added. 
To comply with recent update 
of Sanofi protocol template 
language. 
Section 7.2 
Participant 
discontinuation/ 
Withdrawal from the 
Study 
A few modifications were done in the Section 7.2 “Participant 
discontinuation/ Withdrawal from the Study” to clarify the procedures of 
participant discontinuation/withdrawal from the study. 
To comply with recent update 
of Sanofi protocol template 
language. 
Section 7.3 Lost to 
follow up 
The phrase “he or she” was replaced by “the participant”. 
To comply with EU CTR. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 8 Study 
assessmets and 
procedures 
The following bullet was added: “In the event of a significant 
study-continuity issue (eg, caused by a pandemic), alternate strategies 
for participant visits, assessments, medication distribution and 
monitoring may be implemented by the Sponsor or the Investigator, 
as per local Health Authority/ethics requirements [see Appendix 9 
(Section 10.9)].” 
To comply with EU CTR. 
Section 8.1 
Administrative [and 
general/baseline] 
procedures 
The Section 8.1 “Administrative [and general/baseline] procedures was 
added”. 
To comply with EU CTR. 
Section 8.2 Efficacy 
assessments 
Section 8.2 updated replacing “or initiation of further anti-myeloma 
therapy” by “even if further anti-myeloma therapy is started before PD”. 
To correct inconsistency 
between Section 8.2 versus 
footnote d of the SoA and 
Section 4.5. 
Section 8.4.4 
Clinical safety 
laboratory tests 
The text of this section was updated. 
To comply with EU CTR. 
Section 8.6 Adverse 
events (AEs), 
serious adverse 
events (SAEs) and 
other safety 
reporting 
The text of this section was updated. 
To comply with EU CTR. 
Section 8.6.1 Time 
period and 
frequency for 
collecting AE and 
SAE information 
The sentence “he or she” was replaced by “Investigator”. 
To comply with EU CTR. 
Section 8.6.6 
Adverse event of 
special interest 
The overdose definition was moved from “Section 8.6.6 Adverse event 
of special interest” to “Section 6.7 Treatment of overdose”. 
To comply with EU CTR. 
Section 8.6.7 
Medication errors or 
misuses of 
medicinal product 
The Section “8.6.7 Medication errors or misuses of medicinal product” 
was added. 
To comply with EU CTR. 
Section 8.6.8 
Guidelines for 
reporting product 
complaints 
The abbreviation “NIMP” was replaced by “AxMP”. 
To comply with EU CTR. 
Section 8.9 
Immunogenicity 
assessments 
The text of this section was updated. 
To comply with recent update 
of Sanofi protocol template 
language. 
Section 8.12 Use of 
biological samples 
and data for future 
research 
Major updates were done in this section for the collection, storage and 
future use of biological samples from clinical trial subjects. 
Additional details were included. 
To comply with EU CTR  
Additional details were 
included for better 
clarification. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 10.1.1 
Regulatory and 
ethical 
considerations 
Language from the previous EU directive was replaced with new 
language from the new EU regulation. 
To comply with EU CTR. 
Section 10.1.3 
Informed consent 
process 
The text of this section was updated. 
To comply with EU CTR. 
Section 10.1.4 Data 
Protection 
The subsection “Protection of participant data” was renamed to 
“Protection of participant personal data”. 
Two bullet points were added in the “Protection of participant personal 
data” subsection. 
Small modifications were done (eg “participants” instead of 
“the participant”, addition of “when applicable” etc). 
The subsection “Protection of data related to professionals involved in 
the study” was renamed to “Protection of personal data related to 
professionals involved in the study”. 
The link of the TransCelerate Investigator Registry (IR) project was 
added. 
The address was changed from “54 rue La Boétie 75008” to 
“46 avenue de la Grande Armée – 75017”. 
To comply with EU CTR. 
Section 10.1.6 
Dissemination of 
clinical study data 
and results 
The Section 10.1.6 “Dissemination of clinical study data” was renamed 
to “Dissemination of clinical study data and results”. 
The following 2 sentences were added to this section:  
“At the end of the clinical study, the Sponsor may publish the study 
results in scientific journal(s). As part of the review for publication, 
independent scientists may need to use “coded” data of all the study 
participants to independently verify the study’s results.” 
“For pediatric and adult trials, the results will generally be 
submitted/released 6 and 12 months respectively, after the end of 
the clinical trial worldwide (ie, the last active, participating country).” 
In the subsection “Professionals involved in the study or in the drug 
development program” the guidance “Implementation of Drug Clinical 
Trial Information Registration and Disclosure (‘Notification No. 28’)” 
was renamed to “Drug Clinical Trial Registration and Information 
Disclosure ‘Management Practice (Trial Implementation)’”. 
To comply with EU CTR. 
Section 10.1.8 
Source documents 
The text of this section was updated. 
To comply with EU CTR. 
Section 10.1.9 
Study and site start 
and closure 
The text of the subsection “First act of recruitment” was updated. 
To comply with EU CTR. 
Section 10.3.1 
Definition of AE 
The phrase: “or more severe than expected for the participant’s 
condition” was added at the first bullet point. 
The bullet point: “Signs, symptoms, or the clinical sequelae of any 
medication errors and misuse with the IMP” was added. 
To comply with EU CTR. 
Section 10.3.2 
Definition of SAE 
A few modifications were done in the “f) Other situations subsection”. 
To comply with EU CTR. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 10.3.3 
Recording and 
follow-up of AE 
and/or SAE 
In the subsection “Assessment of intensity” the definitions of mild, 
moderate and severe AEs and SAEs were updated. 
In the subsection “Assessment of causality” the following bullet points 
were updated: 
• 
 For causality assessment, the Investigator will also consult 
the IB and/or product information, for marketed products. 
• 
The Investigator must review and provide an assessment of 
causality for each AE/SAE, and document this in the medical 
notes. 
• 
There may be situations in which an SAE has occurred, and 
the Investigator has minimal information to include in the 
initial report to the Sponsor’s representative. However, it is 
very important that the Investigator always make an 
assessment of causality for every event before the initial 
transmission of the SAE data to the Sponsor’s 
representative. 
To comply with EU CTR. 
Section 10.7 
Appendix 7: Medical 
devices AEs, ADEs, 
SAEs, SADEs, 
USADEs and 
device deficiencies: 
definitions and 
procedures for 
recording, 
evaluating, 
follow-up, and 
reporting in medical 
device studies 
The Section 10.7 Appendix 7: “AEs, ADEs, SAEs, SADEs, USADEs 
and device deficiencies: definitions and procedures for recording, 
evaluating, follow-up, and reporting in medical device studies” was 
renamed to “Medical devices, AEs, ADEs, SAEs, SADEs, USADEs 
and device deficiencies: definitions and procedures for recording, 
evaluating, follow-up, and reporting in medical device studies”. 
To comply with EU CTR. 
Section 10.7.4 
Recording and 
follow-up of medical 
device, AE and/or 
SAE and device 
deficiencies 
The Section 10.7.4 “Recording and follow-up of AE and/or SAE and 
device deficiencies” was renamed to Section 10.7.4 “Recording and 
follow-up of medical device AE and/or SAE and device deficiencies”. 
In the subsection “Assessment of intensity” the definitions of mild, 
moderate and severe AEs and SAEs were updated. 
In the subsection “Assessment of causality” the following bullet points 
were updated: 
• 
The Investigator will also consult the Investigator’s Brochure 
(IB) and Product Information, for marketed products, as part 
of the assessment. 
• 
The Investigator must review and provide an assessment of 
causality for each AE/SAE/device deficiency, and document 
this in the medical notes. 
The subsection “Follow-up of AE/SAE/device deficiency” was renamed 
to “Follow-up of medical device AE/SAE/device deficiency”. 
To comply with EU CTR. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 10.7.5 
Reporting of 
medical device 
SAEs 
The Section 10.7.5 “Reporting of SAEs” was renamed to Section 
10.7.5 “Reporting of medical device SAEs”. 
The subsection “SAE reporting to the Sponsor via an electronic data 
collection tool” was renamed to “Medical device SAE reporting to the 
Sponsor via an electronic data collection tool”. 
To comply with EU CTR. 
Section 10.8 
Appendix 8: 
Country-
specific/region 
requirements 
The Section 10.8 Appendix 8 “Country-specific requirements” was 
renamed to Section 10.8 Appendix 8 “Country-specific/region 
requirements”. 
To comply with EU CTR. 
Section 10.10 
Appendix 10: 
Collection, storage 
and future use of 
data and human 
biological samples 
The Appendix “Collection, storage and future use of data and human 
biological samples” was added. 
To comply with EU CTR. 
Section 10.10.1 
Compliance with 
Member State 
applicable rules for 
the collection, 
storage and future 
use of human 
biological samples 
(Article 7.1h) 
The Section 10.10.1 “Compliance with Member State applicable rules 
for the collection, storage and future use of human biological samples 
(Article 7.1h)” was added. 
To comply with EU CTR. 
Section 10.10.2 
Compliance with 
Member State 
applicable rules for 
the collection, 
storage and future 
use of (personal) 
data (article 7 (1 d) 
of EU Regulation 
536/2014) 
The Section 10.10.2 “Compliance with Member State applicable rules 
for the collection, storage and future use of (personal) data 
(article 7 (1 d) of EU Regulation 536/2014)” was added. 
To comply with EU CTR. 
Throughout 
Minor editorial, typographical error corrections and document 
formatting revisions 
Minor, therefore, have not 
been summarized. 
 
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TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL PROTOCOL 04 .............................................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 2 
TABLE OF CONTENTS .................................................................................................................................. 8 
LIST OF TABLES ......................................................................................................................................... 16 
LIST OF FIGURES ........................................................................................................................................ 16 
1 
PROTOCOL SUMMARY ............................................................................................................... 17 
1.1 
SYNOPSIS ..................................................................................................................................... 17 
1.2 
SCHEMA ........................................................................................................................................ 28 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 29 
2 
INTRODUCTION ............................................................................................................................ 39 
2.1 
STUDY RATIONALE...................................................................................................................... 39 
2.2 
BACKGROUND ............................................................................................................................. 40 
2.2.1 
Isatuximab description ................................................................................................................... 40 
2.2.2 
Nonclinical data .............................................................................................................................. 41 
2.2.3 
Clinical data .................................................................................................................................... 42 
2.2.3.1 
Isatuximab IV in combination with pomalidomide and dexamethasone ........................................ 42 
2.2.3.2 
Isatuximab SC in combination with pomalidomide and dexamethasone ....................................... 44 
2.2.3.3 
Pomalidomide ................................................................................................................................ 48 
2.2.3.4 
Injector device ................................................................................................................................ 48 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 48 
2.3.1 
Risk assessment ............................................................................................................................ 49 
2.3.2 
Benefit assessment ........................................................................................................................ 51 
2.3.3 
Overall benefit: risk conclusion ...................................................................................................... 51 
3 
OBJECTIVES, ENDPOINTS, AND ESTIMANDS ......................................................................... 52 
3.1 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 55 
4 
STUDY DESIGN ............................................................................................................................ 56 
4.1 
OVERALL DESIGN ........................................................................................................................ 56 
4.2 
AT HOME ADMINISTRATION ....................................................................................................... 57 
4.3 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 57 
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4.3.1 
Rationale for the overall design ..................................................................................................... 57 
4.3.2 
Rationale for co-primary endpoints ................................................................................................ 57 
4.3.2.1 
ORR ............................................................................................................................................... 57 
4.3.2.2 
Ctrough at steady state (Cycle 6 D1) ................................................................................................ 58 
4.4 
JUSTIFICATION FOR DOSE ........................................................................................................ 58 
4.4.1 
Justification for intravenous isatuximab, pomalidomide and dexamethasone ............................... 58 
4.4.2 
Justification for subcutaneous dosing of Isatuximab ..................................................................... 58 
4.5 
DURATION OF STUDY PARTICIPATION .................................................................................... 60 
4.6 
END OF STUDY DEFINITION ....................................................................................................... 61 
4.7 
INTERIM ANALYSIS ...................................................................................................................... 61 
4.8 
TIMINING OF PLANNED ANALYSIS ............................................................................................ 62 
4.9 
STUDY COMMITTEES .................................................................................................................. 62 
5 
STUDY POPULATION .................................................................................................................. 63 
5.1 
INCLUSION CRITERIA .................................................................................................................. 63 
5.2 
EXCLUSION CRITERIA ................................................................................................................ 65 
5.3 
LIFESTYLE CONSIDERATIONS ................................................................................................... 67 
5.4 
SCREEN FAILURES...................................................................................................................... 67 
5.5 
CRITERIA FOR TEMPORARILY DELAYING 
ENROLLMENT/RANDOMIZATION/ADMINISTRATION OF STUDY INTERVENTION ................ 68 
6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ................................................... 69 
6.1 
STUDY INTERVENTION(S) ADMINISTERED .............................................................................. 69 
6.1.1 
Investigational medicinal products ................................................................................................. 69 
6.1.1.1 
Isatuximab ...................................................................................................................................... 69 
6.1.1.2 
Dexamethasone ............................................................................................................................. 70 
6.1.1.3 
Pomalidomide ................................................................................................................................ 70 
6.1.1.4 
Study arms ..................................................................................................................................... 72 
6.1.2 
Auxillary medicinal products .......................................................................................................... 72 
6.1.3 
Devices .......................................................................................................................................... 73 
6.2 
PREPARATION, HANDLING, STORAGE, AND ACCOUNTABILITY ........................................... 73 
6.2.1 
Responsibilities .............................................................................................................................. 73 
6.2.2 
Treatment accountability and compliance...................................................................................... 74 
6.2.3 
Return and/or destruction of treatments ........................................................................................ 74 
6.2.4 
Isatuximab subcutaneous formulation ........................................................................................... 74 
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6.2.5 
Isatuximab intravenous formulation ............................................................................................... 75 
6.2.6 
Pomalidomide ................................................................................................................................ 75 
6.2.7 
Dexamethasone ............................................................................................................................. 76 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 76 
6.3.1 
Blinding rules .................................................................................................................................. 76 
6.3.2 
Randomization ............................................................................................................................... 76 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 77 
6.4.1 
Subcutaneous isatuximab at-home administration ........................................................................ 77 
6.4.2 
Dexamethasone and pomalidomide .............................................................................................. 77 
6.5 
DOSE MODIFICATION .................................................................................................................. 77 
6.5.1 
Isatuximab ...................................................................................................................................... 78 
6.5.2 
Pomalidomide ................................................................................................................................ 78 
6.5.3 
Dexamethasone ............................................................................................................................. 78 
6.5.4 
Dose adjustments according to adverse events ............................................................................ 79 
6.5.5 
Management of infusion reactions and injection site reactions ..................................................... 84 
6.5.6 
Tumor lysis syndrome .................................................................................................................... 85 
6.5.7 
Retreatment criteria........................................................................................................................ 86 
6.6 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF THE STUDY....................... 87 
6.7 
TREATMENT OF OVERDOSE ...................................................................................................... 87 
6.8 
PRIOR AND CONCOMITANT THERAPY ..................................................................................... 88 
6.8.1 
Antithrombic therapy ...................................................................................................................... 89 
6.8.2 
G-CSF prophylaxis ......................................................................................................................... 89 
6.8.3 
Antibiotic prophylaxis ..................................................................................................................... 89 
6.8.4 
Prohibited concomitant therapy ..................................................................................................... 89 
6.8.5 
Rescue medicine ............................................................................................................................ 90 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 91 
7.1 
DISCONTINUATION OF STUDY INTERVENTION ...................................................................... 91 
7.1.1 
Permanent discontinuation ............................................................................................................ 91 
7.1.1.1 
List of criteria for permanent discontinuation ................................................................................. 91 
7.1.1.2 
Handling of participants after permanent intervention discontinuation .......................................... 92 
7.1.2 
Temporary discontinuation ............................................................................................................. 92 
7.1.3 
Rechallenge ................................................................................................................................... 93 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 93 
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7.3 
LOST TO FOLLOW UP ................................................................................................................. 94 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 95 
8.1 
ADMINISTRATIVE [AND GENERAL/BASELINE] PROCEDURES ............................................... 95 
8.2 
EFFICACY ASSESSMENTS ......................................................................................................... 95 
8.3 
PHARMACOKINETICS .................................................................................................................. 97 
8.4 
SAFETY ASSESSMENTS ............................................................................................................. 98 
8.4.1 
Body weight and Physical examinations ........................................................................................ 98 
8.4.2 
Vital signs ....................................................................................................................................... 98 
8.4.2.1 
At-home administration .................................................................................................................. 98 
8.4.3 
Electrocardiograms ........................................................................................................................ 99 
8.4.4 
Clinical safety laboratory tests ....................................................................................................... 99 
8.4.5 
Pregnancy testing .......................................................................................................................... 99 
8.4.6 
Suicidal ideation and behavior risk monitoring ............................................................................ 100 
8.4.7 
Assessment of local tolerability .................................................................................................... 100 
8.4.8 
Assessment of frailty .................................................................................................................... 100 
8.5 
PATIENTS REPORTED OUTCOMES......................................................................................... 100 
8.5.1 
EORTC QLQ-C30 ........................................................................................................................ 104 
8.5.2 
EORTC QLQ-MY20 ..................................................................................................................... 105 
8.5.3 
EQ-5D-5L ..................................................................................................................................... 105 
8.6 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS (SAES) AND OTHER 
SAFETY REPORTING ................................................................................................................. 106 
8.6.1 
Time period and frequency for collecting AE and SAE information ............................................. 106 
8.6.2 
Method of detecting AEs and SAEs ............................................................................................. 107 
8.6.3 
Follow-up of AEs and SAEs ......................................................................................................... 107 
8.6.4 
Regulatory reporting requirements for SAEs ............................................................................... 107 
8.6.5 
Pregnancy .................................................................................................................................... 108 
8.6.6 
Adverse event of special interest ................................................................................................. 108 
8.6.7 
Medication errors or misuses of medicinal product ..................................................................... 109 
8.6.8 
Guidelines for reporting product complaints ................................................................................ 110 
8.6.9 
Medical device deficiencies ......................................................................................................... 110 
8.6.9.1 
Time period for detecting medical device deficiencies ................................................................ 110 
8.6.9.2 
Follow-up of medical device deficiencies ..................................................................................... 110 
8.6.9.3 
Prompt reporting of device deficiencies to Sponsor .................................................................... 111 
8.6.9.4 
Regulatory reporting requirements for device deficiencies .......................................................... 111 
8.7 
GENETICS ................................................................................................................................... 111 
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8.8 
BIOMARKERS ............................................................................................................................. 111 
8.9 
IMMUNOGENICITY ASSESSMENTS ......................................................................................... 112 
8.10 
SPECIFICITIES REGARDING COVID-19 SITUATION AND VACCINATION ............................ 112 
8.11 
HEALTH ECONOMICS OR MEDICAL RESOURCE UTILIZATION AND HEALTH 
ECONOMICS ............................................................................................................................... 113 
8.12 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH .............................. 113 
9 
STATISTICAL CONSIDERATIONS ............................................................................................ 115 
9.1 
POPULATIONS FOR ANALYSES ............................................................................................... 115 
9.2 
STATISTICAL ANALYSES .......................................................................................................... 116 
9.2.1 
General considerations ................................................................................................................ 116 
9.2.2 
Primary endpoint(s) analyses ...................................................................................................... 117 
9.2.3 
Secondary endpoint(s) analyses .................................................................................................. 117 
9.2.3.1 
Key Secondary Endpoints ............................................................................................................ 117 
9.2.3.2 
Other Secondary Endpoints ......................................................................................................... 118 
9.2.4 
Tertiary/exploratory endpoint analyses ........................................................................................ 119 
9.2.5 
Multiplicity adjustment .................................................................................................................. 119 
9.2.6 
Other/safety analysis.................................................................................................................... 119 
9.2.6.1 
Adverse events ............................................................................................................................ 119 
9.2.6.2 
Laboratory variables, vital signs, and electrocardiograms (ECGs) .............................................. 120 
9.2.6.3 
Product complaints....................................................................................................................... 121 
9.2.7 
Other analysis .............................................................................................................................. 121 
9.3 
INTERIM ANALYSES .................................................................................................................. 121 
9.4 
TIMING OF PLANNED ANALYSIS .............................................................................................. 121 
9.5 
SAMPLE SIZE DETERMINATION ............................................................................................... 121 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ...................... 123 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ..... 123 
10.1.1 
Regulatory and ethical considerations ......................................................................................... 123 
10.1.2 
Financial disclosure...................................................................................................................... 125 
10.1.3 
Informed consent process ............................................................................................................ 125 
10.1.4 
Data protection ............................................................................................................................. 126 
10.1.5 
Committee’s structure .................................................................................................................. 128 
10.1.5.1 Steering committee ...................................................................................................................... 128 
10.1.5.2 Data monitoring committee .......................................................................................................... 129 
10.1.6 
Dissemination of clinical study data and results .......................................................................... 129 
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10.1.7 
Data quality assurance ................................................................................................................ 130 
10.1.8 
Source documents ....................................................................................................................... 131 
10.1.9 
Study and site start and closure ................................................................................................... 131 
10.1.10 Publication policy ......................................................................................................................... 132 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ....................................................................... 132 
10.2.1 
Modification of diet in renal disease (MDRD) equation................................................................ 134 
10.3 
APPENDIX 3: AES AND SAES: DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING ....................................................................... 134 
10.3.1 
Definition of AE ............................................................................................................................ 134 
10.3.2 
Definition of SAE .......................................................................................................................... 135 
10.3.3 
Recording and follow-up of AE and/or SAE ................................................................................. 137 
10.3.4 
Reporting of SAEs........................................................................................................................ 138 
10.4 
APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE ................................................. 139 
10.4.1 
Risk associated with pregnancy ................................................................................................... 139 
10.4.2 
Contraception guidance ............................................................................................................... 139 
10.4.2.1 Criteria for females of childbearing potential ............................................................................... 139 
10.4.2.2 Contraception guidance for female subjects ................................................................................ 140 
10.4.2.3 Contraception for male subjects .................................................................................................. 141 
10.4.3 
Pregnancy testing ........................................................................................................................ 142 
10.4.3.1 Female participants ...................................................................................................................... 142 
10.4.3.2 Male participants .......................................................................................................................... 142 
10.4.4 
Additional precautions during and after study participation ......................................................... 142 
10.4.4.1 Female participants ...................................................................................................................... 142 
10.4.4.2 Male participants .......................................................................................................................... 143 
10.4.4.3 Precautions related to pomalidomide........................................................................................... 143 
10.5 
APPENDIX 5: GENETICS ........................................................................................................... 143 
10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-UP 
ASSESSMENTS .......................................................................................................................... 144 
10.7 
APPENDIX 7: MEDICAL DEVICES AES, ADES, SAES, SADES, USADES AND DEVICE 
DEFICIENCIES: DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, 
FOLLOW-UP, AND REPORTING IN MEDICAL DEVICE STUDIES ........................................... 144 
10.7.1 
Definition of medical device AE and ADE .................................................................................... 144 
10.7.2 
Definition of medical device SAE, SADE and USADE ................................................................. 145 
10.7.3 
Definition of device deficiency ...................................................................................................... 145 
10.7.4 
Recording and follow-up of medical device AE and/or SAE and device deficiencies ................. 146 
10.7.5 
Reporting of medical device SAEs ............................................................................................... 147 
10.7.6 
Reporting of SADEs ..................................................................................................................... 148 
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10.8 
APPENDIX 8: COUNTRY-SPECIFIC/REGION REQUIREMENTS ............................................. 148 
10.9 
APPENDIX 9: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY ................................. 149 
10.10 
APPENDIX 10: COLLECTION, STORAGE AND FUTURE USE OF DATA AND HUMAN 
BIOLOGICAL SAMPLES ............................................................................................................. 150 
10.10.1 Compliance with Member State applicable rules for the collection, storage and future use 
of human biological samples (Article 7.1h) .................................................................................. 150 
10.10.2 Compliance with Member State applicable rules for the collection, storage and future use 
of (personal) data (Article 7 (1 d) of EU Regulation 536/2014) ................................................... 150 
10.11 
APPENDIX 11: IMWG RESPONSE CRITERIA ........................................................................... 150 
10.12 
APPENDIX 12: EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE 
STATUS SCALE .......................................................................................................................... 153 
10.13 
APPENDIX 13: NATIONAL CANCER INSTITUTE COMMON TERMINOLOGY CRITERIA 
FOR ADVERSE EVENTS ............................................................................................................ 154 
10.14 
APPENDIX 14: CD38 BLOOD TEST INTERFERENCE GUIDELINES ....................................... 154 
10.15 
APPENDIX 15 : GLOBAL POMALIDOMIDE PREGNANCY PREVENTION PLAN .................... 159 
10.16 
APPENDIX 16: PATIENT REPORTED OUTCOMES .................................................................. 173 
10.16.1 European Organization for Research and Treatment of Cancer core quality of life 
questionnaire (EORTC QLQ-C30) ............................................................................................... 173 
10.16.2 European Organization for Research and Treatment of Cancer quality of life myeloma 
module (EORTC QLQ-MY20) ...................................................................................................... 175 
10.16.3 European Quality of Life Group measure with 5 dimensions and 5 levels per dimension 
(EQ-5D-5L) ................................................................................................................................... 177 
10.16.4 Health Resource Utilization and Productivity Questionnaire (HRUPQ) ....................................... 180 
10.16.5 Patient Expectations Questionnaire at Baseline (PEQ-BL) ......................................................... 186 
10.16.6 Patient experience and satisfaction follow-up questionnaire (PESQ-FU) ................................... 188 
10.16.7 Patient experience and satisfaction end-of-treatment questionnaire (PESQ-EOT) .................... 190 
10.16.8 Patient’s Assessment of Treatment questionnaire (PAT) ............................................................ 194 
10.16.9 Local Tolerability at Injection Site After Isatuximab Administration - Patient Assessment 
Using Diary ................................................................................................................................... 195 
10.17 
APPENDIX 17: IADL AND ADL QUESTIONNAIRES .................................................................. 197 
10.18 
APPENDIX 18: ABBREVIATIONS AND DEFINITIONS .............................................................. 199 
10.19 
APPENDIX 19: PROTOCOL AMENDMENT HISTORY .............................................................. 201 
10.19.1 Amended protocol 01 (11-October-2022) .................................................................................... 201 
10.19.2 Amended protocol 02 (15-March-2023) ....................................................................................... 206 
10.19.3 Amended protocol 03 (03-October-2023) .................................................................................... 210 
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11 
REFERENCES ............................................................................................................................. 216 
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LIST OF TABLES  
Table 1 - Schedule of activities ..................................................................................................................... 29 
Table 2 - PK and ADA flowchart - Arm SC .................................................................................................... 37 
Table 3 - PK and ADA flowchart - Arm IV ..................................................................................................... 38 
Table 4 - Mean (CV%) isatuximab PK parameters after the 1st and 4th SC administration at 1000 mg or 
1400 mg QW/Q2W and after the IV administration at 10 mg/kg in TCD15484 – non compartmental analysis
 ....................................................................................................................................................................... 47 
Table 5 - Risk assessment ............................................................................................................................ 49 
Table 6 - Objectives and endpoints ............................................................................................................... 52 
Table 7 - Summary of primary estimands for main endpoints ....................................................................... 55 
Table 8 - Isatuximab intravenous infusion rate ............................................................................................. 69 
Table 9 - Study intervention(s) administered................................................................................................. 71 
Table 10 - Study arm(s) ................................................................................................................................. 72 
Table 11 - Dose reduction steps for pomalidomide ....................................................................................... 78 
Table 12 - Dose reduction steps for dexamethasone ................................................................................... 79 
Table 13 - Guidelines for dose adjustments for hematologic 
toxicities - isatuximab/pomalidomide/dexamethasone combination ............................................................. 79 
Table 14 - Guidelines for dose adjustments for non-hematologic 
toxicities - isatuximab/pomalidomide/dexamethasone combination ............................................................. 81 
Table 15 - Guidelines for management of injection sites reactions (ISRs) and infusion reactions (IRs) for 
Isatuximab subcutaneous administration NCI-CTCAE v5.0 criteria .............................................................. 84 
Table 16 - Guidelines for management of infusion reactions for isatuximab intravenous administration NCI-
CTCAE v5.0 criteria ....................................................................................................................................... 85 
Table 17 - Management of tumor lysis syndrome ......................................................................................... 86 
Table 18 - Normal values for at-home administration* .................................................................................. 99 
Table 19 - Summary of assessment timelines for local tolerability ............................................................. 100 
Table 20 - Populations for analyses ............................................................................................................ 115 
Table 21 - Protocol-required laboratory tests .............................................................................................. 133 
Table 22 - Adapted from updated International Myeloma Working Group response criteria ...................... 150 
 
LIST OF FIGURES  
Figure 1 - Graphical study design ................................................................................................................. 28 
Figure 2 - Simulated isatuximab plasma concentration-time profiles for participants with low (5th percentile), 
median or high (95th percentile) body weight after flat SC dose of 1400 mg - Comparison with body weight 
based IV dose of 10 mg/kg ............................................................................................................................ 60 
 
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1 
PROTOCOL SUMMARY  
1.1 
SYNOPSIS  
Protocol title:  
A randomized, Phase 3, open label study evaluating subcutaneous versus intravenous 
administration of isatuximab in combination with pomalidomide and dexamethasone in adult 
patients with relapsed and/or refractory multiple myeloma (RRMM) 
Brief title: 
 
SC versus IV isatuximab in combination with pomalidomide and dexamethasone in RRMM 
 
Regulatory agency identifier number(s): 
IND: 
143013 
NCT: 
NCT05405166 
WHO: 
U1111-1261-5846 
EUDAMED: 
CIV-22-06-039616 
EU trial number 
2023-508869-32 
Other: 
Not applicable 
Pediatric investigation plan: Not applicable. 
Rationale: 
The combination of intravenous (IV) isatuximab with pomalidomide and dexamethasone has 
demonstrated clinical efficacy with an acceptable and manageable safety profile in 
the ICARIA-MM (NCT02990338) Phase 3 trial. In 2020, the Food and Drug Administration 
(FDA) and the European Medicines Agency (EMA) granted approval to this combination for 
the treatment of adults with RRMM who have received at least two prior therapies including 
lenalidomide and a proteasome inhibitor (PI). 
Isatuximab IV administration is approved with the fixed-volume infusion method allowing 
the IV infusion to be given during 75 minutes from the 3rd infusion onwards. A subcutaneous (SC) 
administration within several minutes allows for a shorter duration of administration compared to 
the currently approved IV route with the intent to optimize the convenience of administration, 
enhance comfort and quality of life of the patients, and reduce health care resources. Therefore, 
SC administration of isatuximab is considered as a desirable alternative to the current approved 
IV administration, in particular for the long duration of treatment required in multiple myeloma 
(MM). 
Device-mediated SC administration can offer a number of benefits to both health care 
professionals (HCPs) and patients, including controlled delivery and simplified user interface, and 
could ultimately be used by a qualified HCP in the outpatient setting or at patient’s home.  
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The EFC15951 study is proposed to evaluate SC administration of isatuximab versus IV, in 
combination with pomalidomide and dexamethasone (Pd) using an Investigational injector device 
in participants with MM who have received at least one prior line of therapy including 
lenalidomide and a PI. 
Objectives and endpoints: 
  
Objectives 
Endpoints 
Primary 
 
• 
Demonstrate the efficacy non-inferiority 
between isatuximab SC and isatuximab IV in 
combination with Pd. 
• 
Overall response rate (ORR): defined as the proportion of 
participants with stringent complete response (sCR), 
complete response (CR), very good partial response 
(VGPR), and partial response (PR) according to the 2016 
International Myeloma Working Group (IMWG) criteria 
assessed by Independent Review Committee (IRC).  
• 
Demonstrate the pharmacokinetic (PK) 
non-inferiority between isatuximab SC and 
isatuximab IV in combination with Pd. 
• 
Observed concentration before dosing (Ctrough) at steady 
state (corresponding to predose at C6D1). 
Secondary 
Key Secondary 
 
• 
Demonstrate the efficacy non-inferiority 
between isatuximab SC and isatuximab IV in 
combination with Pd. 
 
• 
Very Good Partial Response or better rate: defined as 
the proportion of participants with sCR, CR, and VGPR 
according to the 2016 International Myeloma Working 
Group (IMWG) criteria assessed by IRC. 
• 
Demonstrate the PK non-inferiority between 
isatuximab SC and isatuximab IV in 
combination with Pd. 
• 
Observed concentration before dosing (Ctrough) at 4 weeks 
(ie, CT4W corresponding to predose at C2D1). 
 
• 
Assess safety of isatuximab SC and IV in 
combination with Pd. 
• 
Incidence rate of infusion-reactions (IRs). 
 
• 
Assess patient satisfaction with isatuximab 
SC and IV. 
• 
Percentage of participants satisfied or very satisfied with 
the injection method used to administer study medication 
based on the patient experience and satisfaction 
questionnaire (PESQ). 
Other Secondary  
 
• 
Assess efficacy of isatuximab SC compared 
to isatuximab IV in combination with Pd. 
• 
Duration of response (DOR): defined as the time from 
the date of the first response to the date of first occurrence 
of progressive disease (PD) as determined by IRC or 
death from any cause, whichever happens first. DOR is 
determined only for participants who have achieved 
a response (PR or better). In the absence of PD or death 
before the analysis cut-off date, the DOR will be censored 
at the date of the last valid disease assessment performed 
prior to initiation of a further anti-myeloma treatment or 
the analysis cut-off date, whichever is earlier. Patients with 
two or more consecutive missed assessments prior to PD 
or death will be censored at the last valid disease 
assessment. Details about censoring rule will be provided 
in statistical analysis plan (SAP). 
• 
Time to first response (TT1R): defined as the time from 
randomization to the date of first IRC determined response 
(PR or better) that is subsequently confirmed. Details 
about censoring rule will be provided in SAP. 
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Objectives 
Endpoints 
 
• 
Time to best response (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. Details about censoring rule will 
be provided in SAP. 
• 
Progression free survival (PFS): defined as the time from 
the date of randomization to the date of 
first documentation of PD as determined by IRC or 
the date of death from any cause, whichever comes first. 
Responses will be determined according to IMWG criteria. 
Progression based on paraprotein will be confirmed based 
on two consecutive assessments. 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. Patients with two or 
more consecutive missed assessments prior to PD or 
death will be censored at the last valid disease 
assessment. Details censoring rule will be provided in 
the SAP. 
• 
Overall survival (OS): defined as the time from the date of 
randomization to death from any cause. Participants 
without death prior to the analysis cut-off date will be 
censored at the last date the participant was known to be 
alive or the cut-off date, whichever is first. Details 
censoring rule will be provided in SAP. 
• 
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. Same censoring rule applies as in the PFS endpoint. 
• 
Assess safety of isatuximab SC and IV and 
local tolerability of isatuximab SC in 
combination with Pd. 
 
 
 
 
 
 
 
• 
Treatment-emergent adverse events (TEAEs)/serious 
adverse events (SAEs). Treatment-emergent adverse 
events (TEAEs) are defined as adverse events (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. 
• 
Laboratory parameters. 
• 
Injection site reactions (ISRs) – SC arm only. 
• 
Adverse events and laboratory parameters will be graded 
using NCI CTCAE v5.0. 
• 
Characterize PK of isatuximab SC and IV in 
combination with Pd.  
• 
PK concentrations.  
• 
Assess the delivery performance of the 
(investigational) device injector. 
• 
Number of successful injections with (investigational) 
isatuximab injector device defined as completion of 
administration per provided instructions for use with no use 
errors or technical issues, divided by the total number of 
injections. 
• 
Assess the potential immunogenicity of 
isatuximab SC and IV in combination with Pd. 
• 
Incidence of participants with anti-drug antibodies (ADA) 
against isatuximab 
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Objectives 
Endpoints 
• 
Assess the clinical outcome of isatuximab SC 
and IV in combination with Pd. 
• 
Patient expectation at baseline and experience/satisfaction 
with Isatuximab will be assessed using the patient 
expectation questionnaire (PEQ), the patient experience 
and satisfaction PESQ, and the patient’s assessment of 
treatment (PAT) questionnaires. 
 
• 
Health Resources Utilization will be assessed using 
the Health Resource Utilization and Productivity 
Questionnaire (HRUPQ). 
• 
Health-related quality of life will be assessed using 
the European Organization 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 status will be assessed using the European Quality 
of Life Group questionnaire with 5 dimensions and 5 levels 
per dimension (EQ-5D-5L). 
• 
Explore chromosomal abnormalities [mainly 
but not limited to t(4;14), t(14;16), del(17p) 
and gain(1q21+)], and potential association 
with clinical outcomes. 
• 
Impact of abnormal cytogenetic subtypes on participant 
outcome. 
  
For China, please see Section 10.8 details. 
Overall design synopsis: 
The study design, number of participants, study treatments and duration are described below. 
Brief summary:  
This is a randomized, multicenter, Phase 3, open-label study evaluating SC versus IV 
administration of isatuximab in combination with pomalidomide and dexamethasone (IsaPd) in 
RRMM patients (study participants) who have received at least 1 prior line of therapy including 
lenalidomide and a PI. The randomization will be stratified by MM isotype (IgG versus non-IgG), 
body weight (≤65 kg, >65- ≤85 kg, and >85 kg), and number of prior lines (1-2 versus ≥3). 
Eligible participants (approximately 534) will be randomized 1:1 into 1 of 2 study arms: 
• Arm SC: Isatuximab SC at 1400 mg with device injector (N = 267). 
• Arm IV: Isatuximab IV 10 mg/kg (N = 267). 
The efficacy co-primary analysis will be conducted on the Intent-to-Treat (ITT) population, 
defined as all participants who have given their informed consent and for whom there is 
confirmation of successful allocation of a randomization number by the interactive response 
technology (IRT). Participants will be included in a treatment arm as randomized, regardless of 
whether participants receive any study drug or receive a different study drug from which they 
were randomized. The PK co-primary analysis will be conducted on the Per Protocol-PK (PP-PK) 
population defined as all randomized participants who have received at least eleven isatuximab 
doses out of twelve up to C5D15 (one dose omission permitted during Cycle 1), with isatuximab 
C6D1 (predose) concentration results from PK sample collected within the defined per protocol 
time window and adequate documentation of dosing and sampling dates and times. 
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After the first 5 cycles, a home administration by an HCP may be proposed to the participants in 
the SC arm on D15 from Cycle 6 onwards. Visits at Day 1, on the other hand, from C6 onwards 
will always be outpatient visits at clinic. The decision to propose at home administration on D15 
will be based on the absence of infusion reaction (IR) at C4 and C5, the hematology test at Day 1 
of each corresponding cycle and the Investigator’s judgement. Participant willingness and ability 
to adhere to the requirements of home administration need to be taken into account before 
initiating it. 
Myeloma response and progression will be determined by the Independent Review Committee 
(IRC) based on central laboratory M protein analysis and central radiology review using IMWG 
2016 criteria. 
The cut-off date for the primary analysis is approximately 6 months after the Last Patient In (LPI), 
which includes analysis on the primary endpoints and secondary endpoints when applicable. 
There will be an update of PFS and OS analysis approximately 15 months after LPI, and then 
the cut-off date for final OS analysis will be approximately 30 months after LPI. 
Number of participants: 
Approximately 534 participants will be randomized to investigational intervention for 
267 randomized participants in Arm SC and 267 randomized participants in Arm IV. 
Note: Enrolled participants are all participants from screened participants who have been allocated 
to an intervention regardless of whether the intervention was received or not. 
Study arms and duration: 
Study interventions  
Investigational Medicinal Products  
Isatuximab SC (Arm SC): 
• Formulation: The drug product is presented as a solution in a vial containing 10 mL 
(as extractable volume) at a concentration of 140 mg/mL. 
• Route of administration: SC, using investigational device injector. The volume to be 
injected at each administration will be injected at a single site in the periumbilical region. 
• Each cycle will be 28 days in duration.  
• Dose regimen (Cycle 1): Isatuximab will be administered at the nominal dose of 1400 mg 
SC weekly for 4 weeks during Cycle 1 (Days 1, 8, 15, and 22). 
• Dose regimen (Cycle 2 and onwards): Isatuximab will be administered at the nominal dose 
of 1400 mg SC on Day 1 and Day 15 of each subsequent cycle. 
• From Cycle 6 onwards, the Day 15 administration may be performed at home by an HCP. 
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Isatuximab IV (Arm IV, per its currently approved dose, schedule, and infusion method): 
• Formulation: The drug product is presented as a concentrate for solution for IV infusion in 
vials containing 20 mg/mL (500 mg/25 mL and 100 mg/5 mL).  
• Route of administration: Intravenous with a fixed-volume infusion method. 
• Each cycle will be 28 days in duration. 
• Dose regimen (Cycle 1): Isatuximab will be administered at the dose of 10 mg/kg IV 
weekly for 4 weeks during Cycle 1 (Days 1, 8, 15, and 22). 
• Dose regimen (Cycle 2 and onwards): Isatuximab will be administered at the dose of 
10 mg/kg on Day 1 and Day 15 of each subsequent cycle. 
Pomalidomide (both arms): 
• Route of administration: Oral.  
• Dose regimen: 4 mg on Days 1 to 21 of each cycle. Pomalidomide will be taken 
at the time that is the most convenient for the participants prior to or after isatuximab 
administration, preferably at the same time every day. 
Dexamethasone (both arms): 
• Route of administration: Oral. 
• Dose regimen: 40 mg (or 20 mg for participants ≥75 years) on Days 1, 8, 15, and 22 of 
each cycle. 
Dexamethasone will also have the intent of premedication for IRs. On the day of 
co-administration with isatuximab, dexamethasone will be given prior to isatuximab as part of 
premedication. 
Auxilliary Medicinal Products (Premedication) 
At least 15 to 30 minutes (but no longer than 60 minutes) prior to isatuximab administration 
(regardless of route): 
• Montelukast 10 mg orally (or equivalent, Cycle 1 only). 
• Acetaminophen/paracetamol 650 to 1000 mg orally. 
• Diphenhydramine 50 mg orally (or equivalent: eg, cetirizine, promethazine, 
dexchlorpheniramine, according to the approval availability) or Diphenhydramine 
25-50 mg IV (or equivalent). Intravenous route is preferred for at least the first 
4 IV isatuximab infusions. 
The order of premedication administration is the following: 
• Montelukast, dexamethasone, acetaminophen/paracetamol, and then diphenhydramine. 
• Dexamethasone oral (PO) will also be given in the same dose as stated in Section 6.1.1. 
- 
Methylprednisolone (or equivalent):100 mg IV if dexamethasone is discontinued 
earlier than isatuximab and premedication is still needed. 
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• Participants who do not experience IRs after 4 consecutive administrations of isatuximab 
may have their need for subsequent premedication reconsidered at the Investigator’s 
discretion, except montelukast that should be administered only on Cycle 1. 
Device 
The (investigational) isatuximab injector device is a sterile, single-use, disposable, elastomeric, 
user filled wearable injector. The (investigational) isatuximab injector device includes an adhesive 
backing to secure it to the injection site during administration. Injection sites with the device are 
permitted only on the abdominal region. At the end of dosing, the injection needle retracts into 
the device housing and the device enters a locked-out state to prevent reuse. Further instructions 
are provided in the study pharmacy manual. 
Duration of study intervention 
Before the final OS analysis cutoff date, participants will be allowed to continue therapy until 
disease progression, unacceptable adverse events (AEs), participant request to discontinue 
treatment or any other reason, whichever is first. After the final OS analysis cutoff date, 
participants will be allowed to continue therapy until disease progression, unacceptable adverse 
events (AEs), participant request, study treatment is commercially available and reimbursed in 
the participant’s country, switch to a long-term safety study, or any other reason, whichever is 
first. 
Statistical considerations: 
Sample size calculation 
A total sample size of 534 participants (randomization ratio 1:1, ie, 267 randomized participants 
in the SC arm, and 267 randomized participants in the IV arm) was determined to demonstrate 
non-inferiority of SC arm versus IV arm on the proportion ratio of participants who achieved 
ORR, and the geometric mean ratio of Ctrough at steady state (corresponding to predose at C6D1). 
For the co-primary efficacy endpoint of ORR, the non-inferiority test for non-unity null according 
to Farrington and Manning (1990) was implemented. With 2.5% one sided Type I error rate, and 
a non-inferiority margin of 0.839 which was calculated as 40% retention of the observed historical 
clinical benefit of ORR ratio 0.7463 (upper bound of the 95% confidence interval [CI] of rate 
ratio for Pd over CD38+ Pd as demonstrated in ICARIA-MM trial) under the logarithm scale then 
converting back to its original scale, 534 randomized participants provide approximately 
80% power for this efficacy co-primary endpoint assuming that ORR for IV arm is 60.4% and 
the true response rate is 1.02 for SC arm over IV arm. For the PK co-primary endpoint of Ctrough 
at steady state (corresponding to predose at C6D1), assuming Ctrough at steady state follows log 
normal distribution with a true geometric mean ratio of 1, and a CV of 75%, and an assumed 
drop-out rate of no more than 50% to the PK per-protocol population, 534 randomized 
participants will provide at least 86% power to show the lower bound of the 90% CI of 
the geometric mean ratio of Ctrough at steady state is at least 80% (a non-inferiority margin of 
80%). Calculations were made based on SAS 9.4 (1). 
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Main analysis populations 
Intent-to-treat (ITT) population 
The ITT population is the randomized population. All participants 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. Participants will be analyzed according to 
the treatment group allocated by IRT, regardless of whether the participants received any study 
treatment or received a different study treatment from that to which they were randomized. 
This population will be used for the analysis of the co-primary efficacy endpoint. 
All efficacy analyses will be performed on this population. 
Safety Population  
The safety population will include ITT participants who have received at least 1 dose or a part of 
a dose of the study intervention. All analyses using this population will be based on the treatment 
actually received.  
All safety analysis will be performed on this population. 
PP-PK population 
The PP-PK population will include all randomized participants which have received at least 
eleven Isatuximab doses out of twelve up to C5D15 (one dose omission permitted during 
Cycle 1), with isatuximab C6D1 (predose) concentration results from PK sample collected within 
the defined per protocol time window and adequate documentation of dosing and sampling dates 
and times. 
This population will be used for the analysis of the co-primary PK endpoint. 
CT4W-PK population 
The CT4W - PK population for CT4W endpoint will include all randomized participants having 
completed administration of all the first 4 weekly isatuximab doses at Cycle 1, with isatuximab 
C2D1 (predose) concentration results from PK sample collected within the defined per protocol 
time window and adequate documentation of dosing and sampling dates and times.  
This population will be used for the analysis of the CT4W PK endpoint. 
Primary analysis  
The number and proportion of participants who achieve ORR per IRC assessment will be 
calculated for each group. The relative risk of Isa-SC + Pd relative to Isa-IV + Pd and its 
two-sided 95% CI using Farrington and Manning method will be provided. If the lower bound of 
the 95% CI is not less than a non-inferiority margin of 0.839, the non-inferiority of efficacy 
Isa-SC + Pd relative to Isa-IV + Pd will be concluded. 
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For the co-primary PK endpoint of Ctrough at steady state (ie, C6D1 predose), summary statistics 
such as geometric means, coefficient of variation, median and range will be provided for 
treatment group. The ratio of the geometric means of Isa -SC + Pd relative to Isa-IV + Pd and 
corresponding two-sided 90% CI will be provided be provided by calculating the 90% CI under 
the logarithm scale then converting back to its original scale. The non-inferiority of PK 
Isa-SC + Pd relative to Isa-IV + Pd will be concluded if the lower bound of the 90% CI for 
the geometric mean ratio of Ctrough at steady state is at least 80% (a non-inferiority margin of 
80%).  
The non-inferiority of Isa-SC+ Pd relative to Isa-IV + Pd will be concluded if both the efficacy 
and PK endpoints achieve non-inferiority.  
Analysis of key secondary endpoints 
If the co-primary endpoints are significant, the key secondary endpoints will be tested by 
hierarchical testing in the order of VGPR or better rate, CT4W, incidence rate of IRs, and 
the percentage of participants who reported satisfied or very satisfied with the injection method 
used to administer the study medication. 
VGPR or better rate per IRC will be summarized for the ITT population in the same way as for 
ORR endpoint. The non-inferiority test for non-unity null according to Farrington and Manning 
(1990) will be performed for VGPR or better rate. The non-inferiority margin is 0.6312 which 
was calculated as 40% retention of the observed historical clinical benefit of VGPR or better ratio 
0.478 (upper bound of the 95% CI of rate ratio for Pd over CD38+ Pd as demonstrated in 
ICARIA-MM trial) under the logarithm scale then converting back to its original scale. If 
the lower bound of the 95% CI is not less than a non-inferiority margin of 0.6312, 
the non-inferiority of Isa-SC + Pd relative to Isa- IV + Pd on the VGPR or better rate will be 
concluded.  
The PK endpoint of CT4W will be summarized for the PP-PK population for CT4W in the same 
way as for the Ctrough at steady state endpoint. The non-inferiority of Isa- SC + Pd relative to 
Isa-IV + Pd on CT4W will be concluded if the lower bound of the 90% CI for the geometric mean 
ratio of CT4W is at least 80% (a non-inferiority margin of 80%).  
Incidence rate of IRs will be compared between treatment arms on the safety population using 
the Fisher’s exact test. The relative risk, odds ratio of ISA- SC+ Pd relative to Isa- IV + Pd with 
their 95% CI will be provided. 
Percentage of participants who reported satisfied or very satisfied with the injection method used 
to administer the study medication based on the PESQ at C5D15 visit will be compared between 
treatment arms on the ITT population using the stratified Cochran–Mantel–Haenszel (CMH) 
method. 
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Analysis of other secondary endpoints 
The median PFS per IRC assessment and probabilities of being progression free at different time 
points calculated using the Kaplan-Meier methods as well as corresponding 95% CI will be 
presented by treatment arm. The Kaplan-Meier PFS curves will also be provided. The Hazard 
Ratio (HR) estimated from the Cox proportional hazards model as well as its associated 95% CI 
will be provided too. 
The analysis for PFS2, OS, DOR, and time-to-response (TTR) will be similar to that described for 
PFS per IRC assessment. 
PK concentrations (Ctrough and Ceoi - Isa-IV+Pd arm for Ceoi only-) will be summarized per arm 
with descriptive statistics. PK parameters and derived exposure will be summarized and provided 
in a separate report.  
Number (and percentage) of participants experiencing TEAEs by primary system organ class and 
preferred term will be summarized by National Cancer Institute, Common Terminology Criteria 
for Adverse Events (NCI CTCAE) v5.0 grade (all grades and ≥Grade 3) for the safety population. 
The same summaries will be prepared for treatment related TEAEs, TEAEs leading to treatment 
discontinuation, TEAEs leading to dose modification, serious TEAEs and TEAEs with fatal 
outcome and ISRs. Second primary malignancies as an adverse event of special interest (AESI) 
will be reported throughout the study. 
Hematology and biochemistry results will be graded according to NCI CTCAE v5.0. Number 
(and percentage) of participants with laboratory abnormalities (ie, all grades and ≥Grade 3) using 
the worst grade during the on-treatment period will be provided for the safety population.  
Number of successful injections with investigational isatuximab injector device divided by total 
number of actual injections will be assessed. 
Participant expectations at baseline, participant experience and satisfaction and assessment of 
treatment, and Health Resource Utilization and Productivity Questionnaires will be descriptively 
summarized.  
Participant’s health-related quality of life (influenced by both disease and treatment) will be 
assessed by the European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire-Core 30 (EORTC QLQ-C30) and the European Organization for Research and 
Treatment of Cancer Quality of Life Questionnaire-Myeloma Module 20 (EORTC QLQ-MY20) 
via a comparison of change scores in C30 (individual symptom change scores) and MY20 
(disease- and treatment-related summary scores) from baseline to follow-up between treatment 
arms. In addition, responder analyses will be conducted 1) for those who improve and 2) for those 
who deteriorate, utilizing the Clinically Important Differences (CIDs) for all individual symptom 
scores (C30) and disease- and treatment-related summary scores (MY20) for both treatment arms. 
Health status (EQ-5D-5L, including Visual Analogue Scale [VAS]) will be assessed via 
a comparison of EQ-5D-5L health status change scores from baseline to follow-up between 
treatment arms. In addition, responder analyses will be conducted 1) for those who improve and 
2) for those who deteriorate, utilizing the CIDs for health status VAS scores for both treatment 
arms. 
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Data Monitoring/Other committee: Yes 
A Data Monitoring Committee (DMC) has been appointed for this study. The Data Monitoring 
Committee (board) is a group of independent scientists who are appointed to monitor the safety 
and scientific integrity of a human research intervention, and to make recommendations to 
the Sponsor regarding the stopping of a study for harms. The composition of the committee is 
dependent upon the scientific skills and knowledge required for monitoring the particular study. 
The data monitoring committee specific roles and interaction with the Sponsor will be described 
in the DMC charter. 
 
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1.2 
SCHEMA  
Figure 1 - Graphical study design  
 
 
 
 
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1.3 
SCHEDULE OF ACTIVITIES (SOA)  
Table 1 - Schedule of activities  
Evaluation/ 
Procedurea 
Screening/Baseline 
Cycle 1ee 
Cycle 2ee 
Subsequent 
cyclesee 
End of treatment 
Follow-upd 
Notes 
Days -28 to -1 
D1c 
D8 
D15c 
D22 
D1c 
D15c 
D1c 
D15c 
D30 (±5) after last 
study treatment 
administration or 
before the next 
therapy 
 
D = Day 
Informed consentse 
X 
 
 
 
 
 
 
 
 
 
 
 
Training participants 
on ePRO technology 
 
X 
 
 
 
 
 
 
 
 
 
 
Contraceptive 
counselingf 
X 
X 
 
 
 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Randomizationb 
X 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B and C and 
HIV serologiesg 
X 
 
 
 
 
 
 
 
 
 
 
As clinically 
indicated 
Demography, 
medical/surgical and 
disease historyh 
X 
 
 
 
 
 
 
 
 
 
 
 
Performance status 
(ECOG) 
 X 
X 
 
 
 
X 
 
X 
 
X 
 
ECOG = Eastern 
Cooperative 
Oncology Group 
Prior/concomitant 
medication 
Continuously throughout the study period (and within 21 days before first IMP administration) 
 
 
Isatuximab 
administration and 
administration data 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Pomalidomidei 
 
D1 to D21 
D1 to D21 
D1 to D21 
 
 
 
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Evaluation/ 
Procedurea 
Screening/Baseline 
Cycle 1ee 
Cycle 2ee 
Subsequent 
cyclesee 
End of treatment 
Follow-upd 
Notes 
Days -28 to -1 
D1c 
D8 
D15c 
D22 
D1c 
D15c 
D1c 
D15c 
D30 (±5) after last 
study treatment 
administration or 
before the next 
therapy 
 
D = Day 
Dexamethasone 
(before isatuximab 
when co-administered) i  
 
D1, 8, 15, and 22 
D1, 8, 15, 
and 22 
D1, 8, 15, and 22 
 
 
 
Patient expectations 
Questionnaire (PEQ)j 
 
X 
 
 
 
Patient experience and 
satisfaction 
Questionnaire (PESQ) 
and Patient's 
assessment of 
treatment (PAT) 
Questionnaire k 
 
 
X 
X 
X 
X 
X 
on D1 of 
Cycles 3 
and 4  
C5 up to 
EOT 
X 
 
 
HRUPQ questionnaire 
 
X 
X 
X 
X 
X 
 
 
X 
X 
  
 
EORTC QLQ-C30 and 
QLQ-MY20, EQ-5D-5L 
Questionnaires 
 
X 
 
 
 
X 
 
 
X 
X 
  
 
IADL and ADL 
questionnaires 
 
X 
 
 
 
 
 
 
 
 
 
 
Physical examinationl 
X 
X 
 
 
 
X 
 
X 
 
X 
 
 
Weight (height at 
baseline)m  
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
Vital signs (HR, 
Temperature, RR or 
SPO2, BP)n  
X 
X 
X 
 
 
 
Hematologyo 
X 
X 
X 
X 
X 
X 
X 
X 
up to C5  
X 
 
 
Serum chemistryp 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
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Evaluation/ 
Procedurea 
Screening/Baseline 
Cycle 1ee 
Cycle 2ee 
Subsequent 
cyclesee 
End of treatment 
Follow-upd 
Notes 
Days -28 to -1 
D1c 
D8 
D15c 
D22 
D1c 
D15c 
D1c 
D15c 
D30 (±5) after last 
study treatment 
administration or 
before the next 
therapy 
 
D = Day 
PT/INR, PTT 
X 
As clinically indicated 
X 
 
PT/INR = 
prothrombin 
time/international 
normalized ratio 
PTT = partial 
thromboplastin time 
Urinalysisq 
X 
As clinically indicated 
X 
 
 
Thyroid function tests 
(TSH, and free T4)r  
X 
Once a year until EOT or as clinically indicated 
X 
 
TSH = thyroid-
stimulating 
hormone 
EOT = end of 
treatment 
Antibody screening 
tests 
X 
 
 
 
 
X 
 
 
 
 
 
Antibody screening 
test: Blood typing 
and complete blood 
phenotyping and 
antibody screening 
Pregnancy testing 
[FCBP]t  
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
FCBP = female of 
childbearing 
potential 
AE/SAE reportingu 
Continuously through the study periodv 
X 
(related AEs, all 
ongoing SAEs, 
second primary 
malignancy) 
AE = adverse event 
SAE = serious 
adverse event 
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Evaluation/ 
Procedurea 
Screening/Baseline 
Cycle 1ee 
Cycle 2ee 
Subsequent 
cyclesee 
End of treatment 
Follow-upd 
Notes 
Days -28 to -1 
D1c 
D8 
D15c 
D22 
D1c 
D15c 
D1c 
D15c 
D30 (±5) after last 
study treatment 
administration or 
before the next 
therapy 
 
D = Day 
Local tolerability at 
injection site after 
isatuximab SC 
administration– 
participant assessment 
using diaryw 
 
Continuously throughout up to Cycle 9/D1 
 
 
Local tolerability at 
injection site after 
isatuximab SC 
administration – 
investigator 
assessmentx 
 
Continuously throughout the study period up to EOT visit 
 
EOT = end of 
treatment 
12 lead ECG 
X 
As clinically indicated 
X 
 
ECG = 
electrocardiogram 
Extramedullary 
disease 
(plasmacytoma)y  
X 
If present at baseline 
if EOT without 
progressive 
disease 
EOT = end of 
treatment 
 
FAMT= Further 
Anti-Myeloma 
Therapy 
Bone diseasez 
X 
As clinically indicated 
if EOT without 
progressive 
disease 
FAMT= Further 
Anti-Myeloma 
Therapy 
Bone marrow (BM) 
aspiration/biopsy for 
determination of % of 
plasma cells (local 
data)aa  
≤21 days 
As clinically indicated 
 
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Evaluation/ 
Procedurea 
Screening/Baseline 
Cycle 1ee 
Cycle 2ee 
Subsequent 
cyclesee 
End of treatment 
Follow-upd 
Notes 
Days -28 to -1 
D1c 
D8 
D15c 
D22 
D1c 
D15c 
D1c 
D15c 
D30 (±5) after last 
study treatment 
administration or 
before the next 
therapy 
 
D = Day 
Myeloma-specific Lab 
tests (centralized)bb  
X 
X 
 
 
 
X 
 
X 
 
X 
If EOT without 
progressive 
disease 
assessment 
 
Bone marrow 
aspiration for 
cytogenetics 
assessment (central 
data)cc  
X 
 
 
Bone marrow 
aspiration for MRD 
assessment (central 
data)dd 
X 
At time of confirmed CR or VGPR, 12 months after C1D1 and 12 months after first MRD negativity  
CR = complete 
response 
MRD = minimal 
residual disease 
VGPR = very good 
partial response 
Bone marrow 
aspiration for genomic 
and genetic profiling 
(central data) 
X 
 
At time of 
progression 
 
PK (isatuximab)  
 
See PK/ADA Flowchart (Table 2 and Table 3) 
 
Immunogenicity (ADA)  
 
See PK/ADA Flowchart (Table 2 and Table 3) 
 
Other 
Follicle-stimulating hormone and estradiol (as needed in women of non childbearing potential only) 
 
Abbreviations: ADA = Anti-Drug Antibody; AEs = Adverse events; AESI = Adverse events of special interest; ALT = Alanine Aminotransferase; ANC = Absolute Neutrophil Count; anti-HBc = antibody to hepatitis B core 
antigen; anti-HBs = antibody to hepatitis B surface antigen; AP = Alkaline Phosphatase; AST = Aspartate aminotransferase; BMA = Bone marrow aspiration; BP= blood pressure; BUN = Blood urea nitrogen; 
C = Cycle; CBC = Complete blood count; CR = Complete response; CD38 = Cluster of differentiation 38; CT = Computed tomography; D = Day; DNA= deoxyribonucleic acid; ECOG = Eastern Cooperative Oncology 
Group; eCRF = electronic case report form; EORTC QLQ-c30= European Organization for Research and Treatment of Cancer Quality of Life Questionnaire; EORTC QLQ-MY20 = Quality of Life Multiple Myeloma 
module; EQ-5D-5L= The European Quality of Life Group Questionnaire with 5 Dimensions and 5 Levels; EOT= end-of-treatment; FAMT= Further Anti-Myeloma Therapy; FCBP = Female of childbearing potential; FPG 
= Fasting plasma glucose; FISH= fluorescent in Situ Hybridization; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis C virus; HRUPQ = healthcare resource utilization and productivity 
questionnaire; IAT = Indirect antiglobulin test; IFE= immunofixation; IgM = immunoglobulin M; IMWG= International Myeloma Working Group; INR = International Normalized Ratio; IR = Infusion reactions; 
IRT= Interactive Response Technology; ISR = Injection site reactions; IV = Intravenous; LDH= Lactate dehydrogenase; MDRD = Modification of Diet in Renal Disease; MRD = Minimal residual disease; MM = Multiple 
myeloma; MRI = Magnetic resonance imaging; PCR = polymerase chain reaction; PD= Progressive Disease; PAT = patient's assessment of treatment; PEQ = patient expectations questionnaire; PEQ-BL = patient 
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expectations questionnaire at baseline; PESQ = patient experience and satisfaction questionnaire; PET = Positron emission tomography; PK = Pharmacokinetic; PR = Partial response; PS = Performance status; 
PT = Prothrombin time; PTT = partial thromboplastin time; RNA= ribonucleic acid; RR= respiratory rate; sCR = stringent complete response; SC=Subcutaneous; SGOT = Serum glutamate-oxalate transferase; 
SGPT = Serum glutamate-pyruvate transferase; sFLC = Serum free light chain; SAE= serious adverse event; SPEP = Serum M-protein immunoelectrophoresis; TSH = Thyroid stimulating hormone; VGPR = Very 
good partial response; UPEP = Urine M-protein immunoelectrophoresis. 
a Evaluation: Assessments to be performed prior to study treatment/premedication administration unless otherwise indicated. Results should be reviewed by the Investigator. 
b Randomization: To take place once the consented participant has completed all the necessary screening procedures and is deemed eligible (based on assessments including myeloma specific results from 
central laboratory (see footnote “bb”) and hematology/biochemistry local laboratory results) for randomization by the investigator or designee. All eligible participants must be randomized by contacting 
the Interactive Response Technology (IRT). Every effort should be made to start treatment within 3 working days of randomization.  
c Day 1 and Day 15 (28-day cycle [±3 day]): Day 1 of Cycle 1 refers to the day the participants receive the first dose of study treatment administration. Day 1 of Cycle 2 corresponds to D29 of Cycle 1. Day 1 of 
each subsequent cycle corresponds to Day 29 (±3 day) of the previous cycle. Day 8 and Day 22 window (±1 day).  
d Follow-up: Participants who discontinue study treatment due to disease progression will be followed every 3 months (12 weeks) (±7 days after last study treatment administration) for further antimyeloma therapy, 
second primary malignancies, PFS2, and survival until death, or final OS analysis cut-off date, whichever occurs first. Participants who discontinue the study treatment prior to documentation of PD will be followed 
up every 4 weeks until disease progression (even for participants who would initiate further antimyeloma therapy without PD), and then after confirmation of disease progression, every 3 months (12 weeks) for 
further anti-myeloma therapies, secondary malignancies, PFS2, and survival, until death or the final OS analysis cut-off date, whichever comes first. The information on the further antimyeloma therapy will consist 
of drug name, start and stop date, best overall response, and date of progressive disease. 
e Informed consent: Informed consent should be signed before any study-specific procedures. It can be signed more than 28 days prior to inclusion. Screening time indicates in which time frame exams used to 
support eligibility have to be done prior to inclusion. 
f 
Contraceptive counseling: Contraceptive counseling is to be done before initiation of each cycle prior to pomalidomide dispensing. 
g Hepatitis B and C and HIV serologies: Screening with serological tests for hepatitis B, and C to be done prior to randomization/enrollment (HBsAg, anti-HBs, anti-HBc [total and IgM], anti-HCV, HCV RNA level) if 
not performed within 1 year. Participants with anti-HBc positive (HBsAg positive participants being ineligible), HBV DNA testing by PCR will also be done at baseline. In case HBV vaccination will be started before 
first study treatment administration, anti-HBs should be monitored at 1, 2 and 3 months after end of vaccination. HIV serology will be tested at screening only for participants of countries where required as per local 
regulations. 
h Demography: Includes age, gender, and race. Medical/surgical history: Includes relevant history of previous/associated pathologies other than multiple myeloma (MM) including smoking status. Disease 
history: Includes date of initial diagnosis, stage and extent of the disease, previous MM anti-tumor therapy (type and response to), disease status at inclusion, time on treatment, and duration of response. 
i 
Pomalidomide/Dexamethasone administration data: Participants will be asked to maintain a diary to record the doses of pomalidomide/dexamethasone (except those administered by the study 
nurse/Investigator). 
j 
Patient Expectations Questionnaire (PEQ): Patient Expectations Questionnaire (PEQ-BL) will be completed on Cycle 1/D1 by the participant at the site prior to discussing their health/disease status, and prior to 
study treatment administration or other study related procedures. The time estimated to complete this questionnaire is 5 minutes (Appendix 15, Section 10.16).  
k Patient experience and satisfaction Questionnaire (PESQ) and Patient's assessment of treatment (PAT) Questionnaire: Patient Experience and Satisfaction Questionnaire-Follow-Up (PESQ-FU) will be 
completed on Cycle 1/D8, D15, D22, Cycle 2/D1, D15, Cycle 3/D1, Cycle 4/D1 and on Day 15 from Cycle 5 onwards. The overall patient experience and satisfaction questionnaire-end of treatment (PESQ-EOT) 
and PAT will be completed at the EOT visit by the participant at the site prior to discussing their health/disease status, or other study-related procedures. The time estimated to complete this questionnaire is 5 to 
10 minutes (Appendix 15, Section 10.16).  
l 
Physical examination: To be performed at screening, prior to study treatment administration on Day 1 of Cycle 1, and then on Day 1 of each subsequent cycle (a flexibility of a maximum of 24 hours before IMP 
administration is allowed), and at the EOT visit. Consists of examination of major body systems including neurological, digestive, extramedullary myeloma localizations, respiratory, hepatomegaly, splenomegaly, 
and lymphadenopathy.  
m Weight: Weight will be assessed for participants in both arms on screening, at each administration of Cycle 1 and 2, at D1 of subsequent cycles, and at EOT. 
n Vital signs: Heart rate, temperature, respiratory rate (or pulse oximetry for at-home administration), and blood pressure to be assessed pre-administration, one hour after start of first administration and, for the 
IV arm only, 30 minutes after the start of the subsequent infusions. On site, vital signs are to be assessed at end of infusion/injection up to Cycle 5, and as clinically indicated. If at-home administration, vital signs 
are to be taken systematically just before and at the end of injection. 
o Hematology: Complete blood count (CBC) to be performed weekly at Cycle 1, at D1 and D15 from Cycle 2 to Cycle 5 and at D1 only from Cycle 6 onwards, and to be reviewed by the Investigator within 1 working 
day before the day of dosing. If Grade 4 neutropenia is observed, the assessment of neutrophil count will be done every 2 to 3 days until ANC ≥0.5  109/L and at least weekly thereafter until ANC ≥1.0  109/L; 
platelet count can be assessed weekly or until ≥50 000/mm3. 
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p Serum chemistry: To be performed and reviewed by the Investigator within 1 working day before the day of dosing. Chemistry includes: Fasting glucose, albumin, total protein, aspartate aminotransferase (AST) 
(serum glutamate-oxalate transferase [SGOT]), alanine aminotransferase (ALT) (serum glutamate-pyruvate transferase [SGPT]), bilirubin (total and direct), alkaline phosphatase (AP), lactate dehydrogenase 
(LDH), sodium, potassium, chloride, venous bicarbonate/carbon dioxide (if assessed only on arterial blood, should be done only if clinically indicated), total calcium, magnesium, phosphate, uric acid, urea/blood 
urea nitrogen (BUN), serum creatinine, and estimated glomerular filtration rate (MDRD equation – Appendix 2 [Section 10.2]). 
q Urinalysis: Quantitative or alternatively semi-quantitative urinalysis at baseline (including red blood cells, protein, glucose, pH, ketones, bilirubin, and leukocytes) , and qualitative urinalysis (dipstick) after start of 
study treatment (including blood, protein, glucose, pH, ketones, bilirubin, and leukocytes).  
r 
Thyroid function tests (Thyroid stimulating hormone [TSH], and free T4): To be performed at baseline and once a year thereafter until EOT or as clinically indicated, and at EOT. Free T3 to be done only if 
clinically relevant. 
s Antibody screening test: Blood typing and complete blood phenotyping (C,c; E,e; Kell. Kidd; Duffy; S, s is recommended, if not available follow site’s standard) if not already done, and antibody screening 
(indirect Coomb’s test, indirect antiglobulin test [IAT]) to be obtained prior to Cycle 1/D1 study treatment administration. The IAT to be repeated at Cycle 2/D1; if the test is not performed at this visit, it can be done 
at the next blood sampling. Results of IAT will be recorded in the eCRF, including those performed prior to any red blood cells transfusion during study treatment. Red blood cells transfusions are to be recorded in 
the eCRF. During the study treatment the transfusion service should follow the recommendations issued in the AABB bulletin in case of red blood cells transfusion is needed. The web link to the AABB bulletin will 
be indicated on the study participant card (Appendix 13, Section 10.14]). Blood type card will be kept by the participant with the study card and the blood bank needs to be informed that the participant is receiving 
a treatment with an anti-CD38 and a potential interference with the indirect Coombs test is possible.  
t 
FCBP: A female of childbearing potential (FCBP) is a sexually mature woman who: 1) has achieved menarche at some time point, 2) has not undergone a hysterectomy or bilateral oophorectomy and bilateral 
salpingectomy; or 3) has not been naturally postmenopausal for at least 24 consecutive months. Serum or highly sensitive urine pregnancy tests for FCBP must be performed within 10 to 14 days and again within 
24 hours of initiation of study treatment. Repeat pregnancy test every week for the first 4 weeks and then every 28-days while on therapy and during interruptions in therapy (or every 14 days in case of irregular 
menstrual cycles) and for at least 28 days after discontinuation of pomalidomide (14 and 28 days in case of irregular menstrual cycles), and monthly up to 5 months following isatuximab discontinuation, whichever 
occurs last. All participants must be counseled before initiation of each cycle prior to pomalidomide dispensing about pregnancy precautions, risks of fetal exposure and other risks. All participants enrolled into this 
study, must be registered in and must comply with all requirements of the Global Pregnancy Prevention Plan (GPPP) (if pomalidomide was provided by Sponsor) or the country specific risk management plan (if 
commercial pomalidomide is used).  
u Adverse event/Serious AE reporting: 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 any study treatment. After the 30-day follow-up, all ongoing related AEs or new related AEs, and all ongoing SAEs regardless of causal relationship are to be followed up to resolution or 
stabilization. In addition, second primary malignancies newly diagnosed during the entire study, including the post-treatment period, should be reported as AEs or SAEs, regardless of their causal relationship and 
followed up until resolution or stabilization. Severity will be graded according to NCI-CTCAE v5.0. 
v Participants will stay at the site after isatuximab administration for at least 4 hours on Cycle 1/D1 in both SC and IV arms,1 hour after the end of injection for the following Cycle 1 administrations (SC arm only) and 
per investigator judgement subsequently, if not longer for any other reason (eg, PK sampling) and will be monitored closely for IRs and Injection site reactions (ISRs). The HCP will stay at least 30 minutes with 
the participant after the first at-home administration, and per clinical judgement for the subsequent at-home administrations. 
w Local tolerability at injection site after isatuximab SC administration– patient assessment using diary: A participant diary will be used in order to document any type of injection site reaction beyond clinic 
stay. Participants will fill out the questionnaire at home up to Cycle 9/Day 1. These data will support the Investigator to assess retrospectively the local tolerability at injection site and report ISRs, if needed 
(Section 10.16).  
x Local tolerability at injection site after isatuximab SC administration – Investigator assessment: Local tolerability at injection site will be assessed during clinical stay using eCRF hourly (relative to the start 
of administration) for duration of 4 hours at Cycle 1/D1, 1 hour after the end of injection for the following Cycle 1 administrations and at end of injection from Cycle 2 onwards. In case of at-home administration, for 
the first isatuximab injection performed at-home, an additional assessment should be performed 30 min after the end of the injection. Any swelling (unless it lasts longer than 24 hours) as a result of the injection of 
the isatuximab solution volume is not to be reported as an AE/adverse event of special interest (AESI). 
y Soft tissue plasmacytoma assessment (extramedullary disease OR paramedullary disease with a soft tissue lesion of diameter ≥2 cm) 
• 
If known soft tissue plasmacytoma at baseline, CT scan, PET-CT scan or MRI is to be done at baseline, repeated every 12 weeks (±1 week) until progressive disease (PD) from C1D1 (even for participants 
who would initiate further anti-myeloma therapy without PD), and if clinically indicated. From two years after randomization, the radiological assessment will be done every 6 months (±1 month). Assessment 
to be done until PD (even if further anti-myeloma therapy is started without PD as per protocol), or final cut-off date, whichever occurs first.  
• 
If suspected soft tissue plasmacytoma at baseline, CT scan, PET-CT scan or MRI is to be done at baseline and if plasmacytoma confirmed on the exam to be repeated as indicated above. 
• 
To be done in case of suspicion of progression or if clinically indicated in a participant with no previous positive image for soft tissue plasmacytoma.  
• 
The bone component of paramedullary disease with a soft tissue lesion of diameter ≥2 cm will not be used for disease response assessment as per IMWG. 
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• 
Paramedullary (paraskeletal) plasmacytoma (bone plasmacytoma extending beyond the bone cortex into the surrounding tissues) with soft tissue lesions of diameter <2cm will be collected but will not be 
used for disease response assessment as per IMWG. No follow-up with repeated imaging is needed, except if clinically indicated. 
• 
PET-CT should be the preferred option whenever possible. 
• 
Note: For bone lesion assessment and soft tissue plasmacytoma, the same modality (low-dose whole body CT scan; CT scan, PET-CT scan, or MRI) should be used throughout the study for each individual 
participant when radiological follow-up is needed.  
• 
All imagings will be sent for central review. Intravenous contrast is recommended if not medically contra-indicated. Participants who have contra-indication to CT scan with IV contrast may have MRI exams 
performed instead. 
z Bone disease (lytic or focal, depending on the method): Whole-body low-dose CT scan, PET-CT scan or MRI at baseline (within 28 days prior to randomization), once a year (±1 month) from C1D1, and 
anytime during the study if clinically indicated until PD (even if further anti-myeloma therapy is started without PD as per protocol), or final cut-off date, whichever occurs first. PET-CT should be the preferred 
imaging modality whenever possible. 
aa Bone marrow aspiration/biopsy for determination of % of plasma cells (local): Bone marrow aspiration (BMA) or biopsy is required at screening/baseline (within 21 days prior to study treatment 
administration) for determination of % of plasma cells. Repeat bone marrow aspirate or biopsy to confirm CR or stringent complete response (sCR), if CR or sCR is suspected. 
bb Myeloma-specific laboratory tests (centralized): 
• 
β2-microglobulin at baseline only. 
• 
Serum M-protein immunoelectrophoresis (SPEP) and immunofixation: SPEP to be performed at screening, C1D1 (predose, baseline for response assessment), prior to each cycle thereafter and at end of 
treatment (if last tests were >4 weeks or if disease progression was not confirmed on the last test). After baseline, immunofixation (IFE) to be done if SPEP shows no measurable monoclonal protein. For 
subjects with suspected isatuximab interference on serum IFE, the SEBIA HYDRASHIFT 2/4 isatuximab IFE test will be performed to specifically measure the endogenous M-protein. Subjects that meet all 
other IMWG criteria for CR, and for whom negative immunofixation is confirmed after using the HYDRASHIFT isatuximab test, will be considered complete responders. This will define the final CR rate 
as per IMWG criteria. 
• 
Urine M-protein (24-hour urine) immunoelectrophoresis (UPEP) and immunofixation: UPEP to be performed at screening, C1D1 (predose, baseline for response assessment), prior to each cycle thereafter 
and at end of treatment (if last tests were >4 weeks or if disease progression was not confirmed on the last test). If urine M-protein is negative (UPEP and IF) at baseline, UPEP assessment is to be 
repeated every 3 cycles only (Cycle 4, Cycle 7, Cycle 10, etc), and to confirm CR and Very good partial response (VGPR) on blood laboratory parameters. After baseline, immunofixation to be done if UPEP 
shows no measurable monoclonal protein in participants whose disease is evaluable in urine. 
• 
If urine M-protein is measurable or detectable or IF is positive at Cycle 1 Day 1, urine M-protein assessment should be done prior to study treatment administration in all subsequent cycles and at EOT (if 
last tests were >4 weeks or if disease progression was not confirmed on the last test).  
• 
If urine M-protein is negative (UPEP and IF) at screening and Cycle 1 Day 1, this assessment is to be repeated every 3 cycles only (Cycle 4, Cycle 7, Cycle 10, etc), and to confirm CR and VGPR on blood 
laboratory parameters. 
• 
After Cycle 1 Day 1, urine immunofixation is to be done only if urine M-protein is not detected in UPEP. 
• 
Serum free light chain (sFLC) (quantification and ratio involved/uninvolved): To be performed at screening, C1D1 (predose) and prior to each cycle thereafter and at EOT (if last tests were >4 weeks or if 
disease progression was not confirmed on the last test). 
• 
Immunoglobulins (IgG, IgA, IgM, IgD, and IgE): To be performed at screening, baseline and prior to each cycle thereafter and at EOT (if last tests were >4 weeks or if disease progression was not confirmed 
on the last test), (after baseline, IgD or IgE only if the heavy chain component of the disease is known to be E or D). 
• 
Additional blood samples will be collected at all time points at which M-protein is assessed from Cycle 1 onwards, to evaluate new M-protein measurement methods for disease response assessment (such 
as mass spectrometry), (central laboratory).  
• 
For participants who discontinue therapy for reasons other than progression, MM labs will be repeated every month during the follow-up period until progression (even if further anti-myeloma therapy is started 
without PD as per protocol). 
cc Bone marrow aspiration for cytogenetics assessment (central): At screening, bone marrow aspirate will be collected for FISH (including, but may not be limited to, del[17p], t[4;14], t[14;16]), 1q21+ analyses in 
central laboratory. 
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dd Bone marrow aspiration for Minimal Residual Disease (MRD) assessment: To be performed at screening and at the time of maximum confirmed response of either CR or VGPR. For participants with CR 
without previous documentation of VGPR, bone marrow for MRD assessment will be collected at time of confirmation of CR (ie, at the second time point showing CR). For participants with VGPR, when VGPR is 
confirmed, a first bone marrow aspirate for MRD assessment will be collected as per investigator judgement based on kinetic of M protein decrease and/or if a plateau phase is reached (as an example, plateau is 
reached when there is a variation of less than 20% over 12 weeks). Bone marrow will also be collected:  
• 
For participants in VGPR/CR at a fixed timepoint of 12 months after C1D1 (could not be collected if another BMA was collected in the previous 2 months period. 
• 
For participants in VGPR/CR having achieved MRD negativity, 12 months after first MRD negativity. 
ee Within a cycle, the treatment window is ±1 day for each of every week (QW) IMP administrations and ±3 days for each of every 2 weeks (Q2W) IMP administrations. Between cycles, the treatment window is 
±3 days if 4-week cycle. 
Table 2 - PK and ADA flowchart - Arm SC  
Procedure 
Intervention period 
FUP 
C1 
C2 to C5 
C6, C7 
and C8 
C9 then every 
3 cycles (C9, 
C12, C15…)  
D1 
D2 
D5 
D8 
D15 
D22 
D23 
D26 
D1 
D15 
D1 
D1 
90 (±7) days 
after 
last study 
treatment 
administration 
Isatuximab 
SC administration 
X 
 
 
 
X 
X 
X 
 
 
 
X 
X 
X 
X 
RNT (h) Ref. SOI 
SOIa 
8 h 
24 h 
96 h 
SOIa 
SOIa 
SOIa 
6 h 
24h 
96h 
SOIa 
SOIa 
SOIa 
SOIa 
Time window 
(-4h, SOI) 
±1 h 
±5 h 
±5 h 
(-4h, SOI) 
(-4h, SOI) 
(-4h, SOI) ±1 h 
±5 h 
±5 h 
(-4h, SOI) 
(-4h, SOI) 
(-4h, SOI) 
(-4h, SOI) 
PK sample IDb 
P00 
P01 
P02 
P03 
P04 
P05 
P06 
P07 
P08 
P09 
P00 
P01 
P00 
P00 
PF00 
ADA Sample IDb 
AB00 
 
 
 
 
AB01 
 
 
 
 
AB00 
 
AB00 
AB00 
ABF00 
Abbreviations: ADA = Anti-Drug Antibody; C = Cycle; D = Day; P = Plasma; AB = Antibody in Plasma; FUP = Follow-up period; PK = Pharmacokinetic; RNT = Relative Nominal time; SC = subcutaneous; SOI = Start of 
Injection. 
a Samples collected strictly before start of injection. 
b PK and ADA samples will be samples as per PK and ADA flowchart or up to the primary cut-off date, whichever comes first.  
Note: The sampling time points for PK and ADA may be reduced during the course of the study based on the updated knowledge of isatuximab behavior, upon notification from the Sponsor. 
 
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Table 3 - PK and ADA flowchart - Arm IV  
 
Procedure 
Intervention period 
FUP 
C1 
C2 
C3 
C4 to C5 
C6, C7 
and C8 
C9 then 
every 
3 cycles 
(C9, C12, 
C15…) 
D1 
D3 
D8 
D15 
D22 
D1 
D15 
D1 
D15 
D1 
D15 
D1 
D1 
90 (±7) days 
after 
last study 
treatment 
administration 
Isatuximab 
IV 
administration X---------X 
 
 
X 
X---------X 
X 
X---------X 
X 
X 
X 
X---------X 
X 
X 
X 
RNT (h) Ref. 
SOI 
SOIa EOIc EOI+1 h 
48h 
SOIa 
SOIa 
EOIc 
SOIa SOIa EOIc SOIa SOIa 
SOIa 
SOIa 
EOIc 
SOIa 
SOIa 
SOIa 
Time window 
(-4h, 
SOI) 
±10 
min ±10 min ±24 h 
(-4h, 
SOI) 
(-4h, 
SOI) 
±10 min (-4h, 
SOI) 
(-4h, 
SOI) 
±10 
min 
(-4h, 
SOI) 
(-4h, 
SOI) 
(-4h, 
SOI) 
(-4h, 
SOI) 
±10 
min 
(-4h, 
SOI) 
(-4h, SOI) 
(-4h, 
SOI) 
PK sample IDb P00 
P01 
P02 
P03 
P04 
P05 
P06 
P07 
P00 P01 
P02 
P00 
P01 
P00 
P01 
P02 
P00 
P00 
PF00 
ADA  
Sample IDb 
AB00 
 
 
 
 
AB01 
 
 
AB00 
 
 
AB00 
 
AB00 
 
 
AB00 
AB00 
ABF00 
Abbreviations: ADA = Anti-Drug Antibody; C = Cycle; D = Day; EOI= End of Infusion; P = Plasma; FUP = Follow-up period; AB = Antibody in plasma; PK = Pharmacokinetic; RNT = Relative nominal time; SOI = Start 
of infusion. 
a Samples collected strictly before start of infusion. 
b PK and ADA samples will be samples as per PK and ADA flowchart or up to the primary cut-off date, whichever comes first.  
c Actual EOI sample should be taken when the pump beeps (end of fusion) after flush.  
Note: The sampling time points for PK and ADA may be reduced during the course of the study based on the updated knowledge of isatuximab behavior, upon notification from the Sponsor. 
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2 
INTRODUCTION  
2.1 
STUDY RATIONALE  
Isatuximab has so far been administered primarily by IV route. Based on clinical efficacy, safety, 
PK simulations, and PK/pharmacodynamic (PDy) analyses, the dose selected for isatuximab IV in 
combination with approved MM therapies is 10 mg/kg QW  4 administrations followed by 
10 mg/kg Q2W. 
The combination of IV isatuximab with pomalidomide and dexamethasone has demonstrated 
clinical efficacy with a statistically significant and clinically meaningful improvement in PFS, 
as well as an acceptable and manageable safety profile in the ICARIA-MM (NCT02990338) 
Phase 3 trial (2). In 2020, FDA and EMA approved this combination for the treatment of adults 
with RRMM who have received at least two prior therapies including lenalidomide and a PI. 
A trend in OS benefit with approximately 7 months improvement in median OS was shown in 
an updated analysis (3). 
Isatuximab IV administration is approved in most countries with the fixed-volume infusion 
method allowing the IV infusion to be given during 75 minutes from the 3rd infusion onwards. 
A SC administration within several minutes allows for a shorter duration of administration 
compared to the currently approved IV route, optimizing the convenience of administration and 
minimizing the time the participant spent in healthcare facility, which is particularly relevant in 
the context of the current COVID-19 pandemic and in line with recommendations of 
hematology/myeloma societies (4, 5, 6). The SC administration of isatuximab is also intended to: 
• Decrease the incidence of infusion-reactions due to the slower absorption of SC 
administration compared to IV. 
• Reduce the administration volume (10 mL with Isa-SC versus 250 mL with Isa- IV) which 
may be clinically relevant in participants with cardiac or renal impairment. 
• Improve long term treatment adherence to maintain optimal disease control. 
• Reduce health resource utilization and thus overall healthcare cost. 
Aiming to enhance comfort and quality of life of the participants, SC administration of isatuximab 
is considered as a desirable alternative to the approved IV isatuximab administration, in particular 
for the long duration of treatment required in MM. 
Among the approved treatments for MM, Velcade (bortezomib) is approved for administration by 
IV as well as SC route. More recently, in 2020, FDA and EMA approved the combination of 
daratumumab and hyaluronidase-fihj (Darzalex-Faspro) administered subcutaneously for both 
newly diagnosed and RRMM participants. Approval of Darzalex-Faspro was based on 
the evidence from the Phase 3 COLUMBA Study (MMY3012) and the supportive Phase 2 
PLEIADES Study (MMY2040) (7, 8). Data from COLUMBA study demonstrated that 
Darzalex-Faspro efficacy and PK was non-inferior to IV daratumumab, and both studies 
demonstrated that Darzalex-Faspro resulted in fewer IRs and offered a reduced treatment burden. 
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In the COLUMBA trial, a greater satisfaction of the participants with their cancer therapy in 
the DARA SC arm was also suggested, compared to those in the DARA IV group (9). 
Device-mediated SC administration can offer a number of benefits to both HCPs and patients, 
including controlled delivery and simplified user interface, and could ultimately be used by 
a qualified HCP in the outpatient setting or at patient’s home. 
Triplet regimens should be used as the standard therapy for patients with multiple myeloma 
(10, 11). A triplet is defined as a regimen combining two novel agents (PIs, immunomodulatory 
drugs, or monoclonal antibodies) with a steroid (12). At first relapse, prior therapies should be 
taken into consideration when selecting treatment and a monoclonal antibody-based regimen in 
combination with an immunomodulatory drug and/or PI should be considered (12, 13). In 
the 2021 IMWG guidelines, pomalidomide plus bortezomib and dexamethasone is one of 
the 3 preferred options for lenalidomide-refractory patients at first relapse, while several 
pomalidomide-based regimens, including combinations with carfilzomib, daratumumab or 
ixazomib are considered as other options (13). The increasing use of lenalidomide in frontline and 
thus the increased prior exposure to lenalidomide and PI at the moment of first relapse, with 
the standard of care shift of pomalidomide use towards second line, especially in 
lenalidomide-refractory patients, leads to the proposal of a study population of patients with 
RRMM who have received at least one prior line of therapy.  
In the EQUULEUS MMY1001 trial, daratumumab combined with pomalidomide and 
dexamethasone was administered in participants with at least two prior lines of therapy including 
lenalidomide and bortezomib showing an ORR of 60% (14). In the APOLLO trial, the same 
combination administered with SC daratumumab in participants with at least one prior line of 
therapy including lenalidomide and a PI resulted in an ORR of 69% without any unexpected new 
safety signals (15). Isatuximab, in combination with carfilzomib and dexamethasone, has 
demonstrated efficacy and safety in MM participants who have received at least one prior line of 
therapy in the Phase 3 IKEMA trial (16). A similar efficacy and safety profile for the isatuximab, 
pomalidomide and dexamethasone combination is expected in participants at first relapse 
compared to second relapse and beyond. 
The EFC15951 Study is proposed to evaluate SC administration of isatuximab versus IV, in 
combination with pomalidomide and dexamethasone using an Investigational device injector in 
participants with MM who have received at least one prior line of therapy including lenalidomide 
and a PI. 
2.2 
BACKGROUND  
2.2.1 Isatuximab description  
Isatuximab is a naked IgG1, mAb that selectively binds to the human cell surface antigen 
molecule classified as CD38. Cluster of differentiation 38 is expressed in a number of 
hematological malignancies from B-lymphocyte, T-lymphocyte, and myeloid origin and is 
expressed in 98% of MM patients. 
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The biological mechanisms by which isatuximab can induce the killing of CD38-positive tumors 
that have been demonstrated in tumor cell lines are: 
1. Antibody-dependent cellular-mediated cytotoxicity. 
2. Antibody-dependent cellular phagocytosis. 
3. Complement-dependent cytotoxicity. 
4. Induction of apoptosis (proapoptosis). 
5. Activation of natural killer (NK) cells. 
No significant cytokine release, cellular activation, or depletion was induced by isatuximab 
in-vitro assays with normal human peripheral blood mononuclear cells, despite some induction of 
apoptosis in purified NK cells. 
2.2.2 Nonclinical data  
In vivo antitumor activity of isatuximab was demonstrated in several implanted SC or injected 
IV implanted hematological tumor models. As a single agent, antitumor activity was observed in 
MM, non-Hodgkin’s lymphoma, and acute lymphocytic leukemia tumor models. 
In ex vivo primary patient tumor samples, isatuximab has demonstrated a direct proapoptotic 
effect in MM samples and acute myeloid leukemia samples. 
In Good Laboratory Practice (GLP) cross-reactivity studies with normal human tissues, 
isatuximab was bound specifically to lymphoid tissues (spleen, thymus, lymph node, and tonsil), 
BM, pituitary gland (endothelial cells), prostate gland (glandular epithelial cells), and infiltrating 
or resident round cells (macrophages and/or lymphocytes) of the innate immune system including 
Kupffer cells in the liver. In preliminary non-GLP tissue cross-reactivity studies using a different 
isatuximab batch and different mAb concentrations, additional staining had also been observed in 
the brain (astrocytes) and lung (bronchial epithelium). Staining of all nonlymphoid tissue 
elements was interpreted as evidence of cross-reactivity that may possibly indicate potential 
unintended off-target sites. 
Isatuximab is specific for human CD38 protein. In the absence of a relevant animal species for 
toxicity testing, only a repeat-dose IV (once weekly for 3 weeks) study was conducted in 
cynomolgus monkeys (a non-pharmacologically reactive species) in order to evaluate potential 
non-targeted and non-specific general toxicity. In this cynomolgus monkey toxicity study, no 
compound-related changes were noted in any parameters evaluated and the no-observed adverse 
effect level was 100 mg/kg/week (highest dose tested). 
The local tolerance of isatuximab after a single IV injection (intended clinical route), as well 
as after single intra-arterial, intramuscular, SC, or paravenous injection (unintended routes 
that might occur accidentally), was assessed in female New Zealand White rabbits 
(a non-pharmacologically reactive species). Isatuximab produced no compound-related 
clinical signs or body weight changes and there were no compound-related macroscopic or 
microscopic findings at the injection sites for any route of administration at concentrations up to 
5 mg/mL. In addition, isatuximab did not produce compound-related macroscopic or microscopic 
changes at the injection sites following once weekly IV infusion for 3 weeks in cynomolgus 
monkeys up to 20 mg/mL (maximum concentration tested). 
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The local tolerance of isatuximab in its clinical SC formulation has been tested in female minipigs 
(a nonpharmacologically reactive species). The single SC infusion of 12.9 mL isatuximab 
(140 mg/mL, SC formulation) to minipigs equivalent to a total dose of approximately 
1800 mg/minipig at flow rates of 0.5, 1, and 2 mL/min was overall clinically well tolerated. 
Erythema and hemorrhage at injection sites were noted on the day of infusion, only, and were 
similar for the 3 SC flow rates as well as for isatuximab and saline. Swelling at injection site was 
more evident for isatuximab infused at 1 and 2 mL/min compared with 0.5 mL/min and was 
considered related to a physical phenomenon (large volume injected in a short period of time). 
It declined at 4 hours and had disappeared at 24 hours following administration. There were no 
compound-related microscopic findings at the examination of skin biopsies of SC injection sites 
sampled 7 and 28 days following each injection at all administration rates tested. 
Finally, plasma compatibility and the hemolytic potential of isatuximab in human whole blood 
were tested in vitro at concentrations up to 2.5 mg/mL. No hemolytic effect or plasma 
incompatibility was observed. 
2.2.3 Clinical data  
At the cut-off date of 01 March 2021 the clinical development program with isatuximab IV 
consists of Phase 1/2/3 studies of isatuximab as a single agent or in combination with other 
therapies. A total of 1760 participants have been exposed to isatuximab so far. 
2.2.3.1 Isatuximab IV in combination with pomalidomide and dexamethasone  
The overall safety profile of isatuximab, well characterized by clinical studies, is predictable and 
manageable. Infusion reactions have been reported as the most common adverse reactions 
consequent to the IV administration of isatuximab (whether administered as a single agent or in 
combination with other anticancer agents), and therefore is an identified risk. These adverse 
reactions, whether acute or delayed, may be serious and systemic and may include anaphylactic 
reactions. 
The combination of isatuximab IV with pomalidomide and dexamethasone has been evaluated in 
a completed Phase 1b Study (TCD14079) and a completed Phase 3 Study (EFC14335). Following 
the results of the EFC14335 Study, IsaPd was approved in the United States, European Union 
(EU), Canada, Japan, Russia, and Australia for its use in adult patients with MM who have 
received at least 2 prior therapies including lenalidomide and a PI. 
In Study TCD14079 (Pd in RRMM; Part A), 45 participants were treated. Three dose levels of 
isatuximab were evaluated: 5 mg/kg (n = 8), 10 mg/kg (n = 31) and 20 mg/kg (n = 6). The median 
age of participants was 67 years (range: 42 to 82 years). The median time from initial diagnosis to 
first dose was 4.3 years (range: 1.0 to 15.8 years). Median number of lines was 3 (minimum to 
maximum: 2 to 10) with 13 (28.9%) participants having received 3 or more prior lines of 
treatment. 
Overall, the therapy of isatuximab in combination with pomalidomide and dexamethasone in 
participants with RRMM was well tolerated up to the highest planned isatuximab dose 
(20 mg/kg). Three dose limiting toxicities (DLTs) were reported, one at each dose level: Grade 4 
neutropenia, Grade 4 neutropenic infection, and Grade 3 confusional state. All the DLTs resolved 
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with pomalidomide dose omission or reduction and did not lead to treatment discontinuation. 
The isatuximab maximal tolerated dose (MTD) was not reached when isatuximab was 
administered with pomalidomide and dexamethasone. As no MTD was reached in the dose 
escalation cohort, isatuximab recommended dose of 10 mg/kg QW  4, followed by 10 mg/kg 
Q2W was chosen based on PK/PDy modeling and simulations from the Phase 1 Study TCD11863 
(assessing isatuximab in combination with lenalidomide and dexamethasone). 
The ORR was 62.2% (28 out of 45 participants) in total including 2 participants achieving 
a complete response (CR)/stringent complete response (sCR) (4.4%); very good partial response 
(VGPR) was reported in 10 participants (22.2%), and PR in 16 participants (35.6%). 
The 10 mg/kg group had an ORR of 64.5%.  
EFC14335 (ICARIA-MM) was a randomized, open-label, multicenter Phase 3 trial evaluating 
isatuximab in combination with approved doses of pomalidomide and dexamethasone (IsaPd) 
versus pomalidomide and dexamethasone in RRMM (2). The primary objective of this 
Phase 3 trial (NCT02990338) was PFS. Key secondary objectives were ORR and OS. Progression 
free survival and ORR were analyzed based on the assessment of an Independent Review 
Committee using central laboratory data for M-protein and central radiology review. 
Participants with RRMM who received ≥2 prior lines, including lenalidomide and a PI, were 
refractory to last therapy, and had adequate bone marrow, kidney, and hepatic function, could be 
enrolled. Prior exposure to pomalidomide was not allowed. Participants in the Isatuximab (IsaPd) 
arm received Isa 10 mg/kg IV weekly for first 4 weeks, then every 2 weeks. Both arms received 
approved schedules of pomalidomide and dexamethasone (4 mg per os [PO] days 1 to 21; 40 mg 
[20 mg if >75 yrs] PO or IV weekly) every 28 days until progression or unacceptable toxicity.  
Three hundred and seven participants were enrolled (154 IsaPd, 153 Pd). Overall, the median age 
was 67 years (range 36 to 86) and 19.9% of the population was ≥75 years of age, the median prior 
lines of therapy was 3 (2 to 11); estimated glomerular filtration rate was <60 ml/min in 
33.9% participants; 92.5% were refractory to lenalidomide, 72.6% were refractory to both 
lenalidomide and PI, 75.9% to PI and 91.2% were refractory to lenalidomide at their last line 
immediately before their enrolment in the trial. Over the half of participants (56.4%) had received 
prior stem cell transplant; and 19.5% participants had high-risk cytogenetics. 
At median follow-up of 11.6 months, the addition of isatuximab to pomalidomide and 
dexamethasone significantly improved PFS. Median PFS was significantly longer in the IsaPd 
arm (11.53 months, 95% CI: 8.936 to 13.897) than in the Pd arm (6.47 months, 95% CI: 4.468 to 
8.279), respectively. The stratified HR was 0.596 (95% CI: 0.436 to 0.814) characterizing 
a reduction of 40.4% in risk for disease progression or death with IsaPd compared to Pd. All 
sensitivity analyses for PFS showed consistent results with the primary analysis. All PFS 
subgroup analyses showed consistent benefit with HRs in the ranges of 0.5 and 0.6, including 
elderly participants, renal impaired, heavily pretreated, and high-risk cytogenetics. The ORR was 
significantly better in IsaPd (60.4%) versus Pd (35.3%), p<0.0001. The depth of response, 
as measured by the VGPR or better rate, was improved with IsaPd (31.8%) compared to 
Pd (8.5%), p<0.0001. Minimal residual disease negativity (NGS,10-5) was seen in 5.2% IsaPd 
versus 0% Pd participants (ITT analysis). At analysis date, OS was immature (99 events) but 
a trend to OS improvement in IsaPd versus Pd was observed (HR 0.687; 95% CI 0.461-1.023). 
The median treatment duration was 41 weeks on IsaPd versus 24 weeks on Pd.  
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An updated analysis of the ICARIA-MM trial confirmed a trend in overall survival benefit, with 
a median OS of 24.6 months in the IsaPd arm versus 17.7 months in the Pd arm, (HR 0.76; 
95% CI 0.58-1.01) (3). 
Grade ≥3 AEs were observed in 86.8% IsaPd versus 70.5% Pd participants; 7.2% IsaPd 
and 12.8% Pd participants discontinued treatment due to AEs; 7.9% IsaPd and 
9.4% Pd participants died due to AEs. The addition of isatuximab to the Pd regimen was 
characterized by reversible IRs, which were reported in 38.2% (2.6% Grade 3 to 4) of 
the cases and an increase in neutropenia and infection rates. Grade ≥3 infections were seen in 
42.8% of the participants in IsaPd arm versus 30.2% in Pd arm, Grade ≥3 neutropenia in 
84.9% and 70.1%, respectively. Febrile neutropenia was reported in 11.8% IsaPd and 2.0% Pd 
participants. No difference in anemia and thrombocytopenia, and no difference in 
thrombo-embolic events was seen between arms. 
These data from the Phase 3 and the Phase 1 study provide evidence of the efficacy and safety of 
IV IsaPd and support planned investigation of SC isatuximab in this combination. Details are 
provided in the most recent Investigator’s Brochure (IB). 
2.2.3.2 Isatuximab SC in combination with pomalidomide and dexamethasone  
TCD15484 is an ongoing multi-center, open-label, Phase 1b study to assess the safety, PK, and 
efficacy of SC isatuximab administered QW for 4 weeks (Cycle 1) and then Q2W in subsequent 
cycles in combination with pomalidomide and dexamethasone (IsaPd).  
The study includes the following cohorts of participants:  
• Cohort 1  
- 
Cohort 1a: Participants receiving 1000 mg dose of isatuximab by SC route using 
an infusion pump (SC-IP) with a flow rate of 0.8 mL/min in combination with 
pomalidomide/dexamethasone. 
- 
Cohort 1b: Participants receiving 10 mg/kg dose of isatuximab by IV route in 
combination with pomalidomide/dexamethasone. 
• Cohort 2 
- 
Cohort 2a: Participants receiving 1400 mg dose of isatuximab by SC-IP with a flow 
rate of 0.8 mL/min in combination with pomalidomide/dexamethasone. 
- 
Cohort 2b: Participants receiving 10 mg/kg dose of isatuximab by IV route in 
combination with pomalidomide/dexamethasone. 
• Cohort 3: Participants receiving isatuximab by SC route at the recommended Phase 2 dose 
(RP2D) using an On Body Delivery System (OBDS), an (investigational) wearable 
injector device (SC-OBDS) in combination with pomalidomide/dexamethasone.  
In Cohorts 1 and 2, participants were randomized with a 2:1 ratio to SC-IP or IV route. After 
determination of the RP2D based on Cohorts 1 and 2 results using an infusion pump for the SC 
administration of isatuximab, the participants were included in an expansion cohort, Cohort 3, 
using the OBDS. 
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As of the cut-off date of 16 May 2022, a total of 56 participants have been treated in 
the TCD15484 Study from October 2019 to August 2021: 
• 12 participants in the 10 mg/kg IV cohort.  
• 12 participants in the 1000 mg SC with infusion pump (1000 mg SC-IP) cohort. 
• 10 participants in the 1400 mg SC with infusion pump (1400 mg SC-IP) cohort. 
• 22 participants in the 1400 mg SC with the (investigational) injector device (SC-OBDS) 
cohort. 
Due to the sequential nature of the enrollment, the median follow-up duration was higher in 
the IV, 1000 mg SC-IP, and 1400 mg SC-IP cohorts (24.4 months, 28.7 months, and 22.7 months, 
respectively) compared to the SC-OBDS cohort (10.1 months). At the time of the analysis, 
33 participants discontinued treatment: 8 participants in the IV cohort, 9 participants in 
the 1000 mg SC-IP cohort, 7 in the 1400 mg SC-IP cohort, and 9 in the SC-OBDS cohort. 
The main reason for discontinuation was disease progression (26 participants). There was a trend 
for lower pomalidomide relative dose intensity (RDI) in the 1400 mg SC-IP cohort (69.2%) 
versus the IV, SC 1000 mg and the SC-OBDS cohorts (93.5%, 87.8%, and 85.4%, respectively). 
Pomalidomide reduction was mainly due to neutropenia. 
One DLT was reported in each SC-IP cohort (Grade 4 neutropenia in the 1000 mg SC-IP cohort 
and Grade 3 pulmonary infection in the 1400 mg SC-IP cohort). According to the protocol, DLTs 
were not assessed in the isatuximab IV cohorts. DLTs reported with Isa-SC were consistent with 
the DLTs reported in the dose-escalation study of isatuximab IV in combination with Pd 
(Study TCD14079) in which one DLT was reported at each dose level (5 mg/kg: Grade 4 
neutropenia; 10 mg/kg: Grade 4 neutropenic infection; and 20 mg/kg: Grade 3 confusional state). 
The incidence of all-causality Grade ≥3 TEAEs was comparable (≥90%) in all cohorts. There 
were 2 TEAEs leading to death (sudden death not related to treatment or disease and bacterial 
meningitis) in the SC-OBDS cohort. Bacterial meningitis was the only adverse event leading to 
definitive treatment discontinuation in the study. 
Grade ≥3 infections were reported in 3 (25%) participants in both IV and 1000 mg SC-IP cohorts, 
4 (40%) in the 1400 mg SC-IP cohort, and 8 (36.4%) participants in the SC-OBDS cohort, 
including 1 case of Grade ≥3 Covid-19 in the 1400 mg SC-IP and 3 in the SC-OBDS cohorts.  
Grade ≥3 laboratory neutropenia was observed in 10 (83.3%) patients of the IV cohort, 
11 (91.7%) in the 1000 mg SC-IP cohort, 9 (90%) in the 1400 mg SC-IP cohort, and 
20 (90.9%) in the SC-OBDS cohort. 
Febrile neutropenia occurred in 1 (8.3%) patient in the IV cohort, none in the 1000 mg SC-IP 
cohort, 2 (20%) in the 1400 mg SC-IP cohort and 1 (4.5%) in the SC-OBDS cohort. 
Infusion reactions occurred in less than 10% of the patients, with a single episode of IR (all 
Grade 2) in each of the IV, 1000 mg SC-IP, and 1400 mg SC-IP cohorts. These episodes occurred 
at the first administration only and lasted 1 (IV and 1400 mg SC-IP cohorts) to 2 days 
(1000 mg SC-IP cohort). No IR was observed in the SC-OBDS cohort. 
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Patients with at least 1 ISR were 6 (50%) in the 1000 mg SC-IP, 6 (60%) in the 1400 mg SC-IP 
and 5 (22.7%) in the SC-OBDS cohorts, experiencing 23, 46, and 7 episodes of ISR, respectively. 
The local tolerability profile in the SC-OBDS cohort was very good: the 7 episodes of ISR were 
all Grade 1, corresponding to 5 injection site erythema, 1 injection site hemorrhage, and 
1 injection site induration, and representing 1.7% of the OBDS injections (7 out of 
404 administrations). 
The median duration of OBDS injection was 10 minutes at first and subsequent administrations, 
and all injections were successfully completed with no interruption. 
In general, the incidence of TEAEs in any arm of Study TCD15484 compared favorably to 
the incidence of TEAEs in the IsaPd arm of the ICARIA-MM trial. Importantly, there was no new 
safety signal observed in Isa-SC arms compared to the known safety profile of IsaPd established 
with ICARIA-MM and TCD14079 studies. 
With a shorter duration of follow-up of the SC-OBDS cohort (10 months versus ≥22 months in 
the other cohorts), the ORR was 66.7% in both IV and 1000 mg SC-IP cohorts, 80.0% in 
1400 mg SC-IP cohort and 72.7% in the SC-OBDS cohort. At least VGPR rate was similar across 
all cohorts (40% to 50%). The CR rate was 16.5% in the IV cohort, 25% in the 1000 mg SC-IP 
cohort, 20% in the 1400 mg SC-IP cohort, and 22.7% in the SC-OBDS cohort. Overall, ORR, 
at least VGPR rate and CR rates are consistent with the ICARIA-MM trial.  
Saturation of the CD38 receptors on bone marrow plasma cells was reached for all cohorts: mean 
CD38 receptor occupancy of 76.0% (range: 68.2% to 86.1%) for 10 mg/kg isatuximab IV, 
79.8% (range: 74.7% to 84.2%) for 1000 mg SC-IP, 80.5% (range: 78.6% to 83.2%) for 
1400 mg SC-IP, and 78.1% (range: 64.2% to 85.4%) for SC-OBDS. These data demonstrated that 
when administered SC, isatuximab saturates its target receptor similarly to when administered IV. 
After the first Isa-SC administration, the median time to reach maximum concentration (Cmax) was 
approximately 95 hours. The Cmax and area under the plasma concentration time curve over 
the first week (AUC1week) were comparable after the first 1000 mg and 1400 mg Isa-SC dose 
whichever the Isa-SC delivery method used (IP or OBDS) and were lower than those observed 
after 10 mg/kg IV administration (Table 4) which is in agreement with the slow absorption 
observed for the SC administration route. Similar results were observed after the seventh Isa-SC 
administration in the QW/Q2W regimen, with comparable area under the plasma concentration 
time curve over two weeks of dosing (AUC2weeks) after 1000 mg and 1400 mg SC doses. 
A moderate interpatient variability was observed for exposure after the first Isa-SC administration 
(total coefficient of variation [CV] for Cmax, AUC1week or Ctrough of 33% to 52%) or after 
the seventh Isa-SC administration (total CV for Cmax, AUC2weeks or Ctrough of 38% to 65%) 
with the IP and remained of the same extent when using the OBDS (total CV for Cmax, 
AUC2weeks or Ctrough of 33% to 52%). The total variability appeared to be slightly higher for 
the 1400 mg SC-OBDS cohort versus 1400 mg SC-IP cohort but it remained comparable to 
the one observed for 1000 mg SC-IP cohort. 
Previous population PK analysis (POH0503) with IV data has shown that participants with less 
aggressive disease at baseline are expected to have lower linear clearance (CL) and therefore 
higher exposure; similarly, non-IgG participants have higher exposure than the IgG participants. 
The unbalanced covariates distribution between the SC cohorts explains the comparable 
exposure between these cohorts with participants from the 1000 mg SC-IP cohort having less 
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advanced disease, lower tumor burden (higher albumin, lower β2 microglobulin level, 
International Staging System [ISS] stage, M-protein level and bone marrow plasma cell [BMPC]) 
than the 1400 mg SC cohorts. The covariates distribution between 1400 mg cohorts (IP and 
OBDS) was similar with the exception of body weight. For the weight, the distribution was 
similar between participants of 1000 mg SC-IP and 1400 mg SC-OBDS cohorts, but patients in 
the 1400 mg SC-IP cohort were heavier. 
The mean (±standard error [SE]) Ctrough over time after IV and SC isatuximab QW/Q2W show 
comparable Ctrough profiles after 1000 mg and 1400 mg SC which were higher than those observed 
after 10 mg/kg IV. Relative to first administration, the accumulation ratio based on Ctrough ranged 
from 2.65 (1400 mg SC-OBDS) to 3.64 (1000 mg SC-IP) for Cycle 2 Day 1 (fifth administration) 
and from 2.83 (1400 mg SC-OBDS) to 4.04-fold (1000 mg SC-IP) for Cycle 4 Day 1 (ninth 
administration) after the SC administration (1000/1400 mg with IP or OBDS). Accumulation was 
comparable to that observed after IV administration, with accumulation ratio of 3.96 for Cycle 2 
Day 1 and of 3.60 for Cycle 4 Day 1. 
It is important to note that individual CT4W values (best PK predictor of efficacy) after 
1000 mg SC-IP and 1400 mg SC-IP or OBDS QW/Q2W regimens were similar or higher than 
those observed in patients treated by IV route at 10 mg/kg QW/Q2W, with comparable 
inter-patient variability (Table 4). 
Table 4 - Mean (CV%) isatuximab PK parameters after the 1st and 4th SC administration at 1000 mg 
or 1400 mg QW/Q2W and after the IV administration at 10 mg/kg in TCD15484 – non compartmental 
analysis  
Study 
Dose/Route 
Number of 
patients  
Cmax 
(µg/mL) 
tmaxa 
(h) 
CT1W 
(µg/mL) 
AUC1week  
(µg.h/mL) 
CT4W 
(µg/mL) 
TCD15484* 
1000 mg 
SC-IP 
12 
119 (48) 
91.90 
(46.20-168.00) 
101 (44)b 
15200 (52)b  
339 (26)c 
 
1400 mg 
SC-IP 
10 
104 (33) 
92.60 
(68.40-168.00) 92.3 (31)d  
12900 (36) 
338 (36)e 
 
1400 mg 
SC-OBDS 
22 
145 (49) 
95.10  
(46.90-192.00) 
128 (46) 
17400 (49) 
326 (46)f 
 
1400 mg SC 
(OBDS+IP) 
32 
132 (49) 
94.70 
(46.90-192.00) 
118 (46)g 
16000 (48) 
330 (42)h 
TCD15484* 
10 mg/kg  
IV 
12 
234 (29) 
3.63 
(3.33-11.30) 
56.8 (48)b 
19300 (28) 
235 (40)d 
CT4W were used in descriptive statistics calculation even if patients did not receive the 4 doses at Cycle 1. 
Abbreviations: AUC1week = area under the plasma concentration time curve over the first week; Cmax = maximum concentration; Ctrough = 
predose concentration during repeated dosing; CT1W = Ctrough at 1 week; CT4W = Ctrough at 4 weeks; tmax = time to reach Cmax ; NR = No 
Result. 
a Median(min-max), 
b N = 11,  
c N = 8,  
d N = 9,  
e N = 6, 
f 
N = 13, 
g N = 31,  
h N = 19,
  
*based on NCA analysis. 
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2.2.3.3 Pomalidomide  
Pomalidomide is a thalidomide analogue indicated, in combination with dexamethasone for 
participants with MM who have received at least 2 lines of therapies including lenalidomide and 
a PI and have demonstrated disease progression on or within 60 days of completion of 
the last therapy.  
Pomalidomide is an IMiD with multiple cellular effects that inhibit MM cell growth and survival 
blocking the stromal support from the bone marrow (BM) microenvironment that can promote 
myeloma cell growth; in addition, pomalidomide has potent immunomodulatory effects that 
enhance the immune response to myeloma cells by stimulating NK cell and by inhibiting 
regulatory T cells. Pomalidomide has been approved following the data reported in 
Study MM-003 (17) where pomalidomide plus low-dose dexamethasone was compared with 
high-dose dexamethasone. 
In Study MM-003, the most common Grade 3 to 4 hematological AEs in the pomalidomide plus 
low-dose dexamethasone arm were neutropenia (48%), anemia (33%), and thrombocytopenia 
(22%); Grade 3 to 4 non-hematological AEs included pneumonia (13%), bone pain (7%), and 
fatigue (5%). After a median follow-up of 10 months, the ORR in the pomalidomide plus 
low-dose dexamethasone and high-dose dexamethasone was 31% and 10% respectively, the PFS 
was 4 months and 1.9 months. 
Please refer to US or EU labeling for additional details. 
2.2.3.4 Injector device  
In addition to TCD15484, a version of the wearable injector device has been used in clinical trials 
with other medicinal product(s). 
 
2.3 
BENEFIT/RISK ASSESSMENT  
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of isatuximab may be found in the IB. 
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2.3.1 Risk assessment  
Table 5 - Risk assessment  
Potential risk 
of clinical 
significance 
Summary of data/rationale for risk 
Mitigation strategy 
Study intervention(s) 
Infusion reactions 
including 
anaphylactic 
reactions (identified 
risk) and cytokine 
release syndrome 
Infusion reactions have been reported as the most 
common adverse reactions consequent to the 
IV administration of isatuximab (either as a single 
agent or in combination with other anticancer agents); 
this is consistent with the results from clinical studies 
and from extensive postmarketing experience acquired 
with other therapeutic mAb proteins. Extensive clinical 
experience with approved mAbs, in fact, indicates that 
mild to moderate IR (either allergic, or consisting of 
cytokine release, which mimics hypersensitivity 
reactions) are very common, particularly during 
the first infusion; the cytokine release syndrome 
associated with mAbs consists of a pseudo allergic 
Type B (nonimmunoglobulin E mediated) reaction. 
The infusion reactions with IV isatuximab are most 
commonly at the first administration, are not dose 
dependent, and the participants do not appear to 
sustain sequelae. 
Infusion reactions generally do not cause therapy 
discontinuation and tend not to recur at subsequent 
administrations of isatuximab. Occasionally, these 
adverse reactions may be serious and systemic (as 
with anaphylactic reactions, which have been reported 
throughout the isatuximab IV program). Infusion 
reactions, however, are most frequently of Grade 1/2 
severity and are manageable (for more details on 
infusion reactions refer to the most recent IB). 
Similar reactions are expected after SC 
administration of isatuximab. To allow assessment of 
these reactions after isatuximab SC versus IV 
the common term of IRs will be used for this type of 
reactions after administration of either isatuximab SC 
or IV.  
To minimize the incidence and severity of IRs, 
and as it is done in the isatuximab IV program, 
all the participants treated with isatuximab SC 
should routinely receive primary prophylactic 
treatment. See Section 6.1.2. 
Participants who do not experience an IR 
during the first 4 isatuximab administration may 
have their need for subsequent premedication 
reconsidered at the Investigator’s discretion, 
except for montelukast which should be 
administered only on Cycle 1. 
Details for management of IRs and ISRs after 
isatuximab SC administration are provided in 
the Section 6.5.5.  
Infections (identified 
risk) 
Isatuximab modulation of lymphoid and myeloid cells 
due to CD38 expression on normal immune cells, 
effect of other medications like dexamethasone. 
Bone marrow suppression with risk of neutropenia. 
Exclusion of trial participants with active 
infections. 
Close monitoring of clinical and laboratory 
parameters. 
Prophylactic use of antibiotics, antivirals, 
antifungals, and G-CSF as needed. 
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Potential risk 
of clinical 
significance 
Summary of data/rationale for risk 
Mitigation strategy 
Neutropenia 
(identified risk) 
Risk of bone marrow suppression is systematically 
considered with anti-cancer therapies. 
Multiple myeloma is a malignancy that primarily 
affects the bone marrow. 
Clinical manifestations of infections and febrile 
neutropenia can be life-threatening. 
Exclusion of patients with ANC<1000 μL 
(1  109/L). The use of G-CSF is not allowed to 
reach this level. 
Close monitoring of blood cell count at each 
cycle. 
Prophylactic use of antibiotics, antivirals, 
antifungals, and G-CSF. 
Interference with 
blood bank 
serologic tests 
(identified risk) 
CD38 protein is weakly expressed on the surface of 
red blood cells. Because of this, anti CD38 antibodies 
in participants’ plasma can lead to pan reactivity and 
thus interfere with various blood bank serologic tests. 
ABO/RhD typing is not affected by anti CD38 
antibodies. 
Before the first isatuximab infusion, 
conduct blood type and screen tests on 
isatuximab - treated participants. If treatment 
with isatuximab has already started, inform the 
blood bank that the participant is receiving 
isatuximab and isatuximab interference with 
blood compatibility testing can be resolved 
using dithiothreitol treated RBCs. If an 
emergency transfusion is required, non-cross-
matched ABO/RhD-compatible RBCs can be 
given as per local blood bank practices. 
An antibody screen test (indirect Coomb’s test) 
should be done before each red blood cell 
transfusion while on isatuximab treatment. See 
Appendix 13 Section 10.14). 
In all isatuximab studies, participant blood will 
be typed and screened before (if not already 
done) the first administration of the drug and 
a card with blood type will be carried by 
the participant throughout the study. 
Second primary 
malignancies 
(potential) 
CD38 antigen is expressed on normal immune cells; 
suppression of immune system (with its ability to 
detect and destroy cancer cells) may increase risk of 
malignancies. 
Overall incidence of SPMs with isatuximab in ICARIA 
study was 3.6% (6 in Isa arm versus 1 in control). 
Monitoring and measurement of secondary 
cancers. 
Collect information on baseline characteristics, 
individual treatments, time to development, 
clinical characteristics, history of SPMs 
observed. 
Viral reactivation 
(potential) 
Participants with MM undergoing immunosuppressive 
drug therapy are at high risk of viral reactivation 
including hepatitis and herpes zoster reactivation. 
Screening with serological tests for hepatitis B 
(HBV) and hepatitis C (HCV) has to be done 
prior to enrollment if not performed within 
1 year. In case of viral reactivation during study 
treatment, the treatment will be held, specialist 
consulted for initiation of anti-viral treatment, 
and monitoring of the participant. 
Antiviral prophylaxis (such as herpes zoster 
prophylaxis) can be considered during 
treatment. 
Subcutaneous Isatuximab 
Injection-site 
reaction  
Although no Grade >1 ISRs were reported in the 
Phase 1 trial with SC isatuximab, the potential of the 
risk remains.  
Monitoring of ISRs. 
Diary will be provided to patients to report 
potential ISRs during the first 9 cycles in 
the SC-arm. 
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Potential risk 
of clinical 
significance 
Summary of data/rationale for risk 
Mitigation strategy 
Study procedures 
Bone marrow 
aspirate/biopsy  
Bone marrow aspirate is part of standard procedures 
for MM disease assessment. 
Sites with MM expertise will be selected. 
Other 
Not applicable. 
 
 
Abbreviations: ANC = Absolute Neutrophil Count; CD38 = Cluster of differentiation 38; G-CSF = granulocyte-colony stimulating factor; HBV = 
hepatitis B virus; HCV = hepatitis C virus; IB = investigators brochure; IR = Infusion reactions; ISR = Injection site reactions; IV = Intravenous; 
mAb = monoclonal antibody; MM = Multiple myeloma; RBC = red blood cell; SC = Subcutaneous; SPM = second primary malignancies. 
2.3.2 Benefit assessment  
All participants in the trial will receive a combination of isatuximab, pomalidomide and 
dexamethasone. The combination of IV isatuximab with pomalidomide and dexamethasone has 
demonstrated clinical efficacy with an acceptable and manageable safety profile in 
the ICARIA-MM (NCT02990338) Phase 3 trial. Device-mediated SC administration can offer 
a number of benefits to both HCPs and patients, including controlled delivery and simplified user 
interface, and could ultimately be used by a qualified HCP in the outpatient setting or at patient’s 
home. 
2.3.3 Overall benefit: risk conclusion  
Considering the measures taken to minimize risk to participants participating in this study, 
the potential risks identified in association with study intervention are justified by the anticipated 
benefits that may be afforded to participants with RRMM. 
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3 
OBJECTIVES, ENDPOINTS, AND ESTIMANDS  
Table 6 - Objectives and endpoints  
Objectives 
Endpoints 
Primary 
 
• 
Demonstrate the efficacy non-inferiority between 
isatuximab SC and isatuximab IV in combination 
with Pd. 
• 
Overall response rate (ORR): defined as the 
proportion of participants with stringent complete 
response (sCR), complete response (CR), very 
good partial response (VGPR), and partial response 
(PR) according to the 2016 IMWG criteria assessed 
by Independent Review Committee (IRC).  
• 
Demonstrate the pharmacokinetic (PK) 
non-inferiority between isatuximab SC and 
isatuximab IV in combination with Pd. 
• 
Observed concentration before dosing (Ctrough) 
at steady state (corresponding to predose at C6D1).  
Secondary 
Key Secondary 
 
• 
Assess efficacy of isatuximab SC compared to 
isatuximab IV in combination with Pd. 
• 
Very Good Partial Response or better rate: defined 
as the proportion of participants with sCR, CR, and 
VGPR according to the 2016 International Myeloma 
Working Group (IMWG) criteria assessed by IRC.  
• 
Demonstrate the pharmacokinetic (PK) 
non-inferiority between isatuximab SC and 
isatuximab IV in combination with Pd. 
• 
Observed concentration before dosing (Ctrough) 
at 4 weeks (ie, CT4W corresponding to predose 
at C2D1). 
• 
Assess safety of isatuximab SC and IV in 
combination with Pd. 
• 
Incidence rate of infusion-reactions (IRs). 
• 
Assess patient satisfaction with isatuximab SC and 
IV.  
• 
Percentage of participants satisfied or very satisfied 
with the injection method used to administer study 
medication based on the PESQ questionnaire. 
Other Secondary  
 
• 
Assess efficacy of isatuximab SC compared to 
isatuximab IV in combination with Pd. 
• 
Duration of response (DOR): defined as the time 
from the date of the first response to the date of 
first occurrence of progressive disease (PD) 
as determined by IRC or death from any cause, 
whichever happens first. DOR is determined only for 
participants who have achieved a response (PR or 
better). In the absence of PD or death before 
the analysis cut-off date, the DOR will be censored 
at the date of the last valid disease assessment 
performed prior to initiation of a further 
anti-myeloma treatment or the analysis cut-off date, 
whichever is earlier. Patients with two or more 
consecutive missed assessments prior to PD or 
death will be censored at the last valid disease 
assessment.  
• 
Time to first response (TT1R): defined as the time 
from randomization to the date of first IRC 
determined response (PR or better) that is 
subsequently confirmed. 
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Objectives 
Endpoints 
 
• 
Time to best response (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.  
• 
Progression free survival (PFS): defined as the time 
from the date of randomization to the date of 
first documentation of progressive disease 
as determined by IRC or the date of death from any 
cause, whichever comes first. Responses will be 
determined according to IMWG criteria. Progression 
based on paraprotein will be confirmed based on 
two consecutive assessments. 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. Patients with 
two or more consecutive missed assessments prior 
to PD or death will be censored at the last valid 
disease assessment. Details censoring rule will be 
provided in SAP. 
• 
Overall survival (OS): defined as the time from 
the date of randomization to death from any cause. 
Participants without death prior to the analysis 
cut-off date will be censored at the last date 
the participant was known to be alive or the cut-off 
date, whichever is first.  
• 
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. Same censoring 
rule applies as in the PFS endpoint. 
• 
Assess safety of isatuximab SC and IV and local 
tolerability of isatuximab SC in combination with Pd. 
• 
Treatment-emergent adverse events 
(TEAEs)/serious adverse events (SAEs). 
Treatment-emergent adverse events (AEs) are 
defined as AEs that develop, worsen, 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. 
• 
Laboratory parameters. 
• 
Injection site reactions (ISRs) – SC arm only. 
• 
Adverse events and laboratory parameters will be 
graded using NCI CTCAE v5.0. 
• 
Characterize PK of isatuximab SC and IV in 
combination with Pd. 
• 
PK concentrations.  
 
• 
Assess the delivery performance of the 
(investigational) device injector. 
• 
Number of successful injections with 
(investigational) isatuximab injector device defined 
as completion of administration per provided 
instructions for use with no use errors or technical 
issues, divided by the total number of injections. 
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Objectives 
Endpoints 
• 
Assess the potential immunogenicity of isatuximab 
SC and IV in combination with Pd. 
• 
Incidence of participants with anti-drug antibodies 
(ADA) against isatuximab. 
• 
Assess the clinical outcome of isatuximab SC and 
IV in combination with Pd. 
• 
Patient expectation at baseline and 
experience/satisfaction with Isatuximab will be 
assessed using the patient expectation (PEQ), 
the patient experience and satisfaction (PESQ) and 
the Patient’s Assessment of Treatment (PAT) 
questionnaires.  
• 
Health Resources Utilization will be assessed using 
the Health Resource Utilization and Productivity 
Questionnaire (HRUPQ). 
• 
Health-related quality of life will be assessed using 
the European Organization 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 status will be assessed using the European 
Quality of Life Group questionnaire with 
5 dimensions and 5 levels per dimension 
(EQ-5D-5L). 
• 
Explore chromosomal abnormalities [mainly but not 
limited to t(4;14), t(14;16), del(17p), and 1q21+], 
and potential association with clinical outcomes. 
• 
Impact of abnormal cytogenetic subtypes on 
participant outcome. 
 
Exploratory 
 
• 
Assess Minimum Residual Disease (MRD) 
negativity rate of isatuximab SC compared to 
isatuximab IV in combination with Pd. 
• 
Minimum residual disease (MRD) negativity rate: 
Defined as the proportion of participants for whom 
MRD is negative; threshold for negativity will be 
at least 10^-5. 
• 
MRD negative CR rate (MRD[-]CR): defined as 
the proportion of participants with best overall 
response as sCR/CR and for whom MRD is 
negative; threshold for negativity will be at least 
10^-5. 
• 
Explore PK and Pharmacodynamics (PDy) 
relationship. 
• 
Relationship between isatuximab PK exposure and 
safety endpoints of interest may be investigated 
as well as between isatuximab PK exposure and 
efficacy endpoints (eg, ORR, VGPR) if possible 
(SC arm only). 
• 
Explore genomic and genetic profiling at screening 
and at disease progression. 
• 
Characterization of bone marrow (BM) genomic and 
genetic profiles to explore mechanism of drug 
resistance.  
• 
Explore new methods for measuring serum M 
Protein such as mass spectrometry. 
• 
Impact of new serum M-protein measurement 
methods on disease response assessment. 
• 
Explore frailty and potential association with clinical 
outcome. 
• 
Impact of frailty on participant clinical outcome.  
 
 
 
For China, please see Section 10.8 for details. 
Primary estimands defined for co-primary endpoints are summarized in Table 7 below. 
For all these estimands, the comparison of interest will be the comparison of isatuximab- IV + Pd 
versus isatuximab- SC + Pd. 
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Table 7 - Summary of primary estimands for main endpoints  
Endpoint 
Estimands 
Category 
(estimand) 
Endpoint 
Population 
Intercurrent 
event(s) handling 
strategy 
Population-level summary  
(Analysis and missing data 
handling) 
Primary objective: Demonstrate the efficacy and PK non-inferiority between isatuximab SC and isatuximab IV in combination 
with Pd 
Co-Primary 
endpoint 
ORR [stringent 
complete response 
(sCR), complete 
response (CR), very 
good partial 
response (VGPR), 
and partial response 
(PR)]. 
ITT 
While not initiating new 
anti-cancer therapy 
Regardless of IMP 
discontinuation (treatment 
policy strategy). 
This endpoint will be analyzed by 
calculating the relative risk between 
the SC and IV arm and its two-sided 
95% CI using Farrington-Manning 
method and compare its lower CI limit 
with the pre-defined margin. In 
absence of confirmed PR or better, 
participants will be considered 
as non-responders, whatever the 
reason (including participants with 
missing or non-evaluable best overall 
response). 
Co-primary 
endpoint 
Ctrough at steady 
state (corresponding 
to predose at 
C6D1). 
PK-PP 
 (Principal Stratum 
strategy) Doses, 
administration scheme, 
sample collection, 
processing and result, 
time window of collection 
and adequate 
documentation. 
The point estimate (ratio of geometric 
means for Ctrough at steady state of 
SC/IV) together with its two-sided 
90% CI will be calculated. The lower 
bound of the 90% CI will be compared 
with 80%. Participants who do not have 
all administrations up to C5D15 
(one dose omission permitted at C1 
only) and PK sample collected out of 
the prespecified time window are not 
included into the analysis population. 
3.1 
APPROPRIATENESS OF MEASUREMENTS  
Each of the efficacy and safety assessments chosen for use in this study are considered well 
established and relevant in a hemato-oncology setting, and suitable steps have been built into each 
of these assessments to ensure their reliability and accuracy. 
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4 
STUDY DESIGN  
4.1 
OVERALL DESIGN  
This is a randomized, multicenter, Phase 3, open-label study evaluating SC versus 
IV administration of isatuximab in combination with pomalidomide and dexamethasone in adult 
RRMM patients (study participants) who have received at least 1 prior line of therapy including 
lenalidomide and a PI.  
The randomization will be stratified by MM isotype (IgG versus non-IgG), body weight (≤65 kg, 
>65 to ≤85 kg, and >85 kg), and number of prior lines (1-2 versus ≥3). Eligible participants 
(approximately 534) will be randomized 1:1 into 1 of 2 study arms: 
• Arm SC: Isatuximab SC at 1400 mg with device injector (N = 267). 
• Arm IV: Isatuximab IV 10 mg/kg (N = 267). 
Isatuximab IV and SC will be administered weekly for 4 weeks (Cycle 1) and on Day 1 and 
Day 15 of each subsequent cycles, in combination with pomalidomide and dexamethasone. 
SC administration of isatuximab will be done using an investigational isatuximab injector device 
(on body delivery system) (Section 6.1.3). 
IV administration of isatuximab will be done by IV infusion with appropriate rate (refer to 
Table 8, Section 6.1.1.1.1). 
Pomalidomide will be administered from Day 1 to Day 21 of each 28 days cycles and 
dexamethasone will be administered every week.  
Before the final OS analysis cutoff date, participants will be allowed to continue therapy until 
disease progression, unacceptable adverse events (AEs), participant request to discontinue 
treatment or any other reason, whichever is first. After the final OS analysis cutoff date, 
participants will be allowed to continue therapy until disease progression, unacceptable adverse 
events (AEs), participant request, study treatment is commercially available and reimbursed in 
participant’s country, or any other reason, whichever is first. 
The efficacy co-primary analysis will be conducted on the ITT population, defined as all 
participants who have given their informed consent and for whom there is confirmation of 
successful allocation of a randomization number by the IRT. Participants will be included in 
a treatment arm as randomized, regardless of whether participants receive any study drug or 
receive a different study drug from which they were randomized. The PK co-primary analysis will 
be conducted on the Per Protocol-PK (PP-PK) population defined as all randomized participants 
who have received at least eleven isatuximab doses out of twelve up to C5D15 (one dose omission 
permitted during Cycle 1), with isatuximab C6D1 (predose) concentration results from PK sample 
collected within the defined per protocol time window and adequate documentation of dosing and 
sampling dates and times.  
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4.2 
AT HOME ADMINISTRATION  
Home administration may be possible where permitted by national and local regulations. 
After the first 5 cycles, at home administration by an HCP may be proposed to the participants in 
the SC arm on D15 from Cycle 6 onwards. Visits at Day 1, on the other hand, from C6 onwards 
will always be outpatient visits at clinic. The Investigator is responsible for approving 
a participant’s initiation with home injections and is still responsible for all study procedures and 
participant’s safety even when delegating infusion responsibilities to the home care company 
during this clinical study. 
The decision to propose at home administration on D15 will be based on the absence of IR at C4 
and C5, the hematology test at Day 1 of each corresponding cycle and the Investigator’s 
judgement. Participant willingness and ability to adhere to the requirements of home 
administration need to be taken into account before initiating it. 
D15 at home administration will be preceded immediately prior administration by a questionnaire 
comprising heart rate, systemic blood pressure, pulse oximetry, oral temperature, and appearance 
of novel clinical symptoms (Section 6.4.1, Section 8.4.2.1). At-home administration will require 
full completion of the questionnaire (filling of the questionnaire should be recorded) while 
participant should be addressed to investigator site if he or she does not meet all the criteria. 
Reason for non-administration at-home (including data from the questionnaire) should be 
recorded.  
4.3 
SCIENTIFIC RATIONALE FOR STUDY DESIGN  
4.3.1 Rationale for the overall design  
Randomized blinded clinical trials remain the cornerstone of evidence-based practice. However, 
due to the presence of a SC formulation and an IV formulation of isatuximab, participant blinding 
is not feasible. This trial was designed to prove the non-inferiority of SC isatuximab compared to 
intravenous formulation in combination of pomalidomide and dexamethasone in terms of ORR 
and Ctrough at steady state.  
4.3.2 Rationale for co-primary endpoints  
4.3.2.1 ORR  
Achieving deep responses is associated with long-term outcomes in patients with MM  
(18, 19, 20, 21).  
The association between depth of response and PFS in RRMM has been evaluated using results 
from 102 clinical trials (22). Regression analysis indicated a correlation between the overall 
response rates (ORR) and median PFS (R2 = 0.5). Another meta-analysis including 7 recent 
Phase III trials in RRMM demonstrated a strong correlation between ORR and PFS (R2 = 0.84) 
(23).  
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In the ICARIA-MM study, that enrolled RRMM participants who had received at least two prior 
lines of therapy, the ORR were 60.4% versus 35.3% (p<0.0001) in the IPd and Pd arms, 
respectively, with a median PFS higher in the IPd versus Pd arm (11.5 versus 6.5 months, 
p=0.001, respectively).  
In the IKEMA study, that included RRMM participants who had received 1 to 3 prior lines of 
therapy, the ORR was numerically higher in the IKd arm compared to the Kd arm (86.6% and 
82.9%, respectively)  
A margin that corresponds to retaining 40% of the demonstrated clinical effect of CD38+Pd over 
Pd was chosen because the control arm, Pd, is an efficacious standard of care regimen for RRMM 
participants (24, 25). 
Therefore, retaining 40% of the demonstrated clinical benefit of CD38+Pd over Pd results in 
promising efficacy results for the Isa-SC+Pd combination. If the study demonstrates an ORR of 
60.4% in the Isa-IV+Pd arm of Study EFC15951, which is observed ORR in ICARIA-MM study, 
then it takes an observed Isa-SC+Pd arm’s ORR of 58.8% or higher to claim non-inferiority. This 
difference represents less than 2% between the two arms and is considered to be a clinically 
acceptable difference. In addition, the use of the proposed effect retention is aligned with the FDA 
Guidance for Industry “Non-Inferiority Clinical Trials to Establish Effectiveness” 
(November 2016), including: 
• The pharmacological effect of Isa-SC is similar to Isa-IV, as shown in the TCD15484 
study. 
• Isa-SC has some important advantages over Isa-IV including the reduction in 
the frequency of IRs due to the slower SC absorption and the shorter duration of injection 
(10 minutes) allowing to minimize the time the participant spent in healthcare facility. 
Overall, the increased convenience of the delivery method aims to improve the long- term 
treatment adherence and maintain optimal disease control. 
4.3.2.2 Ctrough at steady state (Cycle 6 D1)  
Ctrough at steady state (C6D1 [predose]) was selected based on Health Authorities feedback. 
4.4 
JUSTIFICATION FOR DOSE  
4.4.1 Justification for intravenous isatuximab, pomalidomide and dexamethasone  
Oral pomalidomide, dexamethasone and intravenous isatuximab will be used at the dose reported 
in the ICARIA trial (NCT02990338) and as per recommended posology in the summary of 
products characteristics (SmPC) or Package Insert. 
4.4.2 Justification for subcutaneous dosing of Isatuximab  
As previously stated in Section 2.2.3.2, in Study TCD15484 efficacy was comparable between 
the Isatuximab IV and SC arms. In addition, in the Isatuximab SC arm there were no new safety 
signal, in comparison to the IV arm. The determination of the SC dosing is therefore based on 
the PK parameters.  
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The PK analyses (NCA and population PK modelling) from Study TCD15484 based on 
the first two dose escalation cohorts showed comparable exposure between SC cohorts despite 
the dose increase (1000 versus 1400 mg) due to unbalanced covariates in the 2 cohorts 
(see Section 2.2.3.2). As a consequence, the SC bioavailability of isatuximab is likely to be 
close to that observed for the 1400 mg SC cohort (ie, 60-65%) as participants from IV and 
SC 1400 mg cohorts were generally similar in terms of influential PK covariates.  
In order to select the SC dose, trial simulations were performed to further establish 
the comparability of CT4W between isatuximab SC and IV and predict the probability of success 
as there is a strong relationship between CT4W and efficacy, and there was no apparent 
relationship between drug exposure in the therapeutic dose range and adverse events of interest. 
Model based simulations were conducted using a previously developed structural/covariate model 
(POH0503) (26) for IV isatuximab administration with the addition of SC population PK 
parameters (ie, the absorption rate constant Ka and the bioavailability F) derived from the popPK 
model built with data from TCD15484 only and available at the time of analysis. Different values 
were considered for typical F but the same arbitrary associated inter-individual coefficient of 
variability of 35% was used in all the simulations scenarios. Clinical trial simulations were 
performed to select a SC dose that would be non-inferior to IV 10 mg/kg dose (recommended 
dose for isatuximab IV). For this, a larger scale clinical trial compared to TCD15484 was 
considered with 1000 replicate trials for each dose scenario (eg, SC doses of 1000 mg, or 
1400 mg QW/Q2W with different values for F and to be compared to IV dose of 10 mg/kg 
QW/Q2W). For each trial, 85 participants for a given SC dose of interest and 43 participants for 
10 mg/kg IV were resampled from the subgroup of 198 participants from Studies TCD14079 
Part A and EFC14335 that were included in the previous population PK analysis POH0503. 
The outcome of each individual trial is considered positive if the lower bound of the 90% CI for 
the ratio of the geometric means (SC/IV) is at least 0.80. Then, the probability of success 
calculated on 1000 trial replicates was derived for a given SC dose scenario. Considering the SC 
bioavailability would be in the range of 60-65%, trial simulations show a probability of success of 
at least 90% for a 1400 mg SC dose whereas the PoS was below 50% for a lower dose 
(ie, 1000 mg). 
In addition, isatuximab exposure-driven tumor growth inhibition modeling, with serum M-protein 
as a surrogate for tumor growth, was performed using data from participants who had evaluable 
serum M-protein at baseline and at least one on treatment assessment in Study TCD15484 
(n = 23). Serum M-protein profiles were simulated with the model for IV 10 mg /kg, SC 1000 mg, 
and SC 1400 mg QW/Q2W regimens using individual PK/PD parameters. Predicted change of 
serum M-protein from baseline at Week 8 and time to progression (TTP) defined as the time up to 
an increase of serum M-protein greater than 25% with absolute increase greater than 5 g/L 
compared to the Nadir (criterion based on only M-protein predictions) were used for comparison 
of the different doses/route of administration. SC 1400 mg dose resulted in deeper reductions in 
serum M-protein at Week 8 compared to SC 1000 mg and IV 10 mg/kg, with predicted 
median% change of baseline [5-95th percentile] of -85.6 [-98.5;-58.1], -77.8 [-96.6;-48.8] 
and -79.5 [-97.2; -41.6], respectively, translating into a longer time to progression.  
Further simulations based on the POH0503 typical population model parameters and including SC 
parameters, were performed to evaluate the impact of extreme body weights on drug exposure 
after SC flat dosing. Flat SC dosing results in a higher exposure in lower weight participants 
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compared to higher weight participants. Compared to a typical participant with median weight 
(76 kg), a 50 kg participant (5th percentile of body weight) would have 27-33% higher exposure 
and a 100 kg participant (95th percentile of body weight) would have 15-18% lower exposure 
at 1400 mg SC (Figure 2). The trend was reversed for isatuximab IV given as body weight-based 
dose, where higher exposure is observed at higher body weight. In addition, the simulated Cmax for 
the lower body weight typical participant (50 kg) for SC was comparable to the Cmax in the higher 
body weight typical participant (100 kg) for IV route, but, in general, the Cmax values for the overall 
population would be lower for SC route. Overall, flat SC dosing resulted in generally comparable 
variability as body weight based IV dose, thus supporting the choice of a flat SC dose.  
In conclusion, the PK and PK/PD modeling and simulations support the choice of a flat SC dose 
of 1400 mg in combination therapy. 
Figure 2 - Simulated isatuximab plasma concentration-time profiles for participants with low 
(5th percentile), median or high (95th percentile) body weight after flat SC dose of 
1400 mg - Comparison with body weight based IV dose of 10 mg/kg  
 
For SC, F was set to 0.625 and ka to 0.0105. 
Body weight distribution POH0503 database: 5th percentile :51 kg, median 76 kg and 95%:110 kg. 
Icaria population: Low Body Weight (<50 kg): 2.7% of total; High Body Weight (≥100 kg): 6.0% of total. 
4.5 
DURATION OF STUDY PARTICIPATION  
The participant will be considered in the study from informed consent signature until death, 
consent withdrawal, or the overall survival (OS) analysis cut-off date (approximately 30 months 
after LPI), whichever comes first.  
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The duration of the study for a participant will include a period for screening of up to 28 days. 
A cycle duration is 28 days. All AEs occurring after informed consent signature will be reported 
up to 30 days after last study treatment administration.  
After study treatment discontinuation, participants will return to the study site 30 days after 
the last dose of study treatment for end of treatment (EOT) or before further anti-myeloma 
therapy initiation, whichever comes first (Section 7).  
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. 
Participants who discontinue the study treatment due to PD will be followed up every 3 months 
(12 weeks ±7 days after last study treatment administration) for further anti-myeloma therapies, 
second primary malignancies, PFS2, and survival, until death or the final OS analysis cut-off date, 
whichever comes first. Participants who discontinue the study treatment prior to documentation of 
PD will be followed-up every 4 weeks until disease progression (even for participants who would 
initiate further anti-myeloma therapy without PD), 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 final OS analysis cut-off date, whichever 
comes first.  
Before the final OS analysis cutoff date, participants will be allowed to continue therapy until 
disease progression, unacceptable adverse events (AEs), participant request to discontinue 
treatment or any other reason, whichever comes first. Participants still on treatment at the time of 
the final OS analysis cut-off date, and benefiting from the study treatment, can continue 
the treatment until disease progression, unacceptable AEs, participant wish to discontinue further 
study treatment, until study treatment is commercially available and reimbursed in participant’s 
country, or for any other reason, whichever comes first. For cycles administered with products 
supplied by the Sponsor after the cut-off date, 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), product 
administration, and reason of EOT will continue to be collected. 
4.6 
END OF STUDY DEFINITION  
The end of the study is defined as the last visit of the last participant in the study.  
4.7 
 INTERIM ANALYSIS  
No interim analysis with alpha spending is planned for this study. 
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4.8 
TIMINING OF PLANNED ANALYSIS  
The cut-off date for the primary analysis is approximately 6 months after the LPI, which includes 
analysis on the primary endpoint and secondary endpoints when applicable. An update of PFS and 
OS will be performed 15 months after LPI. The cut-off date for final OS analysis will be 
approximately 30 months after LPI.  
4.9 
STUDY COMMITTEES  
Refer to Section 10.1.5 for Steering Committee and Data Monitoring Committee information. 
An IRC blinded to treatment assignment will determine disease response and progression 
according to efficacy MM laboratory data (central laboratory results), local BM for plasma cell 
infiltration assessment as recorded in the electronic case report form (eCRF), and imaging as per 
IMWG criteria and in line with the IRC charter up to primary analysis. 
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5 
STUDY POPULATION  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
as protocol waivers or exemptions, is not permitted.  
5.1 
INCLUSION CRITERIA  
Participants are eligible to be included in the study only if all the following criteria apply: 
Age 
I 01. Participant must be ≥18 years of age (or the legal age of consent in the jurisdiction in 
which the study is taking place), at the time of signing the informed consent.  
Type of participant and disease characteristics 
I 02. Participants must have a documented diagnosis of multiple myeloma. 
I 03. Participants with measurable disease defined as at least one of the following: 
- 
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 and/or, 
- 
Serum free light chain (FLC) assay: Involved FLC assay ≥10 mg/dL (≥100 mg/L) and 
an abnormal serum FLC ratio (<0.26 or >1.65). 
I 04. Participants must have received at least 1 prior line of anti-myeloma therapy, which must 
include lenalidomide and a PI (bortezomib, carfilzomib or ixazomib) given alone or in 
combination. 
Note: An induction treatment followed by ASCT and consolidation/maintenance is 
considered as one line of treatment. 
I 05. Participants must have documented evidence of progressive disease on or after 
the last regimen.  
I 06. Participants who received only one prior line of therapy must have progressed on or within 
60 days after end of the lenalidomide therapy before signing the informed consent form 
(ICF), ie, lenalidomide refractory.  
Weight 
None. 
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Sex, contraceptive/barrier method and pregnancy testing requirements 
I 07. All 
Contraceptive use by men and women should be consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies. 
a) Male participants 
Male participants agree to practice true abstinence or agree to use contraception and 
refrain from donating sperm as defined in Appendix 4, Section 10.4 while receiving 
study treatment, during dose interruptions and at least 28 days after the last dose of 
pomalidomide or 5 months following the last dose of isatuximab, whichever occurs 
last, even if he has undergone a successful vasectomy. 
b) Female participants 
A female participant is eligible to participate if she is not pregnant, not breastfeeding, 
and either is not a female of childbearing potential (FCBP) or agrees to practice 
complete abstinence or use contraception as described below. 
(Note: A FCBP as defined in Appendix 10.4 [Section 10.4.2.1]). 
A FCBP must have a negative serum or urine pregnancy test with a sensitivity of 
at least 25 mIU/mL within 10 to 14 days prior to and again within 24 hours of starting 
study treatment and must either commit to continue abstinence from heterosexual 
intercourse or begin TWO acceptable methods of birth control, one highly effective 
method and one additional effective method AT THE SAME TIME, at least 28 days 
before she starts study treatment, during dose interruptions and for at least 5 months 
following discontinuation of study treatment. An FCBP must also agree to ongoing 
pregnancy testing during the entire duration of treatment. 
Informed Consent 
I 08. Capable of giving signed informed consent as described in Appendix 1 (Section 10.1.3) 
which includes compliance with the requirements and restrictions listed in the ICF and in 
this protocol. 
Other Inclusion Criteria 
I 09. Introduced as per Protocol Amendment 01: Country-specific requirement applicable for 
Norwegian clinical sites; see Appendix 8, Section 10.8 (Country-specific requirements). 
a) Male participants that agree to not donate semen or sperm during therapy or for at least 
4 weeks following discontinuation of pomalidomide or 5 months following 
discontinuation of isatuximab. 
b) Participants that agree to not donate blood during therapy and for at least 3 months 
following discontinuation of pomalidomide. 
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5.2 
EXCLUSION CRITERIA  
Participants are excluded from the study if any of the following criteria apply: 
Medical conditions 
E 01. Primary refractory multiple myeloma defined as: participants who have never achieved 
at least a minimal response (MR) with any treatment during the disease course. 
E 02. Inability to tolerate thromboprophylaxis or excess risk of bleeding. 
Prior/concomitant therapy 
E 03. Participants with prior anti-CD38 treatment: a) administered less than 9 months before 
randomization or, b) Intolerant to the anti-CD38 previously received.  
E 04. Prior therapy with pomalidomide. 
E 05. Any anti-myeloma drug treatment within 14 days before randomization, including 
dexamethasone. 
E 06. Prior allogenic HSC transplant with active graft versus host disease (GvHD) (GvHD any 
grade and/or being under immunosuppressive treatment within the last 2 months prior to 
randomization). 
E 07. Any major procedure within 14 days before the initiation of the study treatment: 
plasmapheresis, major surgery (kyphoplasty is not considered a major procedure), 
radiotherapy. 
Prior/concurrent clinical study experience 
E 08. Received any other investigational drugs or prohibited therapy for this study within 
28 days or 5 half-lives from randomization, whichever is shorter. 
Diagnostic assessments 
E 09. ECOG status >2. 
E 10. Platelets <50000 cells/µL. Platelet transfusion is not allowed within 7 days before 
the screening hematological test. 
E 11. ANC <1000 μL (1  109/L). The use of granulocyte-colony stimulating factor (G-CSF) 
within 14 days from the screening hematological test is not allowed to reach this level. 
E 12. Estimated Glomerular Filtration Rate (eGFR) <30 mL/min/1.73 m2 (modification of diet in 
renal disease MDRD Formula). 
E 13. Total bilirubin >1.5 × upper limit of normal (ULN) (>3 × ULN if Gilbert syndrome). 
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E 14. Serum calcium (corrected for albumin) level above the ULN range (treatment of 
hypercalcemia is allowed and participants may enroll if hypercalcemia returns to normal 
with standard treatment). 
E 15. Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >3  ULN. 
E 16. Ongoing toxicity (excluding alopecia and those listed in eligibility criteria) from any prior 
anti-myeloma therapy >Grade 1 (Version 5.0 of NCI-CTCAE). 
E 17. Hypersensitivity to IMiDs (thalidomide or lenalidomide) defined as any hypersensitivity 
reaction leading to stop IMiDs within the 2 first cycles or reaction which does meet 
intolerance definition. 
E 18. Known intolerance or hypersensitivity to dexamethasone, to any of isatuximab SC 
formulation excipients (L-histidine; L-histidine hydrochloride monohydrate, L-arginine 
monohydrochloride, sucrose, polysorbate 80, and poloxamer 188), or to any of the 
components study therapy that are not amenable to premedication with steroids, or H2 
blockers, that would prohibit further treatment with these agents. 
E 19. Participants with:  
a) Contraindication to dexamethasone, and/or, 
b) Contraindication to pomalidomide, and/or, 
c) ≥Grade 2 peripheral neuropathy. 
E 20. Significant cardiac dysfunction; myocardial infarction within 12 months of randomization; 
unstable, poorly controlled angina pectoris. 
E 21. Diagnosed or treated for another malignancy within 3 years prior to randomization with 
the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of 
the skin, an in situ malignancy, or low risk prostate cancer after curative therapy. 
E 22. Known acquired immunodeficiency syndrome (AIDS)-related illness or known human 
immunodeficiency virus (HIV) disease requiring antiviral treatment, known active 
hepatitis A infection (defined as positive hepatitis A antigen or positive IgM), and current 
active or chronic hepatitis B (HBV) or hepatitis C (HCV) infection. Participants with 
chronic HBV or HCV disease that is controlled under antiviral therapy are allowed. 
HIV serology will be tested at screening for participants of countries where required as per 
local regulations. Hepatitis B and C serology will be tested at screening for all participants.  
E 23. Malabsorption syndrome or any condition that can significantly impact the absorption of 
pomalidomide. 
E 24. Active primary amyloid light-chain amyloidosis (evidence of end organ damage or 
receiving treatment for amyloidosis). 
E 25. Concomitant plasma cell leukemia. 
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E 26. Daily requirement for corticosteroids (equivalent to >10 mg/day of prednisone) for more 
than 7 days (except for inhalation corticosteroids). 
Other exclusions 
E 27. Individuals accommodated in an institution because of regulatory or legal order; prisoners 
or participants who are legally institutionalized.  
E 28. Any country-related specific regulation that would prevent the participant from entering 
the study; see Appendix 8, Section 10.8 (country-specific requirements). 
E 29. Participants are employees of the clinical study site or other individuals directly involved 
in the conduct of the study, or immediate family members of such individuals 
(in conjunction with Section 1.61 of the ICH-GCP Ordinance E6 [R2]). 
E 30. Any severe acute or chronic medical condition which could impair the ability of 
the participant to participate in the study or interfere with interpretation of study results 
(eg, systemic infection unless specific anti-infective therapy is employed) or participant 
unable to comply with the study procedures. 
E 31. Participant not suitable for participation, whatever the reason, as judged by 
the Investigator, including medical or clinical conditions, or participants potentially at risk 
of noncompliance to study procedures. 
E 32. Any specific situation during study implementation/course that may raise ethics 
considerations. 
 
5.3 
LIFESTYLE CONSIDERATIONS  
Not applicable.  
5.4 
SCREEN FAILURES  
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomized. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure participants to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure reasons, eligibility criteria, 
and any SAE. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened during the open screening period, provided they meet at that time all inclusion and 
none of the exclusion criteria. A different participant identification number will be issued, while 
the other identification for this participant should be recorded as a screen failure. There is no 
requirement for a waiting period between a screen failure date and the rescreening date.  
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Screen failure participants can be re-screened, and all screening procedures will have to be 
re-started for these participants. There is no limitation in the number of times a participant will be 
screened. 
All screening procedures must be repeated except for radiological disease assessment if it has 
been done in the 28 days prior to novel randomization. 
In case the participant is a temporary screen failure, there is no need to have the participant 
reconsent (ie, sign a new ICF) if the participant ends up participating in the study. However, if 
the reason for temporary screen failure is a reason that might have altered the initial agreement 
given by the participant to participate in the study, the Investigator should ensure the willingness 
of the participant to continue or repeat some screening procedures and to confirm his/her 
participation in the trial. This oral agreement should be documented in the participant’s chart. All 
tests outside of the protocol window should be repeated and entered to the additional pages. 
5.5 
CRITERIA FOR TEMPORARILY DELAYING 
ENROLLMENT/RANDOMIZATION/ADMINISTRATION OF STUDY INTERVENTION  
During a regional or national emergency declared by a governmental agency, if the site is unable 
to adequately follow protocol mandated procedures, contingency measures are proposed in 
Section 10.9 (Appendix 9: Contingency measures for a regional or national emergency that is 
declared by a governmental agency) should be considered for 
screening/enrollment/randomization/administration of study intervention. 
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6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY  
Study interventions are all pre-specified IMPs, AxMPs, and medical devices and other 
interventions (eg, surgical and behavioral) intended to be administered to the study participants 
during the study conduct. 
 
6.1 
STUDY INTERVENTION(S) ADMINISTERED  
6.1.1 Investigational medicinal products  
6.1.1.1 Isatuximab  
6.1.1.1.1 Isatuximab IV formulation  
Isatuximab will be administered at the dose of 10 mg/kg weekly for 4 weeks (Cycle 1) and Day 1 
and 15 of subsequent cycles. The calculation of the Isatuximab IV dose will be based on the most 
recent weight available. 
Isatuximab infusion rate are described in Table 8.  
Table 8 - Isatuximab intravenous infusion rate  
 
Dilution 
volume 
Initial 
rate 
Absence of 
infusion-related 
reaction 
Rate increment 
Maximum 
rate 
First infusion 
250 mL 
25 mL/hour 
60 min 
25 mL/hour every 
30 minutes 
150 mL/hour 
Second infusion 
250 mL 
50 mL/hour 
30 mina 
50 mL/hour for 
30 minutes then 
increase to 
100 mL/hour  
200 mL/hour 
Third and subsequent infusion 
250 mL 
200 mL/hour 
 
 
200 mL/hour 
a Applicable to Grade ≥2 infusion reactions. 
 
Regarding potential reduction of infusion rates due to IRs active comparator arm, the following 
steps are recommended:  
• First infusion: in case of Grade 2 IR during first infusion, infusion could be restarted 
at one-half (12.5 mL/hour) of the initial infusion rate 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, up to a maximum of 150 mL/hour, until the total volume is 
infused.  
• Second infusion: in case of Grade 2 IR during second infusion, infusion could be restarted 
at one-half (25 mL/hour) of the initial infusion rate 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, up to a maximum of 200 mL/hour, until the total volume is 
infused.  
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• Third and subsequent infusions: in case of Grade 2 IR during third infusion, infusion 
could be restarted at one-half (100 mL/hour) of the infusion rate 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, up to a maximum of 200 mL/hour, until 
the total volume is infused. 
Please refer to the pharmacy manual for further details with regards to formulation.  
6.1.1.1.2 Isatuximab SC formulation  
Isatuximab will be administered weekly for 4 weeks (Cycle 1) and on Day 1 and Day 15 of each 
subsequent cycle, at the nominal dose of 1400 mg. 
Isatuximab will be administered by an HCP (either on-site or, from Cycle 6, at-home for D-15, 
see Section 4.2) in the periumbilical region at a single site, using an investigational device 
injector; injection site will be rotated from one administration to the other.  
See Table 9 for more detailed description of dose and method of administration. 
6.1.1.2 Dexamethasone  
Dexamethasone will be taken orally at a dose of 40 mg (or 20 mg for participant ≥75 years) on 
Day 1, 8, 15, and 22 (to be repeated every 28 days). 
If a dose of dexamethasone is missed, it should be taken as soon as possible within the next 
2 days. The dose per cycle must not exceed 160 mg (80 mg if the participant is ≥75 years old). 
Participants will be asked to maintain a diary to record the doses of dexamethasone taken orally 
(except those administered by the study nurse/ Investigator). 
When administered on the same day as other investigational medicinal products (IMP)s, 
dexamethasone will be administered before all other IMPs. 
Particular care is needed when treating participants with glaucoma (or family history of 
glaucoma) as well as when treating participants with ocular herpes simplex, because of possible 
corneal perforation, as prolonged use of corticosteroids may produce subcapsular cataracts and 
glaucoma, and may result in impaired vision including loss of vision. Investigators are 
recommended to refer to product SmPC of dexamethasone.  
6.1.1.3 Pomalidomide  
Pomalidomide will be taken orally at a dose of 4 mg on Days 1 to 21 (to be repeated every 
28 days). Pomalidomide may be taken with water and should be swallowed whole. Participants 
are not permitted to break, chew, or open the capsules. Pomalidomide should be taken with or 
without food, preferably at the same time every day. Participants will be asked to maintain a diary 
to record the doses of pomalidomide (except those administered by the study nurse/Investigator). 
If a dose of pomalidomide is missed, it should be taken as soon as possible on the same day. If it 
is missed for the entire day, the dose should not be made up and will be considered omitted (and 
will not be replaced). The next scheduled dose should be taken at the next scheduled time point. 
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Participants should be monitored for any new or worsening neurologic, cognitive or behavioral 
signs and symptoms.  
If progressive multifocal leukoencephalopathy (PML) is suspected, study treatments should be put 
on hold immediately until a diagnosis of PML has been definitively excluded. If suspected, 
the Investigator should refer participant to a specialist and appropriate diagnosis testing should be 
initiated [Serial Magnetic resonance imaging (MRI) with contrast and cerebrospinal fluid analysis 
for John Cunningham Virus] [Please refer to PML diagnostic criteria by American Association of 
Neurology (AAN) (27)]. 
If PML is confirmed, pomalidomide should be discontinued and isatuximab and dexamethasone 
should be put on hold. [Please refer to PML diagnostic criteria by AAN (27)] Isatuximab and 
dexamethasone could be resumed after recovery of PML based on Investigator's judgement and 
after discussion with the Sponsor. 
Table 9 - Study intervention(s) administered  
Intervention 
label 
Isatuximab IV 
Isatuximab SC 
Dexamethasone 
Pomalidomide 
Intervention 
name 
Isatuximab IV 
Isatuximab SC 
Dexamethasone 
Pomalidomide 
Intervention 
description 
Single use vial 
Single use vial 
Tablets 
Capsules 
Type 
Drug 
Drug 
Drug 
Drug 
Dose 
formulation 
Concentrate solution for 
IV infusion 
Solution for 
Subcutaneous 
administration 
Tablets 
Hard capsules 
Unit dose 
strength(s) 
Concentration: 20 mg/mL 
Dosage presentation: 
500 mg/25 mL 
or 
100 mg/5 mL 
140 mg/mL 
isatuximab, 
 
4 mg 
8 mg 
1 mg 
2 mg 
3 mg 
4 mg 
Dosage level(s) 
10 mg/kg QW (Cycle 1) 
10 mg/kg Q2W 
(subsequent cycles) 
1400 mg QW 
(Cycle 1) 
1400 mg Q2W 
(subsequent cycles) 
40 mg QW for participants 
<75 years of age  
20 mg QW ≥75 years of age 
4 mg on Day 1 to 
21 in a 28-days 
cycle 
Route of 
administration 
IV 
SC 
Oral 
Oral 
Use 
Active comparator  
experimental 
Active comparator  
Active comparator  
IMP 
IMP 
IMP 
IMP 
IMP 
Packaging and 
labeling 
Isatuximab (SAR650984) 
will be provided in 1 glass 
vial per box. The content 
of the labeling will be in 
accordance with the local 
regulatory specifications 
and requirements 
Study Intervention 
will be provided in 
one glass vial per 
box. Each vial and 
box will be labeled 
as required per 
country requirement 
Supplied as blisters 
containing 10 tablets each 
(1kit = 2 blisters of 10 tablets 
into a wallet) except for US 
where it is supplied in a child 
resistant bottle containing 
100 tablets each 
Supplied as 
blisters of 7 hard 
capsules each 
(1 kit = 3 blisters 
of 7 hard capsules 
into a wallet).  
[Current/former 
name(s) or 
alias(es)] 
Isatuximab, SAR650984 
Isatuximab, 
SAR650984 
Dexamethasone 
Pomalidomide 
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6.1.1.4 Study arms  
Table 10 - Study arm(s)  
Arm title 
Arm SC. 
Arm IV. 
Arm type 
Experimental. 
Active comparator. 
Arm description 
Participants will receive isatuximab SC 
1400 mg QW (ie, on Day 1, 8, 15, and 22) in 
first cycle (28 days) then 1400 mg Q2W 
(ie, on Day 1 and Day 15) for subsequent 
28-day cycles. 
 
Participants will receive in addition 
dexamethasone 40 mg QW (<75 years of 
age) or 20 mg (≥75 years of age) at Day 1, 
8, 15, and 22 of every 28 days cycle, as well 
as pomalidomide 4 mg/day from Day 1 to 
Day 21 of every 28 days cycle. 
Participants will receive isatuximab IV 
10 mg/kg QW (ie, on Day 1, 8, 15, and 22) in 
first cycle (28 days) and then 10 mg/kg Q2W 
(ie, on Day 1 and Day 15) for subsequent 
28-day cycles. 
 
Participants will receive in addition 
dexamethasone 40 mg QW (<75 years of 
age) or 20 mg (≥75 years of age) at Day 1, 8, 
15, and 22 of every 28 days cycle, as well as 
pomalidomide 4 mg/day from Day 1 to 
Day 21 of every 28 days cycle. 
Associated 
intervention labels 
Isatuximab SC. 
Dexamethasone. 
Pomalidomide. 
Isatuximab IV. 
Dexamethasone.. 
Pomalidomide 
Abbreviations: IV = intravenous; QW = once a week; Q2W =once every 2 weeks; SC = subcutaneous. 
6.1.2 Auxillary medicinal products  
All participants will receive premedication to prevent or reduce the incidence or severity of 
isatuximab-related IRs, at least 15 to 30 minutes (but no longer than 60 minutes) prior to 
isatuximab infusion (regardless of route). Participants who do not experience IRs after 
4 consecutive administrations of isatuximab may have their need for subsequent premedication 
reconsidered at the Investigator’s discretion, except for montelukast which should be administered 
only on Cycle 1. 
The standard premedication regimen will include, in this order: 
• Montelukast (ATC code: R03DC03)10 mg PO (or equivalent; to be administered during 
Cycle 1 only). 
• Dexamethasone (ATC code: H02AB02) PO will also be given in the same dose as stated 
in Section 6.1.1. 
- 
Methylprednisolone (ATC code: H02AB04) (or equivalent):100 mg IV if 
dexamethasone is discontinued earlier than isatuximab and premedication is still 
needed. 
• Acetaminophen (paracetamol ATC code: N02BE01) 650 to 1000 mg orally. 
• Diphenhydramine (ATC code: R06AA02) 50 mg PO (or equivalent: eg, cetirizine, 
promethazine, dexchlorpheniramine, according to the approval availability) or 
Diphenhydramine 25 to 50 mg IV (or equivalent). Intravenous route is preferred for 
at least the first 4 IV isatuximab infusions. 
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6.1.3 Devices  
Dispensing devices have to be used for administration of isatuximab in the SC arm only. 
Preparation and SC administration of isatuximab in the periumbilical region using 
the (investigational) isatuximab injector device will be performed by study staff. 
The (investigational) isatuximab injector device is a sterile, single-use, disposable, elastomeric, 
user-filled wearable injector. The device will be supplied in a blister package into a box. Both 
the blister package and the box will be labeled according to the local requirements. 
The (investigational) isatuximab injector device includes an adhesive backing to secure it to 
the injection site during administration. Injection sites with the device are permitted only on 
the abdominal region. At the end of dosing, the injection needle retracts into the device housing 
and the device enters a locked-out state to prevent reuse. 
The volume to be injected at each administration will be injected at a single site; injection site will 
be rotated from one administration to the next. The administration times including any pauses or 
stoppages will be recorded for all cohorts. 
Further detailed instructions for preparation and administration using the (investigational) 
isatuximab injector device are provided in Pharmacy Manual. Study staff must be trained on 
proper use of the device prior to use.  
All medical device incidents, including those resulting from malfunctions of the device, must be 
detected, documented, and reported by the Investigator throughout the study (see Section 10.7.4). 
6.2 
PREPARATION, HANDLING, STORAGE, AND ACCOUNTABILITY  
6.2.1 Responsibilities  
Only participants enrolled in the study may receive study intervention and only authorized site 
staff may supply, prepare, or administer study intervention. 
The Investigator, the hospital pharmacist, or other personnel allowed to store and dispense 
the study treatment will be responsible for ensuring that the IMP/AxMP/device used in the clinical 
trial is securely maintained as specified by the Sponsor and in accordance with applicable 
regulatory requirements. 
All IMP/AxMP/device will be dispensed in accordance with the Investigator's prescription, and it 
is the Investigator's responsibility to ensure that an accurate record of IMP/AxMP/device issued 
and returned is maintained. 
Any quality issue noticed with the receipt or use of an IMP/AxMP/device (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 pharmacy manual and Section 8.6.8).  
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A potential defect in the quality of IMP/AxMP/device 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 IMP/AxMP/device and 
eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP/AxMP/device to a third party (except 
for DTP shipment, for which a courier company has been approved by the Sponsor), allow 
the IMP/AxMP/device to be used other than as directed by this clinical trial protocol, or dispose 
IMP/AxMP/device in any other manner. 
6.2.2 Treatment accountability and compliance  
Administration of the IMP/AxMP/device will be supervised by the Investigator or 
Subinvestigator. 
The person responsible for dispensing IMP/AxMP/device is required to maintain adequate records 
of the IMP/AxMP/device. These records (eg, drug movement form) include the date 
the IMP/AxMP/device is received from the Sponsor, dispensed for participant, 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 IMP/AxMP/device administration to the participant will record 
precisely the date and the time of the IMP/AxMP/device administration to the participant. 
For dexamethasone PO and pomalidomide PO, a participant diary will be used to document all 
oral dexamethasone or pomalidomide (if not administered at the site level). 
6.2.3 Return and/or destruction of treatments  
Partially used and used IMP/AxMP/device 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. Any study materials provided by the Sponsor (IMP 
and/or medical devices) must be retained for return to the Sponsor for investigation if subject to 
a product technical complaint (see Section 8.6.8). 
The Investigator must not destroy the unused study treatment unless Sanofi provides written 
authorization. 
6.2.4 Isatuximab subcutaneous formulation  
All details of preparation and administration of isatuximab are provided in the Pharmacy Manual. 
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Storage of Isatuximab SC should be in a secure area with restricted access. Isatuximab is to be 
stored at +2°C to +8°C (36°F to 46°F), is not to be frozen, and is to be protected from light. All 
containers must be kept in their box until use. 
For at-home administration, isatuximab will be provided by the site on Day 1 and stored similarly 
(without the secure area) for D-15 administration.  
For first at-home administration, the participant will be followed 30 min after the injection. 
Subsequent follow-up is left as per investigator judgment. 
6.2.5 Isatuximab intravenous formulation  
For participant with IV administration, the appropriate volume of isatuximab will be diluted in 
a 250 mL infusion bag of 0.9% sodium chloride solution or 5% dextrose solution. Please refer to 
the Pharmacy Manual for more information. 
See Section 6.1.1.1.1 for more detailed description of dose and method of administration. 
Storage of isatuximab IV should be in a secure area with restricted access in site. Isatuximab is to 
be stored at +2°C to +8°C (36°F to 46°F), is not to be frozen, and is to be protected from light. All 
containers 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. 
6.2.6 Pomalidomide  
Countries, where commercial supplies are desirable based on the country specific regulatory 
requirements, Pomalidomide from commercial supplies can be used. Otherwise, it will be 
re-labeled by the Sponsor according to Good Manufacturing Practice guidelines before supplies 
are provided by the study sites. 
When commercial supplies will be used: 
• Please refer to package insert or SmPC for further details as regards to formulation, 
storage, and handling procedures. 
• When applicable the Pomalidomide Pregnancy Prevention Plan (Appendix 15, 
Section 10.15) or the country specific risk management plan (in countries where 
pomalidomide is not supplied by the Sponsor) has to be followed to ensure adherence of 
the pregnancy risk mitigation plan already in place in addition to the protocol 
requirements.  
For a regional or national emergency declared by a governmental agency that results in travel 
restrictions, confinement, or restricted site access, pomalidomide 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. 
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Further details as regards to formulation, storage and handling procedures will be provided in 
Package Insert or SmPC of commercial study treatment. 
6.2.7 Dexamethasone  
Dexamethasone PO will be supplied and re-labeled by the Sponsor according to Good 
Manufacturing Practice guidelines before supplies are provided to the sites. 
For a regional or national emergency declared by a governmental agency that results in travel 
restrictions, confinement, or restricted site access, dexamethasone 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. 
Further details as regards to formulation, storage and handling procedures will be provided in 
Package Insert or SmPC of commercial study treatment. 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING  
6.3.1 Blinding rules  
Potential bias will be reduced by the following steps: 
• During the trial, administration of isatuximab SC or IV will be open-label, and no attempts 
will be made to blind administration. An IRT centralized randomization system will be 
used to prevent the investigators from knowing in advance the study intervention 
assignment, as the randomization is the best method to avoid bias. 
• Despite the open-label administration of treatments, assessment of efficacy outcomes will 
be based on objectively collected data, which are radiological assessments for tumor 
response and central laboratory assessment that will be reviewed by an IRC blinded to 
study intervention arms. 
• During the course of the study, an external independent statistician will perform unblinded 
safety and efficacy analyses for the data review of DMC. Access to these data and 
analyses will be restricted to the DMC members. 
• Blinding rules for the Sponsor study team will be detailed in a separate document. 
6.3.2 Randomization  
All eligible participants will be randomly assigned to a treatment group (either SC or IV arm) in 
a 1:1 ratio using an IRT. Participant assignment to a treatment group will be performed according 
to a stratified randomization list as follows:  
• MM isotype (IgG versus non-IgG). 
• Body weight (≤65 kg, >65- ≤85 kg, and >85 kg). 
• Number of prior lines (1-2 versus ≥3). 
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After each participant has completed the necessary screening visit procedures, the corresponding 
baseline eCRFs have been completed and the participant is deemed eligible for randomization by 
the Investigator or designee based on the laboratory evaluations as defined in the study flow chart 
(Section 1.3), the study site will contact the IRT. 
Study intervention will be dispensed at the study visits summarized in the schedule of activities 
(SoA). 
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 is indicated in the IRT manual. 
Study treatment should be initiated within 3 working days after randomization. 
6.4 
STUDY INTERVENTION COMPLIANCE  
6.4.1 Subcutaneous isatuximab at-home administration  
Subcutaneous at-home administration will be performed by an HCP, after completing 
the questionnaire allowing for at-home administration (including vital signs and novel symptoms). 
For at-home administration, filling of this questionnaire should be recorded and in case at-home 
administration is not performed, reason should be collected. 
Participants randomized in the SC arm will receive a participant diary. The purpose of the diary is 
to report potential ISRs during the first 9 cycles in the SC-arm. 
6.4.2 Dexamethasone and pomalidomide  
Compliance to dexamethasone and pomalidomide will be assessed by direct questioning during 
the site visits and documented in the eCRF. Participants will be asked to maintain a diary to 
record the doses of pomalidomide/dexamethasone (except those administered by the study 
nurse/Investigator). Deviation(s) from the prescribed dosage regimen should be recorded. 
6.5 
DOSE MODIFICATION  
Dose modifications are permitted according to the guidelines described in this section.  
The participant may have a dose omitted for any IMP within a cycle if toxicity occurs and 
the participant does not recover within 3 days after the planned day of planned 
infusion/administration. If a participant 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. Within 
a cycle, the treatment window is ±1 day for each of QW IMP administrations and ±3 days for each 
of Q2W IMP administrations.  
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Cycle delays are permitted in case of toxicity (see Section 6.5.7). Cycle is considered delayed if 
Day 1 is performed more than 3 days after the planned Day 1 of this cycle. Once a dose of IMP 
has been decreased, intra-participant re-escalation back to the previous dose level is not permitted, 
except for dexamethasone dose reduction in a context of intercurrent condition neither related to 
dexamethasone adverse event nor related to multiple myeloma that might require a transient dose 
reduction. If a dose reduction is required, it is to be applied compared to the last dose level 
received by the participant.  
Administration of the IMP 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 eCRF. Participants will 
receive the next cycle of study treatment after recovery of the toxicity as described below. If 
one of the IMPs is permanently discontinued, the other IMPs can be continued until PD, 
unacceptable toxicity, or participant’s wish to discontinue further study treatment. The end of 
study treatment in this case will be 30 days after the date of the last study treatment 
administration. 
Recommendations for dose adjustments of IMPs due to AEs are described in Table 13, Table 14, 
Table 15 (SC arm) and Table 16. 
6.5.1 Isatuximab  
No dose reductions for isatuximab are permitted, but flow rate/infusion can be reduced, and 
dosing omissions are allowed in case of toxicity. Within a cycle, a delay of up to 3 days in cases 
of unresolved toxicity at the time of planned readministration is permitted; otherwise, the infusion 
is omitted.  
6.5.2 Pomalidomide  
Dose reduction steps for pomalidomide are shown in Table 11. One or several doses of 
pomalidomide can be omitted. 
Table 11 - Dose reduction steps for pomalidomide  
Starting dose of 
pomalidomide (PO) 
First dose reduction 
Second dose 
reduction 
Third dose reduction 
4 mg 
3 mg 
2 mg 
1 mg 
6.5.3 Dexamethasone  
For participants ≥75 years old, dexamethasone will be administered at 20 mg on Days 1,8,15 and 
22 of a 28-day cycle. One or several doses of dexamethasone can be omitted, or the dose of 
dexamethasone can be decreased to every other week (Table 12).  
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Table 12 - Dose reduction steps for dexamethasone  
Starting dose of 
dexamethasone Days 1, 8, 
15 and 22 (PO) 
First dose 
reduction 
Second dose 
reduction 
Third dose 
reduction  
Fourth dose 
reduction 
40 mg 
20 mg 
12 mg 
8 mg 
Discontinue dexamethasone 
20 mg 
12 mg 
8 mg 
4 mg 
Discontinue dexamethasone 
 
6.5.4 Dose adjustments according to adverse events  
Dose adjustments for participants treated with isatuximab, pomalidomide and dexamethasone 
combination in the case of hematological adverse reaction are shown in Table 13. 
Table 13 - Guidelines for dose adjustments for hematologic 
toxicities - isatuximab/pomalidomide/dexamethasone combination  
Adverse event 
Recommended action 
 
Isatuximaba  
(IV or SC) 
Dexamethasone 
(PO) 
Pomalidomide  
(PO) 
Thrombocytopenia 
Thrombocytopenia 
Grade 3 
Day 1 of cycle: delay until improvement ≥50  109/Lb and administer at same dose levelc. 
Within cycle: maintain full dose of study treatment as planned.  
SC injection of isatuximab: at-home administration at D-15 should not be performed prior alignment with 
the investigator site. 
Thrombocytopenia 
Grade 4 with or 
without bleeding  
Day 1 of cycle: delay until improvement 
≥50  109/Lb and administer at same dose 
levelc. 
 
Within cycle: delay isatuximab until bleeding is 
controlled and platelet recover ≥50  109/L and 
then administer full dose. 
If delay is >3 days omit isatuximab and 
dexamethasone until next planned 
administration. 
SC injection of isatuximab: at-home 
administration at D-15 should not be performed 
prior alignment with the investigator site. 
 
Further episodes: same recommendation. 
Day 1 of cycle: delay Day 1 administration until 
recovery and pomalidomide decreased by one dose 
levelc. 
 
Within cycle: hold pomalidomide until bleeding is 
controlled and platelet recover ≥50  109/L, and then 
re-start with 1 dose level decrease up to planned 
Day 21. Next cycle will be restarted with this 
one dose level decrease. 
 
second episode: same recommendation with 
decrease of pomalidomide by a second dose level. 
 
third episode: discontinue pomalidomide. 
Neutropenia 
Neutropenia 
Grade 3 
Day 1 of cycle: delay until recovery absolute neutrophil count ≥1.0  109/L and administer at same dose 
levelc. 
Within cycle: maintain full dose as planned. 
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Adverse event 
Recommended action 
 
Isatuximaba  
(IV or SC) 
Dexamethasone 
(PO) 
Pomalidomide  
(PO) 
Neutropenia 
Grade 4d 
Day 1 of cycle: delay until absolute neutrophil 
count recovery ≥1.0  109/L and administer 
at the same dose levelc. 
 
 
Within cycle: Maintain same dose as planned. 
 
Further episodes: same recommendations. 
Day 1 of cycle: delay Day 1 
administration until recovery and restart 
pomalidomide decreased by one dose level or 
consider G-CSF use and keep same dose level. 
 
Within cycle: hold pomalidomide until neutrophil 
counts recover ≥0.5  109/L and then: 
• 
Re-start with 1 dose level decrease up to 
planned Day 21. Next cycle will be 
re-started with this one dose level 
decrease. 
• 
Or consider G-CSF use and keep same 
dose level. 
 
Second episode: same recommendations with 
decrease of pomalidomide by a second dose level. 
 
third episode: discontinue pomalidomide. 
Febrile neutropenia 
and/or neutropenic 
infection 
Day 1 of cycle: delay Day 1 administration until fever and infection recover and add G-CSF until 
ANC>1  109/Lc Then administer Day 1 next cycle with isatuximab and dexamethasone at the same 
dose level and pomalidomide with dose recommendations below. 
Within cycle: omit isatuximab and dexamethasone, hold pomalidomide dose and add G-CSF until fever 
and infection have recovered and ANC>1  109/L. Then administer isatuximab and dexamethasone 
at the planned days at the same dose level and re-start pomalidomide up to planned Day 21 with dose 
recommendations below: 
• 
First episode, resume same dose pomalidomide with G-CSF or re-start with 1 dose level 
decrease. 
• 
Second episode, resume with action not done at first episode (same dose with G-CSF or 
1 dose decrement pomalidomide). 
• 
Third episode, resume with one dose decrement of pomalidomide.  
• 
Fourth episode, stop pomalidomide. 
a Participants may have isatuximab dose omission within a cycle if certain toxicities do not recover within 3 days following the day of 
planned infusion (Section 6.5.1). 
b For participants with plasma cells >50% of bone marrow 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 2-4, 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 2-4, D1 next cycle can be administered only if platelet counts 
≥50 000/mm3. For D1 administration beyond Cycle 4, platelet counts should be ≥50 000/mm3. 
c A dose delay of up to 14 days between cycles is permitted in order to recover to the participant´s baseline status. Beyond 14 days, 
the participant should be discontinued from study treatment, unless there is strong evidence of clinical benefit to justify continuation of 
dosing with study treatment (see Section 6.5.7).  
d  If G4 neutropenia, assess ANC every 2-3 days until ANC ≥0.5  109/L and at least weekly thereafter until ANC ≥1.0  109/L. 
IV: intravenous. 
SC: subcutaneous. 
PO: per os. 
Dose adjustments for participants treated with isatuximab, pomalidomide and dexamethasone 
combination in the case of non-hematological adverse reaction are shown in Table 14.  
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Table 14 - Guidelines for dose adjustments for non-hematologic 
toxicities - isatuximab/pomalidomide/dexamethasone combination  
Adverse event 
 
Recommended action 
 
 
Isatuximabc 
Dexamethasonec 
Pomalidomide 
DVT/PE 
 
 
 
Grade 3 
Day 1 of cycle: initiate appropriate anticoagulation therapy and when efficient anticoagulation 
administer cycle at full dose isatuximab and the same dose level of dexamethasone and 
pomalidomidea. 
Within cycle: maintain full dose isatuximab and the same dose level of dexamethasone as planned. 
For pomalidomide: 
• 
First episode: hold pomalidomide, initiate appropriate anticoagulation therapy and restart 
same dose pomalidomide when efficient anticoagulation. 
• 
Second episode: despite appropriate anticoagulation pomalidomide permanently 
discontinued. 
Grade 4 
Day 1 of cycle: delay Day 1 administration until controlled and 
administer the full dose of isatuximab and the same dose level 
of dexamethasonea. 
Within cycle: delay isatuximab and dexamethasone until 
stabilization and resume without dose reduction at the next 
planned dates. If delay is >3 days omit isatuximab and 
dexamethasone until next planned administration. 
Pomalidomide permanently 
discontinued. 
Peripheral Edema  
Grade ≥3 (limiting 
function and 
unresponsive to 
therapy or anasarca), 
excluding infusion 
associated reaction 
Day 1 of cycle or within 
cycle: maintain full 
dose isatuximab 
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. 
Day 1 of cycle or within cycle: 
maintain full dose pomalidomide 
as planned. 
Allergic reaction/hypersensitivity 
 
 
Grade 2 
Hold study treatment until <Grade 2, and participant clinically stable; then, resume study treatment 
at the same dose level for infusion reaction related to isatuximaba. 
For allergic reaction related to pomalidomide, refer to site local protocol. 
In case of D-15 at-home administration: transfer participant to investigator site. 
Grade ≥3 
Permanent discontinuation of the drug responsible of the allergic reaction. 
Grade ≥3 Infections 
without concomitant 
neutropenia 
Hold study treatment until systemic treatment of infection complete. 
Resume all at the same dose level. 
Herpes zoster 
Hold study treatment until lesions are dry, then resume all at the same dose level. 
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Adverse event 
 
Recommended action 
 
 
Isatuximabc 
Dexamethasonec 
Pomalidomide 
Neuropathy 
 
 
Grade 2 with pain or 
Grade 3 
Full dose isatuximab and same dose level of dexamethasone. 
Hold pomalidomide until 
neuropathy improves to Grade ≤2 
without pain. 
First episode: resume 
pomalidomide with a decrease of 
pomalidomide by 1 dose level. 
Second episode: resume 
pomalidomide with a decrease by 
a second dose level. 
Third episode: pomalidomide 
permanently discontinued. 
Grade 4 
Full dose isatuximab and same dose level of dexamethasone. 
pomalidomide permanently 
discontinued. 
Confusion or mood 
alteration Grade ≥2 
(interfering with 
functions ±daily 
activities) 
Day 1 of cycle or within 
cycle: maintain full 
dose isatuximab 
as planned. 
Hold dexamethasone until 
symptoms resolve. Restart with 
1 dose level reduction. If symptoms 
persist despite above measures, 
dexamethasone permanently 
discontinued. 
Day 1 of cycle or within cycle: 
maintain same dose level of 
pomalidomide as planned. 
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. 
Treat with H2 blockers, sucralfate, 
or omeprazole. If symptoms persist 
despite above measures, decrease 
dexamethasone dose by 1 dose 
level. 
Day 1 of cycle or within cycle: 
maintain same dose level of 
pomalidomide as planned. 
≥Grade 3 (requiring 
hospitalization or 
surgery) 
Hold study treatment until symptoms adequately controlled. Then, restart full dose isatuximab and 
same dose level of pomalidomide, and decrease dexamethasone by one dose level of current dose 
along with concurrent therapy with H2 blockers, sucralfate, or omeprazole. If symptoms persist 
despite above measures, dexamethasone permanently discontinued. 
Acute pancreatitis 
Dexamethasone permanently discontinued. 
Day 1 of cycle: delay Day 1 until recoveryc and re-start full dose isatuximab and same dose level of 
pomalidomide. 
Within cycle: hold all study treatment until recovery and re-start full dose isatuximab and same dose 
level of pomalidomide. 
Hyperglycemia 
≥Grade 3 
Day 1 of cycle or within 
cycle: maintain full 
dose isatuximab 
as planned. 
Treatment with insulin or oral 
hypoglycemic agents as needed. If 
uncontrolled despite above 
measures, decrease dose by 
one dose level until levels are 
satisfactory. 
Day 1 of cycle or within cycle: 
maintain same dose level of 
pomalidomide as planned. 
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Adverse event 
 
Recommended action 
 
 
Isatuximabc 
Dexamethasonec 
Pomalidomide 
Muscle weakness 
≥Grade 2 
(symptomatic and 
interfering with 
function ±daily 
activities) 
Day 1 of cycle or within 
cycle: maintain full 
dose isatuximab 
as planned. 
Decrease dexamethasone by 
one dose level. If weakness 
persists despite above measures 
decrease dose by one level. If 
symptoms persist dexamethasone 
permanently discontinued. 
Day 1 of cycle or within cycle: 
maintain same dose level of 
pomalidomide as planned. 
Renal dysfunction 
eGFR 
<30 mL/min/1.73m2 
(MDRD formula) 
Day 1 of cycle: delay Day 1 administration until eGFR returns to ≥30 mL/mina. 
Within cycle: hold study treatment until improvement to ≥30 mL/min. Then re-start full dose 
isatuximab, same dose level of dexamethasone and pomalidomide up to planned Day 21. If delay is 
>3 days, omit isatuximab and dexamethasone. 
Progressive 
multifocal 
leukoencephalopathy 
(PML)d 
If PML is suspected 
Immediately put on hold all study treatments and refer the patient to a specialistd. 
If PML is confirmed 
Put on hold isatuximab and dexamethasone. 
If PML is confirmed  
Pomalidomide must be 
permanently discontinued. 
If PML is recovered 
Isatuximab and dexamethasone can be resumed after 
recovery of PML based on Investigator's judgement and after 
discussion with the Sponsor. 
If PML is recovered  
Pomalidomide must be 
permanently discontinued. 
Any other drug 
related 
nonhematologic 
Grade 3-4 AE 
Day 1 of cycle: delay Day 1 administration until recovery and apply same rules of dose modification 
than the rules belowa. 
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 pomalidomide 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, pomalidomide discontinuation. 
a A dose delay of up to 14 days between cycles is permitted in order to recover to the participant´s baseline status. Beyond 14 days, 
the participant should be discontinued from study treatment, unless there is strong evidence of clinical benefit to justify continuation of 
dosing with study treatment (see Section 6.5.7). 
b See Section 6.1.2 for IR management. Participants may have pomalidomide one or several dose omission at any moment during 
the cycle. 
c Participants may have isatuximab 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 6.5). 
d See Section 6.1.1.3 for monitoring of PML and dose modification of study IMPs. 
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6.5.5 Management of infusion reactions and injection site reactions  
Participants should receive premedications prior to isatuximab infusion as detailed in 
Section 6.1.2 to reduce the risk and severity of IRs commonly observed with mAbs. Infusion 
associated reactions (including, for example, NCI-CTCAE V5.0 terms “infusion related reaction” 
or “anaphylactic reaction”) are defined as AEs related to product administration with onset 
typically within 24 hours from the start of the infusion. 
Please refer to the current edition of the IB for IRs manifestations reported in participants treated 
with isatuximab. 
Management of IR and injection sites reactions ISRs is described in Table 15 for SC injection and 
in Table 16 for IV injections.  
Table 15 - Guidelines for management of injection sites reactions (ISRs) and infusion reactions 
(IRs) for Isatuximab subcutaneous administration NCI-CTCAE v5.0 criteria  
Injection site 
reaction 
Infusion reactions 
Recommendation 
Grade 1 
Tenderness with or 
without associated 
symptoms 
(eg, warmth, 
erythema, itching). 
Grade 1 
Mild transient reaction; 
infusion interruption not 
indicated; intervention not 
indicated. 
ISRs: Continuation of isatuximab administration.  
Report AE. 
If the ISRs occurs during or in the 48 hours after at-home 
administration, subsequent 2 (D15 of subsequent cycle) 
administrations should be done at the investigator site. 
IRs: Continuation of isatuximab administration is per the judgment of 
the Investigator following close direct monitoring of the participant’s 
clinical status.  
Report AE. 
Isatuximab administration may be stopped at any time if deemed 
necessary. If stopped, IR will be classified as Grade 2 as per 
NCI-CTCAE v5.0 definition.  
Grade 2 
Pain; lipodystrophy; 
oedema; phlebitis. 
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). 
ISRs: 
If during administration: Interrupt isatuximab administration and 
resume only with an administration with pauses after recovery to G1 
or better. Report AE and AESI.  
In case the reaction occurs during the D-15 at-home administration, 
definitely stop the at-home injection and contact investigator site. 
 
If post-administration: Continue isatuximab treatment after recovery 
to G1 or better.  
Report AE and AESI. 
IRs: If during administration, interrupt isatuximab administration 
without possibility to restart the current injection. For subsequent 
cycles, give additional medication with IV diphenhydramine 25 mg IV 
(or oral equivalent) and/ or IV methylprednisolone 100 mg (or oral 
equivalent) and/or other supportive care as needed.  
Report AE. 
Grade 3/4 
Grade 3/4 
ISRs: Definitive discontinuation of isatuximab administration.  
Report AE and AESI. 
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Injection site 
reaction 
Infusion reactions 
Recommendation 
Grade 3: Ulceration or 
necrosis severe tissue 
damage operative 
intervention indicated. 
 
Grade 4: 
Life-threatening 
consequences; urgent 
intervention indicated. 
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. 
IRs: If during administration: Definitive stop of the current isatuximab 
administration. Give additional medication with diphenhydramine 
25 mg IV (or equivalent) and/ or IV methylprednisolone 100 mg (or 
equivalent) and/or epinephrine as needed.  
Report AE and AESI. 
In case of Grade 3, isatuximab administration may be resumed 
at the next planned administration at Investigator’s discretion.  
 
If a Grade 3 IR occurs for a 3rd time, treatment with isatuximab will 
be definitively discontinued for that participant.  
 
In case of Grade 4, isatuximab will be permanently discontinued. 
Table 16 - Guidelines for management of infusion reactions for isatuximab intravenous 
administration NCI-CTCAE v5.0 criteria  
Infusion reaction grading 
(NCI-CTCAE V5.0 criteria 
Recommendation 
Grade 1: mild transient reaction; infusion 
interruption not indicated; intervention not 
indicated. 
Continuation of isatuximab infusion is per the judgment of the Investigator 
following close direct monitoring of the participant’s clinical status. 
Isatuximab infusion may be stopped at any time if deemed necessary. If 
stopped, IR will be classified as Grade 2 as per NCI-CTCAE definition. 
Grade 2: moderate reaction; 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 infusion. Give additional medication with IV 
diphenhydramine 25 mg IV (or equivalent) and/or IV methylprednisolone 
100 mg (or equivalent) as needed. 
Isatuximab may be resumed only after participant recovery, at half 
the infusion rate before the interruption, and with close monitoring., and may 
be increased subsequently, at the Investigator’s discretion. 
Grade 3 / 4: severe or life-threatening reaction; 
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 infusion. Give additional medication with diphenhydramine 
25 mg IV (or equivalent) and/or IV methylprednisolone 100 mg (or 
equivalent) and/or epinephrine as needed until the resolution of the AE or 
until the AE improves to Grade 1. Only then, if previous Grade 3, 
the infusion may be restarted at the Investigator’s discretion; if so, 
the infusion rate should be half of the initial infusion rate and it may be 
increased subsequently, at the Investigator’s discretion. If the severity of 
an infusion-related AE returns to Grade 3 after the restart of the infusion, 
the same procedure described above may be repeated at the Investigator’s 
discretion. If a Grade 3 infusion-related AE occurs for a 3rd time, treatment 
with isatuximab will be definitely discontinued for that patient. 
In case of Grade 4, isatuximab will be permanently discontinued. 
6.5.6 Tumor lysis syndrome  
Tumor lysis syndrome may occur and is a life-threatening event. The participants at greatest risk of 
TLS are those with high tumor burden prior to treatment. These participants 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). 
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Tumor lysis syndrome has to be managed according to site usual practice. Table 17 provides some 
parameters to be checked in case of TLS suspicion and high-level recommendations for TLS 
management. Abnormalities listed in Table 17 do not support TLS diagnosis exclusively 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 17 - 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 μmol/L). 
• 
Potassium >6.0 mmol/L. 
• 
Phosphate >4.5 mg/dL (>1.5 mmol/L). 
• 
Corrected calcium <7.0 mg/dL (<1.75 mmol/L), ionized calcium 
<1.12 mg/dL (0.3 mmol/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 μmol/L) or the presence of oliguria, defined as an average urine 
output of <0.5 mL/kg/hour for 6 hours. 
• 
Seizures, sudden death, 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  (4-albumin in grams per 
deciliter). Adapted from Howard et al. 
6.5.7 Retreatment criteria  
A new cycle of study treatment may begin on the scheduled Day 1 of a subsequent cycle if 
the following criteria are met.  
• Absolute neutrophil count ≥1.0 × 109 /L.  
• Platelet count ≥50 × 109 /L.  
• Any other IMP-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 6.5 
of this protocol).  
If these criteria are not met on the scheduled Day 1, Day 1 should be delayed until participants 
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 participant 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. 
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A delay for participant’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. 
6.6 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF THE STUDY  
Participants still on treatment at the time of the final OS analysis cut-off date, and benefiting from 
the study treatment, can continue the treatment until disease progression, unacceptable AEs, 
participant wish to discontinue further study treatment, until study treatment is commercially 
available and reimbursed in participant’s country, or for any other reason, whichever comes first. 
6.7 
TREATMENT OF OVERDOSE  
For the study, IMP overdose is defined as any of the following conditions:  
• Any administration of isatuximab IV or isatuximab SC at least 30% above the intended 
dose at each administration or dose administered in less than half the recommended 
duration of administration. 
• Any administration of an oral IMP (pomalidomide and dexamethasone) at least twice 
the intended dose within the intended therapeutic interval. Of note, dexamethasone dose 
will be evaluated on a whole cycle. 
AxMP overdose is defined as at least twice the intended dose within the intended therapeutic 
interval. 
In case of accidental or intentional overdose with the IMP/AxMP, even if not fulfilling a serious 
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. 
In the event of an overdose, the Investigator should: 
• Closely monitor the participant for any AE/SAE and laboratory abnormalities until study 
treatment can no longer be detected systemically (at least 5 months). 
• Evaluate the participant to determine, if possible, in consultation with the Sponsor, 
whether study intervention should be interrupted or whether the dose should be reduced. 
• Obtain a plasma sample for PK analysis as soon as possible if requested by the Sponsor or 
Sponsor representative(s) (determined on a case-by-case basis). 
• Document appropriately in the eCRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Sponsor or Sponsor representative(s) based on the clinical evaluation of 
the participant.  
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6.8 
PRIOR AND CONCOMITANT THERAPY  
The Sponsor should be contacted if there are any questions regarding concomitant or prior 
therapy. 
Participants must abstain from taking prescription or nonprescription drugs (including vitamins, 
recreational drugs, and dietary or herbal supplements) within 7 days (or 14 days if the drug is 
a potential enzyme inducer) or 5 half-lives (whichever is longer) before the start of study 
intervention until completion of the follow-up visit, unless, in the opinion of the Investigator and 
Sponsor, the medication will not interfere with the study. 
A concomitant medication is any treatment received by the participant concomitantly to any study 
treatment(s). All treatments being taken by the participant 21 days prior to inclusion, 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 participant'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. 
Antifungal and antiviral agents for prophylactic or therapeutic use can be administered 
as considered appropriate by the Investigator. 
Hepatitis B vaccination could be considered, following Investigator’s discretion, for participants 
with negative HBsAg, total antibody to hepatitis B core antigen (anti-HBc), antibody to 
hepatitis B surface antigen (anti-HBs) and HBV-DNA. At least 3 doses of vaccine will be 
administered at monthly intervals, the first one 1 to 2 weeks before start of study treatment. 
Anti-HBs should be monitored at 1, 2 and 3 months after end of vaccination. Anti-HBs above 
100 mU/mL will indicate a good seroconversion, between 10 and 100 mU/mL moderate 
seroconversion that can be limited in time, less than 10 mU/mL will indicate no response to 
vaccination. 
If antiviral therapy for HBV or HCV was started before initiation of study treatment and 
participant was eligible for the trial, the antiviral therapy for HBV or HCV should continue 
throughout the treatment period as recommended by specialist. In case of trial testing combo, it 
should be checked that there is no drug-drug interaction with the drug associated with isatuximab. 
In case of viral reactivation during study treatment (greater than 1 log10 IU/mL increase in HBV 
DNA or reappearance of HBsAg or detection of HBV DNA in participants with resolved infection 
[ie, previous known history of acute or chronic hepatitis B or the presence of total anti-HBc 
with/without anti-HBs; HBsAg negative; undetectable serum HBV DNA; normal L-alanine 
aminotransferase levels] ), study treatment will be held and a specialist consulted for initiation of 
anti-viral treatment and monitoring of the participant. Restart of the study treatment should be 
agreed among the Sponsor, Investigator, and specialist (hepatologist) if infection is controlled. 
Close monitoring of L-alanine aminotransferase and L-aspartate aminotransferase should be done 
every month, up to study treatment discontinuation. Hepatitis B virus DNA testing must be done 
as per specialist advice. 
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6.8.1 Antithrombic therapy  
Pomalidomide increases the risk of venous thromboembolism. Anticoagulation prophylaxis is 
required after an assessment of each participant’s underlying risk factors. Unless there is 
an excess risk of bleeding (those participants are to be excluded from the study; see exclusion 
criterion E2) all participants should receive prophylactic antithrombotic treatment. Patients with 
known risk factors for thromboembolism – including prior thrombosis – should be closely 
monitored. Action should be taken to try to minimise all modifiable risk factors (eg, smoking, 
hypertension, and hyperlipidemia). 
Aspirin prophylaxis is recommended for participants with standard risk. If aspirin is 
contraindicated, participants will receive another form of antithrombotic therapy according 
to hospital guidelines or physician preference. Participants with at least 1 risk factor 
(ie, history of prior venous thromboembolism, immobilization, and concomitant use of 
an erythropoiesis-stimulating agent) should use low-molecular weight heparin or alternatively 
a direct oral anticoagulant (factor Xa inhibitors, direct oral factor IIa inhibitors) or a vitamin K 
antagonist.  
6.8.2 G-CSF prophylaxis  
Prophylactic administration of G-CSF in a participant who is experiencing recurrent neutropenia, 
or therapeutic use in participants with serious neutropenic complications (such as tissue infection, 
sepsis syndrome or fungal infection) may be considered at the Investigator’s discretion, consistent 
with the American Society of Clinical Oncology guidelines (2006) (28) in order to decrease 
the risk of neutropenia specially in participants with baseline extensive BM involvement and/or 
low neutrophil count (29).  
6.8.3 Antibiotic prophylaxis  
Neutropenia is one of the most common adverse events of pomalidomide. A high rate of 
Grade 3/4 neutropenia (>80%) was observed in the isatuximab plus pomalidomide and 
dexamethasone arm of the ICARIA trial, with a quarter of participants experiencing a neutropenic 
complication (2). Antibiotic prophylaxis is thus recommended at start of treatment, with 
fluoroquinolone as the preferred option per NCCN (Prevention and Treatment of Cancer-Related 
Infections, Version 2.2016) guidelines for the participants with an intermediate risk of infection 
(MM and anticipated neutropenia) (30). However, Ciprofloxacin and Clinafloxacin which are 
strong inhibitors of Cytochrome P450 Family 1 Subfamily A Member 2 (CYP1A2) should be 
avoided. Investigators may consider other appropriate antibiotic prophylaxis. Although there is no 
specific NCCN guidelines on duration of prophylaxis when MM treatment is ongoing, 3 months 
of antibiotic prophylaxis is recommended at diagnosis for MM participants at high-risk of 
infections (31). 
6.8.4 Prohibited concomitant therapy  
Concurrent treatment with any other antimyeloma therapy not specified in the protocol, including 
immunotherapy, targeted therapy, biological therapies and curative radiotherapy, as well as any 
other investigational drug, is prohibited. However, palliative radiotherapy may be given to control 
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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. 
Drugs prohibited 28 days prior to randomization include: 
• Any anti-myeloma drug treatment within 14 days before randomization, including 
dexamethasone. 
• Prior allogenic HSC transplant with active GvHD (GvHD any grade and/or being under 
immunosuppressive treatment within the last 2 months prior to randomization). 
• Any major procedure within 14 days before the initiation of the study treatment: 
plasmapheresis, major surgery (kyphoplasty is not considered a major procedure), 
radiotherapy. 
• Any other investigational drugs or prohibited therapy for this study within 28 days or 
5 half-lives from randomization, whichever is shorter. 
• Concomitant systemic long-term corticosteroids, other than as part of 
the protocol-specified therapeutic regimen or for treatment of hypersensitivity reaction or 
for the treatment of adverse reactions, are prohibited. Any short-term corticosteroids are 
allowed to treat AEs.  
• Additional glucocorticoids (or inhaled glucocorticosteroids whenever indicated), 
antihistamines, and analgesics, for the management of IRs are permitted. 
• Live vaccines should be avoided up to 90 days after last dosing of study IMPs. However, 
given the increased risk of infection, non-live vaccines on routine vaccinations are 
recommended for the participants and their contacts. Prophylactic vaccination is 
recommended for influenza A and B virus, pneumococci and Haemophilus influenzae. 
• Avoid co-administration of strong inhibitors of CYP1A2: 
- 
Bai-zhi. 
- 
Clinafloxacin. 
- 
Ciprofloxacin. 
- 
Enoxacin. 
- 
Fluvoxamine. 
- 
Oltipraz. 
- 
Rofecoxib. 
- 
Vemurafenib. 
6.8.5 Rescue medicine  
Not applicable. 
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7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL  
7.1 
DISCONTINUATION OF STUDY INTERVENTION  
The study treatment should be continued whenever possible. Any study treatment discontinuation 
must be fully documented in the eCRF. In any case, the participant should remain in the study 
as long as possible.  
Pregnancy in the female participants will lead to definitive treatment discontinuation in all cases. 
Discontinuation of specific sites or of the study as a whole are detailed in Appendix 1 
(Section 10.1). 
7.1.1 Permanent discontinuation  
Permanent treatment discontinuation is any treatment discontinuation associated with 
the definitive decision from the Investigator not to re-expose the participant to the study treatment 
at any time during the study, or from the participant not to be re-exposed to the study treatment 
whatever the reason. In rare instances, it may be necessary for a participant to permanently 
discontinue study intervention. 
If one of the study treatments is prematurely permanently discontinued, then other drug(s) can be 
continued until disease progression or unacceptable toxicity or participant’s wish to discontinue 
further study treatment. During this period the participant will remain in the study and continue 
being assessed per SoA. If all study treatments are permanently discontinued, the visit will be 
treated as the last dosing day with the IMPs, with subsequent relevant assessments per SoA. 
In case of permanent treatment discontinuation due to disease progression, follow up will be every 
3 months for further antimyeloma therapy, second primary malignancies, PFS2, and survival until 
death, or final OS analysis cut-off date, whichever occurs first. See the SoA for data to be 
collected at the time of discontinuation of study intervention and follow-up and for any further 
evaluations that need to be completed. 
7.1.1.1 List of criteria for permanent discontinuation  
The participants may withdraw from 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, pomalidomide, and/or dexamethasone can be discontinued permanently. 
The participant will remain on study treatment until the last study treatment is discontinued. 
The reason for permanent discontinuation will be captured in the appropriate eCRF page. 
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All efforts should be made to document the reason for discontinuation of treatment with the study 
treatment: 
• At the participant’s request, at any time and irrespective of the reason (consents 
withdrawal). Withdrawal of consent for treatment should be distinguished from 
withdrawal of consent for follow-up visits and from withdrawal of consent for 
non-participant contact follow-up, eg, medical records check. Participants 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 participant, 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 participant’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). 
• Pregnancy in a female participant. 
• Participant is lost to follow-up. 
If participants are clinically stable, and possibly deriving clinical benefit from therapy with 
minimal toxicity, the participant will be maintained on treatment for the maximum period of time 
defined in Section 1.3. 
Participants 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. 
7.1.1.2 Handling of participants after permanent intervention discontinuation  
Participants 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 occurs last. 
If possible, and after the permanent discontinuation of treatment, the participants will complete 
the evaluations scheduled for the EOT and follow-up visits as detailed in the SoA (Section 1.3). 
All cases of definitive intervention discontinuation must be recorded by the Investigator in 
the appropriate pages of the eCRF when considered as confirmed. 
7.1.2 Temporary discontinuation  
Temporary intervention discontinuation may be considered by the Investigator because of 
suspected AEs (Section 8.6) or disruption of the clinical trial due to a regional or national 
emergency declared by a governmental agency (Section 10.9). For all temporary intervention 
discontinuations, duration should be recorded by the Investigator in the appropriate pages of 
the eCRF. 
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7.1.3 Rechallenge  
Re-initiation of intervention with the IMP will be done under close and appropriate clinical and/or 
laboratory monitoring once the Investigator has considered according to his/her best medical 
judgment that the responsibility of the IMP(s) in the occurrence of the concerned event was 
unlikely if the selection criteria for the study are still met (refer to Section 5). 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Section 10.9. 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY  
• A participant may withdraw from the study at any time at the participant’s own request, 
for any reason (or whitout providing any reason). 
• A participant may be withdrawn at any time at the discretion of the Investigator for safety, 
behavioral, or compliance reasons. 
• At the time of discontinuing from the study, if possible, an end-of-treatment visit should 
be conducted, as shown in the SoA (Section 1.3). See SoA for data to be collected 
at the time of study discontinuation and follow-up and for any further evaluations that 
need to be completed. 
• If the participant withdraws consent from the study, the Sponsor will retain and continue 
to use any data collected before such a withdrawal of consent, as per applicable clinical 
regulation(s). 
• If a participant withdraws from the study, the participant may request destruction of any 
samples taken and not tested, and the Investigator must document this in the site study 
records. 
If participants no longer wish to take the IMP, 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. 
Participants 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 should be recorded by the Investigator in the appropriate screens of 
the eCRF and in the participant’s medical records. In the medical record, at least the date of 
the withdrawal and the reason should be documented. 
In addition, a participant may withdraw his/her consent to stop participating in the study. 
Withdrawal of consent for intervention should be distinguished from withdrawal of consent for 
follow-up visits and from withdrawal of consent for non-participant contact follow-up, eg, medical 
record checks. The site should document any case of withdrawal of consent. Participants who 
discontinue study treatment will not be replaced. 
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Participants who have withdrawn from the study cannot be rerandomized/reallocated (treated) in 
the study. Their inclusion and intervention numbers must not be reused. 
7.3 
LOST TO FOLLOW UP  
A participant will be considered lost to follow-up if the participant repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon 
as possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study. 
• Before a participant is deemed lost to follow up, the Investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 
• Should the participant continue to be unreachable, the participant will be considered to 
have withdrawn from the study. 
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8 
STUDY ASSESSMENTS AND PROCEDURES  
• Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed. 
• Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.  
• Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count, urine tests) and obtained before signing of the ICF may be utilized for screening or 
baseline purposes provided the procedures met the protocol-specified criteria and were 
performed within the time frame defined in the SoA. 
• The maximum amount of blood collected from each participant over the duration of 
the study, including any extra assessments that may be required, will not exceed 244 mL 
per participant in Cycle 1 to 3 and will be lower in subsequent cycles. 
• Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples. 
• In the event of a significant study-continuity issue (eg, caused by a pandemic), alternate 
strategies for participant visits, assessments, medication distribution and monitoring may 
be implemented by the Sponsor or the Investigator, as per local Health Authority/ethics 
requirements [see Appendix 9 (Section 10.9)]. 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Section 10.9 (Appendix 9: Contingency measures for a regional or national 
emergency that is declared by a governmental agency). 
8.1 
ADMINISTRATIVE [AND GENERAL/BASELINE] PROCEDURES  
Not applicable. 
8.2 
EFFICACY ASSESSMENTS  
The primary and secondary efficacy endpoints will be determined by IRC based on central 
laboratory M-protein analysis, local BM for plasma cell infiltration assessment as recorded in 
the electronic case report form (eCRF) and central radiology review according to IMWG criteria 
(Section 10.10, Appendix 10). IRC will be blinded to treatment assignment. Please 
see the schedule of activities for more information (Section 1.3).  
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The following myeloma-specific lab tests will be performed at screening (for eligibility) and again 
within 24 hours prior to the start of study treatment administration at Cycle 1/Day 1 (baseline for 
response assessment) and then Day 1 of every cycle during treatment up to progression and for 
participants who discontinue study treatment for reasons other than progression, every 4 weeks 
during follow-up until PD: 
• M-protein quantification (serum and 24-hour urine, protein immunoelectrophoresis, and 
immunofixation) by central laboratory. After Cycle 1/Day 1, immunofixation will be done 
in case of undetectable M-protein (serum and urine). 
• Serum free light chain levels by central laboratory. 
• Quantitative immunoglobulins (IgG, IgA, IgM, IgD, and IgE) by central laboratory. 
Other examinations for disease assessment will be done as below: 
• Bone marrow aspiration (BMA) (or biopsy as clinically indicated) for quantification of 
percentage plasma cells is required at screening/baseline (within 21 days prior to study 
treatment administration). Repeat BM aspirate or biopsy to confirm CR or sCR if CR or 
sCR is suspected (local laboratory).  
• Bone marrow aspiration for MRD assessment: At screening, at time of maximum 
confirmed CR or VGPR, 12 months after C1D1 and 12 months after first MRD negativity. 
• Bone marrow aspiration for cytogenetics assessment: At screening, bone marrow aspirate 
will be collected for Fluorescent in Situ Hybridization (FISH) (including, but may not be 
limited to, del[17p], t[4;14], t[14;16]), 1q21+) analyses in central laboratory.  
• Bone marrow aspiration for genomic and genetic profiling at screening and at time of 
progression (central laboratory). 
• Bone imaging: Whole-body low-dose (WBLD) computed tomography (CT) scan, Positron 
emission tomography-Computed tomography (PET-CT) scan or MRI at baseline (within 
28 days prior to randomization), once a year (±1 month) from C1D1, and anytime during 
the study if clinically indicated, until PD (even if further anti-myeloma therapy is started 
without PD as per protocol), or final cut-off date, whichever occurs first. PET-CT should 
be the preferred imaging modality whenever possible. 
• Soft tissue plasmacytoma assessment (extramedullary disease OR paramedullary disease 
with a soft tissue lesion of diameter ≥2 cm): 
- 
If known soft tissue plasmacytoma at baseline, CT scan, PET-CT scan or MRI is to be 
done at baseline, repeated every 12 weeks (±1 week) until progressive disease (PD) 
from C1D1 (even for participants who would initiate further anti-myeloma therapy 
without PD), and if clinically indicated. From two years after randomization, 
the radiological assessment will be done every 6 months (±1 month). Assessment to be 
done until PD (even if further anti-myeloma therapy is started without PD as per 
protocol), or final cut-off date, whichever occurs first.  
- 
If suspected soft tissue plasmacytoma at baseline, CT scan, PET-CT scan or MRI is to 
be done at baseline and if plasmacytoma confirmed on the exam to be repeated 
as indicated above. 
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- 
To be done in case of suspicion of progression or if clinically indicated in a participant 
with no previous positive image for soft tissue plasmacytoma.  
- 
The bone component of paramedullary disease with a soft tissue lesion of diameter 
≥2 cm will not be used for disease response assessment as per IMWG. 
- 
Paramedullary (paraskeletal) plasmacytoma (bone plasmacytoma extending beyond 
the bone cortex into the surrounding tissues) with soft tissue lesions of diameter <2 cm 
will be collected but will not be used for disease response assessment as per IMWG. 
No follow-up with repeated imaging is needed, except if clinically indicated.  
- 
PET-CT should be the preferred option whenever possible. 
Note: For bone lesion assessment and soft tissue plasmacytoma, the same modality (whole-body 
low-dose CT scan; CT scan, PET-CT scan, or MRI) should be used throughout the study for each 
individual participant when radiological follow-up is needed. 
Intravenous contrast is recommended if not medically contra-indicated. 
In case of both serum and urine M-protein become below level of eligibility on efficacy 
laboratory performed on Cycle 1/Day 1, please refer to the IMWG Response Criteria  
(Appendix 10, Section 10.10) for assessment of progression and overall response. 
8.3 
 PHARMACOKINETICS  
Blood samples will be collected for the measurement of isatuximab concentration as described in 
the PK/ADA flowcharts (Section 1.3). The actual date and time of each sample will be recorded. 
Instructions for the collection and handling of PK samples will be provided by the Sponsor or 
Sponsor’s designee in a separate laboratory manual. These samples will be tested by the Sponsor 
or Sponsor’s designee. Pharmacokinetic samples may be used for additional testing of analytical 
method performance such as incurred sample reproducibility. These data will not be included in 
the study report but will be kept on file. 
Descriptive statistics on Ctrough, and Ceoi - Isa-IV+Pd arm for Ceoi only-) such as the mean, standard 
deviation, coefficient of variation, geometric mean, median, and range will be provided by 
treatment Arms (Isa-SC+Pd or Isa-IV+Pd) as well as Ctrough ratio (SC/IV) over time. 
For the co-primary endpoint observed Ctrough at steady state, ie, Ctrough corresponding to predose 
at C6D1, see Section 9.2.2. 
For the key secondary PK endpoint, observed CT4W, ie corresponding to predose at C2D1, 
see Section 9.2.3.1. 
In addition, isatuximab concentrations will be used for population PK analysis by non-linear 
mixed effects modeling. Data from other studies might be added for model development. 
The population PK analysis will involve an estimation of inter-individual PK variability, 
the determination of the population PK parameters estimates and possibly the quantitative 
evaluation of potential effect of participant characteristics on the main PK parameters. More 
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precisely the impact of body weight on exposure will be assessed for justification of the flat 
dosing across body weight. Empirical Bayesian estimation of individual exposure parameters such 
as Cmax, Ctrough, and area under the curve (AUC) will also be computed. Those individual exposure 
parameters will then be investigated as predictive factors for clinical outcomes including safety 
and efficacy endpoints, if possible. Additional details of the analysis plan and the results will be 
provided in separate documents. 
8.4 
SAFETY ASSESSMENTS  
Planned time points for all safety assessments are provided in the SoA (Section 1.3). Participants 
will stay at the site between 1 and 4 hours after each administration in Cycle 1. For subsequent 
cycles, participant’s surveillance will be left at the Investigator’s judgement.  
For the first at-home administration, the HCP administering the SC formulation of isatuximab will 
stay for 30 minutes to ensure safety of the administration.  
8.4.1 Body weight and Physical examinations  
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
Body weight (kg) for all the participants will be recorded in eCRF. Physical examination consists 
of an examination of major body systems including neurological, digestive, extramedullary 
myeloma localizations, respiratory, hepatomegaly, splenomegaly, and lymphadenopathy. 
Only clinically relevant findings will be reported in the eCRF as AEs. 
8.4.2 Vital signs  
The following vitals will be measured at site: heart rate, body temperature, respiratory rate (RR), 
and blood pressure (BP). 
Note: Vital signs are assessed pre-administration, one hour after start of first administration and, 
for the IV arm only, 30 minutes after the start of the subsequent infusions. On site, vital signs are 
to be assessed at end of infusion/injection up to Cycle 5, and as clinically indicated.  
8.4.2.1 At-home administration  
For at-home administration, the following vital signs will be measured systematically just before 
and at the end of SC injection:  
• Heart rate. 
• Systemic blood pressure. 
• Body temperature. 
• Pulse oximetry (SPO2). 
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Normal parameters are described in Table 18. These are given as a guide but might be adapted by 
the investigator based on the clinical history and participant basal values. 
In case of abnormal parameters, investigator should be called prior to D-15 injections and if 
deemed appropriate by the investigator, the participant should be transferred to the investigator 
site. 
Table 18 - Normal values for at-home administration*  
Vital sign 
Normal range 
Heart rate 
[50-100] bpm. 
Systolic blood pressure 
≥90 mmHg (or no lower than 20mmHg below the participant normal value). 
Diastolic blood pressure 
≥50 mmHg. 
Body temperature 
Oral temperature <38°C (or equivalent with other measurement). 
Pulse oximetry 
SPO2 ≥95% or below the participant normal value in the context of prior chronic respiratory 
disease.  
* Given as a guide, should be adapted to the participant medical history. 
8.4.3 Electrocardiograms  
A 12-lead electrocardiogram (ECG) will be obtained as outlined in the SoA (Section 1.3). 
8.4.4 Clinical safety laboratory tests  
• See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and 
to the SoA (Section 1.3) for the timing and frequency. 
• The Investigator must review the laboratory results, document this review, and record any 
clinically significant changes occurring during the study as an AE. The laboratory results 
must be retained with source documents. See Appendix 3 (Section 10.3) for abnormal 
laboratory results reporting. Abnormal laboratory findings associated with the underlying 
disease are not considered clinically significant, unless judged by the Investigator to be 
more severe than expected for the participant’s condition.  
8.4.5 Pregnancy testing  
• Refer to Section 5.1 Inclusion criteria for pregnancy testing criteria; the Investigator is 
responsible for review of medical history, menstrual history, and recent sexual activity to 
decrease the risk for inclusion of a female participant with an early undetected pregnancy. 
• Pregnancy testing (urine or serum as required by local regulations) should be conducted 
weekly during Cycle 1, and then on D1 of each cycle from Cycle 2, ie monthly at intervals 
during intervention (at study visits and if needed, at home in between visits). 
• Pregnancy testing (urine or serum as required by local regulations) must be conducted 
corresponding with the time frame for female participant contraception in Section 5.1 
Inclusion criteria.  
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• Additional serum or urine pregnancy tests may be performed, as determined necessary by 
the Investigator, or required by local regulation, to establish the absence of pregnancy 
at any time during the participant’s participation in the study. 
• Refer to Section 10.4.3 for duration of pregnancy testing. 
8.4.6 Suicidal ideation and behavior risk monitoring  
Not applicable.  
8.4.7 Assessment of local tolerability  
Local tolerability at injection site after SC administration of isatuximab will be assessed during 
clinical stay using eCRF hourly (relative to the start of administration) for duration of 4 hours 
at Cycle 1/D1, 1 hour after the end of injection for the following Cycle 1 administrations and 
at end of injection from Cycle 2 onwards (Section 1.3). In case of at-home administration, for 
the first isatuximab injection performed at-home, an additional assessment should be performed 
30 min after the end of the injection. 
Table 19 - Summary of assessment timelines for local tolerability  
On site administration 
Cycle 1 Day 1: End of Injection (EoI), 1h, 2h, 3h, 4h 
Cycle 1 Day 8 & Cycle 1 Day 15: EoI, 1h 
Cycle 2 and subsequent cycles: EoI. 
At-home administration 
 
1st injection from Cycle 6: EoI, 30 min 
Rest of cycles: EoI. 
Any swelling (unless it lasts longer than 24 hours) as a result of the injection of the isatuximab 
solution volume is not to be reported as an AE/ AESI. 
8.4.8 Assessment of frailty  
Frailty in multiple myeloma patient will be evaluated using functional assessments, at Cycle 1 
Day 1. This will be done using the Katz index of independence in activities of daily living (ADL) 
(32) and the Lawton instrumental activities of daily living scale (IADL) (33). 
8.5 
PATIENTS REPORTED OUTCOMES  
Patient-reported outcome (PRO) measures to be included are the European Organization for 
Research and Treatment of Cancer (EORTC) core quality of life questionnaire with 30 questions 
(QLQ-C30), the EORTC myeloma module with 20 items (QLQ-MY20), the EQ-5D-5L, 
the Health Resource Utilization and Productivity will be assessed using the HRUPQ, the Patient 
Expectations Questionnaire at baseline (PEQ-BL), the Patient Experience and Satisfaction 
Questionnaires during treatment Follow-Up and at the End Of Treatment (PESQ-FU and 
PESQ-EOT) and the PAT. All questionnaires are described in this section and presented in 
Appendix 16 (Section 10.16). 
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All questionnaires have been designed for self-completion. All PROs are in electronic form 
(electronic patient-reported outcomes [ePRO]) and will be completed by the patient 
(study participant) using either the study mobile phone provided or the patient's own device. 
Alternatively, a dedicated website could be proposed to collect PROs as a backup solution in case 
of unavailability of handheld devices. To minimize any bias, participants 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 participant’s perception and feelings prior to 
responding to the questions. Timing for each assessment is detailed in SoA section. 
Since participants are to complete ePRO questionnaires on their own, there will be 20 minutes 
time allocated for training participants on ePRO technology at Cycle 1 Day 1 visit. Meanwhile, 
assistance will be provided if a participant needs longer time to learn or have training questions 
(eg, a refresher) during subsequent cycles. For the ePRO data it is mandatory that a key person 
(eg, research nurse) at each site is responsible for ePRO data collection, in order to optimize 
participant compliance and to ensure data completeness. 
Compliance rates for completion will be generated based on number of assessments completed 
divided by number of assessments expected (per protocol). Reason for non-completion will be 
documented. 
The planned statistical analysis of the PROs will be detailed in the SAP. 
European Organization for Research and Treatment of Cancer core quality of life 
questionnaire (EORTC QLQ-C30) 
The EORTC QLQ-C30 is a cancer-specific instrument that contains 30 items and provides 
a multi-dimensional assessment of HRQL (34, 35, 36). The validity and reliability of the EORTC 
QLQ-C30 has been established in various types of cancers (37). This instrument 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, 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 both multi-item scales and single-item measures. These include 
5 functional scales (physical, role, emotional, cognitive, and social functioning), 3 symptom 
scales (fatigue, nausea and vomiting, and pain), a Global Health Status (GHS)/quality of life scale, 
and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial 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/healthier level of functioning/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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European Organization for Research and Treatment of Cancer quality of life myeloma 
module (EORTC QLQ-MY20) 
The EORTC QLC-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 participants 
with multiple myeloma (38, 39). This instrument contains 20 items in 4 independent subscales 
covering 2 functional domains (future perspective and body image) and 2 symptom 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.  
Both EORTC QLQ-C30 and EORTC QLQ-MY20 are reliable and valid measures of HRQL in 
cancer patients and the 2 instruments together (50 items) take approximately 15 minutes on 
average to complete. The instruments have been validated and used in many countries. 
European Quality of Life Group measure with 5 dimensions and 5 levels per dimension 
(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 VAS. The descriptive system consists 
of 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. 
Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, 
and extreme problems. 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. 
The EQ-5D-5L is designed for self-completion by participants. Response options are measured 
with a 5-point Likert scale with higher scores indicate better HRQL.  
Health Resource Utilization and Productivity Questionnaire (HRUPQ) 
Medical resource utilization and participant productivity will be collected from participants 
through the specific HRUPQ questionnaire developed for this study (initially adapted to early 
Phase TCD15484 and modified for EFC15951). The data collected include number, nature 
(emergency or routine) and duration of hospitalizations, emergency room visits and outpatient 
medical encounters and employment history. The HRUPQ contains 46 items and takes 
approximately 10-15 minutes to complete.  
Patient expectation, experience and satisfaction questionnaires  
Patient Expectations Questionnaire (PEQ-BL) 
The PEQ-BL will be completed at baseline prior to study treatment administration or other study 
related procedures. This questionnaire has been designed to assess the expectations of 
the participants regarding both the treatment (side effects, worth taking) and the administration 
method (confidence, comfortability, pain, side effects, potential time-savings), as well as to 
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understand previous treatment experience from the participant (experience with injection methods 
for oncology medication). This questionnaire has been developed by Sanofi as internal measure 
and has been debriefed and adapted based on qualitative interviews with oncology participants.  
This questionnaire contains 7 items and take approximately 5 minutes to complete. 
Patient experience and satisfaction questionnaires (PESQ; PESQ-FU and PESQ-EOT)  
The PESQ-FU has been designed to follow up on participant experience and satisfaction 
regarding the treatment (side effects, worth taking and overall satisfaction) and the administration 
method (confidence, comfortability, pain, side effects, potential time-savings and overall 
satisfaction). This questionnaire has been developed by Sanofi as internal measure and has been 
debriefed and adapted based on qualitative interviews with oncology participants. The PESQ-FU 
contains 9 items and take approximately 5 minutes to complete. 
The PESQ-EOT has been designed to assess participant experience and satisfaction regarding 
the treatment (side effects, worth taking and overall satisfaction) and the administration method 
(confidence, comfortability, pain, side effects, potential time-savings and overall satisfaction). 
This questionnaire includes also additional items to assess participant preference on injection 
method (SC or IV) and location of administration (at home or at clinic). This questionnaire has 
been developed by Sanofi as internal measure and has been debriefed and adapted based on 
qualitative interviews with oncology participants. The PESQ-EOT contains 17 items and take 
approximately 5-10 minutes to complete. 
Patient’s Assessment of Treatment questionnaire (PAT) 
In order to demonstrate from participant perspective that the overall benefits outweigh 
the disadvantages in the target patient population, Sanofi has developed an internal measure; 
the Patient Assessment of Treatment questionnaire (PAT). The PAT provides patient insights on 
the benefits and disadvantages of treatment, including an overall B/D ratio using a final question 
that provides a quantitative assessment of the patient’s perceived B/D. The 4-item PAT is 
an internally developed non-disease specific and self-administered assessment. The PAT is 
a modification from the Sanofi developed Patients’ Qualitative Assessment of Treatment (PQAT; 
initially developed for diabetes (40) and has been debriefed with oncology patients during 
qualitative interviews. This questionnaire contains 4 items and take approximately 2-3 minutes to 
complete.  
Timing of Assessments 
Cycle 1 Day 1 will serve as the baseline assessment for all participants. While on treatment, 
ePROs are to be completed prior to treatment on Day 1 of every cycle, and at the EOT visit. 
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. 
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Since the participants are to complete ePRO questionnaires on their own, there will be 20 minutes 
time allocated for training participants on ePRO technology at Cycle 1 Day 1 visit. Meanwhile, 
assistance will be provided if a participant 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 participant and to ensure completeness of the data. The planned statistical 
analysis of the 3 ePROs will be detailed in the SAP. 
8.5.1 EORTC QLQ-C30  
The EORTC QLQ-C30 is a cancer-specific instrument that contains 30 items and provides 
a multidimensional assessment of HRQL (34, 35, 36). The validity and reliability of the EORTC 
QLQ-C30 has been established in various types of cancers (37).  
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 (1 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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8.5.2 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 participants 
with MM (38, 39). 
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 participants 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. 
8.5.3 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 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. 
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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. 
The instrument is designed for self-completion by participants. 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. 
8.6 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS (SAES) AND OTHER 
SAFETY REPORTING  
The definitions of AEs and SAEs can be found in Appendix 3 (Section 10.3). The definition of 
AESI is provided in Section 8.6.6. 
The definitions of unsolicited and solicited adverse events can be found in Appendix 3 
(Section 10.3). 
The definitions of device-related safety events, (adverse device effects [ADEs] and serious 
adverse device effects [SADEs]), can be found in Appendix 7 (Section 10.7). Device deficiencies 
are covered in Section 8.6.8. 
AEs and ADEs will be reported by the participant.  
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE, SAE, ADE or SADE and remain responsible 
for following up AEs and ADEs that are serious, considered related to the study intervention or 
study procedures, or that caused the participant to discontinue the study intervention  
(see Section 7). This includes events reported by the participant (or, when appropriate, by 
a caregiver, surrogate, or the participant’s legally authorized representative). 
The method of recording, evaluating, and assessing causality of AEs, ADEs, SAEs and SADEs 
and the procedures for completing and transmitting SAE reports are provided in Appendix 3 
(Section 10.3). 
8.6.1 Time period and frequency for collecting AE and SAE information  
All AEs (serious or nonserious) will be collected from the signing of the ICF until at the time 
points specified in the SoA (Section 1.3). 
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All SAEs and AESI will be recorded and reported to the Sponsor or designee immediately and 
under no circumstance should this exceed 24 hours, as indicated in Appendix 3 (Section 10.3). 
The Investigator will submit any updated SAE data to the Sponsor within 24 hours of it being 
available. 
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion of 
the study participation. However, if the Investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and the Investigator considers 
the event to be reasonably related to the study intervention or study participation, the Investigator 
must promptly notify the Sponsor. 
8.6.2 Method of detecting AEs and SAEs  
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.6.3 Follow-up of AEs and SAEs  
After the initial AE/ADE/AESI/SAE/SADE report, the Investigator is required to proactively 
follow each participant at subsequent visits/contacts. At the pre-specified study end-date, all 
SAEs, SADEs and AESI (as defined in Section 8.6.6), will be followed until resolution, 
stabilization, the event is otherwise explained, or the participant is lost to follow-up (as defined in 
Section 7.3). Further information on follow-up procedures is provided in Appendix 3 
(Section 10.3). 
8.6.4 Regulatory reporting requirements for SAEs  
• Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met. 
• The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and Investigators. 
• Serious adverse events that are considered expected will be specified in the reference 
safety information section of the Investigator’s Brochure.  
• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to Investigators as necessary. 
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• An Investigator who receives an Investigator safety report describing an SAE, SUSAR or 
any other specific safety information (eg, summary or listing of SAEs) from the Sponsor 
will review and then file it along with the Investigator’s Brochure / package insert 
(as applicable) and will notify the IRB/IEC, if appropriate according to local requirements. 
It is the responsibility of the Sponsor to assess whether an event meets the criteria for 
a SUSAR, and therefore, is expedited to regulatory authorities. 
8.6.5 Pregnancy  
• Details of all pregnancies in female participants and, if indicated, female partners of male 
participants will be collected after the start of study intervention and until 5 months after 
the last isatuximab administration.  
• If a pregnancy is reported, the Investigator will record pregnancy information on 
the appropriate form and submit it to the Sponsor within 24 hours of learning of the female 
participant pregnancy or a female partner of male participants. 
• Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs and will be reported as such. 
• The participant will be followed to determine the outcome of the pregnancy. 
The Investigator will collect follow-up information on the participant and the neonate, and 
the information will be forwarded to the Sponsor. 
• Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the Investigator will be reported to the Sponsor as described in 
Section 8.6.4. While the Investigator is not obligated to actively seek this information in 
former study participants he or she may learn of an SAE through spontaneous reporting. 
• Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention or be withdrawn from the study. 
8.6.6 Adverse event of special interest  
An AESI is an AE (serious or nonserious) of scientific and medical concern specific to 
the Sponsor’s product or program, 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. 
• Infusion reactions Grade ≥3. Infusion reactions (for example, NCI CTCAE Version 5.0 
terms “infusion related reaction”, “allergic reaction”, or “cytokine release syndrome”) are 
defined as AEs related to isatuximab and/or to novel agent with onset typically within 
24 hours from the start of the infusion. 
• ISRs: Grade 2 or higher.  
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• Pregnancy of a female participant entered in a study as well as pregnancy occurring in 
a female partner of a male participant entered in a study with IMP:  
- 
Pregnancy occurring in a female participant entered in the clinical trial or in a female 
partner of a male participant entered in the clinical trial. It will be qualified as an SAE 
only if it fulfills one of the seriousness criteria (see Appendix 3 [Section 10.3]). 
- 
In the event of pregnancy in a female participant, IMP should be discontinued.  
- 
Follow-up of the pregnancy in a female participant or in a female partner of a male 
participant is mandatory until the outcome of the pregnancy. The Investigator will 
collect follow-up information on the participant or pregnant female partner and the 
neonate. The information will be forwarded to the Sponsor. Follow-up will be up to 
1 year after the delivery of a newborn. (See Appendix 4 [Section 10.4]). 
• Symptomatic overdose (serious or nonserious) with IMP/AxMP (see definition of 
an overdose in Section 6.7). 
• Second primary malignancies are to be reported using the AE report form and must be 
considered as AESIs; these AEs must also be documented in the appropriate page(s) of 
the eCRF and participant’s source documents. Diagnosis and tests completed as per 
standard clinical practice of the second primary malignancy must be provided at the time 
of reporting (eg, any confirmatory histology or cytology results, X-rays, computed 
tomography [CT] scans, etc). 
8.6.7 Medication errors or misuses of medicinal product  
All reports of medication error or misuse in relation to the IMP with or without an AE must be 
recorded on the corresponding page(s) of the CRF and transmitted to the Sponsor’s representative 
following standard processes. 
A medication error is an unintended failure in the drug treatment process (ie, mistake in 
the process of prescribing, storing, dispensing, preparing, or administering medicinal products in 
clinical practice) that leads to, or has the potential to lead to harm to the participant. 
This includes situations in which a participant was involved or not (eg, even if the error was 
recognized and intercepted before the participant received or used the product), and whether it 
resulted in harm to the participant or not. 
A misuse refers to situations where the medicinal product is intentionally and inappropriately 
used, ie, not in accordance with the terms of the marketing authorization or outside what is 
foreseen in the protocol, by the participant for a therapeutic purpose. 
Of note, if a medication error or misuse meets the protocol definition of an overdose, it will be 
recorded in the overdose page of the CRF. 
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8.6.8 Guidelines for reporting product complaints  
Any defect in the IMP/ AxMP/device 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. 
8.6.9 Medical device deficiencies  
Medical devices are being provided for use in this study as the study intervention. To fulfill 
regulatory reporting obligations worldwide, the Investigator is responsible for the detection and 
documentation of events meeting the definitions of device deficiencies that occur during the study 
with such devices. 
The definition of a medical device deficiency can be found in Appendix 7 (Section 10.7). 
NOTE: Deficiencies fulfilling the definition of an AE/SAE will follow the processes outlined in 
Appendix 7 (Section 10.7) of the protocol. 
8.6.9.1 Time period for detecting medical device deficiencies  
• SADEs, as well as medical device deficiencies that might have led to a SAE if appropriate 
action had not been taken, intervention had not occurred, or circumstances had been less 
fortunate will be detected and documented during all periods of the study in which 
the medical device is used. 
• SADEs as well as medical device deficiencies that might have led to a SAE if appropriate 
action had not been taken, intervention had not occurred, or circumstances had been less 
fortunate will be reported during all periods of the study in which the medical device is 
used. 
Similarly, any new finding in relation to an ADE or SADE will be detected, documented, and 
reported during all periods of the study in which the medical device is used. 
• If the Investigator learns of any device deficiency at any time after a participant has been 
discharged from the study, and such deficiency is considered reasonably related to 
a medical device provided for the study, the Investigator will promptly notify the Sponsor. 
The method of documenting medical device deficiency is provided in Appendix 7 (Section 10.7). 
8.6.9.2 Follow-up of medical device deficiencies  
• Follow-up applies to all participants, including those who discontinue study intervention. 
• The Investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality of the deficiency. 
• New or updated information will be recorded on the originally completed form with all 
changes signed and dated by the Investigator. 
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8.6.9.3 Prompt reporting of device deficiencies to Sponsor  
• Device deficiencies will be reported to the Sponsor within 24 hours after the Investigator 
determines that the event meets the protocol definition of a medical device deficiency. 
• The medical device deficiency report form will be sent to the Sponsor by the Product 
Technical Complaint (PTC) form completed in the pharmacy manual.  
• The Sponsor will be the contact for the receipt of device deficiency reports. 
8.6.9.4 Regulatory reporting requirements for device deficiencies  
• The Investigator will promptly report all device deficiencies occurring with any medical 
device provided for use in the study in order for the Sponsor to fulfill the legal 
responsibility to notify appropriate regulatory authorities and other entities about certain 
safety information relating to medical devices being used in clinical studies. 
• The Investigator, or responsible person according to local requirements (eg, the head of 
the medical institution), will comply with the applicable local regulatory requirements 
relating to the reporting of device deficiencies to the IRB/IEC. 
• Sponsor will retain medical devices subject to a complaint/deficiency for return to sponsor 
for investigation. 
8.7 
GENETICS  
No congenital genetic testing is planned in this study; however, tumoral genetic and genomic 
analyses will be performed on bone marrow samples. 
8.8 
BIOMARKERS  
Bone marrow and blood samples will be collected and analyzed at a central lab for the following 
biomarker analyses: 
• Minimal residual disease will be assessed by next generation sequencing or any other 
validated technology in BM aspirates and correlated with parameters of clinical response. 
Bone marrow aspirate samples will be collected at screening for all participants and 
at the time of maximum confirmed response of either CR or VGPR, 12 months after C1D1 
and 12 months after first MRD negativity.  
• Characterization of tumoral genomic and genetic profiles to explore mechanism of drug 
resistance: Bone marrow aspirate samples will be collected at screening and at disease 
progression. 
• Impact of new serum M-protein measurement methods (such as mass spectrometry) on 
disease response assessment: blood samples will be collected at all timepoints at which 
M-protein is assessed. 
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• Cytogenetics assessment: At screening, bone marrow aspirate will be collected for FISH 
analyses including, but may not be limited to, del[17p], t[4;14], t[14;16]), 1q21+,in central 
laboratory.  
• Samples collected for biomarker analyses and their derivatives will be stored for a period 
of up to 5 years after last participant last visit for potential re-analyses for future research. 
8.9 
IMMUNOGENICITY ASSESSMENTS  
Antibodies to isatixumab will be evaluated in plasma samples collected from all participants 
according to the SoA. Additionally, plasma samples should also be collected at the final visit from 
participants who discontinued study intervention or were withdrawn from the study. 
Blood samples will be collected for assessing the presence of ADA against isatuximab in plasma 
from all participants as described in the PK/ADA flowcharts (Section 1.3).  
Instructions for the collection and handling of PK/ADA samples will be provided by the Sponsor 
or Sponsor’s designee in a separate laboratory manual. These samples will be tested by 
the Sponsor or Sponsor’s designee. 
Plasma samples will be screened for antibodies binding to isatuximab and the titer of confirmed 
positive samples will be reported. Other analyses may be performed to verify the stability of 
antibodies to isatuximab and/or further characterize the immunogenicity of isatuximab by 
evaluating for their ability to neutralize the activity of isatuximab. 
8.10 
SPECIFICITIES REGARDING COVID-19 SITUATION AND VACCINATION  
With regards to EFC15951 there are currently no specific restrictions on the use of vaccines 
authorized today by local regulatory health authorities to prevent COVID-19. Sanofi will continue 
to monitor vaccine authorizations moving forward and inform you if this position changes.  
Participants being actively treated with daratumumab (another CD38 directed monoclonal 
antibody) and low-dose dexamethasone were successfully immunized for S. pneumoniae and 
H. influenzae (41) supporting the safety of continuing active treatment with isatuximab while 
undergoing vaccination for COVID-19. In addition, the half-life of isatuximab of 28 days (refer 
SARCLISA SmPC or package insert) is such that a short-term interruption of the administration 
schedule is not expected to substantially modify immune responsiveness. 
Based on recommendations or statements from scientific societies, if at least one vaccine has been 
authorized by your national competent regulatory health authority(ies) to prevent COVID-19 and 
a participant in isatuximab study is both eligible, based on the local vaccination guidelines or 
recommendations, and willing to receive this authorized COVID-19 vaccine, the study participant 
should proceed with vaccination. Ultimately the decision for each individual participant will need 
to be made on a case-by-case basis and informed by sound clinical judgement and your local 
recommendations and guidelines.  
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There is no recommendation to alter the isatuximab administration schedule in light of 
the vaccination schedule. Other anti-myeloma agents administered during the study, in particular 
high dose steroids, may be considered to be temporarily held as per the official recommendations 
and investigator judgment. 
With regards to COVID-19 vaccination, please report the following in the appropriate eCRF 
pages according to the revised CRF completion instructions: 
1. Each COVID-19 vaccine injection. 
2. Any observed adverse event following the administration of the COVID-19 vaccine during 
study treatment period phase. 
3. COVID-19 antibody titers if measured after vaccination. 
Please ensure that all the above steps are well documented in the participant’s health records 
at the study site. 
8.11 
HEALTH ECONOMICS OR MEDICAL RESOURCE UTILIZATION AND HEALTH 
ECONOMICS  
Medical resource utilization will be collected through the specific HRUPQ questionnaire. 
Protocol-mandated procedures, tests, and encounters are excluded. The data collected will include 
number, nature (emergency or routine) and duration of hospitalizations, emergency room visits 
and outpatient medical encounters. 
8.12 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH  
Future research may help further the understanding of disease and the development of new 
medicines. Reuse of coded data and biological samples (leftover and additional) will be limited to 
future scientific research conducted under a research plan for the purpose of diagnosing, 
preventing or treating diseases. The future research projects will be conducted under the 
Sponsor’s and/or its affiliates’ and/or, if applicable, the partner of the Sponsor which has licensed 
the study drug to the Sponsor or which is co-developing the study drug with the Sponsor’s 
control, acting alone or in collaboration with research partners such as universities, research 
institutions or industrial partners with whom the coded data may be shared.  
Coded study data and biological samples will be stored and used for future research only when 
consented to by participants (see Section 10.1.3) and, when applicable, further information on 
the future research has been provided to the study participant, unless prohibited by local laws or 
IRBs/IECs (in such case, consent for future use of sample will not be included in the local ICF). 
The conditions for reuse will be adapted locally with the appropriate language in the ICF. 
In any case, a specific consent will be collected for the performance of genetic analyses on 
leftover and/or additional samples.  
For participants who consent to the storage and use of their data and remaining (leftover) and/or 
extra clinical samples, data and samples may be used after the study ends for future research 
related either to the drug, the mechanism of action, and the disease or its associated conditions. 
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Such research may include, but is not limited to, performing assessments on DNA, RNA, proteins, 
or metabolites. If future research on genetic material is performed, this will also be limited to 
the purpose of addressing research questions related to the drug, the mechanism of action, 
the disease, or its associated conditions.  
Data protection – Processing of coded clinical data  
The study participant will be provided with all mandatory details of the data processing in 
Section 2 of the core ICF. 
The Sponsor adopts safeguards for protecting participant confidentiality and personal data 
(see Section 10.1.4). 
Use of leftover samples and additional samples for future research 
Remaining leftover samples will be used only after the study ends, ie, end of study as defined in 
the study protocol. Additional/extra samples can be collected and used during the study conduct 
at a given timepoint (eg, at randomization visit) as defined in the study protocol.  
The study participant will be provided with all mandatory details of the use of the human 
biological samples (leftover and additional) in Section 2 of the Core ICF. 
Study participant data will be stored for up to 25 years for regulatory purposes. Biological 
samples for future use will be stored for a maximum of 25 years after the end of the study unless 
local regulations require a different retention period. Any samples remaining at the end of 
retention period will be destroyed. If a participant requests destruction of his/her samples before 
the end of the retention period, the Investigator must notify the Sponsor (or its contract 
organization) in writing. In such case, samples will be destroyed, and related coded data will be 
anonymized unless otherwise required by applicable laws. 
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9 
STATISTICAL CONSIDERATIONS  
9.1 
POPULATIONS FOR ANALYSES  
The following populations for analyses are defined:  
Table 20 - Populations for analyses  
Population 
Description 
Intent-to-treat (ITT) 
The intent-to-treat (ITT) population is the randomized population. All participants 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. Participants will be 
analyzed according to the treatment group allocated by IRT, regardless of whether 
the participants received any study treatment or receive a different study treatment from that to 
which they were randomized. 
This population will be used for the analysis of the co-primary efficacy endpoint. 
Per Protocol-PK (PP-PK) 
population 
The Per Protocol PK population will include all randomized participants who have received at least 
eleven Isatuximab doses out of twelve up to C5D15 (one dose omission permitted during 
Cycle 1), with isatuximab C6D1 (predose) concentration results from PK sample collected within 
the defined per protocol time window and adequate documentation of dosing and sampling dates 
and times. 
This population will be used for the analysis of the co-primary PK endpoint. 
CT4W-PK population 
The CT4W-PK population for CT4W endpoint will include all randomized participants having 
completed administration of all the first 4 weekly isatuximab doses at Cycle 1, with isatuximab 
C2D1 (predose) concentration results from PK sample collected within the defined per protocol 
time window and adequate documentation of dosing and sampling dates and times. 
This population will be used for the analysis of the CT4W PK endpoint. 
Per Protocol population 
The PP is defined as all treated subjects who have measurable disease at baseline and have no 
major protocol deviations with respect to eligibility.  
This population will be used for sensitivity analysis of ORR in the context of a non-inferiority 
design.  
Safety 
The safety population will include ITT participants who have received at least 1 dose or a part of 
a dose of the study intervention. All analyses using this population will be based on the treatment 
actually received.  
All safety analysis will be performed on this population. 
Pharmacokinetic (PK) 
The PK population will include all participants with at least 1 available isatuximab concentration 
post-baseline (whatever the cycle and even if dosing is incomplete) with adequate documentation 
of dosing and sampling dates and times. 
This population will be used for the analysis of PK secondary endpoints. 
ADA 
The immunogenicity population will include all participants from safety population with at least 
1 ADA result (negative, positive or inconclusive) post-baseline. 
Screened participants are defined as any participants who signed the ICF. 
Participants exposed to study intervention before or without being randomized will not be 
considered randomized and will not be included in any analysis population. The safety experience 
of these participants will be reported separately. 
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Randomized participants for whom it is unclear whether they took the study intervention will be 
considered as exposed and will be included in the safety population as randomized. 
For any participant 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 reported separately. 
9.2 
STATISTICAL ANALYSES  
The SAP will include a more technical and detailed description of the statistical analyses 
described in this section. This section is a summary of the planned statistical analyses of the most 
important endpoints including primary and secondary endpoints. 
9.2.1 General considerations  
Myeloma response and progression will be determined by Independent Review Committee based 
on central laboratory M-protein analysis and central radiology review using IMWG 2016 criteria. 
The following stratification factors will be used:  
• MM isotype (IgG versus non-IgG). 
• Body weight (≤65 kg, >65 to ≤85 kg, and >85 kg). 
• Number of prior lines (1-2 versus ≥3). 
Primary and secondary endpoints will be analyzed by treatment arm. 
Study treatment is defined as isatuximab (SC/IV) in combination with pomalidomide and 
dexamethasone. First dose of study treatment is defined as the first starting dose of any study 
intervention of isatuximab, pomalidomide or dexamethasone. Last dose of study treatment is 
defined as the last dose of any study intervention of isatuximab, pomalidomide, or 
dexamethasone. 
For each of the safety parameters, the baseline will be defined as the last value or measurement 
taken up to the first dose of study treatment. 
The observation period will be divided into 3 segments:  
• The pre-treatment period is defined as the time the ICF is signed until the first dose of 
the study treatment administration. 
• The treatment-emergent (TE) period is defined as the period from the first study 
treatment administration to the last study treatment administration +30 days. 
• The post-treatment period is defined as the time starting 31 days after the last study 
treatment is administered to study closure or death, whichever comes first.  
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9.2.2 Primary endpoint(s) analyses  
The number and proportion of participants who achieve ORR per IRC assessment will be 
calculated for each group. The relative risk of Isa-SC + Pd relative to Isa-IV + Pd and its 
two-sided 95% CI using Farrington and Manning method will be provided. If the lower bound of 
the 95% CI is not less than a non-inferiority margin of 0.839, the non-inferiority of efficacy 
Isa- SC + Pd relative to Isa- IV + Pd will be concluded. The odds ratio of ISA- SC+ Pd relative to 
Isa- IV + Pd with their 95% CI will also be provided. 
For the co-primary PK endpoint of Ctrough at steady state (corresponding to predose at C6D1), 
summary statistics such as geometric means, coefficient of variation, median and range will be 
provided for treatment group. The ratio of the geometric means of Isa-SC+ Pd relative to 
Isa- IV + Pd and corresponding two-sided 90% CI will be provided by calculating the 90% CI 
under the logarithm scale then converting back to its original scale. The non-inferiority of PK 
Isa- SC + Pd relative to Isa- IV + Pd will be concluded if the lower bound of the 90% CI for the 
geometric mean ratio of Ctrough at steady state is at least 80% (a non-inferiority margin of 80%).  
The non-inferiority of ISA- SC+ Pd relative to Isa- IV + Pd will be concluded if both the efficacy 
and PK endpoints achieve non-inferiority.  
9.2.3 Secondary endpoint(s) analyses  
9.2.3.1 Key Secondary Endpoints  
VGPR or better rate per IRC assessment will be summarized for the ITT population in the same 
way as for ORR endpoint. The non-inferiority test for non-unity null according to Farrington and 
Manning (1990) will be performed for VGPR or better rate. The non-inferiority margin is 
0.6312 which was calculated as 40% retention of the observed historical clinical benefit of VGPR 
or better ratio 0.478 (upper bound of the 95% CI of rate ratio for Pd over CD38+ Pd as 
demonstrated in ICARIA-MM trial) under the logarithm scale then converting back to its original 
scale. If the lower bound of the 95% CI is not less than a non-inferiority margin of 0.6312, 
the non-inferiority of Isa-SC + Pd relative to Isa- IV + Pd on the VGPR or better rate will be 
concluded.  
The PK endpoint of CT4W will be summarized for the CT4W-PK population in the same way as 
for the Ctrough at steady state endpoint. The non-inferiority of Isa- SC + Pd relative to Isa-IV + Pd 
on CT4W corresponding to predose at C2D1 will be concluded if the lower bound of the 90% CI 
for the geometric mean ratio of CT4W is at least 80% (a non-inferiority margin of 80%).  
Incidence rate of IRs will be compared between treatment arms on the safety population using 
the Fisher’s exact test. The relative risk, odds ratio of ISA- SC+ Pd relative to Isa- IV + Pd with 
their 95% CI will be provided. 
Percentage of participants who reported satisfied or very satisfied with the injection method used 
to administer the study medication based on the PESQ questionnaire at C5D15 visit will be 
compared between treatment arms on the ITT population using the stratified CMH method. 
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9.2.3.2 Other Secondary Endpoints  
The CR rate will be summarized in the same way as for ORR endpoint. 
The median PFS per IRC assessment and probabilities of being progression free at different time 
points calculated using the Kaplan-Meier methods as well as corresponding 95% CI will be 
presented by treatment arm. The Kaplan-Meier PFS curves will also be provided. Additionally, 
the HR estimated from the Cox proportional hazards model as well as its associated 95% CI will 
be provided too.  
The analysis for PFS2, OS, DOR, and TTR (TT1R and TTBR) as well as the impact of abnormal 
cytogenetic subtypes will be similar to that described for PFS per IRC assessment. 
PK parameters and derived exposure will be summarized and provided in a separate report. PK 
concentrations (Ctrough and Ceoi - Isa-IV+Pd arm for Ceoi only) will be summarized per arm with 
descriptive statistics.  
Incidence of participants with ADA against isatuximab will be provided in a separate table. 
Number (and percentage) of participants experiencing TEAEs by primary system organ class and 
preferred term will be summarized by NCI CTCAE (v5.0) grade (all grades and ≥Grade 3) for 
the safety population. The same summaries will be prepared for treatment related TEAEs, TEAEs 
leading to treatment discontinuation, TEAEs leading to dose modification, serious TEAEs and 
TEAEs with fatal outcome and ISRs. Second primary malignancies as AESI will be reported 
throughout the study.  
Hematology and biochemistry results will be graded according to NCI CTCAE v5.0. Number 
(and percentage) of participants with laboratory abnormalities (ie, all grades and ≥Grade 3) using 
the worst grade during the on-treatment period will be provided for the safety population.  
Number of successful injections with investigational isatuximab injector device will be assessed. 
Participant expectations at baseline, participant experience, and satisfaction, assessment of 
treatment, and Health Resource Utilization and Productivity questionnaires will be descriptively 
summarized.  
Participants’ health-related quality of life (influenced by both disease and treatment) will be 
assessed by EORTC QLQ-C30 and EORTC QLQ-MY20 via a comparison of change scores in 
C30 (individual symptom change scores) and MY20 (disease- and treatment-related summary 
scores) from baseline to follow-up between treatment arms. In addition, responder analyses will 
be conducted 1) for those who improve and 2) for those who deteriorate, utilizing the CIDs for all 
individual symptom scores (C30) and disease- and treatment-related summary scores (MY20) for 
both treatment arms. 
Health status (EQ-5D-5L, including VAS) will be assessed via a comparison of EQ-5D-5L health 
status change scores from baseline to follow-up between treatment arms. In addition, responder 
analyses will be conducted 1) for those who improve and 2) for those who deteriorate, utilizing 
the CIDs for health status VAS scores for both treatment arms. 
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9.2.4 Tertiary/exploratory endpoint analyses  
Statistical analysis for exploratory endpoints will be described in the SAP. 
9.2.5 Multiplicity adjustment  
Both co-primary endpoints will need to achieve non-inferiority as specified in Section 9.2.2, in 
order to claim the non-inferiority of ISA SC+ PomDex relative to Isa IV + PomDex.  
Hypothesis testing of key secondary endpoints (VGPR or better rate per IRC assessment and 
CT4W) for non-inferiority, and key secondary endpoints (incidence of IRs and percentage of 
participants satisfied or very satisfied based on the PESQ questionnaire) for superiority will be 
carried out. A hierarchical test procedure will be used to control the familywise Type I error rate 
at one-sided significance level of 0.025 meaning that testing of key secondary endpoints will be 
performed only if the non-inferiority for both co-primary endpoints are established and testing on 
subsequent endpoints will continue only if the null hypothesis for the previously tested endpoint is 
rejected. The hierarchical procedure for testing the key secondary endpoints comparing SC arm 
with IV arm will be performed according to the following order: 
• VGPR or better rate for non-inferiority.  
• CT4W for non-inferiority.  
• Incidence of IRs for superiority. 
• Percentage of participants who reported satisfied or very satisfied with the injection 
method used to administer the study medication at C5D15 visit for superiority.  
9.2.6 Other/safety analysis  
9.2.6.1 Adverse events  
General common rules for adverse events 
The AEs will be analyzed in the following 3 categories: 
• Pre-treatment AEs: AEs that developed, worsened, or became serious during 
the pre-treatment period. 
• TEAEs: AEs that developed, worsened, or became serious during the treatment-emergent 
period. 
• Post-treatment AEs: AEs that developed, worsened, or became serious during 
the post-treatment period. 
Similarly, the deaths will be analyzed in the pre-treatment, treatment-emergent and post-treatment 
periods.  
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.  
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Analysis of all adverse events 
Adverse event incidence table will be provided by treatment group for all types of TEAEs: all 
TEAEs, all treatment emergent AESI (defined with a PT or a prespecified grouping), all treatment 
emergent SAEs and all TEAEs leading to permanent treatment discontinuation. 
The AE summaries will be generated with number (and percentage) of participants experiencing 
at least one event.  
Deaths will also be analyzed. 
9.2.6.2 Laboratory variables, vital signs, and electrocardiograms (ECGs)  
Quantitative analyses 
For laboratory variables, vital signs and ECG variables, the following analyses will be applied for 
each planned visit on safety population. 
Clinical laboratory values will be analyzed after conversion into standard international units. 
(International units will be used in all listings and tables). 
Hematology and clinical chemistry results will be graded according to the NCI-CTCAE V5.0, 
when applicable. Number (and percentage) of participants with laboratory abnormalities (ie, all 
grades and by grade) using the worst grade during the treatment period will be provided for 
the safety population. Analyses will be performed according to PCSA. 
For laboratory tests for which NCI-CTCAE v5.0 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 treatment-emergent 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. 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 SC arm will also be summarized. 
For laboratory variables graded by NCI-CTCAE. The number (and percentage) of participants 
with abnormal laboratory tests at baseline will be presented by grade.  
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The number (and percentage) of participants with abnormal laboratory tests during 
the treatment-emergent period will be summarized by grade. When appropriate, the number (and 
percentage) of participants with abnormality of any grade and with Grade 3-4 abnormalities will 
be provided. 
For ECG, the incidence of participants with at least one abnormal ECG during 
the treatment-emergent period will be summarized regardless of the baseline level and according 
to the following baseline status categories:  
• Normal/missing. 
• Abnormal. 
9.2.6.3 Product complaints  
Product complaints will be summarized in the safety population.  
9.2.7 Other analysis  
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix 9 (Section 10.9): Contingency measures for a regional or national 
emergency that is declared by a governmental agency.  
9.3 
INTERIM ANALYSES  
No interim analysis with alpha spending is planned for this study. 
9.4 
TIMING OF PLANNED ANALYSIS  
The cut-off date for the primary analysis is approximately 6 months after the LPI, which includes 
analysis on the primary endpoint and secondary endpoints when applicable. An update of PFS and 
OS will be performed approximately 15 months after LPI. The cut-off date for final OS analysis 
will be approximately 30 months after LPI.  
9.5 
SAMPLE SIZE DETERMINATION  
A total sample size of 534 participants (randomization ratio 1:1, ie, 267 randomized participants 
in the SC arm, and 267 randomized participants in the IV arm) was determined to demonstrate 
non-inferiority of SC arm versus IV arm on the proportion ratio of participants who achieved 
ORR, and the geometric mean ratio of Ctrough at steady state (corresponding to predose at C6D1). 
For the co-primary efficacy endpoint of ORR, the non-inferiority test for non-unity null according 
to Farrington and Manning (1990) was implemented. With 2.5% one sided Type I error rate, and 
a non-inferiority margin of 0.839 which was calculated as 40% retention of the observed historical 
clinical benefit of ORR ratio 0.7463 (upper bound of the 95% CI of rate ratio for Pd over 
CD38+Pd as demonstrated in ICARIA-MM trial) under the logarithm scale then converting back 
to its original scale, 534 randomized participants provide approximately 80% power for this 
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efficacy co-primary endpoint assuming that ORR for IV arm is 60.4% and the true response rate 
ratio is 1.02 for SC arm over IV arm. For the PK co-primary endpoint of Ctrough at steady state, 
assuming Ctrough at steady state follows log normal distribution with a true geometric mean ratio of 
1 and a CV of 75%, and an assumed drop-out rate of no more than 50% to the PK per-protocol 
population, 534 randomized participants will provide at least an 86% power to show the lower 
bound of the 90% CI of the geometric mean ratio of Ctrough at steady state is at least 80% 
(a non-inferiority margin of 80%). 
Calculations were made based on SAS 9.4 (1). 
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10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS  
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS  
10.1.1 Regulatory and ethical considerations  
• This study will be conducted in accordance with the protocol and with the following: 
- 
Consensus ethical principles derived from international guidelines including 
the Declaration of Helsinki and the applicable amendments and Council for 
International Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines. 
- 
Applicable ICH Good Clinical Practice (GCP) Guidelines. 
- 
The Regulation (EU) No 536/2014 of the European Parliament and the Council of 
16 April 2014 on clinical trials on medicinal products for human use, as applicable. 
- 
The General Data Protection Regulation - (GDPR) and any other applicable data 
protection laws. 
- 
Any other applicable laws and regulations. 
• The protocol, protocol amendments, ICF, IB, [IDFU] and other relevant documents 
(eg, advertisements) must be submitted to an IRB/IEC by the Investigator and reviewed 
and approved by the IRB/IEC before the study is initiated. 
• Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
• Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate hazard 
to study participants. 
• The Investigator will be responsible for the following, as applicable: 
- 
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. 
- 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures. 
- 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, Regulation No 536/2014 of 
the European Parliament and the Council of the European Union for clinical studies, 
European Medical Device Regulation 2017/745 for clinical device research, and all 
other applicable local regulations. 
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Determining whether an incidental finding (as per Sanofi policy) 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. 
- 
As applicable, according to requirements of the Regulation No536/2014 of 
the European Parliament and the Council of the European Union 
The Sponsor will be responsible for obtaining approval from the Competent Authorities of the EU 
Member States and/or Ethics Committees, as appropriate, for any amendments to the clinical 
trial that are deemed as “substantial” (ie, changes which are likely to have a significant impact on 
the safety or physical or mental integrity of the clinical trial participants or on the scientific value 
of the trial) prior to their implementation. 
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-EU/EEA 
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. 
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 48h 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 
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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. 
10.1.2 Financial disclosure  
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
10.1.3 Informed consent process  
The ICF will be provided to the study participant in paper version. When feasible, an eConsent 
process may be used at global level and/or locally if permitted by country regulations.  
• The Investigator or the Investigator’s representative will explain the nature of the study 
including the risk and benefits to the potential participants, and answer all questions 
regarding the study, including what happens to the participants when their participation 
ends (post-trial access strategy for the study).  
• Potential participants must be informed that their participation is voluntary. They will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 
50, local regulations, ICH guidelines, Privacy and Data Protection requirements including 
those of the General Data Protection Regulation (GDPR) and of the French law, Health 
Insurance Portability and Accountability Act (HIPAA) requirements, where applicable, 
and the IRB/IEC or study center.  
• The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
• In case of ICF amendment while the participants are still included in the study, they must 
be re-consented to the most current version of the ICF(s). Where participants are not in 
the study anymore, teams in charge of the amendment must define if those participants 
must or not re-consent or be informed of the amendment (eg, if the processing of personal 
data is modified, if the Sponsor changes, etc). 
• A copy of the ICF(s) must be provided to the participant. 
The ICF contains 2 separate sections that addresses the use for research of participants’ data 
and/or samples (remaining mandatory ones or new extra samples collected for optional research). 
Optional exploratory research must be detailed in the section “Optional tests/procedures” and 
future research is to be defined in Core Study Informed Consent Form (CSICF) Part 2. Each 
option is subject to an independent consent and must be confirmed by checkboxes in CSICF 
Part 3, each checkbox corresponding to a specific use: consent for the performance of an optional 
exploratory research; consent for storage and use of coded data for future research; consent for 
use of leftover samples and associated coded data for future research; consent for collection of 
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additional biological samples for storage and use for future research, and consent for performance 
of genetic analyses on biological samples. The Investigator or authorized designee will explain to 
each participant the objectives of the exploratory research and why data and samples are 
important for future research. Participants will be told that they are free to refuse to participate 
and may withdraw their consent at any time and for any reason during the storage period. 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Section 10.9, Appendix 9: Contingency measures for a regional or national 
emergency that is declared by a governmental agency.  
10.1.4 Data protection  
All personal data collected and/or processed in relation to this study will be handled in 
compliance with all applicable Privacy & Data Protection laws and regulations, including 
the GDPR (General Data Protection Regulation). The study Sponsor is the Sanofi company 
responsible for ensuring compliance with this matter, when processing data from any individual 
who may be included in the Sanofi databases, including trial participants, Investigators, nurses, 
experts, service providers, Ethics Committee members, etc.  
When archiving or processing personal data pertaining to the Investigator and/or to 
the participants, the Sponsor takes all appropriate measures to safeguard and prevent access to this 
data by any unauthorized third party. 
Protection of participant personal data 
Data collected must be adequate, relevant, and not excessive, in relation to the purposes for which 
they are collected. Each category of data must be properly justified and in line with the study 
objective. 
“Participant race and ethnicity will be collected in this study because they are expected to modify 
the drug response. They will not be collected in the countries where this is prohibited by local 
regulation. 
• Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor or its service providers, when applicable, will 
be identifiable only by the unique identifier; participant names or any information which 
would make the participant identifiable will not be transferred to the Sponsor.  
• Participants must be informed that their personal study-related data will be used by 
the Sponsor in accordance with applicable data protection laws. The level of disclosure 
must also be explained to the participant as described in the informed consent.  
• Participants must be informed that their medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
• 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 
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detail in the notification the nature of the breach, the categories (eg, Sponsor's personnel, 
study participants or their relatives, 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. 
• Information technology systems used to collect, process, and store study-related data are 
secured by technical and organizational security measures designed to protect such data 
against accidental or unlawful loss, alteration, or unauthorized disclosure or access. 
• Participants must be informed that their study-related data will be used for the whole “drug 
development program”, ie, for this trial as well as for the following steps necessary for 
the development of the investigational product, including to support negotiations with 
payers and publication of results. 
Protection of personal data related to professionals involved in the study  
• Personal data (eg, contact details, affiliation(s) details, job title and related professional 
information, role in the study, professional resume, training records) are necessary to 
allow Sanofi to manage involvement in the study and/or the related contractual or 
pre-contractual relationship. They may be communicated to any company of the Sanofi 
group (“Sanofi”) or to Sanofi service providers, where needed. 
• Personal data can be processed for other studies and projects. At any time, objection to 
processing can be made by contacting the Sanofi Data Protection Officer (link available 
at Sanofi.com). 
• In case of refusal to the processing of personal data by or on behalf of Sanofi, it will be 
impossible to involve the professionals in any Sanofi study. In case the professionals have 
already been involved in a Sanofi study, they will not be able to object to the processing of 
their personal data as long as they are required to be processed by applicable regulations. 
The same rule applies in case the professionals are listed on a regulatory agencies 
disqualification list. 
• Personal data can be communicated to the following recipients:  
- 
Personnel within Sanofi or partners or service providers involved in the study.  
- 
Judicial, administrative and regulatory authorities, in order to comply with legal or 
regulatory requirements and/or to respond to specific requests or orders in 
the framework of judicial or administrative procedures. Contact details and identity 
may also be published on public websites in the interest of scientific research 
transparency. 
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• Personal data may be transferred towards entities located outside the Economic European 
Area, in countries where the legislation does not necessarily offer the same level of data 
protection or in countries not recognized by the European Commission as offering 
an adequate level of protection. Those transfers are safeguarded by Sanofi in accordance 
with the requirement of European law including, notably:  
- 
The standard contractual clauses of the European Commission for transfers towards 
our partners and service providers. 
- 
Sanofi’s Binding Corporate Rules for intra-group transfers.  
• Professionals have the possibility to lodge a complaint with Sanofi leading Supervisory 
Authority, the “Commission Nationale de l’Informatique et des Libertés” (CNIL) or with 
any competent local regulatory authority. 
• Personal data of professionals will be retained by Sanofi for up to thirty (30) years, unless 
further retention is required by applicable regulations. 
• In order to facilitate the maintenance of Investigators personal data, especially if they 
contribute to studies sponsored by several pharmaceuticals companies, Sanofi participates 
in the Shared Investigator Platform (SIP) and in the TransCelerate Investigator Registry 
(IR) project (https://transceleratebiopharmainc.com/initiatives/investigator-registry). 
Therefore, personal data will be securely shared by Sanofi with other pharmaceutical 
company members of the TransCelerate project. This sharing allows Investigators to keep 
their data up-to-date once for all across pharmaceutical companies participating in 
the project, with the right to object to the transfer of the data to the TransCelerate project.  
• Professionals have the right to request the access to and the rectification of their personal 
data, as well as their erasure (where applicable) by contacting the Sanofi Data Protection 
Officer: Sanofi DPO - 46 avenue de la Grande Armée - 75017 PARIS - France (to contact 
Sanofi by email, visit https://www.sanofi.com/en/our-responsibility/sanofi-global-privacy-
policy/contact). 
10.1.5 Committee’s structure  
10.1.5.1 Steering committee  
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. 
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10.1.5.2 Data monitoring committee  
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 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 participant safety or protect the scientific integrity of the trial. The Sponsor 
will make the final decision(s). 
The DMC procedures will be detailed in the DMC charter and approved by the DMC members. 
The charter will be discussed during a kick-off meeting before the first participant in DMC 
members will then meet 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 participants, as well as the course of 
action regarding the conduct of the trial. 
10.1.6 Dissemination of clinical study data and results 
Study participants 
At the end of the clinical study, the Sponsor may publish the study results in scientific journal(s). 
As part of the review for publication, independent scientists may need to use “coded” data of all 
the study participants to independently verify the study’s results. 
Sanofi shares information about clinical trials and results on publicly accessible websites, based 
on company commitments, international and local legal and regulatory requirements, and other 
clinical trial disclosure commitments established by pharmaceutical industry associations. These 
websites include ClinicalTrials.gov, euclinicaltrial.eu, and sanofi.com, as well as some national 
registries. For pediatric and adult trials, the results will generally be submitted/released 6 and 
12 months respectively, after the end of the clinical trial worldwide (ie, the last active, 
participating country). 
In addition, results from clinical trials of participants are required to be submitted to 
peer-reviewed journals following internal company review for accuracy, fair balance, and 
intellectual property. For those journals that request sharing of the analyzable data sets that are 
reported in the publication, interested researchers are directed to submit their request to vivli.org. 
Individual anonymized participant data and supporting clinical documents are available for 
request at vivli.org. While making information available we continue to protect the privacy of 
participants in our clinical trials. Details on data sharing criteria and process for requesting access 
can be found at this web address: vivli.org. 
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Professionals involved in the study or in the drug development program 
Sanofi undertakes the legal obligation to disclose the full name of the Investigator and his/her 
affiliated institute/ hospital’s name and location on the China Trial Disclosure website as required 
by the National Medical Products Administration (NMPA) in its guidance Drug Clinical Trial 
Registration and Information Disclosure “Management Practice (Trial Implementation)” 
requesting name disclosure of Chinese and foreign investigational sites and Investigators in any 
eligible clinical trial.  
Sanofi may publicly disclose, and communicate to relevant authorities/institutions, the funding, 
including payments and transfers of value, direct or indirect, made to healthcare organizations and 
professionals and/or any direct or indirect advantages and/or any related information or document 
if required by applicable law, by regulation or by a code of conduct such as the “EFPIA Code on 
Disclosure of Transfers of Value from Pharmaceutical Companies to Healthcare Professionals and 
Healthcare Organisations”. 
10.1.7 Data quality assurance  
• All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the Sponsor or designee electronically (eg, laboratory data). 
The Investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 
• Guidance on completion of CRFs will be provided in the eCRF. 
• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• Quality tolerance limits (QTL)s will be pre-defined in the QTL specification document to 
identify systematic issues that can impact participant safety and/or reliability of study 
results. These pre-defined parameters will be monitored during the study and important 
deviations from the QTLs and remedial actions taken will be summarized in the clinical 
study report. 
• Monitoring details describing strategy including definition of study critical data items and 
processes (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. 
• The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
• The Sponsor assumes accountability for actions delegated to other individuals 
(eg, Contract Research Organizations). 
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• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator for 25 years after the signature of the final study 
report unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of 
the Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor. 
10.1.8 Source documents  
• Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the Investigator’s site. 
• Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The Investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
• Source documents are original documents, data, and records (eg, hospital records, clinical 
and office charts, laboratory notes, memoranda, participant 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, participant 
files, and records kept at the pharmacy, at the laboratories, and at medical-technical 
departments) involved in the clinical study.  
• The Investigator must maintain accurate documentation (source data) that supports 
the information entered in the CRF. 
• The Sponsor or designee will perform monitoring to confirm that data entered into 
the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study 
is being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
10.1.9 Study and site start and closure  
First act of recruitment 
The first act of recruitment is the first participant screened and will be the study start date. 
Study/Site termination 
The Sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
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Reasons for study termination by the Sponsor, as well as reasons for the early closure of a study 
site by the Sponsor or Investigator may include but are not limited to: 
• For study termination: 
- 
Information on the product leads to doubt as to the benefit/risk ratio. 
- 
Discontinuation of further study intervention development. 
• For site termination: 
- 
Failure of the Investigator to comply with the protocol, the requirements of 
the IRB/IEC or local health authorities, the Sponsor’s procedures, or GCP guidelines. 
- 
Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the Investigator. 
- 
Total number of participants included earlier than expected. 
If the study is permanently terminated or suspended, the Sponsor shall promptly inform 
the Investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. The Investigator shall promptly inform the participant and 
should assure appropriate participant therapy and/or follow-up. 
10.1.10 Publication policy  
• The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor 
before submission. This allows the Sponsor to protect proprietary information and to 
provide comments. 
• The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In 
this case, a coordinating Investigator will be designated by mutual agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS  
• The tests detailed in Table 21 will be performed by the local laboratories. 
• Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol. 
• Additional tests may be performed at any time during the study as determined necessary 
by the Investigator or required by local regulations. 
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Table 21 - Protocol-required laboratory tests  
 
Laboratory tests 
Parameters 
Hematology 
 
 
Platelet count 
 
Red blood cell (RBC) count 
 
Hemoglobin 
 
Hematocrit 
 
White blood cell (WBC) count with differential: 
 
Neutrophils 
 
Lymphocytes 
 
Monocytes 
 
Eosinophils 
 
Basophils 
Coagulation 
Prothrombin time (PT)/international normalized ratio (INR) 
Partial thromboplastin time (PTT) 
Clinical chemistry 
 
 
Urea/Blood urea nitrogen (BUN) 
 
Creatinine 
• 
Estimated glomerular filtration rate (MDRD) (see Section 10.2.1)  
 
Glucose (fasting) 
 
Potassium 
 
Sodium 
 
Calcium 
 
Aspartate aminotransferase (AST)/ Serum glutamic-oxaloacetic transaminase (SGOT) 
 
Alanine aminotransferase (ALT)/ Serum glutamic-pyruvic transaminase (SGPT) 
 
Alkaline phosphatasea 
 
Total and direct bilirubin 
 
Total protein 
Thyroid function test 
• 
Thyroid-stimulating hormone (TSH) 
• 
Free T3  
• 
Free T4 
Albumin 
Lactate dehydrogenase (LDH) 
Venous bicarbonate/carbon dioxide 
Uric acid 
Chloride 
Magnesium 
Phosphate 
Routine urinalysis 
• 
RBCs, protein, glucose, pH, ketones, bilirubin, and leukocytes by dipstick. 
Pregnancy testing 
• 
Serum or highly sensitive urine human chorionic gonadotropin (hCG) pregnancy 
test (as needed for women of childbearing potential)b.  
Other screening tests 
• 
Follicle-stimulating hormone and estradiol (as needed in women of 
non-childbearing potential only). 
• 
Serology (HIV antibody, hepatitis B (HBsAg, anti-HBs, anti-HBc total and IgM) 
and hepatitis C (anti-HCV, HCV RNA level). 
• 
Bone marrow aspirate or biopsy. 
NOTES : 
a If alkaline phosphatase is elevated, consider fractionating.  
b Local urine testing will be standard for the protocol unless serum testing is required by local regulation or IRB/IEC. 
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Investigators must document their review of each laboratory safety report. 
10.2.1 Modification of diet in renal disease (MDRD) equation  
Estimated Glomerular filtration rate (mL/mins/1.73 m2) = 175  (Scr)-1.154  (Age)-0.203  (0.742 if 
Female)  (1.212 if African-American). 
10.3 
APPENDIX 3: AES AND SAES: DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING  
10.3.1 Definition of AE  
AE definition 
• An AE is any untoward medical occurrence in a participant or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered related 
to the study intervention. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention. 
Definition of unsolicited and solicited AE 
• An unsolicited AE is an AE that was not solicited using a participant diary and that is 
communicated by a participant who has signed the informed consent. Unsolicited AEs 
include serious and non-serious AEs. 
• Potential unsolicited AEs may be medically attended (ie, symptoms or illnesses requiring 
a hospitalization, or emergency room visit, or visit to/by a health care provider). 
The participants will be instructed to contact the site as soon as possible to report 
medically attended event(s), as well as any events that, though not medically attended, are 
of participant concern. Detailed information about reported unsolicited AEs will be 
collected by qualified site personnel and documented in the participant’s records. 
• Unsolicited AEs that are not medically attended nor perceived as a concern by participant 
will be collected during interview with the participants and by review of available medical 
records at the next visit. 
• Solicited AEs are predefined local at the injection site and systemic events for which 
the participant is specifically questioned, and which are noted by the participants in their 
diary. 
Events meeting the AE definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the Investigator (ie, not related to progression of underlying 
disease), or more severe than expected for the participant’s condition), eg: 
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- 
Leading to IMP discontinuation or modification of dosing, and/or,  
- 
Fulfilling a seriousness criterion, and/or,  
- 
Defined as an AESI. 
• Exacerbation of a chronic or intermittent pre-existing condition including either 
an increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. 
• Signs, symptoms, or the clinical sequelae of any medication errors and misuse with 
the IMP. 
• "Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as AE or SAE if they fulfill the definition of an AE or SAE. 
Events NOT meeting the AE definition 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by 
the Investigator to be more severe than expected for the participant’s condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
10.3.2 Definition of SAE  
An SAE is defined as any adverse event that, at any dose: 
a) Results in death. 
b) Is life-threatening. 
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant 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. 
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c) Requires inpatient hospitalization or prolongation of existing hospitalization. 
- 
In general, hospitalization signifies that the participant has been admitted (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in 
the physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered serious. 
- 
Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE. 
d) Results in persistent or significant disability/incapacity 
- 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
- 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
e) Is a congenital anomaly/birth defect. 
f) Other situations: 
- 
Medical or scientific judgment should be exercised by the Investigator in deciding 
whether SAE 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 participant or may require medical or 
surgical intervention to prevent one of the other outcomes listed in the above 
definition. These events should usually be considered serious. 
Note: The following list of medically important events is intended to serve 
as a guideline for determining which condition has to be considered as a medically 
important event. The list is not intended to be exhaustive:  
- 
Intensive treatment in an emergency room or at home for:  
- 
Allergic bronchospasm.  
- 
Blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow aplasia, 
myelodysplasia, pancytopenia, etc). 
- 
Convulsions (seizures, epilepsy, epileptic fit, absence, etc).  
- 
Development of drug dependence or drug abuse.  
- 
ALT >3 × ULN + total bilirubin >2 × ULN or asymptomatic ALT increase 
>10 × ULN.  
- 
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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10.3.3 Recording and follow-up of AE and/or SAE  
AE and SAE recording 
• When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
• The Investigator will then record all relevant AE/SAE information. 
• It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to the Sponsor’s representative in lieu of completion of the required form. 
• There may be instances when copies of medical records for certain cases are requested by 
the Sponsor’s representative. In this case, all participant identifiers, with the exception of 
the participant number, will be redacted on the copies of the medical records before 
submission to the Sponsor’s representative. 
• The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during 
the study and assign it to 1 of the following categories: 
• Mild: An event that is easily tolerated by the participant, causing minimal discomfort and 
not interfering with everyday activities. 
• Moderate: An event that causes sufficient discomfort to interfere with normal everyday 
activities. 
• Severe: An event that prevents normal everyday activities. An AE that is assessed 
as severe should not be confused with an SAE. “Severe” is a category used for rating 
the intensity of an event; and both AEs and SAEs can be assessed as severe. 
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as described 
in the definition of an SAE, NOT when it is rated as severe. 
Assessment of causality 
• The Investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. 
• A "reasonable possibility" of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than that a relationship cannot be ruled 
out. 
• The Investigator will use clinical judgment to determine the relationship. 
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• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• For causality assessment, the Investigator will also consult the IB and/or product 
information, for marketed products. 
• The Investigator must review and provide an assessment of causality for each AE/SAE, 
and document this in the medical notes. 
• There may be situations in which an SAE has occurred, and the Investigator has minimal 
information to include in the initial report to the Sponsor’s representative. However, it is 
very important that the Investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to the Sponsor’s 
representative. 
• The Investigator may change his/her opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment. 
• The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
Follow-up of AEs and SAEs 
• The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Sponsor’s 
representative to elucidate the nature and/or causality of the AE or SAE as fully 
as possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals. 
• If a participant dies during participation in the study or during a recognized follow-up 
period, the Investigator will provide the Sponsor with a copy of any post-mortem findings 
including histopathology. 
• New or updated information will be recorded in the originally submitted documents. 
• The Investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information. 
10.3.4 Reporting of SAEs  
SAE reporting to the Sponsor via an electronic data collection tool 
• The primary mechanism for reporting an SAE to the Sponsor’s representative will be 
the electronic data collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE data collection 
tool (see next section) to report the event within 24 hours. 
• The site will enter the SAE data into the electronic system as soon as it becomes available. 
• After the study is completed at a given site, the electronic data collection tool will be taken 
off-line to prevent the entry of new data or changes to existing data. 
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• If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, then the site can report this information on a paper SAE form (see next section) or 
to the Sponsor’s representative by telephone. 
• Contacts for SAE reporting can be found in the investigator site file. 
SAE reporting to the Sponsor via paper data collection tool 
• Facsimile transmission of the SAE paper data collection tool is the preferred method to 
transmit this information to the Sponsor’s representative. 
• In rare circumstances and in the absence of facsimile equipment, notification by telephone 
is acceptable with a copy of the SAE data collection tool sent by overnight mail or courier 
service. 
• Initial notification via telephone does not replace the need for the Investigator to complete 
and sign the SAE data collection tool within the designated reporting time frames. 
• Contacts for SAE reporting can be found in the investigator site file. 
10.4 
APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE  
10.4.1 Risk associated with pregnancy  
The effects of isatuximab on reproductive toxicity, pregnancy and lactation have not been 
investigated in formal toxicity studies. Therefore, the effects of isatuximab on reproductive organs 
in males and females are unknown. However, isatuximab is an IgG antibody, it may cross into 
the placenta and possibly affect embryonal or fetal growth and development. Therefore, 
the following contraceptive measures are required for males and females of childbearing potential.  
Pomalidomide is structurally related to thalidomide. Pomalidomide was found to be teratogenic in 
both rats and rabbits when administered during the period of major organogenesis. If 
pomalidomide is taken during pregnancy, a teratogenic effect of pomalidomide in humans is 
expected. Therefore, a risk minimization plan to prevent pregnancy must be observed. All study 
participants must comply with the requirements of Pomalidomide Pregnancy Prevention Plan 
recommendations (Appendix 15, Section 10.15) or the country specific risk management plan in 
countries where pomalidomide is not supplied by the Sponsor. 
10.4.2 Contraception guidance  
10.4.2.1 Criteria for females of childbearing potential  
This protocol defines a FCBP as a sexually mature female who: 
• Has achieved menarche at some time point. 
• Has not undergone a permanent sterilization method including:  
- 
Documented hysterectomy. 
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- 
Documented bilateral salpingectomy. 
- 
Documented bilateral oophorectomy. 
• Has not been naturally postmenopausal (amenorrhea following cancer therapy does not 
rule out childbearing potential) for at least 24 consecutive months (ie, has had menses 
at any time in the preceding 24 consecutive months). 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 24 months of amenorrhea, a single FSH measurement is 
insufficient. 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first administration of study intervention, additional evaluation should be 
considered. 
10.4.2.2 Contraception guidance for female subjects  
• If locally required, acceptable contraceptive methods are limited to those which inhibit 
ovulation as the primary mode of action. 
• Females of childbearing potential enrolled in this protocol must agree to use two reliable 
forms of contraception simultaneously or to practice complete abstinence from 
heterosexual intercourse during the following time periods related to this study:  
- 
For at least 28 days before starting study treatment,  
- 
And throughout the entire duration of pomalidomide treatment, 
- 
And during dose interruptions, 
- 
And for at least 5 months after study treatment discontinuation. 
• The two methods of reliable contraception must include one highly effective method and 
one additional effective (barrier) method.  
• Highly effective contraception with low user dependency is preferred. 
• A FCBP must be referred to a qualified provider of contraceptive methods if needed. 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
Highly effective methodsb that have low user dependency Failure rate of <1% per year when used 
consistently and correctly. 
• 
Implantable progestogen-only hormone contraception associated with inhibition of ovulation. 
• 
Intrauterine device (IUD). 
• 
Intrauterine hormone-releasing system (IUS). 
• 
Bilateral tubal occlusion. 
• 
Azoospermic partner (vasectomized or due to a medical cause). 
Azoospermia 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 of contraception should be used.  
Note: documentation of azoospermia for a male participant can come from the site personnel’s 
review of the participant’s medical records, medical examination, or medical history interview. 
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Highly effective methodsb that are user dependent Failure rate of <1% per year when used 
consistently and correctly. 
• 
Combined (estrogen- and progestogen-containing) hormonal contraceptionc associated with 
inhibition of ovulation. 
- 
Intravaginal. 
- 
Transdermal. 
- 
Injectable. 
• 
Progestogen-only hormone contraception associated with inhibition of ovulation. 
- 
Oral. 
- 
Injectable. 
• 
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 intervention. 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 participant. 
a Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive methods for those 
participating in clinical studies. 
b Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those when used consistently and 
correctly. 
c A patient can use ‘oral’ combination if they have discontinued pomalidomide. 
As per pomalidomide Summary of Product Characteristics (SmPC), combined oral contraceptive pills are not recommended because of 
the increased risk of venous thromboembolism in patients with multiple myeloma taking pomalidomide and dexamethasone. 
Note: Periodic abstinence (calendar, ovulation, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhea method (LAM) are not acceptable methods of 
contraception for this study. Male condom and female condom should not be used together (due to risk of failure 
from friction). 
10.4.2.3 Contraception for male subjects  
Male subjects with heterosexual partners of reproductive potential (FCBP) 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) while taking 
pomalidomide/isatuximab, during dose interruptions and for at least 28 days after 
the last dose of pomalidomide or 5 months following the last dose of isatuximab, 
whichever occurs last, even if he has undergone a successful vasectomy. 
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10.4.3 Pregnancy testing  
Medically supervised pregnancy tests with a minimum sensitivity of 25 mIU/mL must be 
performed for FCBP, including FCBP who commit to complete abstinence, as outlined below. 
10.4.3.1 Female participants  
Females of childbearing potential must have two negative pregnancy tests (sensitivity of at least 
25 mIU/mL) prior to prescribing pomalidomide. 
The first pregnancy test must be performed within 10 to 14 days prior initiation of pomalidomide, 
and the second pregnancy test must be performed within 24 hours prior pomalidomide 
administration.  
The participant may not receive pomalidomide until the Investigator has verified that the results of 
these pregnancy tests are negative.  
Pregnancy testing is also required weekly during 1st month of treatment and then every 28 days 
while on therapy (14 and 28 days in case of irregular menstrual cycles) and during interruptions in 
therapy (or every 14 days in case of irregular menstrual cycles) and for at least 28 days after 
discontinuation of pomalidomide (14 and 28 days for in case of irregular menstrual cycles), or 
monthly up to 5 months following isatuximab discontinuation, whichever occurs last. 
10.4.3.2 Male participants  
Females of childbearing potential, who have male partners receiving pomalidomide, must use 
highly effective contraception during his treatment and during dose interruptions and for at least 
4 weeks after his last dose of pomalidomide or at least 5 months after his last dose of isatuximab, 
whatever occurs last. 
Note: True abstinence is acceptable when this is in line with the preferred and usual lifestyle of 
the participant. Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation 
methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea method 
(LAM) are not acceptable methods of contraception. 
10.4.4 Additional precautions during and after study participation  
10.4.4.1 Female participants  
At each visit, the Investigator must confirm with the FCBP that she is continuing to use a highly 
effective form of contraception (see definition above) at each visit during the time that birth 
control is required. 
If pregnancy or a positive pregnancy test does occur in a study participant, pomalidomide and 
isatuximab must be immediately discontinued. 
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Pregnancy testing and counseling must be performed if a participant misses her period or if her 
pregnancy test or her menstrual bleeding is abnormal. Pomalidomide and isatuximab treatment 
must be temporarily discontinued during this evaluation. 
Females must agree to abstain from breastfeeding during study participation and for at least 
28 days after discontinuation of pomalidomide or 5 months after discontinuation of isatuximab, 
whichever occurs last. 
10.4.4.2 Male participants  
If pregnancy or a positive pregnancy test does occur in the partner of a male study participant 
during study participation, the Investigator must be notified immediately. 
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. The female 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, the follow-up will be up to 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 the procedure. 
Male participants should not donate semen or sperm during therapy or for at least 4 weeks 
following discontinuation of pomalidomide or 5 months following discontinuation of isatuximab. 
10.4.4.3 Precautions related to pomalidomide  
Female caregivers of childbearing potential should not touch the pomalidomide capsules or bottles 
unless they are wearing gloves. 
Participants should be instructed never to give pomalidomide to another person. 
Participants should not donate blood during therapy and for at least 3 months following 
discontinuation of study treatment. 
Only enough pomalidomide for one cycle of therapy may be prescribed with each cycle of 
therapy. 
Any unused pomalidomide must be returned as instructed in the Pomalidomide Pregnancy 
Prevention Plan (Appendix 15, Section 10.15) or the country specific risk management plan in 
countries where pomalidomide is not supplied by the Sponsor. 
10.5 
APPENDIX 5: GENETICS  
Not applicable. 
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10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND 
FOLLOW-UP ASSESSMENTS  
Not applicable. 
10.7 
APPENDIX 7: MEDICAL DEVICES AES, ADES, SAES, SADES, USADES AND DEVICE 
DEFICIENCIES: DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, 
FOLLOW-UP, AND REPORTING IN MEDICAL DEVICE STUDIES  
The definitions and procedures detailed in this appendix are in accordance with ISO 14155 and 
European Medical Device Regulation (MDR) 2017/745 for clinical device research (if 
applicable). 
Both the Investigator and the Sponsor will comply with all local medical device reporting 
requirements for medical devices. 
The detection and documentation procedures described in this protocol apply to all Sponsor 
medical devices provided for use in the study (see Section 6.1.3) for the list of Sponsor medical 
devices). 
10.7.1 Definition of medical device AE and ADE  
Medical device AE and ADE definition 
• A medical device AE is any untoward medical occurrence in a clinical study participant, 
users, or other persons, temporally associated with the use of study intervention, whether 
or not considered related to the investigational medical device. An AE can therefore be 
any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease (new or exacerbated) temporally associated with the use of 
an investigational medical device. This definition includes events related to 
the investigational medical device or comparator and events related to the procedures 
involved except for events in users or other persons, which only include events related to 
investigational devices. 
• An adverse device effect (ADE) is defined as an AE related to the use of an investigational 
medical device. This definition includes any AE resulting from insufficient or inadequate 
instructions for use, deployment, implantation, installation, or operation, or any 
malfunction of the investigational medical device as well as any event resulting from use 
error or from intentional misuse of the investigational medical device. 
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10.7.2 Definition of medical device SAE, SADE and USADE  
A medical device SAE is any adverse event that: 
a) Led to death. 
b) Led to serious deterioration in the health of the participant, that either resulted in: 
- 
A life-threatening illness or injury. The term “life-threatening” in the definition of 
“serious” refers to an event in which the participant 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. 
- 
A permanent impairment of a body structure or a body function. 
- 
Inpatient or prolonged hospitalization. Planned hospitalization for a pre-existing 
condition, or a procedure required by the protocol, without serious deterioration in 
health, is not considered an SAE. 
- 
Medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function. 
- 
Chronic disease (MDR 2017/745). 
c) Led to fetal distress, fetal death, or a congenital abnormality or birth defect. 
SADE definition 
• A SADE is defined as an adverse device effect that has resulted in any of 
the consequences characteristic of an SAE. 
• Any device deficiency that might have led to an SAE if appropriate action had not been 
taken, intervention had not occurred, or circumstances had been less fortunate. 
Unanticipated SADE (USADE) definition 
• An USADE (also identified as UADE in US Regulations 21 CFR 813.3), is defined 
as a serious adverse device effect that by its nature, incidence, severity, or outcome has not 
been identified in the current version of the risk analysis report (see Section 2.3). 
10.7.3 Definition of device deficiency  
Device deficiency definition 
• A device deficiency is an inadequacy of a medical device with respect to its identity, 
quality, durability, reliability, safety, or performance. Device deficiencies include 
malfunctions, use errors, and inadequacy of the information supplied by the manufacturer. 
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10.7.4 Recording and follow-up of medical device AE and/or SAE and device deficiencies  
Medical device AE, SAE, and device deficiency recording 
• When an AE/SAE/device deficiency occurs, it is the responsibility of the Investigator to 
review all documentation (eg, hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event. 
• The Investigator will then record all relevant AE/SAE/device deficiency information in 
the participant’s medical records, in accordance with the Investigator’s normal clinical 
practice and on the appropriate form. 
• It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE/SAE/device deficiency form. 
• There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be redacted on the copies of the medical records before submission to 
the Sponsor. 
• The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE. 
• For device deficiencies, it is very important that the Investigator describes any corrective 
or remedial actions taken to prevent recurrence of the deficiency. 
- 
A remedial action is any action other than routine maintenance or servicing of 
a medical device where such action is necessary to prevent recurrence of a device 
deficiency. This includes any amendment to the device design to prevent recurrence. 
Assessment of intensity 
The Investigator will make an assessment of intensity for each AE/SAE/device deficiency 
reported during the study and assign it to one of the following categories:  
• Mild: An event that is easily tolerated by the participant, causing minimal discomfort, and 
not interfering with everyday activities. 
• Moderate: An event that causes sufficient discomfort to interfere with normal everyday 
activities. 
• Severe: An event that prevents normal everyday activities. An AE that is assessed 
as “severe” should not be confused with an SAE. Severe is a category used for rating 
the intensity of an event; and both AEs and SAEs can be assessed as severe. 
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as described 
in the definition of an SAE, not when it is rated as severe. 
Assessment of causality 
• The Investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE/device deficiency. 
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• A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
• The Investigator will use clinical judgment to determine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• The Investigator will also consult the Investigator’s Brochure (IB) and Product 
Information, for marketed products, as part of the assessment. 
• The Investigator must review and provide an assessment of causality for each 
AE/SAE/device deficiency, and document this in the medical notes. 
• There may be situations in which an SAE has occurred, and the Investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the Investigator always make an assessment of causality for every event before 
the initial transmission of the SAE data to the Sponsor. 
• The Investigator may change his/her opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment. 
• The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
Follow-up of medical device AE/SAE/device deficiency 
• The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Sponsor to 
elucidate the nature and/or causality of the AE/SAE/device deficiency as fully as possible. 
This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
• If a participant dies during participation in the study or during a recognized follow-up 
period, the Investigator will provide the Sponsor with a copy of any post-mortem findings 
including histopathology.  
• New or updated information will be recorded in the originally completed form. 
• The Investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information. 
10.7.5 Reporting of medical device SAEs  
Medical device SAE reporting to the Sponsor via an electronic data collection tool 
• The primary mechanism for reporting an SAE to the Sponsor will be the electronic data 
collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE data collection 
tool to report the event within 24 hours. 
• The site will enter the SAE data into the electronic system as soon as it becomes available. 
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• After the study is completed at a given site, the electronic data collection tool will be taken 
offline to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
offline, then the site can report this information on a paper SAE form (see next table) or to 
the Sponsor/medical monitor/SAE coordinator by telephone. 
• Contacts for SAE reporting can be found in investigator site file. 
10.7.6 Reporting of SADEs  
SADE reporting to the Sponsor  
NOTE: There are additional reporting obligations for medical device deficiencies that are 
potentially related to SAEs that must fulfill the legal responsibility to notify appropriate 
regulatory authorities and other entities about certain safety information relating to medical 
devices being used in clinical studies.  
• Any device deficiency that is associated with an SAE must be reported to the Sponsor 
within 24 hours after the Investigator determines that the event meets the definition of 
a device deficiency. 
• The Sponsor will review all device deficiencies and determine and document in writing 
whether they could have led to an SAE. These device deficiencies will be reported to 
the regulatory authorities and IRBs/IECs as required by national regulations. 
• Contacts for SAE reporting can be found in investigator site file. 
10.8 
APPENDIX 8: COUNTRY-SPECIFIC/REGION REQUIREMENTS  
Upon a request from the Human Genetics Resource Administration of China (HGRAC) 
regulation, the Chinese sites will not participate to the collection (and analyses) of samples for 
exploratory endpoints. 
Introduced as per Protocol Amendment 01: Country-specific requirement applicable for 
Norwegian clinical sites: 
A) Male participants that agree to not donate semen or sperm during therapy or for at least 
4 weeks following discontinuation of pomalidomide or 5 months following 
discontinuation of isatuximab. 
B) Participants that agree to not donate blood during therapy and for at least 3 months 
following discontinuation of pomalidomide. 
Per local regulations in France, Direct-to-Patient supply of isatuximab SC from the Site/Sponsor 
is allowed for home-based administration of isatuximab SC. Agreement from participant for 
Direct-to-Patient supply should always be sought in such situation. 
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10.9 
APPENDIX 9: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY  
For European countries contingency measures are currently only applicable for the COVID-19 
pandemic.  
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 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, disease 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 dexamethasone and pomalidomide from the site/sponsor 
where allowed by local regulations and agreed upon by participant. 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 summarized (eg, study discontinuation or discontinuation/delay/omission of 
the intervention due to the emergency). Any additional analyses and methods required to evaluate 
the impact on efficacy (eg, missing data due to the emergency) and safety will be detailed in 
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the SAP. For a regional or national emergency declared by a governmental agency, contingency 
procedures may be implemented for the duration of the emergency. The participant 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). 
 
10.10 APPENDIX 10: COLLECTION, STORAGE AND FUTURE USE OF DATA AND HUMAN 
BIOLOGICAL SAMPLES  
Appendices to be provided for studies conducted in European countries. 
10.10.1 Compliance with Member State applicable rules for the collection, storage and 
future use of human biological samples (Article 7.1h)  
This appendix is provided separately. 
10.10.2 Compliance with Member State applicable rules for the collection, storage and 
future use of (personal) data (Article 7 (1 d) of EU Regulation 536/2014)  
This appendix is provided separately. 
10.11 APPENDIX 11: IMWG RESPONSE CRITERIA  
Disease response will be assessed using the updated International Myeloma Working Group 
Response Criteria (IMWG) (42). A confirmation assessment for disease response within 4 weeks 
is required in this protocol (either PR or better, or PD). 
Table 22 - Adapted from updated International Myeloma Working Group response criteria  
IMWG MRD criteria (requires a complete response 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 bone marrow aspirates 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 bone marrow aspirate in which presence of a clone is defined as 
less than two identical sequencing reads obtained after DNA sequencing of bone marrow aspirates 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. 
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• 
<5% plasma cells in bone marrow aspirates and, 
• 
A normal FLC ratio of 0.26–1.65 is required for FLC disease only. 
Two consecutive assessments are needed. No known evidence of progressive disease or new 
bone/soft tissue 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 bone marrow biopsy 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/soft tissue 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 h or, 
• 
≥90% decrease in the sum of maximal perpendicular diameter compared to baseline in soft tissue 
plasmacytoma. 
• 
FLC only: a ≥90% decrease in the difference between involved and uninvolved FLC levels. 
Two consecutive assessments are needed. No known evidence of progressive disease or new 
bone/soft tissue 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 h. 
• 
If serum and urine M-protein are unmeasurable, a ≥50% decrease in the difference between 
involved and uninvolved FLC levels is required in place of the M-protein criteria. 
• 
In addition to the above listed criteria, if present at baseline, a ≥50% reduction in the size (SPD) 
of soft tissue plasmacytomas is also required. 
Two consecutive assessments are needed. No known evidence of progressive disease or new 
bone/soft tissue lesions if radiographic studies were performed 
MR 
 
≥25% but ≤49% reduction in serum M-protein and reduction in 24 h urine M-protein by 50%-89%, which still 
exceed 200 mg/24 h. 
In addition to the above listed criteria, if present at baseline, ≥50% reduction in size (SPD) of soft tissue 
plasmacytomas is also required. 
No known evidence of progressive disease or new bone/soft tissue 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/soft tissue lesions if radiographic studies 
were performed 
Progressive 
disease 
Any one or more of the following criteria: 
Increase of ≥25% from lowest confirmed value in any one 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 h). 
• 
In patients without measurable serum and urine M-protein levels, the difference between involved 
and uninvolved FLC levels (absolute increase must be >10 mg/dL). 
• 
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 serum and or urine. If radiological progression is 
documented, no need to repeat the assessment.  
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; 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. 
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A plasmacytoma that has been radiated is not suitable for response assessment; however, it must 
be monitored to assess for progressive disease. 
For participants 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 for serum 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. 
Reminder: definitions of Response and Progression are based on IMWG Uniform Reporting 
Criteria: 
• Any response category (sCR, CR, VGPR, PR, and MR) 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, 
bone marrow PC counts, where one time point is adequate for confirmed response or 
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 VGPR. 
• 
 Documentation of response requires two consecutive readings of the applicable disease 
parameter (serum M-protein, urine M-protein or serum FLC), performed at any time (no 
minimum interval is required, it can be done the same day); however, to confirm response 
or progressive disease, two discrete samples are required; testing cannot be based upon 
the splitting of a single sample. 
• Participants will continue in the last confirmed response category until there is 
confirmation of progression or improvement to a higher response status; participants 
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 zero as a baseline for documentation of 
subsequent progressive disease. Participants will be considered to have progressive disease 
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if they meet the criteria for progression by a variable that was not considered measurable 
at baseline; however, for participants who had a measurable serum or urine M-spike 
at baseline, progression cannot be defined by increases in serum FLC alone. 
Radiographic and BM assessments do not need to be confirmed. 
Participants with measurable serum and/or urine M-protein and/or sFLC during screening, 
but below level of eligibility on efficacy laboratory performed on Cycle 1 Day 1 
(eg, participants with M-protein value >0 [or IF positive] and <0.5 g/dL): 
• These participants can have only 3 possible overall responses: CR, non-PD, or PD. 
• Participants with previous measurable M-protein (urine and/or serum) but at Cycle 1 
Day 1 below the level of measurability and no measurable sFLC can have CR, non-PD, or 
PD responses only according to the increase or decrease of M-protein or extra/para 
medullary soft tissue plasmacytoma if applicable, following the IMWG criteria. 
• If measurable sFLC at Cycle 1 Day 1, the participant will be followed on this value, based 
on IMWG criteria. 
• If during screening only serum M-protein was measurable, but at Cycle 1 Day 1 only urine 
M-protein becomes measurable, the participant will be followed on this last parameter 
during the treatment, regardless of sFLC level. 
• Inversely, if during screening only urine M-protein was measurable, but at Cycle 1 Day 1 
only serum M-protein becomes measurable, the participant will be followed on this last 
parameter during the treatment, regardless of sFLC level. 
10.12 APPENDIX 12: 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 housework, 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, Robert L. Comis, MD, Group Chair.  
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10.13 APPENDIX 13: NATIONAL CANCER INSTITUTE COMMON TERMINOLOGY CRITERIA 
FOR ADVERSE EVENTS  
Refer to NCI CTCAE v5.0 in the Study Reference Manual, or online at the following NCI 
website: https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm#ctc_60 
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. 
10.14 APPENDIX 14: CD38 BLOOD TEST INTERFERENCE GUIDELINES  
When they exist, local guidelines shall be applicable. Otherwise, the following guidelines should 
be followed. 
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10.15 APPENDIX 15 : GLOBAL POMALIDOMIDE PREGNANCY PREVENTION PLAN  
 
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10.16 APPENDIX 16: PATIENT REPORTED OUTCOMES  
10.16.1 European Organization for Research and Treatment of Cancer core quality of life 
questionnaire (EORTC QLQ-C30)  
 
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10.16.2 European Organization for Research and Treatment of Cancer quality of life 
myeloma module (EORTC QLQ-MY20)  
 
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10.16.3 European Quality of Life Group measure with 5 dimensions and 5 levels per 
dimension (EQ-5D-5L)  
 
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10.16.4 Health Resource Utilization and Productivity Questionnaire (HRUPQ)  
 
 
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10.16.5 Patient Expectations Questionnaire at Baseline (PEQ-BL)  
 
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10.16.6 Patient experience and satisfaction follow-up questionnaire (PESQ-FU)  
 
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10.16.7 Patient experience and satisfaction end-of-treatment questionnaire (PESQ-EOT)  
 
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10.16.8 Patient’s Assessment of Treatment questionnaire (PAT)  
 
 
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10.16.9 Local Tolerability at Injection Site After Isatuximab Administration - Patient 
Assessment Using Diary  
 
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10.17 APPENDIX 17: IADL AND ADL QUESTIONNAIRES  
 
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10.18 APPENDIX 18: ABBREVIATIONS AND DEFINITIONS  
 
ADA: 
anti-drug antibodies  
ADE: 
adverse device effect 
ADL: 
index of independence in activities of daily living 
AE: 
adverse event 
AESI: 
adverse event of special interest 
ALT: 
alanine aminotransferase 
ANC: 
absolute neutrophil count 
anti-HBc: 
antibody to hepatitis B core antigen 
anti-HBs: 
antibody to hepatitis B surface antigen 
AST: 
aspartate aminotransferase 
AUC: 
area under the curve 
AUC1week: 
area under the plasma concentration time curve over the first week 
AUC2weeks: 
area under the plasma concentration time curve over two weeks 
AxMP: 
auxiliary medicinal product 
BM: 
bone marrow 
CI: 
confidence interval 
CID: 
clinically important difference 
Cmax: 
maximum concentration 
CR: 
complete response 
Ctrough: 
observed concentration before dosing 
CV: 
coefficient of variation 
CYP1A2: 
cytochrome P450 family 1 subfamily A member 2 
DLT: 
dose limiting toxicity 
DMC: 
Data Monitoring Committee 
DOR: 
duration of response 
EC: 
ethics committee 
ECG: 
electrocardiogram 
eCRF: 
electronic case report form 
eGFR: 
estimated glomerular filtration rate 
EMA: 
European Medicines Agency 
EORTC QLQ-C30: 
European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire-Core 30 
EORTC QLQ-MY20: 
European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire- Myeloma Module 20 
EOT: 
end of treatment 
ePRO: 
electronic patient-reported outcome 
EQ-5D-5L: 
the European Quality of Life Group Questionnaire with 5 Dimensions and 5 
Levels 
EU: 
European Union 
FCBP: 
female of childbearing potential 
FDA: 
Food and Drug Administration 
FISH: 
fluorescent in situ hybridization 
FLC: 
free light chain 
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G-CSF: 
granulocyte-colony stimulating factor 
GLP: 
good laboratory practice 
GvHD: 
graft versus host disease 
HA: 
health authority 
HBC: 
hepatitis C virus 
HBV: 
hepatitis B virus 
HCP: 
health care professional 
HIV: 
human immunodeficiency virus 
HR: 
hazard ratio 
HRUPQ: 
health resource utilization and productivity questionnaire 
IADL: 
instrumental activities of daily living 
IB: 
Investigator's brochure 
ICF: 
informed consent form 
IEC: 
Independent Ethics Committee 
IMP: 
investigational medicinal product  
IMWG: 
international myeloma working group 
IR: 
infusion reaction 
IRB: 
Institutional Review Boards 
IRC: 
Independent Review Committee 
IRT: 
interactive response technology 
IsaPd: 
isatuximab in combination with pomalidomide and dexamethasone 
ISRs: 
injection site reactions 
ITT: 
intent-to-treat 
IV: 
intravenous 
LPI: 
last patient in 
MDRD: 
modification of diet in renal disease 
MM: 
multiple myeloma 
MR: 
minimal response 
MRD: 
minimal residual disease 
MRI: 
magnetic resonance imaging  
MTD: 
maximal tolerated dose 
NCI CTCAE: 
National Cancer Institute, Common Terminology Criteria for Adverse Events 
NK: 
natural killer 
NMPA: 
National Medical Products Administration 
OBDS: 
on body delivery system 
ORR: 
overall response rate 
OS: 
overall survival 
PAT: 
patient's assessment of treatment 
PCSA: 
potentially clinically significant abnormality 
Pd: 
pomalidomide and dexamethasone 
PD: 
progressive disease 
PDy: 
pharmacodynamic 
PEQ: 
patient expectation questionnaire 
PEQ-BL: 
patient expectations questionnaire at baseline 
PESQ: 
patient experience and satisfaction questionnaire 
PESQ-EOT: 
patient experience and satisfaction end of treatment questionnaire 
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PESQ-FU: 
patient experience and satisfaction follow-up questionnaire 
PET-CT: 
positron emission tomography- Computed tomography  
PFS: 
progression free survival 
PI: 
proteasome inhibitor 
PK: 
pharmacokinetic 
PML: 
progressive multifocal leukoencephalopathy  
PO: 
per os 
PP-PK: 
per protocol PK 
PR: 
partial response 
PRO: 
patient-reported outcome 
Q2W: 
every 2 weeks 
QTL: 
quality tolerance limit 
QWx4: 
every week for 4 weeks 
RP2D: 
recommended Phase 2 dose 
RRMM: 
relapsed/refractory multiple myeloma 
SADE: 
serious adverse device effect 
SAE: 
serious adverse event 
SAP: 
statistical analysis plan 
SC: 
subcutaneous 
SC-IP: 
subcutaneous route using an infusion pump 
SC-OBDS: 
subcutaneous on body delivery system 
sCR: 
stringent complete response 
SmPC: 
summary of product characteristics 
SoA: 
schedule of activities 
SPD: 
sum of the products of the maximal perpendicular diameters of measured lesions 
SUSAR: 
suspected unexpected serious adverse reaction 
TEAE: 
treatment emergent adverse event 
TT1R: 
time to first response 
TTBR: 
time to best response 
TTR: 
time-to-response 
ULN: 
upper limit of normal 
USADE: 
unanticipated serious adverse device effect 
VAS: 
visual analogue scale 
VGPR: 
very good partial response 
 
10.19 APPENDIX 19: PROTOCOL AMENDMENT HISTORY  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the table of contents (TOC). 
10.19.1 Amended protocol 01 (11-October-2022)  
This amended protocol is considered to be 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. 
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OVERALL RATIONALE FOR THE AMENDMENT 
The purpose of this amended protocol is to incorporate feedback received from health authorities 
(HA) and ethics committees (EC), to ensure consistency across sections and across program 
documents, and to provide clarifications in several sections. 
Protocol amendment summary of changes table 
Section # and 
Name 
Description of Change 
Brief Rationale 
1.1 Synopsis  
6.1.2 Non 
investigational 
medicinal 
products 
Under heading Non-Investigational Medicinal Products (Premedication):  
Montelukast 10 mg orally (C1 only) changed to Montelukast 10 mg orally 
(Cycle 1 only). 
Added “except montelukast that should be administered only on Cycle 1” in 
the statement where it is mentioned that premedication reconsidered 
at the Investigator’s discretion. 
Section 6.1.2: Text updated to include that Montelukast is to be administered 
on Cycle 1 only. 
Clarification and 
readability 
improvement. 
1.2 Schema 
Add additional details on key secondary endpoints: 
• 
Ctrough at 4 weeks (CT4W corresponding to C2D1 predose). 
• 
Patient satisfaction: PESQ. 
Consistency between 
sections. 
1.3 Schedule of 
Activities (SoA) 
• 
Hepatitis viral assessment changed to Hepatitis B and C. 
• 
Footnote “g” also updated with same change. 
Consistency between 
sections. 
1.3 Schedule of 
Activities (SoA) 
• 
Updated the assessment name: Patient experience and satisfaction 
questionnaire (PESQ) and Patient's assessment of treatment (PAT) 
Questionnaire. 
• 
Corresponding footnotes also updated. 
Consistency between 
sections. 
1.3 Schedule of 
Activities (SoA) 
8.4 Patients 
Reported 
Outcomes 
• 
Patient experience and satisfaction Questionnaire (PESQ) and 
Patient's assessment of treatment (PAT) 
Questionnaire - assessment removed from follow-up visit, and 
updated corresponding footnote ‘k’ to remove “90 ±7 days after 
last study treatment administration”. 
• 
Section 8.4 in timing of assessments, removed “and at 90 ±7 days 
after last study treatment administration”. 
Correction in 
assessment timepoint. 
2.2.3.2 Isatuximab 
SC in combination 
with 
pomalidomide and 
dexamethasone 
TCD15484 study results updated as per cutoff date of 16 May 2022. 
New data. 
2.3.1 Risk 
assessment 
Updates in Table 5 – Risk assessment 
• 
Identified risk neutropenia: Following text added in mitigation 
strategy. 
Exclusion of patients with ANC <1000 μL (1  109/L). The use of 
G-CSF is not allowed to reach this level. 
• 
Potential risk second primary malignancies: Following text deleted 
from mitigation strategy. 
International Myeloma Working Group (IMWG) guidelines: specific 
routine screening for SPMs not recommended in MM. 
Consistency across 
program documents. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
• 
Potential risk Viral reactivation: added “herpes zoster” reactivation 
and added text for antiviral prophylaxis. 
• 
Injection site reaction: Updated text to mention that no Grade >1 
ISRs were reported in the Phase 1 trial with SC isatuximab. 
4.9 Study 
committees, 
6.3.1 Blinding 
rules and 8.1 
Efficacy 
assessments 
Added information that an IRC is blinded to treatment assignment. 
Updated as per 
feedback from HA. 
5.1 Inclusion 
criteria 
Updated text in Inclusion criterion 6 (I 06), from “before study entry” to “before 
signing the informed consent form (ICF)”. 
Further clarification on 
text. 
5.1 Inclusion 
criteria 
Added Inclusion criterion 9 (I 09), other inclusion criteria included for country 
specific requirement applicable for Norwegian clinical sites. 
Updated as per 
feedback from HA. 
5.2 Exclusion 
criteria 
Updated exclusion criterion 18 (E18) text from previous wording: 
Hypersensitivity to dexamethasone, sucrose histidine (as base and 
hydrochloride salt) and polysorbate 80 or any of the components of study 
therapy that are not amenable to premedication with steroids, or H2 blockers 
that would prohibit further treatment with these agents. 
to 
Known intolerance or hypersensitivity to dexamethasone, to any of isatuximab 
subcutaneous formulation excipients (L-histidine; L-histidine hydrochloride 
monohydrate, L-arginine monohydrochloride, sucrose, polysorbate 80, and 
poloxamer 188), or to any of the components study therapy that are not 
amenable to premedication with steroids, or H2 blockers, that would prohibit 
further treatment with these agents. 
Updated as per 
feedback from HA. 
5.2 Exclusion 
criteria 
Additional sub-criteria added for exclusion criterion E19; E 19 b): Participants 
with contraindication to pomalidomide and E 19 c): with ≥Grade 2 peripheral 
neuropathy. 
Updated as per 
feedback from HA. 
5.2 Exclusion 
criteria 
Updated text in exclusion criterion 22 (E 22) to include details of participants 
with hepatitis B and hepatitis C: 
Known acquired immunodeficiency syndrome (AIDS)-related illness or known 
human immunodeficiency virus (HIV) disease requiring antiviral treatment, 
known active hepatitis A infection (defined as positive hepatitis A antigen or 
positive IgM), and current active or chronic hepatitis B (HBV) or hepatitis C 
(HCV) infection. Participants with chronic HBV or HCV disease that is 
controlled under antiviral therapy are allowed. HIV serology will be tested 
at screening for participants of countries where required as per local 
regulations. Hepatitis B and C serology will be tested at screening for all 
participants. 
Updated as per 
feedback from HA. 
6.1.1.2 
Dexamethasone 
Details added for requirement of particular care when treating patients with 
glaucoma and ocular herpes simplex. 
Updated as per 
feedback from HA. 
6.1.1.3 
Pomalidomide 
Details on monitoring and management of worsening neurologic, cognitive or 
behavioral signs and symptoms, including progressive multifocal 
leukoencephalopathy (PML) suspicion. 
Updated as per 
feedback from HA. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
6.1.1.4 Study 
arms (Table 10) 
Timepoints of administration of intervention (isatuximab SC/IV) added: on 
Day 1, 8, 15, and 22 in the first Cycle and on Day 1 and Day 15 for subsequent 
cycles. 
Timepoints of administration of dexamethasone added: Day 1, 8, 15, and 22 of 
every 28 days cycle. 
Clarification following 
comments from HA. 
6.3.1 Blinding 
rules 
Added statement regarding use of an IRT centralized randomization. 
Additional steps which reduce potential bias are described: 
• 
Despite the open-label administration of treatments, assessment of 
efficacy outcomes will be based on objectively collected data, which 
are radiological assessments for tumor response and central 
laboratory assessment that will be reviewed by an IRC blinded to 
study intervention arms. 
• 
During the course of the study, an external independent statistician 
will perform unblinded safety and efficacy analyses for the data 
review of DMC. Access to these data and analyses will be restricted 
to the DMC members. 
Updated as per 
feedback from HA. 
6.4.1 
Subcutaneous 
isatuximab at-
home 
administration 
Mention clear instructions for participants on ISRs at injection site in 
participants diary and timing for same. 
 
Consistency across 
program documents. 
6.5.5 
Management of 
infusion reactions 
and injection site 
reactions and 
8.5.6 Adverse 
event of special 
interest 
Table 15: Deleted “Report AESI if the reaction lasts >24 hours” as only ISR 
≥Grade 2 to be considered as an AESI and not ISR Grade 1 lasting more than 
24 hours. 
Section 8.5.6: Deleted “Grade 1 lasting >24 hours” from ISRs AESI criteria. 
Consistency across 
program documents. 
6.5.5 
Management of 
infusion reactions 
and injection site 
reactions 
Table 15: Changed “SC isatuximab administration” to “isatuximab 
administration” for ISRs and following additional details added for Grade 3 and 
Grade 4 IRs: 
In case of Grade 3, isatuximab administration may be resumed at the next 
planned administration at Investigator’s discretion.  
If a Grade 3 IR occurs for a 3rd time, treatment with isatuximab will be 
definitively discontinued for that participant.  
In case of Grade 4, isatuximab will be permanently discontinued. 
Consistency with 
the IB. 
6.8.4 Prohibited 
concomitant 
therapy 
Added time frame: Live vaccines should be avoided up to 90 days after 
last dosing of study IMP. 
Added word “non-live vaccines” for routine vaccinations. 
Updated as per 
feedback from HA. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
7.1.1 Permanent 
discontinuation 
Details added on the management of permanent treatment discontinuation and 
follow up period changed from 90 days to 3 months (following text added). 
If one of the study treatments is prematurely permanently discontinued, then 
other drug(s) can be continued until disease progression or unacceptable 
toxicity or patient’s wish to discontinue further study treatment. During this 
period the participant will remain in the study and continue being assessed per 
SoA. If all study treatments are permanently discontinued, the visit will be 
treated as the last dosing day with the IMPs, with subsequent relevant 
assessments per SoA. 
In case of permanent treatment discontinuation due to disease progression, 
follow up will be every 3 months for further antimyeloma therapy, second 
primary malignancies, PFS2, and survival until death, or final OS analysis 
cut-off date, whichever occurs first.  
Updated as per 
feedback from HA and 
correction. 
7.1.1.1 List of 
criteria for 
permanent 
discontinuation 
Pregnancy in a female participant added as criteria for permanent treatment 
discontinuation. 
Updated as per 
feedback from HA. 
8.3 Safety 
assessments 
"Participants will stay at the site after each administration for at least 4 hours in 
Cycle 1" re-worded to.  
"Participants will stay at the site between 1 and 4 hours after each 
administration in Cycle 1". 
Reworded for 
clarification and 
consistency among 
sections. 
8.3.7 Assessment 
of local tolerability 
Table 19 summarizing the assessment of local tolerability added for better 
visualization. 
Clarification and 
readability 
improvement. 
8.4 Patients 
reported 
outcomes 
Updated text to mention that patient’s own device can also be used and added 
text on dedicated website. 
All PROs are in electronic form (electronic patient reported outcomes [ePRO]) 
and will be completed by the patient (study participant) using either the study 
mobile phone provided or the patient's own device. 
Alternatively, a dedicated website could be proposed to collect PROs 
as a backup solution in case of unavailability of handheld devices.  
Updated as per 
feedback from HA. 
8.5 Adverse 
Events (AEs), 
Serious Adverse 
Events (SAEs) 
and Other Safety 
Reporting 
Included words ADE, SADE, and their definitions as these are also reportable 
events as per MDR Article 80 at applicable places (Sections 8.5, 8.5.3, and 
8.5.7.1.1). 
Updated as per 
feedback from HA. 
8.5.6 Adverse 
events of special 
interest 
Clarified and updated timing of collection of follow up information on 
a participant pregnancy or female partner of a male participant up to 1 year 
after delivery of a newborn from previously 6 to 8 weeks.  
Aligned with protocol 
program template. 
8.6 Genetics 
Clarified further that “No congenital genetic testing is planned in this study; 
however, tumoral genetic and genomics analyses will be performed on bone 
marrow samples.” 
Comment from IRB. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
10.1.3 Informed 
consent process 
Removed word “their legally authorized representative “. 
Consistency with 
Exclusion criteria. 
Following comments 
from EC. 
10.1.6 
Dissemination of 
clinical study data 
Replace clinicalstudydatarequest.com in this protocol with https://vivli.org. 
Update as per template 
change. 
10.4.2.2 
Contraception 
guidance for 
female subjects 
Table Contraceptives allowed during the study include: 
… 
Highly effective methods (b) that are user dependent… 
Oral contraceptive method removed and added footnote “c” for “combined 
(estrogen- and progestogen-containing) hormonal contraception” for 
clarification. 
A patient can use ‘oral’ combination if they have discontinued pomalidomide. 
As per pomalidomide/Imnovid Summary of Product Characteristics (SmPC), 
combined oral contraceptive pills are not recommended because of 
the increased risk of venous thromboembolism in patients with multiple 
myeloma taking pomalidomide and dexamethasone. 
Updated as per 
feedback from HA. 
10.4.4.2 Male 
participants 
Clarified and updated timing of follow up of partner pregnancy to 1 year 
as previously captured 6 to 8 weeks after estimated delivery date. 
Aligned with protocol 
program template. 
10.8 Country-
specific 
requirements 
Included country specific requirement applicable for Norwegian clinical sites 
(inclusion criteria) and France (regarding home-based administration). 
Updated as per 
feedback from HA. 
10.13 Appendix 
13: CD38 Blood 
test interference 
guidelines 
Added following text: 
When they exist, local guidelines shall be applicable. Otherwise, the following 
guidelines should be followed. 
Clarification and 
readability 
improvement. 
10.15.4 Health 
Resource 
Utilization and 
Productivity 
Questionnaire 
(HRUPQ) 
Specify more details on Question 34: 
New/updated Health Resource Utilization and Productivity Questionnaire 
(HRUPQ) provided. 
Clarification to avoid 
open text questions; 
Data management 
requirement. 
Throughout 
Minor editorial, typographical error corrections and document formatting 
revisions. 
Minor, therefore, have 
not been summarized. 
 
10.19.2 Amended protocol 02 (15-March-2023)  
This amended protocol is considered to be non-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. 
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OVERALL RATIONALE FOR THE AMENDMENT 
The main purpose of this amended protocol is to allow MRI for bone lytic disease assessment 
according to feedback from sites in Germany where MRI is used for annual assessment as per 
local recommendations. Secondary purposes are to remove reference to bone plasmocytoma and 
to clarify definition and follow-up of extramedullary disease (EMD) and paramedullary disease; 
to allow switching of patients to long-term follow-up study after the final OS analysis cut-off; to 
clarify guidelines for Urine 24-hour M-protein (UPEP); to definie overdose for non-IMPs; to 
clarify overdose for IMPs following an internal audit finding; and to apply minor corrections 
(inconsistencies) following internal audit findings. 
Protocol amendment summary of changes table 
Section # 
and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
Adding “switching to a long-term safety study”. 
Specifying additional 
possibility of study treatment 
access after final analysis. 
1.1 Synopsis 
“Montelukast 10 mg orally (Cycle 1 only)” has been changed by 
“Montelukast 10 mg orally (or equivalent, Cycle 1 only)”. 
Adding the possibility to use 
a Montelukast equivalent. 
1.3 Schedule of 
Activities 
(SOA), Table 1, 
Footnote d 
Removing redundant sentence: “After confirmation of disease progression 
or the start of further antimyeloma therapy, participants will be followed up 
every 3◦months (12 weeks) for information on antimyeloma therapy, 
second primary malignancies, PFS2 and survival, until death or final study 
cut-off date, whichever occurs first.” 
Editorial. 
1.3 Schedule of 
Activities 
(SOA), Table 1, 
Footnote y 
Chaging the footnote by “Soft tissue plasmacytoma assessment 
(extramedullary disease OR paramedullary disease with a soft tissue lesion 
of diameter >= 2cm):  
• If known soft tissue plasmacytoma at baseline, CT scan, PET-CT scan or 
MRI is to be done at baseline, repeated every 12 weeks (±1 week) until 
progressive disease (PD) (even for participants who would initiate further 
anti-myeloma therapy without PD), and if clinically indicated. PET-CT 
should be the preferred option whenever possible. From two years 
post-randomization, the radiological assessment frequency will be done 
every 6 months (±1 month),  
• If suspected soft tissue plasmacytoma at baseline, CT scan, PET-CT scan 
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 
participants who would initiate further anti-myeloma therapy without PD) 
and if clinically indicated. PET-CT should be the preferred option whenever 
possible,  
• To be done in case of suspicion of progression or if clinically indicated in 
a participant with no previous positive image for soft tissue plasmacytoma,  
• The bone component of paramedullary disease with a soft tissue lesion of 
diameter >= 2cm will not be used for disease response assessment as per 
IMWG,  
Guidelines clarification and 
definition. 
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Section # 
and Name 
Description of Change 
Brief Rationale 
• Paramedullary (paraskeletal) plasmacytoma (bone plasmacytoma 
extending beyond the bone cortex into the surrounding tissues) with soft 
tissue lesions of diameter <2cms will be collected but will not be used for 
disease response assessment as per IMWG. No follow-up with repeated 
imaging is needed, except if clinically indicated Note: For bone lesion 
assessment and soft tissue plasmacytoma, the same modality (low-dose 
whole body CT scan; CT scan, PET-CT scan, or MRI) should be used 
throughout the study for each individual participant when radiological 
follow-up is needed. All imaging will be sent for central review. Intravenous 
contrast is recommended if not medically contra-indicated. Participants who 
have contra-indication to CT scan with IV contrast may have MRI exams 
performed instead”. 
1.3 Schedule of 
Activities 
(SOA), Table 1, 
Footnote z 
Adding “lytic”. 
Adding “MRI”. 
Adding “(±1 month)”. 
To align with current clinical 
practice in some 
countries/sites. 
1.3 Schedule of 
Activities 
(SOA), Table 1, 
Footnote bb 
Removed “Urine M-protein (24-hour urine) immunoelectrophoresis (UPEP) 
and immunofixation: UPEP to be performed at screening, C1D1 (predose), 
prior to each cycle thereafter and at end of treatment (if last tests were 
>4 weeks or if disease progression was not confirmed on the last test). If 
urine M-protein is negative (UPEP and IF) at baseline, UPEP assessment 
is to be repeated every 3 cycles only (Cycle 4, Cycle 7, Cycle 10, etc), and 
to confirm CR and Very good partial response (VGPR) on blood laboratory 
parameters. After baseline, immunofixation to be done if UPEP shows no 
measurable monoclonal protein in participants whose disease is evaluable 
in urine.” 
Added “Urine M-protein (24-hour urine) immunoelectrophoresis (UPEP) 
and immunofixation: UPEP to be performed at screening, C1D1 (predose), 
prior to each cycle thereafter and at end of treatment (if last tests were 
>4 weeks or if disease progression was not confirmed on the last test). If 
urine M-protein is negative (UPEP and IF) at baseline, UPEP assessment 
is to be repeated every 3 cycles only (Cycle 4, Cycle 7, Cycle 10, etc), and 
to confirm CR and Very good partial response (VGPR) on blood laboratory 
parameters. After baseline, immunofixation to be done if UPEP shows no 
measurable monoclonal protein in participants whose disease is evaluable 
in urine. 
Urine M-Protein (24-hour urine), immunoelectrophoresis (UPEP) and IF: to 
be performed at screening and Cycle 1 Day 1.  
If urine M-protein is measurable or detectable or IF is positive at Cycle 1 
Day 1, urine M-protein assessment should be done prior to study treatment 
administration in all subsequent cycles and at EOT (if last tests were 
>4 weeks or if disease progression was not confirmed on the last test).  
If urine M-protein is negative (UPEP and IF) at screening and Cycle 1 
Day 1, this assessment is to be repeated every 3 cycles only (Cycle 4, 
Cycle 7, Cycle 10, etc), and to confirm CR and VGPR on blood laboratory 
parameters. 
After Cycle 1 Day 1, urine immunofixation is to be done only if urine 
M-protein is not detected in UPEP.” 
Guidelines clarification. 
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Section # 
and Name 
Description of Change 
Brief Rationale 
1.3 Schedule of 
Activities 
(SOA), Table 1, 
Footnote bb 
Removing “(maximum of 1 year)”. 
To align with follow-up. 
2.3.1 Risk 
assessment, 
Table 5 
Removing “, and in consultation with the Sponsor to avoid unnecessary 
sedation.” 
Adding ”, except for montelukast which should be administered only on 
Cycle 1”. 
To be consistent throughout 
the protocol. 
5.2 Exclusion 
criteria, E27 
Adding “(R2)”. 
Updating version according 
to German Medicinal 
Products Act (AMG), 
the GCP Ordinance (GCP-V) 
and the Guideline for Good 
Clinical Practice (ICH-GCP 
E6 (R2)) apply in Germany. 
6.1.1.1.1 
Isatuximab IV 
formulation 
Replacing “in experimental” by “active comparator”. 
Correction following audit 
finding. 
6.1.2 Non 
investigational 
medicinal 
products 
Adding “or equivalent”. 
Adding the possibility to use 
a Montelukast equivalent. 
6.5.4 Dose 
adjustments 
according to 
adverse events, 
Table 14, Renal 
dysfunction 
Replacing “CrCl” by “eGFR”. 
Replacing “CrCl” by “eGFR”. 
Consistency across the 
protocol, the study is 
considering eGFR instead of 
CrCl. 
6.7 Treatment 
of overdose 
Replacing “For this study, any administration of an IMP at least twice 
the intented administered dose at each cycle will be considered 
as an overdose. Of note, dexamethasone dose will be evaluated on 
a whole cycle. For intravenous product, increase of at least 30% of 
the infusion rate will be considered as an overdose. Non investigational 
medicinal product overdose is defined as at least twice the intented dose 
within the intended therapeutic interval.” by “For the study, IMP overdose is 
defined as any of the following conditions:  
- any administration of isatuximab IV or isatuximab SC at least 30% above 
the intended dose at each administration.  
- any administration of an oral IMP (pomalidomide and dexamethasone) 
at least twice the intended dose within the intended therapeutic interval. Of 
note, dexamethasone dose will be evaluated on a whole cycle.  
Non-investigational medicinal product overdose is defined as at least 
twice the intended dose within the intended therapeutic interval.” 
Consistency between 
sections, following audit 
finding. 
6.7 Treatment 
of overdose 
Replace “study treatment” by “IMP/NIMP”. 
Consistency across protocol. 
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Section # 
and Name 
Description of Change 
Brief Rationale 
8.5.6 Adverse 
event of special 
interest 
Adding “or injctable adminstration” and “NIMP”. 
Removing “injectable administration: at least twice the dose during 
the planned intervals”. 
Consistency across protocol. 
10.2 Appendix 
2: Clinical 
Laboratory 
Tests, Table 21 
Replacing “surface antigen [HBsAg]” by “(HBsAg, anti-HBs, anti-HBc total 
and IgM) and hepatitis C”. 
Consistency across protocol 
(following an audit finding). 
10.10 Appendix 
10: IMWG 
Response 
Criteria 
Removing “Two consecutive assessments are needed.” 
To be aligned with IMWG 
response criteria. 
Throughout 
Minor editorial, typographical error corrections and document formatting 
revisions. 
Minor, therefore, have not 
been summarized. 
10.19.3 
Amended protocol 03 (03-October-2023)  
This amended protocol is considered to be 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. 
OVERALL RATIONALE FOR THE AMENDMENT 
The purpose of this amendment is to provide simplification and clarifications on different sections 
as well as to align with the isatuximab program, including the updated IB Edition 14 date 
30 May 2023.  
Inclusion criterion I04 and exclusion criterion E03 have been reworded for simplification 
purposes. A 14-day timeframe was introduced following granulocyte-colony stimulating factor 
(G-CSF) use in exclusion criterion E11 following request from Ethics Committee. 
Recommendations regarding antithrombotic prophylaxis were modified to allow for oral 
anticoagulants in patients with at least one risk factor for thromboembolism, so to align with 
general recommendations in pomalidomide SmPC, while still making the difference between 
patients with standard risk versus patients with at least one risk factor. Semi-quantitative 
urinalysis is allowed at baseline as several countries faced operational issues performing 
quantitative analysis. 
Protocol amendment summary of changes table 
Section # and 
Name 
Description of Change 
Brief Rationale 
1.3 Schedule of 
Activities (SOA) 
From timelines of vital signs/ECOG/weight/physical examination in 
the SoA, the indication "≤7 days before randomization" is removed. 
The same change has been made in Footnotes l and m. 
Allowing more flexibility on 
the timing to perform physical 
examination, vital signs 
assessments, weight 
measurement and ECOG 
assessment for operational 
and patient comfort reasons. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
1.3 Schedule of 
Activities (SOA), 
Table 1, Footnote l 
Added “(a flexibility of a maximum of 24 hours before IMP 
administration is allowed)” to give flexibility for performance of physical 
examination on Day 1 of each cycle. 
Flexibility given for 
performance of physical 
examination on Day 1 of 
each cycle. 
1.3 Schedule of 
Activities (SOA), 
Table 1, Footnote q 
Footnote q updated as “Quantitative or alternatively semi-quantitative 
urinalysis at baseline (including red blood cells, protein, glucose, pH, 
ketones, bilirubin, and leukocytes), and qualitative urinalysis (dipstick) 
after start of study treatment (including blood, protein, glucose, pH, 
ketones, bilirubin, and leukocytes)”. 
Clarification, to align with 
clinical sites not performing 
a full quantitative urinalysis 
assessment. 
1.3 Schedule of 
Activities (SOA), 
Table 1, Footnote y 
First and second sub-pointers in foontnote y updated as follows: 
• 
“If known soft tissue plasmacytoma at baseline, CT scan, 
PET-CT scan or MRI is to be done at baseline, repeated 
every 12 weeks (±1 week) until progressive disease (PD) 
from C1D1 (even for participants who would initiate further 
anti-myeloma therapy without PD), and if clinically indicated. 
From two years after randomization, the radiological 
assessment will be done every 6 months (±1 month). 
Assessment to be done until PD, or initiation of further 
anti-myeloma therapy, or final cut-off date, whichever occurs 
first. 
• 
If suspected soft tissue plasmacytoma at baseline, CT scan, 
PET-CT scan or MRI is to be done at baseline and if 
plasmacytoma confirmed on the exam to be repeated 
as indicated above.” 
After sub pointer 5, the following subpointer is added: 
• 
“PET-CT should be the preferred option whenever possible.” 
For clarification, to align with 
isatuximab program. 
1.3 Schedule of 
Activities (SOA), 
Table 1, Footnote z 
Footnote z updated as follows: 
“Bone disease (lytic or focal depending on the method): Whole-body 
low-dose CT scan, PET-CT scan or MRI at baseline (within 28 days 
prior to randomization), once a year (±1 month), and anytime during 
the study if clinically indicated, until PD, initiation of further anti-
myeloma therapy, or final cut-off date, whichever occurs first. PET-CT 
should be the preferred imaging modality whenever possible.” 
To align with isatuximab 
program. 
1.3 Schedule of 
Activities (SOA), 
Table 1, 
Footnote bb 
For Serum M-protein immunoelectrophoresis (SPEP) and 
immunofixation, “C1D1 (predose)” changed to “C1D1 (predose, 
baseline for response assessment),” 
Similar change is also done for Urine M-protein (24-hour urine) 
immunoelectrophoresis (UPEP) and immunofixation. 
For clarification and 
alignment with rest of 
isatuximab program. 
4.8 Study 
Committees 
Removed “on PFS” from the text. 
For clarification. 
5.1 Inclusion 
criteria,  
I 04 
Removed “at least 2 consecutive cycles of” from inclusion criteria I 04. 
Criterion simplification as to 
align to intended future 
product label. 
 
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Section # and 
Name 
Description of Change 
Brief Rationale 
5.1 Inclusion 
criteria,  
I 05 
Inclusion criteria I 05 modified as “Participants must have documented 
evidence of progressive disease on or after the last regimen.” 
For clarification. 
 
5.2 Exclusion 
criteria, E 03 
Modified criteria E 03 from  
“Participants with prior anti-CD38 treatment are excluded if: 
a) 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) with a washout period inferior to 9 months before 
randomization or, b) Intolerant to the anti-CD38 previously received.” 
To 
“Participants with prior anti-CD38 treatment: a) administered less than 
9 months before randomization or, b) Intolerant to the anti-CD38 
previously received.” 
Clarification. 
5.2 Exclusion 
criteria, E 11 
Added the timeframe “within 14 days from the screening hematological 
test” for granulocyte-colony stimulating factor (G-CSF). 
Following Ethics Committee 
request. 
6.1.1.3 
Pomalidomide 
The guidance for treatment with pomalidomide in cases of suspected 
or confirmed progressive multifocal leukoencephalopathy is amended 
as follows. 
“If progressive multifocal leukoencephalopathy (PML) is suspected, 
study treatments should be put on hold immediately until a diagnosis of 
PML has been definitively excluded. If suspected, the Investigator 
should refer participant to a specialist and appropriate diagnosis testing 
should be initiated [Serial Magnetic resonance imaging (MRI) with 
contrast and cerebrospinal fluid analysis for John Cunningham Virus] 
[Please refer to PML diagnostic criteria by American Association of 
Neurology (AAN)]. 
If PML is confirmed, pomalidomide should be discontinued and 
isatuximab and dexamethasone should be put on hold. [Please refer to 
PML diagnostic criteria by AAN]. Isatuximab and dexamethasone could 
be resumed after recovery of PML based on Investigator's judgement 
and after discussion with the Sponsor.” 
Clarification on guidance on 
detecting and managing PML 
as per diagnostic criteria by 
AAN. 
6.5 Dose 
Modification 
Removed the first line of paragraph 2 which is “Cycle delay (ie, delay of 
all study treatments at Day 1) are permitted in case of toxicity.” 
In the next line, “by the day” is removed and “within 3 days after 
the planned day” is added there. 
The line “Within a cycle, the treatment window is ±1 day for each of 
QW IMP administrations and ±3 days for each of Q2W IMP 
administrations.” Is moved to the paragraph above. 
First sentence of next paragraph is replaced from “Between cycles, 
the treatment window is ±3 days if 4-week cycle” to “Cycle delays are 
permitted in case of toxicity (see Section 6.5.7). Cycle is considered 
delayed if Day 1 is performed more than 3 days after the planned 
Day 1 of this cycle.” 
For consistency through 
the protocol and through 
the isatuximab program. 
 
The top paragraph is about 
delay WITHIN a cycle, while 
the following paragraph is 
about delay BETWEEN 
cycles. 
6.5.1 Isatuximab 
Removed the portion “starting from Cycle 2” for the second sentence 
and removed the last sentence “No more than 2 isatuximab 
consecutive administrations omitted per patient are permitted (study 
stopping rule).” 
Correction and consistency 
throughout the protocol. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
6.5.4 Dose 
adjustments 
according to 
adverse events, 
Table 13, footnote c 
Modified the footnote c as – “A dose delay of up to 14 days between 
cycles is permitted in order to recover to the participant´s baseline 
status. Beyond 14 days, the participant should be discontinued from 
study treatment, unless there is strong evidence of clinical benefit to 
justify continuation of dosing with study treatment (see Section 6.5.7).” 
and removed the portion “must be permanently discontinued from 
the study (Section 7.1.1).” 
For consistency throughout 
the protocol. 
6.5.4 Dose 
adjustments 
according to 
adverse events, 
Table 14, footnote a 
Modified the footnote a as – “A dose delay of up to 14 days between 
cycles is permitted in order to recover to the participant´s baseline 
status. Beyond 14 days, the participant should be discontinued from 
study treatment, unless there is strong evidence of clinical benefit to 
justify continuation of dosing with study treatment (see Section 6.5.7).” 
and removed the portion “the participant must be permanently 
discontinued from the study Section 6.5.7).” 
For consistency throughout 
the protocol. 
6.5.4 Dose 
adjustments 
according to 
adverse events, 
Table 14 
Added an additional row to Table 14 providing guidance for treatment 
with IMPs in cases of suspected or confirmed PML.  
Additionally footnote d added as – “See Section 6.1.1.3 for monitoring 
of PML and dose modification of study IMPs.” 
Clarification on guidance on 
detecting and managing PML 
as per diagnostic criteria by 
AAN.  
 
6.5.5 Management 
of infusion reactions 
and injection site 
reactions, Table 15 
Recommendation for Grade 2 and Grade 3/4 ISRs occurring 
post-administration modified from “Report AE/AESI” to “Report AE and 
AESI”; and “premedication” changed to “medication.” 
In recommendation for Grade 2 IRs, “definitive stop of current” 
removed and statement amended as “If during administration, interrupt 
isatuximab administration without possibility to restart the current 
injection. For subsequent cycles, give additional medication with 
IV diphenhydramine 25 mg IV (or oral equivalent) and/ or 
IV methylprednisolone 100 mg (or oralequivalent) and/or other 
supportive care as needed.  
Report AE.”  
Update according to IB 
Edition 14 date 30 May 2023. 
6.5.5 Management 
of infusion reactions 
and injection site 
reactions, Table 16 
In infusion reaction grading (NCI-CTCAE) V5.0 criteria, specification 
added to Grade 2 as “moderate reaction” and Grade 3/4 as “severe or 
life-threatening reaction.” 
Grade 2 recommendation is amended as “Stop isatuximab infusion. 
Give additional medication with IV diphenhydramine 25 mg IV (or 
equivalent) and/or IV methylprednisolone 100 mg (or equivalent) 
as needed. 
Isatuximab may be resumed only after participant recovery, at half 
the infusion rate before the interruption, and with close monitoring, and 
may be increased subsequently, at the Investigator’s discretion.” 
In Grad 3/4 recommendation “definitive treatment discontinuation” is 
removed and recommendation is amended as “Stop the isatuximab 
infusion. Give additional medication with diphenhydramine 25 mg IV (or 
equivalent) and/or IV methylprednisolone 100 mg (or equivalent) 
and/or epinephrine as needed until the resolution of the AE or until 
the AE improves to Grade 1. Only then, if previous Grade 3, 
the infusion may be restarted at the Investigator’s discretion; if so, 
the infusion rate should be half of the initial infusion rate and it may be 
increased subsequently, at the Investigator’s discretion. If the severity 
Update according to IB 
Edition 14 date 30 May 2023. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
of an infusion-related AE returns to Grade 3 after the restart of 
the infusion, the same procedure described above may be repeated 
at the Investigator’s discretion. If a Grade 3 infusion-related AE occurs 
for a 3rd time, treatment with isatuximab will be definitely discontinued 
for that patient. 
In case of Grade 4, isatuximab will be permanently discontinued.” 
6.8.1 Antithrombic 
therapy 
This section is amended as “Pomalidomide increases the risk of 
venous thromboembolism. Anticoagulation prophylaxis is required after 
an assessment of each participant’s underlying risk factors. Unless 
there is an excess risk of bleeding (those participants are to be 
excluded from the study; see exclusion criterion E2) all participants 
should receive prophylactic antithrombotic treatment. Patients with 
known risk factors for thromboembolism – including prior 
thrombosis - should be closely monitored. Action should be taken to try 
to minimise all modifiable risk factors (eg, smoking, hypertension, and 
hyperlipidemia). 
Aspirin prophylaxis is recommended for participants with standard risk. 
If aspirin is contraindicated, participants will receive another form of 
antithrombotic therapy according to hospital guidelines or physician 
preference. Participants with at least 1 risk factor (ie, history of prior 
venous thromboembolism, immobilization, and concomitant use of 
an erythropoiesis-stimulating agent) should use low-molecular weight 
heparin or alternatively a direct oral anticoagulant (factor Xa inhibitors, 
direct oral factor IIa inhibitors) or a vitamin K antagonist.” 
To align with general 
recommendations in 
pomalidomide SmPC, while 
still making the difference 
between patients with 
standard risk versus patients 
with at least 1 risk factor.  
8.1 Efficacy 
assessments 
The Bone imaging point is amended as “Whole-body low-dose (WBLD) 
computed tomography (CT) scan, Positron emission 
tomography-Computed tomography (PET-CT) scan or MRI at baseline 
(within 28 days prior to randomization), once a year (±1 month) from 
C1D1, and anytime during the study if clinically indicated, until PD, 
initiation of further anti-myeloma therapy, or final cut-off date, 
whichever occurs first. PET-CT should be the preferred imaging 
modality whenever possible.” 
Additional point added to section as  
• 
“Soft tissue plasmacytoma assessment (extramedullary 
disease OR paramedullary disease with a soft tissue lesion 
of diameter ≥2 cm): 
- 
If known soft tissue plasmacytoma at baseline, CT scan, 
PET-CT scan or MRI is to be done at baseline, repeated 
every 12 weeks (±1 week) until progressive disease 
(PD) from C1D1 (even for participants who would 
initiate further anti-myeloma therapy without PD), and if 
clinically indicated. From two years after randomization, 
the radiological assessment will be done every 
6 months (±1 month). Assessment to be done until PD, 
or initiation of further anti-myeloma therapy, or final 
cut-off date, whichever occurs first.  
- 
If suspected soft tissue plasmacytoma at baseline, CT 
scan, PET-CT scan or MRI is to be done at baseline 
and if plasmacytoma confirmed on the exam to be 
repeated as indicated above. 
To align with isatuximab 
program. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
- 
To be done in case of suspicion of progression or if 
clinically indicated in a participant with no previous 
positive image for soft tissue plasmacytoma.  
- 
The bone component of paramedullary disease with 
a soft tissue lesion of diameter ≥2 cm will not be used 
for disease response assessment as per IMWG. 
- 
Paramedullary (paraskeletal) plasmacytoma (bone 
plasmacytoma extending beyond the bone cortex into 
the surrounding tissues) with soft tissue lesions of 
diameter <2cm will be collected but will not be used for 
disease response assessment as per IMWG. No 
follow-up with repeated imaging is needed, except if 
clinically indicated.  
- 
PET-CT should be the preferred option whenever 
possible. 
Note: For bone lesion assessment and soft tissue plasmacytoma, 
the same modality (whole-body low-dose CT scan; CT scan, PET-CT 
scan, or MRI) should be used throughout the study for each individual 
participant when radiological follow-up is needed. 
Intravenous contrast is recommended if not medically 
contra-indicated.” 
10.2 Appendix 2: 
Clinical Laboratory 
tests, table 21 
Parameter “Prothrombin time (PT)/international normalized ratio (INR) 
Partial thromboplastin time (PTT)” shifted from Hematology test and 
added under “coagulation” test. 
Based on request from GER 
EC to separate hematology 
from coagulation tests. 
10.2 Appendix 2: 
Clinical Laboratory 
tests, table 21 
Removed from routine urinalysis  
• 
“Microscopic examination (if blood or protein is abnormal)”. 
For simplification following 
acceptance of semi-
quantitaitve urinalysis 
at baseline. 
10.2.1 Modification 
of diet in renal 
disease (MDRD) 
equation 
Added the word “Estimated” to glomerular filtration rate. 
Clarification. 
10.4.2.2 
Contraception 
guidance for female 
subjects 
Under sub-heading c, the portion “pomalidomide/Imnovid Summary of 
Product Characteristics (SmPC),” changed to “pomalidomide Summary 
of Product Characteristics (SmPC),” 
Clarification. 
10.7.2 Definition of 
medical device 
SAE, SADE and 
USADE 
The definition of a medical device SAE reworded as “A medical device 
SAE is any adverse event that”. 
Correction to align with EU 
MDR. 
10.10 APPENDIX 
10: IMWG 
RESPONSE 
CRITERIA, 
Table 22 
Under Standard IMWG criteria, the last point on IMWG criteria for CR 
amended as “A normal FLC ratio of 0.26-1.65 is required for FLC 
disease only.” 
For alignment with IMWG 
criteria. 
Throughout 
Minor editorial, typographical error corrections and document 
formatting revisions. 
Minor, therefore, have not 
been summarized. 
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11 
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